PubMed Search Results
| PubMed Results |
| 1. | Inflamm Res. 2009 Dec;58(12):855-62. Epub 2009 Jun 18.Recombinant human growth hormone improves survival and protects against acute lung injury in murine Staphylococcus aureus sepsis.Yi C, Cao Y, Mao SH, Liu H, Ji LL, Xu SY, Zhang M, Huang Y.Department of Abdominal Cancer, Huaxi Hospital, Sichuan University, Chengdu, China. yicheng6834@163.com OBJECTIVE: To investigate whether recombinant human growth hormone (rhGH) reduces mortality and protects against Staphylococcus aureus sepsis-induced acute lung injury. METHODS: The bacteria-positive rate of blood smears and bacteria colony counts in bacteria plate culture, TNFalpha and IL-10 plasma levels, lung injury score, expression of intercellular adhesion molecule-1 (ICAM-1) as well as activation of nuclear factor-kappa B (NF-kappaB) in the lungs were determined 6, 12 and 24 h after 140 KM mice were injected with physiologic saline (i.p. group C, n = 20); S. aureus E311122 (1.75 x 10(12) cfu/L, 40 ml/kg, i.p. group S, n = 60); or S. aureus (as group S) with a subsequent treatment of rhGH (1.0 U kg(-1) day(-1)), i.m. group T, n = 60). The cumulative survival rate of an additional 15 mice from each group was followed for 7 days post S. aureus injection. RESULTS: rhGH treatment significantly increased IL-10 plasma levels and the 7-day cumulative survival rate, whereas the bacteria-positive rate of blood smears, bacteria colony counts in bacteria plate cultures, lung injury score, ICAM-1 and NF-kappaB expression in the lungs were significantly reduced. In addition, rhGH treatment significantly suppressed the S. aureus sepsis-induced elevation of TNFalpha plasma levels. CONCLUSIONS: These results indicate an ability of rhGH to prevent S. aureus sepsis-induced acute lung injury in mice, which may be attributed to attenuation of increased plasma TNFalpha levels, and elevated IL-10 plasma levels as well as reduced ICAM-1 expression and inhibited NF-kappaB activity in the lungs. |
| PMID: 19536455 [PubMed - indexed for MEDLINE] | |
| Related articles | |
 | |
MeSH Terms:
Substances:
|
| 2. | J Chemother. 2009 Apr;21(2):159-64.A combination of thalidomide and augmentin protects BALB/c mice suffering from Klebsiella pneumoniae B5055-induced sepsis.Kumar V, Harjai K, Chhibber S.Department of Microbiology, Panjab University, Chandigarh, India. vij_tox@yahoo.com Despite extensive research, the mortality associated with sepsis in hospitals remains very high. We have evaluated the protective immunomodulatory effect of thalidomide alone or with Augmentin in Klebsiella pneumoniae B5055-induced sepsis in BALB/c mice. The mouse model of sepsis was developed by placing K. pneumoniae B5055 entrapped in fibrin and thrombin clots in the peritoneal cavity of mice. The septic mice were treated with thalidomide alone (30 mg/kg/day/po), Augmentin alone (20 microg/ml/ip) and with their combination. the thalidomide-alone treated mice showed 75% survival whereas 60% of the Augmentin-alone treated group survived. Combination treatment provided 100% survival. Treatment with thalidomide alone significantly (p<0.05) decreased interleukin-1 alpha (IL-1alpha), nitric oxide (NO) and malondialdehyde (MDA) levels in the serum without significantly (p<0.05) decreasing the bacterial count in blood. Augmentin alone only decreased the bacterial load in blood significantly (p<0.05). However, a combination of thalidomide with Augmentin significantly (p<0.05) decreased both the bacterial count and inflammatory mediators. |
| PMID: 19423468 [PubMed - indexed for MEDLINE] | |
| Related articles | |
 | |
Publication Types:
MeSH Terms:
Substances:
|
| 3. | Crit Care Med. 2009 May;37(5):1567-73.Stratification is the key: inflammatory biomarkers accurately direct immunomodulatory therapy in experimental sepsis.Osuchowski MF, Connett J, Welch K, Granger J, Remick DG.Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA, USA. Comment in: OBJECTIVE: This study examined the effectiveness of prospective stratification to identify and target high-dose glucocorticoid therapy for subjects developing lethal sepsis. DESIGN: Prospective, randomized, laboratory-controlled experiment. SETTING: University research laboratory. SUBJECTS: Adult female outbred CD-1 mice. INTERVENTIONS: Mice (n = 88) were subjected to sepsis induced by cecal ligation and puncture (CLP). Mice were prospectively divided into two groups, predicted to die (P-DIE) or predicted to live (P-LIVE), based on plasma levels of interleukin (IL)-6 obtained 6 hours after CLP. Following stratification, dexamethasone (DEX, 2.5 mg/kg, two doses) was administered to half the animals in each group whereas the other half received saline. MEASUREMENTS AND MAIN RESULTS: Without stratification, DEX conferred no benefit. In the P-DIE group, none of saline-treated mice lived whereas 40% of the DEX-treated mice survived. Of the nonsurvivors, 67% had death delayed by 24-48 hours compared with saline-treated mice. Twenty-four hours post-CLP, the lymphocyte count was higher in the P-DIE than in the P-LIVE mice regardless of treatment status, whereas the opposite trend was noted for neutrophils. Plasma cytokine and cytokine inhibitor levels in the saline-treated animals showed that levels in the P-DIE group were higher than those in the P-LIVE group (e.g., 60 vs. 10 ng/mL for IL-6 and 453 vs.129 ng/mL for IL-1 receptor antagonist). Interestingly, DEX therapy did not decrease 24 hours post-CLP circulating cytokines in either the P-DIE or the P-LIVE group. CONCLUSIONS: Following CLP-induced sepsis, early and accurate survival prediction allows targeted immunosuppression that improves survival. Better survival occurred without suppression of the typical proinflammatory mediators, suggesting that the deaths were not mediated by excessive cytokine-driven inflammation. Nonspecific anti-inflammatory/immunosuppressive treatment administered to more rigorously defined cohorts may be more successful than mediator-specific drugs used indiscriminately. |
| PMID: 19325479 [PubMed - indexed for MEDLINE] | |
| Related articles | |
 | |
Publication Types:
MeSH Terms:
Substances:
Grant Support:
|
| 4. | Int Immunopharmacol. 2009 Apr;9(4):478-90.Pretreatment with R(+)-verapamil significantly reduces mortality and cytokine expression in murine model of septic shock.Wyska E.Department of Pharmacokinetics and Physical Pharmacy, Collegium Medicum, Jagiellonian University, Cracow, Poland. mfwyska@cyf-kr.edu.pl It is well known that cytokines play an important role in the pathogenesis of sepsis and septic shock. There is evidence indicating that the membrane transporter, P-glycoprotein (P-gp), may be involved in the release of cytokines, such as IL-2, IL-4 or IFN-gamma. The aim of this study was to assess the influence of P-gp inhibitor, R(+)-verapamil, on cytokine expression in serum and tissues as well as survival rate of mice with LPS-induced septic shock. These effects were compared with the response to treatment with pentoxifylline, lisofylline, and prednisolone administered alone or after pretreatment with R(+)-verapamil. When given as a single agent, R(+)-verapamil significantly decreased serum levels of TNF-alpha and IFN-gamma and protected mice from endotoxin lethality. Moreover, it decreased up-regulated by LPS TNF-alpha gene expression in the liver and lungs. Given concomitantly with immunomodulatory compounds, it enhanced their beneficial impact on the survival of mice with septic shock. The highest increase in survival rate was observed in combination with pentoxifylline (7% vs. 67%). The most striking differences observed between saline and R(+)-verapamil pretreated animals on combination therapy included down-regulation of TNF-alpha, higher levels of IL-6, and decreased IFN-gamma concentrations. These results suggest that P-gp may be involved in the release of IFN-gamma, and possibly also TNF-alpha, in mice with septic shock. R(+)verapamil improves survival of mice receiving a lethal dose of LPS and significantly potentiates the protective effect of pentoxifylline and prednisolone against LPS-induced lethality, probably as a result of both P-gp inhibition and a synergistic interaction at the gene level. |
| PMID: 19291858 [PubMed - indexed for MEDLINE] | |
| Related articles | |
Publication Types:
MeSH Terms:
Substances:
|
| 5. | Crit Care Med. 2009 Mar;37(3):889-98.Therapeutic effects of erythropoietin in murine models of endotoxin shock.Aoshiba K, Onizawa S, Tsuji T, Nagai A.First Department of Medicine, Tokyo Women's Medical University, Tokyo, Japan. kaoshiba@chi.twmu.ac.jp Comment in: OBJECTIVE: Erythropoietin has recently emerged as a cytoprotective cytokine, which possesses the ability to protect many tissues, including the brain, heart, and kidneys, against ischemia or traumatic injury. We investigated the therapeutic effects of erythropoietin in a murine model of endotoxin shock. DESIGN: Prospective, randomized study. SETTING: University-based research laboratory. SUBJECTS: Male BALB/c mice. INTERVENTIONS: Mice intraperitoneally received either lipopolysaccharide (LPS) from Escherichia coli or vehicle. Erythropoietin was administered at a dose of 1000 IU/kg subcutaneously at different time points after LPS administration. We also investigated the effect of erythropoietin on the development of septic shock caused by cecal perforation. MEASUREMENTS AND MAIN RESULTS: Treatment of mice with erythropoietin, within 2 hours after LPS administration, improved the mortality rate. Treatment of cecal perforated mice with erythropoietin extended survival by 12 hours, but all animals died by 72 hours in both groups. Erythropoietin attenuated apoptosis in the lungs, liver, small intestine, thymus, and spleen, as assessed by terminal deoxynucleotidyl transferase-mediated nucleotide nick-end labeling staining, active caspase-3 immunostaining and immunoblotting, and measurements of caspase-3/7 activity. Erythropoietin also reduced inducible nitric oxide synthase expression, nitric oxide production, peroxynitrite formation, and tissue hypoxia. In contrast, erythropoietin did not affect the degree of LPS-induced inflammation, as assessed by measurements of blood levels of interleukin-1beta, interleukin-6, tumor necrosis factor-alpha, growth-related oncogene/keratinocyte-derived cytokine, and high mobility group box 1, the phosphorylation levels of nuclear factor kappaB, and the number of neutrophils infiltrating the lungs and the liver. CONCLUSIONS: The results of the study demonstrate that administration of a large dose of erythropoietin after induction of experimental endotoxemia improved survival and that the beneficial effects of erythropoietin were associated with inhibition of apoptosis, nitric oxide production, and tissue hypoxia, without alterations in inflammatory responses. |
| PMID: 19237893 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
Publication Types:
MeSH Terms:
Substances:
|
| 6. | Braz J Infect Dis. 2008 Oct;12(5):416-22.Inadequate timing between corticosteroid and antibiotics applications increases mortality due to sepsis.Fadel MV, Repka JC, Cunha CL, Leão MT.Federal University of Paraná, Curitiba, PR, Brazil. marcusvtf@gmail.com This study tested the hypothesis that the use of corticosteroids prior to antibiotics can lower the mortality rate in severe infections by S. aureus or Gram-negative bacilli, using an animal model. This study was a prospective and controlled study, placed in a university laboratory. Seven hundred and sixty mice distributed into three groups (Staphylococcus aureus, Escherichia coli and Klebsiella pneumoniae infected). The interventions in each group were: I) infection control (intra-peritoneal); II) treatment solely with antibiotics (teicoplanin or amikacin); III) antibiotics administered prior to the corticosteroid (methylprednisolone); IV) antibiotics administered after the corticosteroid. Mortality in the E. coli group, subgroup I: 100%; subgroup II: 55% (p<0.001); subgroup III: 62.5% (p=0.2488, compared to subgroup II); subgroup IV: 20% (p<0.01 compared to subgroups II and III). Mortality in the K. pneumoniae group: subgroup I: 100%; subgroup II: 72.5% (p<0.01); subgroup III: 80% (p=0.215 compared to subgroup II); subgroup IV: 45% (p<0.01 compared to subgroups II and III). Mortality in the S. aureus group: subgroup I: 82.5%; II: 42.5% (p<0.001); subgroup III: 77.5% (p=0.2877 compared to subgroup I); subgroup IV: 32.5% (p=0.1792 compared to subgroup II). The use of corticosteroids prior to antibiotics lowered the mortality rate caused by Gram-negative bacteria and did not affect the mortality caused by S. aureus. When used after starting treatment with antibiotics, the corticosteroid was not superior to the use of antibiotics alone in the case of the Gram-negative bacteria, and was not significantly different from non-treatment of the infection, in the case of S. aureus. |
| PMID: 19219282 [PubMed - indexed for MEDLINE] | |
| Related articles Free article | |
 | |
Publication Types:
MeSH Terms:
Substances:
|
| 7. | J Trauma. 2009 Feb;66(2):411-7.Tetrandrine increased the survival rate of mice with lipopolysaccharide-induced endotoxemia.Lin TY, Tseng SH, Li SJ, Chen JC, Shieh JS, Chen Y.Department of Anesthesiology, Far-Eastern Memorial Hospital, Taipei, Taiwan. BACKGROUNDS: Endotoxemia usually causes significant morbidity and mortality, and treatment of endotoxemia is often ineffective. The effects of tetrandrine (a bisbenzylisoquinoline alkaloid) on lipopolysaccharide (LPS)-induced endotoxemia were investigated in mice. METHODS: The peritoneal macrophages were stimulated with LPS and treated with or without tetrandrine. The amounts of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, and IL-10 secreted by peritoneal macrophages were measured by enzyme-linked immunosorbent assay. Mice were intraperitoneally injected with LPS to induce endotoxemia and were treated or not treated with oral gavage with 150 mg/kg tetrandrine 1 hour before or after LPS injection. The survival rate of the mice was determined after they were treated with various regiments. The amounts of TNF-alpha, IL-1beta, IL-6, and IL-10 in the serum of the mice were measured by enzyme-linked immunosorbent assay, and the high mobility group box 1 (HMGB1) concentration was studied by Western blot analysis. RESULTS: Tetrandrine suppressed the LPS-induced increase of TNF-alpha, IL-1beta, and HMGB1 secretion by peritoneal macrophages but did not affect the IL-6 and IL-10 concentrations. The animals treated with tetrandrine either 1 hour before or after LPS injection had a 100% survival rate, which was significantly higher than that of the control group (40%) (p = 0.005). The LPS-induced increase in serum TNF-alpha, IL-1beta, and HMGB1 concentrations was reduced by tetrandrine treatment administered either 1 hour before or after LPS injection (p < 0.0001). In contrast, tetrandrine prolonged the LPS-induced elevation in serum IL-10 concentrations only mildly changed the serum IL-6 concentrations. CONCLUSIONS: Tetrandrine treatment either 1 hour before or 1 hour after LPS injection reduced the mortality rate of the mice with LPS-induced endotoxemia. The effects of tetrandrine on LPS-induced endotoxemia might be related to the suppression of TNF-alpha, IL-1beta, and HMGB1 concentrations. |
| PMID: 19204515 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
Publication Types:
MeSH Terms:
Substances:
|
| 8. | J Surg Res. 2009 Mar;152(1):46-53. Epub 2008 May 16.NF-kappaB and p38 MAPK inhibition improve survival in endotoxin shock and in a cecal ligation and puncture model of sepsis in combination with antibiotic therapy.O'Sullivan AW, Wang JH, Redmond HP.Department of Academic Surgery, University College Hospital, Cork, Ireland. awmos@btinternet.com BACKGROUND: Nuclear factor-kappa B (NF-kappaB) and p38 mitogen-activated protein kinase (MAPK) are critical intracellular signal transduction pathways that mediate the systemic inflammatory response syndrome. Antibiotics induce bacterial lysis, which also contributes to cytokine production and the inflammatory response by activating NF-kappaB and p38 kinase. In this study, we set out to examine the effects of inhibition of p38 MAPK and NF-kappaB translation in in vivo models of sepsis. MATERIALS AND METHODS: Intraperitoneal lipopolysaccharide (30 mg/kg), tail vein injection of bacteria (Staphylococcus aureus + Salmonella Typhimurium, 5 x 10(7) colony forming units/kg) and cecal ligation and puncture (CLP) with or without antibiotics (Augmentin, 100 mg/kg) were the septic models used. Animals received control, SB-202190 (a p38 inhibitor), or SN-50 (an NF-kappaB inhibitor), and mortality was assessed by log-rank analysis. Blood was collected at different time points for cytokine analysis, and splenic tissue was used for cytoplasmic protein extraction to assess kinase activation. RESULTS: SB-202190 and SN-50 resulted in significant survival benefit in the lipopolysaccharide model (P = 0.0006) but not bacterial or CLP models (P = 0.9 and 0.3, respectively). SB-202190 and SN-50, in combination with antibiotic, resulted in a significant survival benefit in the CLP model (P = 0.0001 and 0.006, respectively). Circulating levels of both tumor necrosis factor-alpha and interleukin-6 were significantly reduced at 2 h (P = 0.047 and 0.036, respectively) and Western blot demonstrated down-regulation of p38 kinase 2 h after CLP in animals treated with p38MAPK and SN-50 inhibitors in combination with antibiotics. CONCLUSIONS: We have demonstrated that p-38 and NF-kappaB inhibition improve survival in endotoxin shock, whereas the survival benefit in polymicrobial sepsis requires coexistent antibiotic treatment. |
| PMID: 19027920 [PubMed - indexed for MEDLINE] | |
| Related articles | |
 | |
MeSH Terms:
Substances:
|
| 9. | Mol Immunol. 2009 Feb;46(5):848-57. Epub 2008 Oct 28.Recombinant protein glutathione S-transferases P1 attenuates inflammation in mice.Luo L, Wang Y, Feng Q, Zhang H, Xue B, Shen J, Ye Y, Han X, Ma H, Xu J, Chen D, Yin Z.State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China. We have reported that intracellular glutathione S-transferases P1 (GSTP1) suppresses LPS (lipopolysaccharide)-induced excessive production of pro-inflammatory factors by inhibiting LPS-stimulated MAPKs (mitogen-activated protein kinases) as well as NF-kappaB activation. But under pathogenic circumstances, physiologic levels of GSTP1 are insufficient to stem pro-inflammatory signaling. Here we show that LPS-induced up-regulation of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in RAW246.7 cells is significantly reduced by incubating cells with recombinant GSTP1 protein. In vivo study demonstrates that treatment of mice (i.p.) with recombinant GSTP1 protein effectively suppresses the devastating effects of acute inflammation, which includes reduction of mortality rate of endotoxic shock, alleviation of LPS-induced acute lung injury and abrogation of thioglycolate (TG)-induced peritoneal deposition of leukocytes and polymorphonuclear cells (PMNs). Meanwhile, GSTP1 prevented LPS-induced TNF-alpha, IL-1beta, MCP-1 and NO production. Further investigation by using confocal microscopy and flow cytometry shows that recombinant GSTP1 protein can be delivered into RAW246.7 cells, mouse peritoneal macrophages and HEK 293 cells suggesting that extracellular GSTP1 protein could be transported across plasma membrane and act as a cytosolic protein. In conclusion our research demonstrates a new finding that increasing cellular GSTP1 level by supplement of recombinant GSTP1 effectively suppresses the devastating effects of acute inflammation. |
| PMID: 18962899 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
Publication Types:
MeSH Terms:
Substances:
|
| 10. | Biochem J. 2009 Feb 15;418(1):103-12.Netropsin improves survival from endotoxaemia by disrupting HMGA1 binding to the NOS2 promoter.Grant MA, Baron RM, Macias AA, Layne MD, Perrella MA, Rigby AC.Division of Molecular and Vascular Medicine, Center for Vascular Biology Research, Department of Medicine, Beth Israel Deaconess Medical Center, 99 Brookline Avenue, Boston, MA 02215, USA. The inducible form of nitric oxide synthase (NOS2) plays an important role in sepsis incurred as a result of infection with Gram-negative bacteria that elaborate endotoxin. The HMGA1 (high-mobility group A1) architectural transcription factor facilitates NOS2 induction by binding a specific AT-rich Oct (octamer) sequence in the core NOS2 promoter via AT-hook motifs. The small-molecule MGB (minor-groove binder) netropsin selectively targets AT-rich DNA sequences and can interfere with transcription factor binding. We therefore hypothesized that netropsin would improve survival from murine endotoxaemia by attenuating NOS2 induction through interference with HMGA1 DNA binding to the core NOS2 promoter. Netropsin improved survival from endotoxaemia in wild-type mice, yet not in NOS2-deficient mice, supporting an important role for NOS2 in the beneficial effects of MGB administration. Netropsin significantly attenuated NOS2 promoter activity in macrophage transient transfection studies and the AT-rich HMGA1 DNA-binding site was critical for this effect. EMSAs (electrophoretic mobility-shift assays) demonstrated that netropsin interferes with HMGA1 NOS2 promoter binding and NMR spectroscopy was undertaken to characterize this disruption. Chemical shift perturbation analysis identified that netropsin effectively competes both HMGA1 DNA-binding AT-hooks from the AT-rich NOS2 promoter sequence. Furthermore, NOESY data identified direct molecular interactions between netropsin and A/T base pairs within the NOS2 promoter HMGA1-binding site. Finally, we determined a structure of the netropsin/NOS2 promoter Oct site complex from molecular modelling and dynamics calculations. These findings represent important steps toward refined structure-based ligand design of novel compounds for therapeutic benefit that can selectively target key regulatory regions within genes that are important for the development of critical illness. |
| PMID: 18937643 [PubMed - indexed for MEDLINE] | |
| Related articles | |
 | |
Publication Types:
MeSH Terms:
Substances:
Grant Support:
|
| 11. | J Mol Med. 2008 Nov;86(11):1287-95. Epub 2008 Sep 30.Licochalcone A isolated from licorice suppresses lipopolysaccharide-stimulated inflammatory reactions in RAW264.7 cells and endotoxin shock in mice.Kwon HS, Park JH, Kim DH, Kim YH, Park JH, Shin HK, Kim JK.Center for Efficacy Assessment and Development of Functional Foods and Drugs, Hallym University, Hallymdaehak-gil 39, Chuncheon, 200-702, Republic of Korea. Licochalcone A (LicA), a major phenolic constituent of the licorice species Glycyrrhiza inflata, exhibits various biological properties, including chemopreventive, anti-bacterial, and anti-spasmodic activity. We report that LicA inhibits inflammatory reactions in macrophages and protects mice from endotoxin shock. Our in vitro experiments showed that LicA suppressed not only the generation of nitric oxide (NO) and prostaglandin (PG)E(2), but also the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 induced by lipopolysaccharide (LPS) in RAW264.7 cells. Similarly, LicA inhibited the production of inflammatory cytokines induced by LPS in RAW264.7 cells, including IL-1 beta and IL-6. In an animal model, LicA protected BALB/c mice from LPS-induced endotoxin shock, possibly through inhibiting the production of inflammatory cytokines and NO. Collectively, LicA inhibited the production of inflammatory mediators and may be a potential target for treatment of various inflammatory diseases. |
| PMID: 18825356 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
Publication Types:
MeSH Terms:
Substances:
|
| 12. | Int Immunopharmacol. 2008 Dec 10;8(12):1646-51. Epub 2008 Aug 17.PACAP inhibit the release and cytokine activity of HMGB1 and improve the survival during lethal endotoxemia.Tang Y, Lv B, Wang H, Xiao X, Zuo X.Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan 410078, PR China. victor443@sina.com.cn The pathogenesis of sepsis is mediated in part by bacterial endotoxin (lipopolysaccharide; LPS), which stimulates macrophages/monocytes to sequentially release early (e.g., TNF-alpha, IL-1beta) and late [e.g., high mobility group box 1 (HMGB1) protein] pro-inflammatory cytokines. Specifically targeting early mediators has not been effective clinically, in part, because peak mediator activity often has passed before therapy can be initiated. Recent discovery of HMGB1 as a late mediator of lethal sepsis has provided a new target for the treatment of septic shock. Here, we demonstrate that pituitary adenylate cyclase-activating polypeptide (PACAP), an endogenous neuropeptide, significantly attenuated circulating HMGB1 levels and increased survival in animals with established endotoxemia, even if treatment began after acute cytokine response has occurred. In vitro, PACAP suppressed LPS-induced HMGB1 release from macrophages/monocytes, even when given 2-4 h after LPS stimulation. PACAP also suppressed HMGB1 release induced by TNF-alpha or IFN-gamma. Moreover, PACAP inhibits HMGB1-induced cytokine release in vitro and in vivo. These results indicate that PACAP inhibits the release and pro-inflammatory activity of HMGB1 and improves survival during lethal endotoxemia, which confirms this peptide as a candidate for therapy of septic shock. |
| PMID: 18713653 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
Publication Types:
MeSH Terms:
Substances:
|
| 13. | Int Immunopharmacol. 2008 Jul;8(7):982-8. Epub 2008 Mar 31.Effects of florfenicol on early cytokine responses and survival in murine endotoxemia.Zhang X, Song Y, Ci X, An N, Fan J, Cui J, Deng X.Department of Veterinary Pharmacology, College of Animal Science and Veterinary Medicine, Jilin University, Changchun, Jilin 130062, People's Republic of China. Some antibacterials have been reported to regulate the host immune and inflammatory responses both in vitro and in vivo. Florfenicol is an antibiotics used in treatment of infection. We investigated the effects of florfenicol on cytokine production by lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages in vitro, and the results showed that florfenicol reduced tumor necrosis factor (TNF) and interleukin-6 (IL-6) production but had little effect on interleukin-1beta (IL-1beta) and interleukin IL-10 (IL-10) secretion. This inspired us to further study the effects of florfenicol in vivo. Florfenicol significantly attenuated TNF and IL-6 production in serum from mice challenged with LPS, and in consistent with the results in vitro. In murine model of endotoxemia, mice were prophylactically or therapeutically treated with florfenicol prior to or after LPS challenge. The results showed that florfenicol significantly increased mouse survival. Further studies revealed that florfenicol prevented the LPS-induced nuclear factor-kappaB (NF-kappaB) translocation from cytoplasm into nuclear in RAW 264.7 macrophages. These observations indicate that florfenicol modulates early cytokine responses by blocking NF-kappaB pathway, and thus, increases mouse survival. This effect of the drug may be of potential usefulness in treatment of bacterial shock. |
| PMID: 18486909 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
Publication Types:
MeSH Terms:
Substances:
|
| 14. | Parasitol Res. 2008 Jul;103(2):413-21. Epub 2008 May 4.Benznidazole therapy during acute phase of Chagas disease reduces parasite load but does not prevent chronic cardiac lesions.Caldas IS, Talvani A, Caldas S, Carneiro CM, de Lana M, da Matta Guedes PM, Bahia MT.Núcleo de Pesquisas em Ciências Biológicas, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brazil. The goals of this study were to evaluate the efficacy of benznidazole (Bz) treatment in decreasing of the parasitic load during the acute phase of experimental Chagas disease and to analyze its influence in the development of cardiac chronic alterations in mice inoculated with drug-resistant Trypanosoma cruzi strains. Our results showed that the early Bz treatment (started at 4th day of infection) was efficient in reducing the parasite load in animals from both acute and chronic phase of the infection. Moreover, this reduction in the parasite load could not be associated with the intensity of the cardiac chronic lesions. The histopathological evaluation of cardiac tissue of Bz-treated mice showed three different patterns of response: (1) presence of a small number of inflammatory cells and fibrotic area similar to noninfected mice; (2) similar intensity of inflammatory infiltrate and smaller fibrotic area in relation to nontreated animals; (3) similar intensity of inflammatory infiltrated and fibrosis area among the Bz-treated and nontreated animals. Each specific pattern was obtained with different T. cruzi strain, suggesting that the pattern of the heart lesions in chronic phase of Bz-treated animals was T. cruzi strain dependent but not related with drug resistance levels. |
| PMID: 18454349 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
Publication Types:
MeSH Terms:
Substances:
|
| 15. | Cell Physiol Biochem. 2008;21(5-6):481-8. Epub 2008 Apr 24.Influence of NO synthase inhibitor L-NAME on parasitemia and survival of Plasmodium berghei infected mice.Koka S, Lang C, Niemoeller OM, Boini KM, Nicolay JP, Huber SM, Lang F.Department of Physiology, University of Tübingen, Germany. Accelerated suicidal death or eryptosis of infected erythrocytes may delay development of parasitemia in malaria. Eryptosis is inhibited by nitric oxide (NO). The present study has been performed to explore, whether inhibition of NO synthase by L-NAME modifies the course of malaria. We show here that L-NAME (>or=10 microM) increased phosphatidylserine exposure of Plasmodium falciparum infected human erythrocytes, an effect significantly more marked than in noninfected human erythrocytes. We further show that parasitemia in Plasmodium berghei infected mice was significantly decreased (from 50% to 18% of circulating erythrocytes 20 days after infection) by addition of 1 mg/ml L-NAME to the drinking water. According to CFSE labelling L-NAME treatment accelerated the clearance of both, noninfected and infected, erythrocytes from circulating blood, but did not significantly extend the life span of infected animals. In conclusion, treatment with L-NAME shortens the life span of circulating erythrocytes and thus delays development of parasitemia during malaria. (c) 2008 S. Karger AG, Basel. |
| PMID: 18453756 [PubMed - indexed for MEDLINE] | |
| Related articles | |
 | |
Publication Types:
MeSH Terms:
Substances:
|
| 16. | Homeopathy. 2008 Apr;97(2):65-9.Effects of homeopathy in mice experimentally infected with Trypanosoma cruzi.de Almeida LR, Campos MC, Herrera HM, Bonamin LV, da Fonseca AH.Department of Animal Parasitology, Universidade Federal Rural do Rio de Janeiro, RJ, Brazil. rodrigues_lu@yahoo.fr Comment in: AIM: The aim of this study was to evaluate the action of homeopathic treatment on mice experimentally infected with Trypanosoma cruzi. METHODS: Eighty adult male C57BL/6 inbred mice were randomly allocated to five groups treated with biotherapy (nosode) of T. cruzi 12dH (12x) pre- and post-infection; Phosphorus 12dH post-infection; infected control treated with control solution and uninfected control. The biotherapy was prepared by the Costa method from the blood of mice experimentally infected with the Y strain of T. cruzi. Phosphorus was used because of its clinical and reportorial similarity to Chagas disease. T. cruzi (10(4)) sanguineous forms were inoculated intraperitoneally per animal. Parasitaemia was monitored, leukocyte and serological responses were evaluated at 0, 7, 14 and 42 days after infection. The prepatent and patent periods of parasitaemia, maximum of parasitaemia, day of maximum parasitaemia and mortality rates were compared between groups. RESULTS: A significantly shorter period of patent parasitaemia was observed in the group treated with the biotherapy before infection (p<0.05) than in the other groups. This group also had the lowest parasitaemias values at 9, 13, 15 (p<0.05), 17 (p<0.05), 22, 24 and 28 days, a lower rate of mortality and a significant increase of lymphocytes compared to the infected control group. The Phosphorus group had the longest period of patent parasitaemia, higher maximum parasitaemia, and a significant reduction of lymphocyte numbers, but no mortality. The infected control group had the highest mortality rate (not statistically significant), and the highest IgG titres at 42 days post-infection (p<0.05). CONCLUSIONS: The results suggest that pre-treatment with biotherapy modulates host immune response to T. cruzi, mainly during the acute phase of the infection. Phosphorus shows an action on the pathogenicity by T. cruzi infection. Homeopathic treatment of T. cruzi infection should be further investigated. |
| PMID: 18439966 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
MeSH Terms:
Substances:
|
| 17. | Am J Pathol. 2008 May;172(5):1297-307. Epub 2008 Apr 1.Neuropeptides rescue mice from lethal sepsis by down-regulating secretion of the late-acting inflammatory mediator high mobility group box 1.Chorny A, Delgado M.Institute of Parasitology and Biomedicine, Spanish Council of Scientific Research, Granada, Spain. Comment in: Originally described as a nuclear protein that bends DNA, the high mobility group box 1 protein (HMGB1) has recently emerged as a necessary and sufficient late mediator of severe sepsis. HMGB1 is therefore a molecular target that provides a wide window for clinical intervention in sepsis. Vasoactive intestinal peptide (VIP) and urocortin are two well known anti-inflammatory neuropeptides that protect against several immune disorders by regulating a wide panel of inflammatory mediators. In this study, we demonstrate the therapeutic effect of VIP and urocortin in various models of established sepsis: both agents reduced lethality induced by cecal ligation and puncture or by injection of live Escherichia coli. The therapeutic effect of VIP and urocortin was accompanied by a decrease in systemic levels of HMGB1. In addition, administration of recombinant HMGB1 completely reversed the protective effect of VIP and urocortin in experimental sepsis. In vitro and ex vivo studies show that both VIP and urocortin down-regulate translocation of HMGB1 from the nucleus to the cytoplasm and its subsequent secretion by activated macrophages, suggesting that macrophages are major targets in the inhibitory activity of these neuropeptides. To our knowledge, VIP and urocortin are the first endogenous inhibitors of HMGB1 secretion shown to improve sepsis survival in a clinically relevant time frame. PMCID: PMC2329838 |
| PMID: 18385521 [PubMed - indexed for MEDLINE] | |
| Related articles Free article | |
  | |
Publication Types:
MeSH Terms:
Substances:
|
| 18. | Mem Inst Oswaldo Cruz. 2008 Feb;103(1):21-6. Epub 2008 Jan 31.Importance of TNF-alpha in the course of acute infection with Trypanosoma cruzi: influence of its inhibition by pentoxifylline treatment.Andrade SG, Magalhães Ldos A, Pessina DH.Laboratório de Chagas Experimental, Autoimunidade e Imunidade Celular, Centro de Pesquisas Gonçalo Moniz, Fiocruz, Salvador, Bahia, 40295-001, Brasil. sgandrade@cpqgm.fiocruz.br Infection of C3H/He mice with the Peruvian strain of Trypanosoma cruzi (Biodeme type I, Z2b), a macrophagotropic strain, determined severe parasitism of macrophages, necrosis of the spleen, and high host mortality. In the present study, pentoxifylline (PTX), an inhibitor of TNF-alpha was investigated on its action upon splenic necrosis, parasitemia and host survival. Immunohistochemical data suggested the importance of this cytokine in parasite destruction and decreasing of parasitemia, although paradoxically contributing to the high mortality of infected mice. Necrotic lesions involving several organs, specially the heart, in acute Chagas disease, are important aggravating factors, increasing cardiac morbidity. Advantage of inhibiting TNF-alpha action was herein investigated. Infected mice were divided into two groups: untreated (n = 24), and PTX treated mice (n = 25). PTX was administered in two daily doses of 30 mg/kg/bw, by intraperitoneal route. Normal controls either treated with PTX or saline were also included. Histopathology of the spleen and in situ immunolabeling of TNF-alpha, using anti-TNF-alpha monoclonal antibody, were performed. Necrotic areas were evaluated by morphometry. Mice treated with PTX showed a significant decrease of necrotic areas and diminution of TNF-alpha expression in spleen tissue, suggesting that PTX treatment could control TNF-alpha effects, and thus be used as an adjuvant in the treatment of acute Chagas' disease. |
| PMID: 18345460 [PubMed - indexed for MEDLINE] | |
| Related articles Free article | |
| | |
MeSH Terms:
Substances:
|
| 19. | Intensive Care Med. 2008 Jul;34(7):1304-12. Epub 2008 Feb 19.Pioglitazone reduces systematic inflammation and improves mortality in apolipoprotein E knockout mice with sepsis.Haraguchi G, Kosuge H, Maejima Y, Suzuki J, Imai T, Yoshida M, Isobe M.Department of Cardiovascular Medicine, Tokyo Medical and Dental University, 113-8519, Tokyo, Japan. goh.cvm@tmd.ac.jp OBJECTIVE: To determine whether peroxisome proliferator-activated receptor (PPAR) gamma ligands improve survival of patients with septic shock we treated a mouse model of sepsis [apolipoprotein (Apo) E) knockout mice] with pioglitazone, a PPAR-gamma ligand. ApoE knockout mice have a high mortality rate due to sepsis because the endotoxin is not cleared. DESIGN AND SETTING: Prospective study in a university laboratory. SUBJECTS: We assorted 87 male ApoE knockout mice and 60 wild-type C57/B6 mice randomly into three groups (sepsis, pretreatment, posttreatment). INTERVENTIONS: Cecal ligation and puncture (CLP) was carried out in the sepsis and treatment groups. Mice were injected with pioglitazone (5 mg/kg per day) on the day before CLP or 6 h after surgery. MEASUREMENTS AND RESULTS: Both pre- and post-CLP treatment with pioglitazone improved survival of ApoE knockout and wild-type mice. Serum levels of cytokines and chemokines and myeloperoxidase activity in lung and liver were suppressed in the pioglitazone-treated group. Pioglitazone also suppressed monocyte adhesion to vascular endothelium under flow conditions. CONCLUSIONS: Pioglitazone improved survival of ApoE knockout mice after onset of septic shock through suppression of inflammatory responses. |
| PMID: 18283431 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
Publication Types:
MeSH Terms:
Substances:
|
| 20. | Crit Care. 2008;12(1):201. Epub 2008 Jan 9.Bench-to-bedside review: The inflammation-perpetuating pattern-recognition receptor RAGE as a therapeutic target in sepsis.Bopp C, Bierhaus A, Hofer S, Bouchon A, Nawroth PP, Martin E, Weigand MA.Department of Anesthesiology, University of Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany. Comment in: Sepsis still represents an important clinical and economic challenge for intensive care units. Severe complications like multi-organ failure with high mortality and the lack of specific diagnostic tools continue to hamper the development of improved therapies for sepsis. Fundamental questions regarding the cellular pathogenesis of experimental and clinical sepsis remain unresolved. According to experimental data, inhibiting macrophage migration inhibitory factor, high-mobility group box protein 1 (HMGB1), and complement factor C5a and inhibiting the TREM-1 (triggering receptor expressed on myeloid cells 1) signaling pathway and apoptosis represent promising new therapeutic options. In addition, we have demonstrated that blocking the signal transduction pathway of receptor of advanced glycation endproducts (RAGE), a new inflammation-perpetuating receptor and a member of the immunoglobulin superfamily, increases survival in experimental sepsis. The activation of RAGE by advanced glycation end-products, S100, and HMGB1 initiates nuclear factor kappa B and mitogen-activated protein kinase pathways. Importantly, the survival rate of RAGE knockout mice was more than fourfold that of wild-type mice in a septic shock model of cecal ligation and puncture (CLP). Additionally, the application of soluble RAGE, an extracellular decoy for RAGE ligands, improves survival in mice after CLP, suggesting that RAGE is a central player in perpetuating the innate immune response. Understanding the basic signal transduction events triggered by this multi-ligand receptor may offer new diagnostic and therapeutic options in patients with sepsis. PMCID: PMC2374592 |
| PMID: 18226173 [PubMed - indexed for MEDLINE] | |
| Related articles Free article | |
| | |
Publication Types:
MeSH Terms:
Substances:
|
| 21. | Recent Pat Antiinfect Drug Discov. 2006 Jan;1(1):57-65.C5a, a therapeutic target in sepsis.Guo RF, Ward PA.Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109-0602, USA. grf@med.umich.edu The complement activation product, C5a, is a potent inflammatory peptide with a broad spectrum of biological functions. Plasma levels of C5a are increased in sepsis, accompanied by increased content of C5a receptor (C5aR) in various organs. In the mouse and rat models of sepsis (cecal ligation and puncture, CLP), C5a blockade by anti-C5a antibody, anti-C5aR antibody or use of a C5aR antagonist (C5aRa) significantly improved survival in CLP animals. C5a blockade in sepsis attenuated the systemic inflammatory response syndrome (SIRS) by reducing plasma levels of IL-6 and decreasing bacteria counts in blood and organs. Anti-C5a treatment in CLP rodents markedly attenuated sepsis-induced defects in the coagulation/fibrinolytic system, while liver and kidney functions were remarkably preserved in contrast to CLP animals not receiving anti-C5a in which multi-organ failure occurs. In CLP rats treated with anti-C5a, thymus atrophy was diminished and thymocyte apoptosis was inhibited. Defective neutrophil functions (chemotaxis, phagocytosis, respiratory burst) caused by sepsis were significantly improved in CLP rats treated with anti-C5a. These data suggest during CLP-induced sepsis C5a has very harmful consequences and that its blockade might be a promising therapeutic strategy for the treatment of humans with sepsis. This review will summarize the beneficial effects of anti-C5a treatment in the rodent model of sepsis and will introduce the most recent patents on this line of research. |
| PMID: 18221134 [PubMed - indexed for MEDLINE] | |
| Related articles | |
Publication Types:
MeSH Terms:
Substances:
Grant Support:
|
| 22. | Shock. 2008 Jul;30(1):36-42.Epidermal growth factor treatment decreases mortality and is associated with improved gut integrity in sepsis.Clark JA, Clark AT, Hotchkiss RS, Buchman TG, Coopersmith CM.Department of Surgery, Washington University School of Medicine, St. Louis, Missouri 63110, USA. ABSTRACT: Epidermal growth factor (EGF) is a cytoprotective peptide that has healing effects on the intestinal mucosa. We sought to determine whether systemic administration of EGF after the onset of sepsis improved intestinal integrity and decreased mortality. FVB/N mice were subjected to either sham laparotomy or 2 x 23 cecal ligation and puncture (CLP). Septic mice were further randomized to receive injection of either 150 microg kg(-1) d(-1) (i.p.) EGF or 0.9% saline (i.p.). Circulating EGF levels were decreased after CLP compared with sham animals but were unaffected by giving exogenous EGF treatment. In contrast, intestinal EGF levels increased after CLP and were further augmented by exogenous EGF treatment. Intestinal EGF receptor was increased after CLP, whether assayed by immunohistochemistry, real-time polymerase chain reaction, or Western blot, and exogenous EGF treatment decreased intestinal EGF receptor. Villus length decreased 2-fold between sham and septic animals, and EGF treatment resulted in near total restitution of villus length. Sepsis decreased intestinal proliferation and increased intestinal apoptosis. This was accompanied by increased expression of the proapoptotic proteins Bid and Fas-associated death domain, as well as the cyclin-dependent kinase inhibitor p21 cip1/waf Epidermal growth factor treatment after the onset of sepsis restored both proliferation and apoptosis to levels seen in sham animals and normalized expression of Bid, Fas-associated death domain, and p21 cip1/waf . To determine whether improvements in gut homeostasis were associated with a decrease in sepsis-induced mortality, septic mice with or without EGF treatment after CLP were followed 7 days for survival. Mortality decreased from 60% to 30% in mice treated with EGF after the onset of sepsis (P < 0.05). Thus, EGF may be a potential therapeutic agent for the treatment of sepsis in part due to its ability to protect intestinal integrity. PMCID: PMC2551558 |
| PMID: 18004230 [PubMed - indexed for MEDLINE] | |
| Related articles Free article | |
 | |
Publication Types:
MeSH Terms:
Substances:
Grant Support:
|
| 23. | Intensive Care Med. 2008 Mar;34(3):568-77. Epub 2007 Nov 9.Risk of death does not alter the efficacy of hydrocortisone therapy in a mouse E. coli pneumonia model: risk and corticosteroids in sepsis.Li Y, Cui X, Li X, Solomon SB, Danner RL, Banks SM, Fitz Y, Annane D, Natanson C, Eichacker PQ.Critical Care Medicine Department, Clinical Center, Building 10, Room 7D43, National Institutes of Health, Bethesda, MD 20892, USA. BACKGROUND: Risk of death may influence the efficacy of anti-inflammatory agents in sepsis. "Physiologic" dose corticosteroids, while improving survival in earlier trials with higher control mortality rates (>50%), were not beneficial in the recent CORTICUS trial with lower control mortality (31%). We investigated whether risk of death altered the effects of hydrocortisone in a mouse pneumonia model. METHODS: Mice (n=637) challenged with high, medium or low intratracheal E. coli doses were randomized to receive one of three hydrocortisone doses (5, 25 or 125 mg/kg) or normal saline (NS) only (control) for 4 days. All animals were treated with similar volumes of ceftriaxone and NS support following E. coli and were observed for 168 h. RESULTS: Decreasing E. coli doses reduced control mortality rates (from 94 to 12%). In similar patterns (not significant) each hydrocortisone dose increased the odds ratio (OR) of survival (95% confidence interval) with each E. coli dose (ORs ranging from 1.2 [0.4, 3.7] to 6.1 [0.6, 61.0]). The effect of hydrocortisone on the OR was not related to control mortality rate (r=-0.13, p=0.29) and overall was highly significant (2.04 [1.37, 3.03], p=0.0004). In randomly selected animals 48 h after the highest E. coli dose, compared with the control, hydrocortisone (125 mg/kg) significantly decreased IL-6, INFgamma, and nitric oxide levels. CONCLUSIONS: In this mouse model the beneficial effects of hydrocortisone were independent of risk of death. These findings suggest that factors other than risk of death may underlie the differing effects of corticosteroids in recent sepsis trials. |
| PMID: 17992512 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
Publication Types:
MeSH Terms:
Substances:
|
| 24. | Inflammation. 2008 Feb;31(1):57-64. Epub 2007 Oct 9.Etoposide attenuates zymosan-induced shock in mice.Remichkova M, Yordanov M, Dimitrova P.Department of Immunology, Institute of Microbiology, Bulgarian Academy of Sciences, Sofia, Bulgaria. Zymosan-induced generalized inflammation is a convenient model to study the process of acute and chronic inflammatory processes resulting in multiple organ dysfunction syndrome. Macrophages as a source of many pro-inflammatory mediators are the major players in shock and further organ failure. Etoposide is a cytostatic drug known to reduce macrophages and monocytes in blood circulation. In the present study we have investigated whether the ability of etoposide to diminish macrophage number would have an impact on the course of zymosan-induced shock. The drug injected at a dose of 10 mg/kg 1 day before zymosan, significantly reduced the mortality and decreased the organ toxicity in Balb/c mice. Simultaneously, an inhibition of TNF-alpha production by alveolar and peritoneal macrophages was observed. Etoposide administered into mice with severe combined immunodeficiency (SCID) did not change the survival rate and had a little influence on organ toxicity. Our findings suggest that the beneficial action of etoposide might be attributed to the reduction of macrophages and alteration of their functions. Its effect depends on the presence of functional T and B lymphocytes. The results deserve further investigation of etoposide as a perspective therapeutic tool for inhibiting the excessive inflammatory response and to be helpful for revealing mechanisms of shock development. |
| PMID: 17924177 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
Publication Types:
MeSH Terms:
Substances:
|
| 25. | Proc Natl Acad Sci U S A. 2007 Oct 9;104(41):16239-44. Epub 2007 Oct 2.Activin A is a critical component of the inflammatory response, and its binding protein, follistatin, reduces mortality in endotoxemia.Jones KL, Mansell A, Patella S, Scott BJ, Hedger MP, de Kretser DM, Phillips DJ.Monash Institute of Medical Research, Monash University, Clayton, Victoria 3168, Australia. Activin A is a member of the transforming growth factor-beta superfamily, which we have identified as having a role in inflammatory responses. We show that circulating levels of activin increase rapidly after LPS-induced challenge through activation of Toll-like receptor 4 and the key adaptor protein, MyD88. Treatment with the activin-binding protein, follistatin, alters the profiles of TNF, IL-1beta, and IL-6 after LPS stimulation, indicating that activin modulates the release of several key proinflammatory cytokines. Further, mice administered one 10-mug dose of follistatin to block activin effects have increased survival after a lethal dose of LPS, and the circulating levels of activin correlate with survival outcome. These findings demonstrate activin A's crucial role in the inflammatory response and show that blocking its actions by the use of follistatin has significant therapeutic potential to reduce the severity of inflammatory diseases. PMCID: PMC2042191 |
| PMID: 17911255 [PubMed - indexed for MEDLINE] | |
| Related articles Free article | |
 | |
Publication Types:
MeSH Terms:
Substances:
|
| 26. | Microbiol Immunol. 2007;51(9):851-9.Antibiotics protect against septic shock in mice administered beta-glucan and indomethacin.Nameda S, Miura NN, Adachi Y, Ohno N.Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Yokyo, Japan. We have developed an animal model of sepsis in mice by repeatedly administering beta-glucan, a biological response modifier, and indomethacin (IND), a nonsteroidal anti-inflammatory drug. The combination of these drugs induced bacteremia by translocation of the enterobacterial flora, resulting in increasing the number of activated leukocytes, and inducing hyper cytokinemia. In the present study, we examined the effect of antibiotics on beta-glucan and IND-induced septic shock. Treatment with antibiotics inhibited microbial translocation, inhibited contraction of the colon, reduced lipopolysaccharides (LPS)-elicited production of TNF-alpha and IL-6, and finally prolonged survival. However, the efficacy of antibiotics treatment was limited in mice administered IND orally. These findings strongly suggested that the antibiotics controlled the gut-associated action of IND and reduced various symptoms accompanying sepsis. |
| PMID: 17895602 [PubMed - indexed for MEDLINE] | |
| Related articles Free article | |
 | |
Publication Types:
MeSH Terms:
Substances:
|
| 27. | Blood. 2007 Nov 15;110(10):3673-81. Epub 2007 Aug 9.Treatment with GITR agonistic antibody corrects adaptive immune dysfunction in sepsis.Scumpia PO, Delano MJ, Kelly-Scumpia KM, Weinstein JS, Wynn JL, Winfield RD, Xia C, Chung CS, Ayala A, Atkinson MA, Reeves WH, Clare-Salzler MJ, Moldawer LL.Department of Surgery, University of Florida College of Medicine, Gainesville, FL 32610-0286, USA. Apoptosis of CD4(+) T cells and T(H)2 polarization are hallmarks of sepsis-induced immunoparalysis. In this study, we characterized sepsis-induced adaptive immune dysfunction and examined whether improving T-cell effector function can improve outcome to sepsis. We found that septic mice produced less antigen-specific T-cell-dependent IgM and IgG(2a) antibodies than sham-treated mice. As early as 24 hours after sepsis, CD4(+) T cells proliferated poorly to T-cell receptor stimulation, despite normal responses to phorbol myristate acetate and ionomycin, and possessed decreased levels of CD3zeta. Five days following immunization, CD4(+) T cells from septic mice displayed decreased antigen-specific proliferation and production of IL-2 and IFN-gamma but showed no difference in IL-4, IL-5, or IL-10 production. Treatment of mice with anti-GITR agonistic antibody restored CD4(+) T-cell proliferation, increased T(H)1 and T(H)2 cytokine production, partially prevented CD3zeta down-regulation, decreased bacteremia, and increased sepsis survival. Depletion of CD4(+) T cells but not CD25(+) regulatory T cells eliminated the survival benefit of anti-GITR treatment. These results indicate that CD4(+) T-cell dysfunction is a key component of sepsis and that improving T-cell effector function may be protective against sepsis-associated immunoparalysis. PMCID: PMC2077315 |
| PMID: 17690255 [PubMed - indexed for MEDLINE] | |
| Related articles Free article | |
 | |
Publication Types:
MeSH Terms:
Substances:
Grant Support:
|
| 28. | Bioorg Med Chem. 2007 Sep 1;15(17):5694-709. Epub 2007 Jun 10.Protection from endotoxic shock by EVK-203, a novel alkylpolyamine sequestrant of lipopolysaccharide.Nguyen TB, Adisechan AK, Suresh Kumar EV, Balakrishna R, Kimbrell MR, Miller KA, Datta A, David SA.Department of Medicinal Chemistry, University of Kansas, Multidisciplinary Research Building, Lawrence, KS 66047, USA. Lipopolysaccharides (LPS) play a key role in the pathogenesis of septic shock, a major cause of mortality in the critically ill patient. The only therapeutic option aimed at limiting downstream systemic inflammatory processes by targeting lipopolysaccharide is Toraymyxin, an extracorporeal hemoperfusion device using solid phase-immobilized polymyxin B (PMB). While PMB is known to effectively sequester LPS, its severe systemic toxicity proscribes its parenteral use, and hemoperfusion may not be feasible in patients in shock. In our continuing efforts to develop small-molecule mimics which display the LPS-sequestering properties, but not the toxicity of PMB, a series of mono- and bis-substituted dialkylpolyamines were synthesized and evaluated. We show that EVK-203, an alkylpolyamine compound, specifically binds to and neutralizes the activity of LPS, and affords complete protection in a murine model of endotoxic shock. EVK-203 is without any apparent toxicity when administered to mice at multiples of therapeutic doses for several days. The specific endotoxin-sequestering property along with a very favorable therapeutic index renders this compound an ideal candidate for preclinical development. PMCID: PMC2039869 |
| PMID: 17583517 [PubMed - indexed for MEDLINE] | |
| Related articles Free article | |
| | |
Publication Types:
MeSH Terms:
Substances:
Grant Support:
|
| 29. | Crit Care Med. 2007 Aug;35(8):1955-60.Soluble vascular endothelial growth factor receptor-1 protects mice in sepsis.Tsao PN, Chan FT, Wei SC, Hsieh WS, Chou HC, Su YN, Chen CY, Hsu WM, Hsieh FJ, Hsu SM.Department of Pediatrics, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan. tsaopn@ntu.edu.tw OBJECTIVE: To determine the putative role in the modulation of inflammation of a soluble form of Flt-1 (sFlt), a potent vascular endothelial growth factor antagonist, in experimental endotoxemia and sepsis. DESIGN: Randomized prospective experimental study. SETTING: University medical laboratory. SUBJECTS: Male C56BL/6 strain mice. INTERVENTIONS: We investigated the expression patterns and the effects of vascular endothelial growth factor and soluble Flt-1 in experimental endotoxic shock and sepsis. The possible anti-inflammatory mechanism of soluble Flt-1 was also evaluated. MEASUREMENTS AND MAIN RESULTS: Both vascular endothelial growth factor and sFlt-1 were rapidly released from macrophages activated in vitro by lipopolysaccharide and in the plasma of endotoxemic mice. Administration of vascular endothelial growth factor enhanced proinflammatory cytokine production and mediated a dramatic increase in mortality in endotoxemic mice. Treatment with sFlt-1 attenuated inflammatory responses, inhibited recruitment of inflammatory cells into the peritoneal cavity, and improved survival in a lethal endotoxemia and cecal ligation and puncture-induced sepsis model, even when administered as late as 24 hrs after the onset of sepsis. CONCLUSIONS: These findings support a critical protective role of sFlt-1 in endotoxic shock and sepsis. sFlt-1 may therefore have utility as an adjunctive agent for the treatment of sepsis syndrome. |
| PMID: 17568329 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
Publication Types:
MeSH Terms:
Substances:
|
| 30. | Shock. 2007 Sep;28(3):353-9.The green tea polyphenol epigallocatechin-3-gallate improves systemic hemodynamics and survival in rodent models of polymicrobial sepsis.Wheeler DS, Lahni PM, Hake PW, Denenberg AG, Wong HR, Snead C, Catravas JD, Zingarelli B.Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039, USA. derek.wheeler@cchmc.org Epigallocatechin-3-gallate (EGCG) is the main polyphenolic flavonoid found in green tea. Recent in vitro studies have suggested that EGCG inhibits activation of the nuclear factor-kappaB (NF-kappaB) pathway. The NF-kappaB is a transcriptional factor required for gene expression of many inflammatory mediators, including the inducible isoform of nitric oxide synthase (NOS2). Excessive NO production by NOS2 is directly linked to the vasoplegia, shock, and mortality associated with sepsis. Accordingly, we hypothesized that EGCG administration would inhibit NOS2 gene expression and thereby improve survival in a rodent model of polymicrobial sepsis. Polymicrobial sepsis was induced in male Sprague-Dawley rats (hemodynamic study) and C57BL6 mice (mortality study) via cecal ligation and double puncture (CL2P). Rodents were treated with either EGCG (10 mg/kg intraperitoneally) or vehicle at 1 and 6 h after CL2P and every 12 h thereafter. In the hemodynamic study, mean arterial blood pressure was monitored for 18 h, and rats were killed at 3, 6, and 18 h after CL2P. In the mortality study, survival was monitored for 72 h after CL2P in mice. In vehicle-treated rodents, CL2P was associated with profound hypotension and greater than 80% mortality rate. Epigallocatechin-3-gallate treatment significantly improved both the hypotension and survival. In vitro experiments further showed that EGCG inhibited activation of NF-kappaB and subsequent NOS2 gene expression in a primary culture of rat aortic smooth muscle cells. Epigallocatechin-3-gallate may therefore represent a potential nutritional supplement or pharmacologic agent in patients with sepsis. |
| PMID: 17545942 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
Publication Types:
MeSH Terms:
Substances:
Grant Support:
|
| 31. | Exp Parasitol. 2007 Sep;117(1):43-50. Epub 2007 Mar 24.Trypanosoma cruzi: treatment with the iron chelator desferrioxamine reduces parasitemia and mortality in experimentally infected mice.Arantes JM, Pedrosa ML, Martins HR, Veloso VM, de Lana M, Bahia MT, Tafuri WL, Carneiro CM.Núcleo de Pesquisas em Ciências Biológicas (NUPEB), Instituto de Ciências Exatas e Biológicas (ICEB), Universidade Federal de Ouro Preto (UFOP), Rua Costa Sena 171, 35 400-000 Ouro Preto, MG, Brazil. The effects of prolonged treatment with iron chelator (desferrioxamine) on the development of infection in mice inoculated with Y Trypanosoma cruzi were determined. Infected/treated mice presented lower levels of parasitemia and reduced mortality rate compared with infected/non-treated animals. The five out of twenty infected/treated mice that survived the acute phase of infection showed negative hemoculture and positive ELISA in the acute and chronic phases and positive PCR in the acute phase: in the chronic phase, three of the animals presented negative PCR. The single surviving infected/non-treated animal exhibited positive hemoculture, PCR and ELISA in both phases of infection. Infected groups presented lower levels of iron in the liver compared with treated/non-infected or non-treated/non-infected animals. The serum iron levels of the infected/non-treated group were higher on the 21st day post-infection in comparison with control and infected/treated groups. These results suggest that decrease of iron in the host leads to T. cruzi infection attenuation. |
| PMID: 17521632 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
Publication Types:
MeSH Terms:
Substances:
|
| 32. | Nephrol Dial Transplant. 2007 Aug;22(8):2349-53. Epub 2007 Apr 16.Erythropoietin ameliorates renal dysfunction during endotoxaemia.Mitra A, Bansal S, Wang W, Falk S, Zolty E, Schrier RW.University of Colorado Health Sciences Center, 4200 East 9th Ave. Box C-281, Denver, CO 80262, USA. BACKGROUND: Sepsis has a high mortality (50-80%) when associated with acute renal failure (ARF). Oxidant injury and proinflammatory cytokines and chemokines have been shown to increase with endotoxaemia-related ARF. Since erythropoietin (EPO) has been demonstrated to possess anti-oxidant and anti-inflammatory properties, EPO may have therapeutic efficacy for treating ARF associated with endotoxaemia. METHODS: Wild-type mice were given 2.5 mg/kg of intraperitoneal (i.p.) endotoxin, lipopolysaccharide (LPS), and studied 16 h later. Thirty minutes prior to LPS, the mice were given either EPO or vehicle. RESULTS: During endotoxaemia, EPO was found to significantly attenuate the renal dysfunction, as assessed by glomerular filtration rate (48.1 +/- 12.4 microl/min vs 136.7 +/- 30.2, P < 0.05). Renal blood flow and mean arterial pressure were not significantly different between the two groups. The renal dysfunction during endotoxaemia was associated with a decrease in renal superoxide dismutase (SOD). The EPO-related renal protection was associated with reversal of the effects of endotoxin on renal SOD. CONCLUSION: This is the first demonstration of a renal protective effect of EPO on endotoxin-related renal dysfunction. |
| PMID: 17438005 [PubMed - indexed for MEDLINE] | |
| Related articles Free article | |
 | |
MeSH Terms:
Substances:
|
| 33. | Shock. 2007 Apr;27(4):373-9.Isoflurane improves survival and protects against renal and hepatic injury in murine septic peritonitis.Lee HT, Emala CW, Joo JD, Kim M.Department of Anesthesiology, College of Physicians and Surgeons, Columbia University, New York, New York 10032-3784, USA. tl128@columbia.edu We have demonstrated that volatile anesthetics reduce inflammation after renal ischemia/reperfusion injury in vivo. As hyperactive uncontrolled inflammation can lead to mortality and morbidity during early sepsis, we questioned whether the volatile anesthetic isoflurane could reduce mortality and protect against sepsis induced renal and hepatic dysfunction. Mice were anesthetized with isoflurane or with pentobarbital and subjected to cecal ligation and puncture (CLP) to induce septic peritonitis. Mice were anesthetized for an additional 3 h after CLP with either isoflurane or pentobarbital. Renal and hepatic function was assessed 24 h later and survival after CLP was assessed for 7 days. To determine if isoflurane protects by reducing inflammation, we quantified renal tubular expression of pro-inflammatory (intercellular adhesion molecule 1, tumor necrosis factor alpha [TNF-alpha], and interleukin [IL] 1beta) messenger RNA with reverse transcriptase-polymerase chain reaction. We also measured the plasma levels of the pro-inflammatory cytokines TNF-alpha, keratinocyte-derived chemokine (KC), and IL-6 and an anti-inflammatory cytokine IL-10. Renal cortical apoptosis was also assessed 24 h after CLP. Twenty-four hours after the septic insult, isoflurane-treated mice had significantly improved renal and hepatic function compared with mice anesthetized with pentobarbital. Renal cortices of isoflurane-treated mice had significantly reduced expression of intercellular adhesion molecule 1, TNF-alpha, and IL-1beta messenger RNA and showed less apoptosis. Isoflurane-treated mice had lower plasma levels of TNF-alpha, KC, and IL-6. Isoflurane-anesthetized mice also had significantly prolonged and increased survival compared with pentobarbital-anesthetized mice. Therefore, isoflurane anesthesia conferred significant protection against renal and hepatic dysfunction and death after septic peritonitis and attenuated renal inflammation and apoptosis compared with pentobarbital anesthesia. |
| PMID: 17414419 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
Publication Types:
MeSH Terms:
Substances:
Grant Support:
|
| 34. | Int Immunopharmacol. 2007 May;7(5):687-700. Epub 2007 Feb 7.Shrimp (Penaeus monodon) anti-lipopolysaccharide factor reduces the lethality of Pseudomonas aeruginosa sepsis in mice.Pan CY, Chao TT, Chen JC, Chen JY, Liu WC, Lin CH, Kuo CM.Marine Research Station, Institute of Cellular and Organismic Biology, Academia Sinica, 23-10 Dahuen Road, Jiaushi, Ilan 262, Taiwan. We investigated the efficacy of amino acids 55-76 of the synthetic shrimp anti-lipopolysaccharide factor peptide (SALF(55-76) cyclic peptide), the C-terminal part of the shrimp anti-lipopolysaccharide factor. This study was conducted to elucidate the effects of the antiseptic action of this peptide. The SALF(55-76) cyclic peptide was tested against bacterial clinical isolates and showed broad-spectrum antimicrobial activity. Transmission electron microscopic (TEM) examination of SALF(55-76) cyclic peptide-treated Pseudomonas aeruginosa showed that severe swelling preceded cell death and breakage of the outer membrane; the intracellular inclusion was found to have effluxed extracellularly. When mice were treated with the SALF(55-76) cyclic peptide before bacterial challenge with P. aeruginosa, the peptide highly protected mice against death by sepsis. The P. aeruginosa recovered from SALF(55-76) cyclic peptide-treated mice after 4 h exhibited reduced bacterial growth similar to that recovered from vancomycin-treated mice. In addition, the syntheses of inflammatory cytokines, such as interleukin (IL)-2, IL-4, IL-10, IL-12, IL-13, interferon-gamma, and tumor necrosis factor [TNF]-alpha, were significantly upregulated 4 h after SALF(55-76) cyclic peptide treatment except for IL-4 in the liver. The expressions of Toll-like receptor 4 (Tlr4), Irf3, myd88, and Tram, were considerably elevated, but only Tlr4 existed in the spleen 4 h after SALF(55-76) cyclic peptide treatment. The prophylactic administration of SALF(55-76) cyclic peptide was begun the TNF-alpha response in comparison to untreated mice by an ELISA analysis. Due to its multifunctional properties, the SALF(55-76) cyclic peptide may become an important prophylaxis against and therapy for bacterial infectious diseases, as well as for septic shock. |
| PMID: 17386416 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
Publication Types:
MeSH Terms:
Substances:
|
| 35. | J Med Chem. 2007 Apr 19;50(8):1993-7. Epub 2007 Mar 27.Phenolic hydrazones are potent inhibitors of macrophage migration inhibitory factor proinflammatory activity and survival improving agents in sepsis.Dabideen DR, Cheng KF, Aljabari B, Miller EJ, Pavlov VA, Al-Abed Y.Laboratory of Medicinal Chemistry, The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, New York 11030, and The New York School of Medicine, New York, New York 10016, USA. A series of phenolic hydrazones were synthesized and evaluated for their inhibition of macrophage migration inhibitory factor (MIF) tautomerase activity. Compound 7 emerged as a potent inhibitor of MIF with an IC50 of 130 nM. Compound 7 dose-dependently suppressed TNFalpha secretion from lipopolysaccharide stimulated macrophages. The therapeutic importance of the MIF inhibition by 7 is demonstrated by the significant protection from the lethality of sepsis when administration of the compound was initiated in a clinically relevant time frame. |
| PMID: 17385848 [PubMed - indexed for MEDLINE] | |
| Related articles | |
 | |
Publication Types:
MeSH Terms:
Substances:
Grant Support:
|
| 36. | FEBS J. 2007 Apr;274(8):2135-47. Epub 2007 Mar 20.Attenuation of cardiac mitochondrial dysfunction by melatonin in septic mice.Escames G, López LC, Ortiz F, López A, García JA, Ros E, Acuña-Castroviejo D.Instituto de Biotecnología, Departamento de Fisiología, Universidad de Granada, Spain. The existence of an inducible mitochondrial nitric oxide synthase has been recently related to the nitrosative/oxidative damage and mitochondrial dysfunction that occurs during endotoxemia. Melatonin inhibits both inducible nitric oxide synthase and inducible mitochondrial nitric oxide synthase activities, a finding related to the antiseptic properties of the indoleamine. Hence, we examined the changes in inducible nitric oxide synthase/inducible mitochondrial nitric oxide synthase expression and activity, bioenergetics and oxidative stress in heart mitochondria following cecal ligation and puncture-induced sepsis in wild-type (iNOS(+/+)) and inducible nitric oxide synthase-deficient (iNOS(-/-)) mice. We also evaluated whether melatonin reduces the expression of inducible nitric oxide synthase/inducible mitochondrial nitric oxide synthase, and whether this inhibition improves mitochondrial function in this experimental paradigm. The results show that cecal ligation and puncture induced an increase of inducible mitochondrial nitric oxide synthase in iNOS(+/+) mice that was accompanied by oxidative stress, respiratory chain impairment, and reduced ATP production, although the ATPase activity remained unchanged. Real-time PCR analysis showed that induction of inducible nitric oxide synthase during sepsis was related to the increase of inducible mitochondrial nitric oxide synthase activity, as both inducible nitric oxide synthase and inducible mitochondrial nitric oxide synthase were absent in iNOS(-/-) mice. The induction of inducible mitochondrial nitric oxide synthase was associated with mitochondrial dysfunction, because heart mitochondria from iNOS(-/-) mice were unaffected during sepsis. Melatonin treatment blunted sepsis-induced inducible nitric oxide synthase/inducible mitochondrial nitric oxide synthase isoforms, prevented the impairment of mitochondrial homeostasis under sepsis, and restored ATP production. These properties of melatonin should be considered in clinical sepsis. |
| PMID: 17371545 [PubMed - indexed for MEDLINE] | |
| Related articles | |
 | |
Publication Types:
MeSH Terms:
Substances:
|
| 37. | J Formos Med Assoc. 2007 Feb;106(2):97-104.Ulinastatin alone does not reduce caspase 3-mediated apoptosis in protease-positive Aeromonas hydrophilia-induced sepsis.Su BH, Chiu HY, Soga T, Lin KJ, Hsu CT.Department of Pediatrics, China Medical University Hospital, Taichung, Taiwan. BACKGROUND/PURPOSE: To evaluate the effect of ulinastatin, a protease inhibitor, on survival and apoptosis in protease-positive Aeromonas hydrophilia (PPAH)-induced sepsis. METHODS: Thirty mice were randomly allocated to receive intraperitoneal injection of either phosphate buffered saline (PBS) (control mice, n = 10) or PPAH (PPAH mice, n = 20). After 30 minutes, control mice received an additional intraperitoneal PBS injection, 10 PPAH mice received intraperitoneal PBS injection (non-treated PPAH mice), and the remaining 10 PPAH mice received an intraperitoneal injection of ulinastatin (ulinastatin-treated PPAH mice). RESULTS: Survival at 24 hours was 100% in control mice, and 35% (p < 0.05) in PPAH mice; the survival rate in non-treated and ulinastatin-treated PPAH mice were 30% and 40% (p > 0.05), respectively. The thymus weight (mg) decreased significantly in PPAH mice (51.1 +/- 14.9) compared to control mice (69.7 +/- 14.4; p < 0.001); there was no difference between ulinastatin-treated (52 +/- 13.9; p > 0.05) and non-treated PPAH mice (50.4 +/- 16). The thymus gland cell count reduced significantly in PPAH mice (8.1 +/- 4.7 x 10(7)) compared to control mice (12.8 +/- 6.6 x 10(7); p < 0.01), and immunofluorescence analysis demonstrated that the reduced cells were mostly CD4+ CD8+, in contrast to the increase in CD4+ CD8- cells. There was no difference in cell count between ulinastatin-treated (8.7 +/- 4.9 x 10(7)) and non-treated PPAH mice (7.4 +/- 4.6 x 10(7); p > 0.05). Caspase 3-mediated apoptosis was not detectable in control mice in contrast to the pronounced manifestation in PPAH mice. CONCLUSION: PPAH-induced sepsis has a high mortality that is related to lymphocyte apoptosis. Ulinastatin alone does not significantly reduce caspase 3-mediated lymphocyte apoptosis. |
| PMID: 17339152 [PubMed - indexed for MEDLINE] | |
| Related articles Free article | |
 | |
Publication Types:
MeSH Terms:
Substances:
|
| 38. | Braz J Med Biol Res. 2007 Mar;40(3):317-22.Antagonic effect of the inhibition of inducible nitric oxide on the mortality of mice acutely infected with Escherichia coli and Bacteroides fragilis.Astolfi RS, Khouri DG, Brandizzi LI, Avila-Campos MJ, Andrade HF Jr.Departamento de Patologia, Faculdade de Medicina, Universidade de São Paulo, Universidade de São Paulo, Av. Dr. Enéas Carvalho Aguiar 470, 05403-000 São Paulo, SP, Brazil. Sepsis, the leading cause of death in intensive care units, is associated with overproduction of nitric oxide (NO) due to inducible NO synthase (iNOS), responsible for some of the pathologic changes. Aminoguanidine (AG) is a selective iNOS inhibitor with reported inconsistent actions in sepsis. To investigate the influence of iNOS, we studied models of acute bacterial sepsis using acute challenges with aerobic (Escherichia coli) and anaerobic (Bacteroides fragilis) bacteria in the presence of AG. Six-week-old, 23 g, male and female BALB/c and C57Bl/6j mice, in equal proportions, were inoculated (ip) with bacteria in groups of 4 animals for each dose and each experiment in the absence or presence of AG (50 mg/kg, ip, starting 24 h before challenge and daily until day 6) and serum nitrate was measured by chemiluminescence. Both types of bacteria were lethal to mice, with an LD50 of 6 nephelometric units (U) for E. coli and 8 U for B. fragilis. Nitrate production peaked on the second day after E. coli inoculation with 8 and 6 U (P < 0.05), but was absent after non-lethal lower doses. After challenge with B. fragilis this early peak occurred at all tested doses after 24 h, including non-lethal ones (P < 0.05). AG-treated mice challenged with E. coli presented higher survival (P < 0.05) and increased LD50. AG-treated mice challenged with B. fragilis had lower LD50 and higher mortality. Control AG-treated animals presented no toxic effects. The opposite effect of iNOS blockade by AG in these models could be explained by restriction of oxygen for immune cells or an efficient action of NO in anaerobic localized infections. The antagonic role of NO production observed in our bacterial models could explain the reported discrepancy of NO action in sepsis. |
| PMID: 17334528 [PubMed - indexed for MEDLINE] | |
| Related articles Free article | |
| | |
Publication Types:
MeSH Terms:
Substances:
|
| 39. | Crit Care Med. 2007 Apr;35(4):1139-44.Selective alpha7-nicotinic acetylcholine receptor agonist GTS-21 improves survival in murine endotoxemia and severe sepsis.Pavlov VA, Ochani M, Yang LH, Gallowitsch-Puerta M, Ochani K, Lin X, Levi J, Parrish WR, Rosas-Ballina M, Czura CJ, Larosa GJ, Miller EJ, Tracey KJ, Al-Abed Y.Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, NY, USA. vpavlov@nshs.edu Comment in: OBJECTIVE: Tumor necrosis factor and high mobility group box 1 are critical cytokine mediators of inflammation. The efferent vagus nerve inhibits cytokine release through alpha7-nicotinic acetylcholine receptor-mediated cholinergic signaling. Here we studied whether GTS-21, a selective alpha7-nicotinic acetylcholine receptor agonist, inhibits proinflammatory cytokines in vitro and in vivo and improves survival in murine endotoxemia and severe sepsis. DESIGN: Randomized and controlled in vitro and in vivo study. SETTINGS: Research laboratory and animal facility rooms. SUBJECTS: RAW 264.7 cells and BALB/c mice treated with endotoxin or subjected to cecal ligation and puncture (CLP). INTERVENTIONS: RAW 264.7 cells were exposed to endotoxin (4 ng/mL or 10 ng/mL) in the presence or absence of GTS-21 (1-100 muM), and tumor necrosis factor and high mobility group box 1 release and nuclear factor-kappaB activation were analyzed. Mice were treated with GTS-21 (0.4 mg/kg or 4 mg/kg, intraperitoneally) or saline 30 mins before endotoxin (6 mg/kg, intraperitoneally), and serum tumor necrosis factor was analyzed 1.5 hrs after the onset of endotoxemia. In survival experiments, mice were treated with GTS-21 (0.4 or 4.0 mg/kg, intraperitoneally) or saline 30 mins before and 6 hrs after endotoxin and then twice daily for 3 days. Severe sepsis was induced by CLP. Mice were treated with GTS-21 (4 mg/kg) or saline immediately and 6 hrs and 24 hrs after CLP, and serum high mobility group box 1 was analyzed 30 hrs after CLP. In survival experiments, GTS-21 (0.4 or 4 mg/kg) treatment was initiated 24 hrs after CLP and continued twice daily for 3 days. MEASUREMENTS AND MAIN RESULTS: GTS-21 dose-dependently inhibited tumor necrosis factor and high mobility group box 1 release and nuclear factor-kappaB activation in vitro. GTS-21 (4 mg/kg) significantly inhibited serum tumor necrosis factor during endotoxemia and improved survival (p < .0001). GTS-21 (4 mg/kg) significantly inhibited serum high mobility group box 1 levels in CLP mice and improved survival (p < .0006). CONCLUSION: These findings are of interest for the development of alpha7-nicotinic acetylcholine receptor agonists as a new class of anti-inflammatory therapeutics. |
| PMID: 17334244 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
Publication Types:
MeSH Terms:
Substances:
Grant Support:
|
| 40. | J Surg Res. 2007 Jun 1;140(1):99-108. Epub 2007 Feb 8.Synergistic therapeutic potential of dexamethasone and L-arginine in lipopolysaccharide-induced septic shock.Chatterjee S, Premachandran S, Shukla J, Poduval TB.Immunology and Hyperthermia Section, Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Trombay, Mumbai, India. BACKGROUND: Dexamethasone (DEX) is demonstrated to have anti-inflammatory properties and known to induce hemodynamic improvement in sepsis and septic shock. L-arginine (L-arg), a semi-essential amino acid, depending on its metabolic pathway, becomes very essential in stress situations such as heatstroke, burns, sepsis, trauma, and wound healing. The aim of this study was to evaluate the synergistic therapeutic effect of DEX and L-arg in rescuing the mice from experimental septic shock induced by bacterial lipopolysaccharide (LPS). The experiments were designed to delineate the molecular mechanisms responsible for the increased therapeutic benefit of the combination therapy (CT) in LPS-induced septic shock. METHODS: Acute endotoxemia was induced in Swiss male mice by i.p. injection of LPS (18 mg kg(-1)) at 0 h. LPS-treated mice were divided into four groups. The first group (DEX group) received DEX (2 mg kg(-1)) i.p. at +2 h of LPS. The second group (L-arg group) received L-arg i.p. at a dose of 120 mg/kg at +6 h of LPS injection. The third group (CT group) received DEX (2 mg kg(-1)) at +2 h LPS followed by L-arg at +6 h of LPS injection. The fourth group received saline in place of L-arg or DEX (LPS group). A sham group was also included, where normal mice received saline in place of LPS or L-arg or DEX. At +6 h, mice from sham group, LPS group, and DEX group were sacrificed at +24 h. Mice from sham group, DEX group, L-arg group, and CT group were sacrificed to examine various parameters associated with LPS endotoxemia. RESULTS: The CT with DEX followed by L-arg significantly increased the survival of mice injected with a lethal dose of LPS. Monotherapy with either DEX or L-arg given at the same dose and time did not increase the survival of the mice injected with LPS. DEX administration could significantly reduce the levels of serum TNF-alpha, IL-1beta, IFN-gamma, aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), and nitrite. DEX also down-regulated the expression of liver-inducible nitric oxide synthase (iNOS), and up-regulated the levels of serum anti-inflammatory cytokines like TGF-beta1 and IL-4, hepatic and splenic arginase, in LPS-injected mice. The enhanced therapeutic effect of CT correlated with reduced pathological symptoms, decreased Th1 cytokines, increased TGF-beta1 and arginase levels compared to the mice administered with either of the monotherapies. The CT group had significantly increased expression of hepatic Hsp 70 and reduced septic shock associated histopathology, in lung and liver, compared to the mice treated with either DEX or L-arg. CONCLUSIONS: The therapeutic combination therapy with DEX and L-arg, at the appropriate dose, time, and sequence of administration, changed the cytokine profile, in favor of reducing the inflammatory response. The significantly enhanced survival observed in the CT group was accompanied by an increased hepatic Hsp 70, hepatic arginase, splenic arginase, and decreased organ injury. This novel concept of combined therapy could form the basis of an effective therapeutic approach in the treatment of sepsis and septic shock. |
| PMID: 17292408 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
MeSH Terms:
Substances:
|
| 41. | Crit Care Med. 2007 Mar;35(3):849-55.Plasma gelsolin is a marker and therapeutic agent in animal sepsis.Lee PS, Waxman AB, Cotich KL, Chung SW, Perrella MA, Stossel TP.Pulmonary and Critical Care Division Brigham and Women's Hospital, Boston, MA, USA. Comment in: OBJECTIVE: Plasma gelsolin is a circulating actin-binding protein that serves a protective role against tissue injuries. Depletion of plasma gelsolin in systemic inflammation may contribute to adverse outcomes. We examined the role of plasma gelsolin in animal models of sepsis. DESIGN: Animal and laboratory experiments. SETTING: Academic research laboratory. SUBJECTS: Adult male mice. INTERVENTIONS: Mice subjected to endotoxin or cecal ligation and puncture (CLP) were treated with exogenous plasma gelsolin or placebo. MEASUREMENTS AND MAIN RESULTS: We document the depletion of plasma gelsolin (25-50% of normal) in murine models of sepsis associated with the presence of circulating actin within 6 hrs of septic challenge. Repletion of plasma gelsolin leads to solubilization of circulating actin aggregates and significantly reduces mortality in endotoxemic mice (survival rates were 88% in the gelsolin group vs. 0% in the saline group, p < .001) and in CLP-challenged mice (survival rates were 30% in the gelsolin group vs. 0% in the saline group, p = .001). Plasma gelsolin repletion also shifted the cytokine profile of endotoxemic mice toward anti-inflammatory (plasma interleukin-10 levels were 205 +/- 108 pg/mL in the gelsolin group vs. 39 +/- 29 pg/mL in the saline group, p = .02). CONCLUSIONS: We propose that circulation of particulate actin is a marker for sepsis-induced cell injury, that plasma gelsolin has a crucial protective role in sepsis, and that gelsolin replacement represents a potential therapy for this common lethal condition. |
| PMID: 17205019 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
Publication Types:
MeSH Terms:
Substances:
|
| 42. | Immunopharmacol Immunotoxicol. 2006;28(4):601-7.A pilot study of an anti-MRSA bio-engineered lacteal complex (anti-MRSA BLC) in a murine septicemia model.Stoff JA, Nix DE, DeYoung DW.Tiburon Laboratory, Tucson, Arizona 85745, USA. thedoc@drstoff.com Methicillin-resistant Staphylococcus aureus (MRSA) is an important pathogen of humans and other animals, causing septicemia, abcessation, toxemia, and other infectious diseases. Refined bioengineered lacteal complex (BLC), made specifically against MRSA, is a novel complex of low molecular weight immunogenic and antimicrobial molecules. It was evaluated in vivo using a mouse model of MRSA-induced peritonitis. Intraperitoneal dosing of anti-MRSA BLC demonstrated a therapeutic effect (83% survival) against an intraperitoneal MRSA challenge that caused 100% mortality in untreated animals. Anti-MRSA BLC is a promising therapeutic modality for MRSA infection. |
| PMID: 17190737 [PubMed - indexed for MEDLINE] | |
| Related articles | |
 | |
Publication Types:
MeSH Terms:
Substances:
|
| 43. | J Biomed Sci. 2006 Nov;13(6):833-43. Epub 2006 Nov 9.Beneficial effects of LK-4, an analog of dextromethorphan on lipopolysaccharide-induced sepsis in rats.Jiau SS, Cheng PY, Lee YM, Huang WH, Ko YF, Yen MH.Division of Cardiology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan. Dextromethorphan (DM), an anti-tussive agent, has been claimed to have anti-inflammatory and immunomodulatory effects in vitro. In our preliminary screening test, LK-4, an analog of DM, can afford more protection against circulatory failure induced by LPS than that of DM. Thus, the aim of this study was to evaluate the effects of LK-4 on sepsis induced by intravenous (i.v.) administration of lipopolysaccharide (LPS; 10 mg/kg) in anesthetized Wistar rats and survival rate by intraperitoneal administration of LPS (70 mg/kg) in conscious ICR mice. Results demonstrated that posttreatment with LK-4 (3 and 5 mg/kg, i.v.) significantly attenuated the deleterious hemodynamic changes (e.g., hypotension and tachycardia) in rats treated with LPS. Meanwhile, LK-4 (3 mg/kg) significantly inhibited the elevation of plasma tumor necrosis factor-alpha, as well as values of GOT and GPT, and BUN and creatinine caused by LPS. The induction of inducible NO synthase and the overproduction of NO and superoxide anions by LPS were also reduced by LK-4. Moreover, infiltration of neutrophils into the lungs and liver of rats 8 h after treatment with LPS was also reduced by LK-4. Furthermore, LK-4 increased the survival rate of mice insulted by toxic dose of LPS. In conclusion, the beneficial effects of LK-4 on LPS-induced sepsis result from its anti-inflammatory and anti-oxidant effects. Thus, LK-4 can be potentially used as a therapeutic agent for sepsis in the future. |
| PMID: 17091389 [PubMed - indexed for MEDLINE] | |
| Related articles | |
Publication Types:
MeSH Terms:
Substances:
|
| 44. | Int J Exp Pathol. 2006 Oct;87(5):369-72.Modulation of inflammatory response in sepsis by proteasome inhibition.Safránek R, Ishibashi N, Oka Y, Ozasa H, Shirouzu K, Holecek M.Department of Surgery, School of Medicine, Kurume University, Kurume, Japan. SafranekR@lfhk.cuni.cz The Ubiquitin-proteasome system has recently been shown to be involved in the regulation of cytokine expression. We tested the hypothesis of whether the in vivo administration of proteasome inhibitor MG-132 can modulate cytokine response and mortality in sepsis. Sepsis was induced in mice by caecal ligation and puncture (CLP). Animals were divided into four groups: control, CLP, CLP and 1 microg MG-132/g of b.w. intraperitoneally, and CLP and 10 microg MG-132/g of b.w. Plasma levels of interleukin (IL)-1, tumour necrosis factor-alpha (TNF-alpha, IL-6 and IL-10 were determined by ELISA 6 h after the induction of sepsis. CLP induced significant increase in plasma levels of all measured cytokines. MG-132 treatment resulted in lower increase in IL-1, TNF-alpha and IL-10 levels. IL-6 was not significantly affected. A mortality study revealed prolonged survival in MG-132 treated mice. We conclude that MG-132 treatment decreases inflammatory response and prolongs survival in the CLP model of sepsis. |
| PMID: 16965564 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
Publication Types:
MeSH Terms:
Substances:
|
| 45. | Ann N Y Acad Sci. 2006 Jul;1070:405-10.PAC1 receptor: emerging target for septic shock therapy.Martínez C, Arranz A, Juarranz Y, Abad C, García-Gómez M, Rosignoli F, Leceta J, Gomariz RP.Department of Cell Biology, Faculty of Medicine, Complutense University, Ciudad Universitaria, 28040 Madrid, Spain. cmmora@bio.ucm.es Septic shock is a systemic response to severe bacterial infections, generally caused by Gram-negative bacterial endotoxins, with multiple manifestations such as hypotension, tissue injury, disseminated intravascular coagulation, and multi-organ failure. All these effects, are induced by the generation of pro-inflammatory and vasodilator mediators, cell adhesion molecules, coagulation factors, and acute-phase proteins. Vasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are two immunopeptides with anti-inflammatory properties exerted through type 1 and 2 VIP receptors (VPAC1 and VPAC2, respectively), and PACAP receptor (PAC1). The present results recapitulate the protective role of PAC1 in an experimental model of lethal endotoxemia using a knockout for the PAC1 receptor. Our results demonstrate that VIP and PACAP decrease lipopolysaccharide (LPS)-induced interleukin-6 (IL-6) production, neutrophil infiltration and intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and fibrinogen expression through PAC1 receptor, providing an advantage to design more specific drugs complementing standard intensive care therapy in septic shock. |
| PMID: 16888200 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
Publication Types:
MeSH Terms:
Substances:
|
| 46. | Microcirculation. 2006 Sep;13(6):477-87.Glucocorticoids inhibit the cerebral microvascular dysfunction associated with sepsis in obese mice.Vachharajani V, Vital S, Russell J, Scott LK, Granger DN.Critical Care Medicine, Louisiana State University Health Sciences Centre, Shreveport, Louisiana 71130, USA. Vvachh@lsuhsc.edu OBJECTIVES: Obesity is associated with increased morbidity and mortality in critically ill patients. It is unclear whether this increase is due to exaggerated inflammatory response alone or due to lack of response to therapeutic agents used. The objective of this study was to determine whether low-dose steroid therapy, which has proven effective in clinical setting, affords any benefit in the increased morbidity to sepsis in genetically obese (ob/ob) mice. METHODS: Intravital videomicroscopy was used to monitor and quantify the adhesion of platelets and leukocytes in the brain microcirculation of lean (WT) and ob/ob mice subjected to cecal ligation and puncture (CLP) with or without dexamethasone 4 mg/kg within 15 min of surgery. The dual radiolabeled monoclonal antibody method was used to measure P-selectin expression in the microcirculation, while the sepsis-induced behavioral deficit was quantified using a multicompartment chamber test. RESULTS: Dexamethasone completely prevented the accumulation of adherent leukocytes and platelets observed at 4 h after CLP in both WT and ob/ob mice. The steroid also prevented the CLP-induced upregulation of P-selectin in the brain and other vascular beds, and it attenuated the behavioral deficit in ob/ob, but not in lean, mice. CONCLUSION: Low-dose glucocorticoid therapy is beneficial in experimental sepsis in obese animals compared to lean animals. |
| PMID: 16864414 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
Publication Types:
MeSH Terms:
Substances:
|
| 47. | Int Immunopharmacol. 2006 Aug;6(8):1355-62. Epub 2006 Apr 5.Liu-Shen-Wan, a traditional Chinese medicine, improves survival in sepsis induced by cecal ligation and puncture via reducing TNF-alpha levels, MDA content and enhancing macrophage phagocytosis.Ma H, Kou J, Zhu D, Yan Y, Yu B.Department of Traditional Chinese Prescription, China Pharmaceutical University, 1 Shennong Road, Nanjing 210038, PR China. Sepsis in humans is a difficult condition to treat and is often associated with a high mortality rate. Here, we investigated putative protective effects of Liu-Shen-Wan (LSW), a well-known Chinese formula used in treating infectious diseases, against polymicrobial sepsis induced by cecal ligation and puncture (CLP). The oral administration of LSW, at the first dose of 60 mg/kg and then 30 mg/kg every 12 h, significantly improved the survival of CLP mice during a 4-day observation period. The effects of LSW on the inflammatory response (circulating tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1) levels and malondialdehyde (MDA) content-an index of lipid peroxidation), infectious degree (peritoneal bacteria counts), and innate immunity function (leukocyte counts, macrophage phagocytosis and neutrophil respiratory burst) were further examined in rats. We demonstrated that treatment of LSW significantly decreased elevated levels of circulating TNF-alpha at 4 h and further reduced plasma MDA levels at 24 h after CLP, at first doses of 15 and 30 mg/kg and then 7.5 and 15 mg/kg every 12 h. Moreover, LSW markedly enhanced clearance of intraperitoneal bacteria associated with the increasing count of peritoneal leukocytes and enhancing phagocytic activity of macrophages partly impaired at 24 h after CLP. In contrast, LSW lightly reduced IL-1 levels at 4 h and failed to improve deactivated respiratory burst activity of neutrophils at 24 h after CLP. Thus, LSW exerts protective effects against sepsis induced by CLP, mainly by reducing plasma TNF-alpha and MDA levels and enhancing peritoneal macrophage phagocytosis, suggesting that it is a potential agent in the prevention and treatment of sepsis. |
| PMID: 16782549 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
Publication Types:
MeSH Terms:
Substances:
|
| 48. | Am J Trop Med Hyg. 2006 Jun;74(6):1020-5.Beneficial effect of erythropoietin administration on murine infection with Trypanosoma congolense.Suzuki T, Ueta YY, Inoue N, Xuan X, Saitoh H, Suzuki H.Research Unit for Functional Genomics, National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido, Japan. The effect of erythropoietin treatment on Trypanosoma congolense infection in mice was studied. Survival rates of mice were dramatically improved by treatment with recombinant human erythropoietin (r-hu-EPO; 5,000 U/kg) when infected with 1,000 cells of T. congolense IL3000 (P < 0.05). All the untreated mice infected with T. congolense IL3000 died by day 9 of infection; however, 100%, 50%, and 25% of the mice treated with r-hu-EPO for 8 days survived to day 20, day 40, and day 60 of the parasitical infection, respectively. Anti-8-hydroxy-2'-deoxyguanosine antibody, a biomarker for oxidative damage of DNA, yielded positive reactions in the cytoplasm of the parasites recovered from the mice treated with r-hu-EPO. These results, taken together, indicate that erythropoietin administration is effective for the treatment of T. congolense infection. |
| PMID: 16760514 [PubMed - indexed for MEDLINE] | |
| Related articles Free article | |
 | |
Publication Types:
MeSH Terms:
Substances:
|
| 49. | J Antimicrob Chemother. 2006 Aug;58(2):462-5. Epub 2006 May 30.Efficacy of telavancin in a murine model of bacteraemia induced by methicillin-resistant Staphylococcus aureus.Reyes N, Skinner R, Benton BM, Krause KM, Shelton J, Obedencio GP, Hegde SS.Theravance, Inc., 901 Gateway Boulevard, South San Francisco CA 94080, USA. OBJECTIVES: The efficacy of telavancin, a bactericidal lipoglycopeptide, was compared with vancomycin against methicillin-resistant Staphylococcus aureus (MRSA) in an immunocompromised murine model of bacteraemia. METHODS: Immunocompromised mice were inoculated intraperitoneally with S. aureus ATCC 33591 and treated with two subcutaneous doses (once every 12 h) of vehicle or test compound. Mouse pharmacokinetic data were generated and used to choose doses of telavancin (40 mg/kg) and vancomycin (110 mg/kg) in order to equate clinical exposures. Reduction in bacterial titre (in blood and spleen) and mortality were the two pharmacodynamic endpoints of the study. RESULTS: Mortality was 100% in animals treated with vehicle or vancomycin but was significantly lower (7%) in telavancin-treated animals. Telavancin produced significantly greater reductions in blood and spleen bacterial titres compared with vancomycin. CONCLUSIONS: The data described here demonstrate that telavancin's in vivo bactericidal activity is superior to that of vancomycin against a single strain of MRSA and results in successful infection resolution and, consequently, improved survival in the murine bacteraemia model. |
| PMID: 16735425 [PubMed - indexed for MEDLINE] | |
| Related articles Free article | |
| | |
Publication Types:
MeSH Terms:
Substances:
|
| 50. | J Pharmacol Exp Ther. 2006 Aug;318(2):762-71. Epub 2006 May 16.Polymyxin B-conjugated alpha 2-macroglobulin as an adjunctive therapy to sepsis: Modes of action and impact on lethality.Birkenmeier G, Nicklisch S, Pockelt C, Mossie A, Steger V, Gläser C, Hauschildt S, Usbeck E, Huse K, Sack U, Bauer M, Schäfer A.Institute of Biochemistry, University of Leipzig, Leipzig, Germany. birg@medizin.unileipzig.de A drug targeting both the inflammatory initiators (lipopolysaccharide; LPS) and mediators [tumor necrosis factor-alpha (TNF-alpha)] should have advantage over a "single-factor targeting strategy" in sepsis prevention trials. We have prepared conjugates of polymyxin B (PMB) and the cytokine binding protein alpha2-macroglobulin (A2M). The conjugate binds TNF-alpha as well as LPS as studied by electrophoresis and phase partitioning. Compared with free PMB, the conjugate is nontoxic to cells and does not affect the viability of human monocytes. The A2M-PMB conjugate binds to the A2M receptor (CD91/low-density lipoprotein receptor-related protein 1) with affinity similar to that of the nonmodified protein. Fluorescein isothiocyanate-labeled LPS in the presence of A2M-PMB is rapidly transported into fibroblasts for degradation via receptor-mediated endocytosis. In vitro, A2M-PMB demonstrated inhibition of LPS-induced secretion of TNF-alpha from isolated monocytes as well as in the whole blood assay. The efficacy of the drug was tested in mice after induction of acute inflammation (LPS model) and after induction of a polymicrobial sepsis by cecal ligation and puncture (CLP) model. Treatment of mice with A2M-PMB up to 250 microg/g body weight was not toxic to the animal. When the drug was administered 30 min before or 30 min after the LPS challenge, a survival rate of 90 and 70%, respectively, was obtained compared with the placebo control group (5%). A2M-PMB also protected mice after induction of polymicrobial sepsis when administered 30 min before CLP. These results support our hypothesis that A2M-PMB acts as a polyvalent drug to target different host mediators as well as sepsis inducer at the same time. |
| PMID: 16705081 [PubMed - indexed for MEDLINE] | |
| Related articles Free article | |
 | |
Publication Types:
MeSH Terms:
Substances:
|
| 51. | Shock. 2006 Apr;25(4):420-5.An extract of the mushroom Agaricus blazei Murill protects against lethal septicemia in a mouse model of fecal peritonitis.Bernardshaw S, Hetland G, Grinde B, Johnson E.Department of Gastroenterological Surgery, Ulleval University Hospital, Oslo, Norway. sorn@ulleval.no Bacterial septicemia is frequently occurring during gastroenterological surgery. Because of increasing problems in hospitals with bacteria developing multiresistance against antibiotics, prophylactic treatment using immunomodulators is interesting. We have examined the putatively anti-infective immunomodulatory action of the edible mushroom, Agaricus blazei Murill (AbM), in an experimental peritonitis model in BALB/c mice. The mice were orally given an extract of AbM or phosphate-buffered saline 1 day before the induction of peritonitis with various concentrations of feces from the mice. The state of septicemia, as measured by the number of colony-forming units of bacteria in blood, and the survival rate of the animals were compared between the groups. Mice that were orally treated with AbM extract before bacterial challenge showed significantly lower levels of septicemia and improved survival rates. Our findings suggest that the AbM extract, when given prophylactically, may improve health. Further studies are needed on humans when considering whether AbM could be used as an alternative treatment modality for patients at risk of contracting serious bacterial peritonitis. |
| PMID: 16670646 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
Publication Types:
MeSH Terms:
Substances:
|
| 52. | Phytother Res. 2006 May;20(5):359-63.Protective effects of sugar cane extract on endotoxic shock in mice.Motobu M, Amer S, Koyama Y, Hikosaka K, Sameshima T, Yamada M, Nakamura K, Koge K, Kang CB, Hayasidani H, Hirota Y.National Institute of Animal Health, National Agriculture and Bio-oriented Research Organization, Tsukuba, Ibaraki, Japan. Sugar cane extract (SCE) has been shown to have an immunostimulating effect in chickens. This study evaluated the effect of SCE on Salmonella Abortusequi lipopolysaccharide (LPS)-induced lethal shock in d-galactosamine (GalN)-sensitized mice. Mice were administered intraperitoneally SCE (500 mg/kg) or phosphate buffered saline before or after injection of LPS and GalN. All the mice injected with LPS and GalN (control group) died of histopathologically congestive and hemorrhagic hepatic insufficiency within 24 h, showing significantly increased activities of plasma aspartate aminotransferase (AST; 380 IU/mL) and alanine aminotransferase (ALT; 130 IU/mL). Pretreatment of mice with SCE at 3 h before challenge with LPS and GalN (SCE treated group) resulted in significantly improved survival rates (92.3%) and a decrease in liver injury. These surviving mice in the SCE treated group showed no changes in the mean levels of plasma AST (60 IU/mL) and ALT (18 IU/mL). However, the level of tumor necrosis factor-alpha in the SCE treated group was not significantly different when compared with that in the control group challenged with LPS and GalN. These results suggest that SCE has protective effects on LPS-induced mortality in this mouse model. Copyright 2006 John Wiley & Sons, Ltd. |
| PMID: 16619363 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
Publication Types:
MeSH Terms:
Substances:
|
| 53. | Life Sci. 2006 Jun 6;79(2):210-5. Epub 2006 Mar 6.Beneficial effects of ApoA-I on LPS-induced acute lung injury and endotoxemia in mice.Yan YJ, Li Y, Lou B, Wu MP.Department of Biochemistry, School of Pharmacy, Fudan University, Shanghai, 200032, China. High density lipoprotein (HDL) binds lipopolysaccharide (LPS) and neutralizes its toxicity. The aim of our study was to investigate the effects of Apolipoprotein (ApoA-I), the major apolipoprotein of HDL, on LPS-induced acute lung injury (ALI) and endotoxemia. BALB/c mice were challenged with LPS, followed by ApoA-I or saline administration for 24h. The mice were then sacrificed and histopathological analysis of the lung was performed. We found that ApoA-I could attenuate LPS-induced acute lung injury and inflammation. To investigate the mechanisms, we measured tumor necrosis factor alpha (TNF-alpha), interleukin-1beta (IL-1beta) and interleukin-6 (IL-6) levels in the serum and bronchoalveolar lavage (BAL) fluid and found that ApoA-I could significantly inhibit LPS-induced increases in the IL-1beta and TNF-alpha levels in serum (P<0.05, respectively), as well as in the IL-1beta, TNF-alpha, and IL-6 levels in BAL fluid (P<0.01 and P<0.05, P<0.05, respectively). Moreover, we evaluated the effect of ApoA-I on the mortality of L-929 cells which were attacked by LPS-activated peritoneal macrophages. We found that ApoA-I could significantly inhibit the LPS-induced cell death in a dose-dependent fashion. Furthermore, we investigated in vivo the effects of ApoA-I on the mortality rate and survival time after LPS administration and found that ApoA-I significantly decreased the mortality (P<0.05) and increased the survival time (P<0.05). In summary, the results suggest that ApoA-I could effectively protect against LPS-induced endotoxemia and acute lung damage. The mechanism might be related to inhibition of inflammatory cytokine release from macrophages. |
| PMID: 16574162 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
MeSH Terms:
Substances:
|
| 54. | Kidney Int. 2006 May;69(9):1535-42.Simvastatin improves sepsis-induced mortality and acute kidney injury via renal vascular effects.Yasuda H, Yuen PS, Hu X, Zhou H, Star RA.Renal Diagnostics and Therapeutics Unit, NIDDK, NIH, Bethesda, Maryland, USA. Acute kidney injury (AKI) occurs in about half of patients in septic shock and the mortality of AKI with sepsis is extremely high. An effective therapeutic intervention is urgently required. Statins are 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors that also have pleiotropic actions. They have been reported to increase the survival of septic or infectious patients. But the effect of simvastatin, a widely used statin, on sepsis-induced AKI is unknown. The effects of simvastatin and tumor necrosis factor (TNF)-alpha neutralizing antibody were studied in a clinically relevant model of sepsis-induced AKI using cecal ligation and puncture (CLP) in elderly mice. Simvastatin significantly improved CLP-induced mortality and AKI. Simvastatin attenuated CLP-induced tubular damage and reversed CLP-induced reduction of intrarenal microvascular perfusion and renal tubular hypoxia at 24 h. Simvastatin also restored towards normal CLP-induced renal vascular protein leak and serum TNF-alpha. Neither delayed simvastatin therapy nor TNF-alpha neutralizing antibody improved CLP-induced AKI. Simvastatin improved sepsis-induced AKI by direct effects on the renal vasculature, reversal of tubular hypoxia, and had a systemic anti-inflammatory effect. PMCID: PMC2377392 |
| PMID: 16557230 [PubMed - indexed for MEDLINE] | |
| Related articles Free article | |
 | |
Publication Types:
MeSH Terms:
Substances:
Grant Support:
|
| 55. | FEMS Immunol Med Microbiol. 2006 Mar;46(2):187-97.Protection of Staphylococcus aureus-infected septic mice by suppression of early acute inflammation and enhanced antimicrobial activity by ginsan.Ahn JY, Song JY, Yun YS, Jeong G, Choi IS.Laboratory of Immunology, Korea Institute of Radiological & Medical Sciences, Seoul, Korea. Ginsan, an acidic polysaccharide prepared from Panax ginseng, demonstrated multiple immunomodulatory effects in previous studies. This study was conducted to elucidate the antiseptic mechanism induced by ginsan in mice infected with Staphylococcus aureus. When mice were treated with ginsan before the bacterial challenge with S. aureus, they were highly protected from sepsis-induced death. The numbers of S. aureus recovered from ginsan-treated mice were considerably lower than those recovered from nontreated mice. The in vivo depletion of monocytes/macrophages caused more S. aureus to be recovered from the bacteria-infected mice. Nevertheless, mice treated with both etoposide and ginsan were able to maintain an antibacterial activity. In addition, the phagocytic activity of ginsan-treated macrophage against S. aureus was considerably enhanced. The synthesis of inflammatory cytokines, such as tumor necrosis factor-alpha interleukin (IL)-1beta, IL-6, IFN-gamma, IL-12, IL-18 and interferon gamma, was significantly downregulated at the early phase of sepsis in mice that were treated with ginsan before the bacterial challenge. Expression of Toll-like receptors (TLRs), including TLR2, TLR4, and TLR9, as well as the adaptor molecule MyD88, was considerably reduced in peritoneal macrophages that were treated with ginsan before a subsequent contact with S. aureus. These data indicated that ginsan protected mice from S. aureus-induced sepsis through the suppression of acute inflammatory responses at an early phase and the enhancement of antimicrobial activities at subsequent phases of infection. |
| PMID: 16487300 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
MeSH Terms:
Substances:
|
| 56. | J Mol Med. 2006 May;84(5):389-95. Epub 2006 Feb 2.Local thymic caspase-9 inhibition improves survival during polymicrobial sepsis in mice.Oberholzer C, Tschoeke SK, Moldawer LL, Oberholzer A.Department of Trauma and Reconstructive Surgery, CHARITE-University Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany. Caspase-9 is believed to play an essential role in sepsis-induced lymphocyte apoptosis. The aim of this study was therefore to evaluate its contribution within the caspase-dependent apoptosis pathway in a murine model of polymicrobial sepsis. Local injections of Z-LEHD-fmk, a specific caspase-9 inhibitor, into thymi of septic mice led to the complete inhibition of caspase-9, decreased apoptosis of resident tissue cells, and, in addition, reduced further downstream caspase-3 activity. In contrast to its systemic administration, only local injections improved the overall survival of septic mice. However, local injections of a pancaspase inhibitor (Z-VAD-fmk) did not improve survival, although caspase-3 activity was reduced to a similar degree as by the administration of Z-LEHD-fmk. These results indicate that local apoptosis of lymphatic tissue in polymicrobial sepsis is processed dependent of caspase-9 and suggests alternative caspase-dependent beneficial effects, which may determine a positive outcome. |
| PMID: 16453149 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
Publication Types:
MeSH Terms:
Substances:
Grant Support:
|
| 57. | Int Immunopharmacol. 2006 Feb;6(2):234-40. Epub 2005 Sep 1.Protective effects of antimicrobial peptides derived from the beetle Allomyrina dichotoma defensin on endotoxic shock in mice.Koyama Y, Motobu M, Hikosaka K, Yamada M, Nakamura K, Saido-Sakanaka H, Asaoka A, Yamakawa M, Sekikawa K, Kitani H, Shimura K, Nakai Y, Hirota Y.Department of Epidemiology, National Institute of Animal Health, Tsukuba, Ibaraki, Japan. Synthetic peptides, Arg-Leu-Tyr-Leu-Arg-Ile-Gly-Arg-Arg-NH2 (peptide A) and Arg-Leu-Arg-Leu-Arg-Ile-Gly-Arg-Arg-NH2 (peptide B), derived from the beetle Allomyrina dichotoma defensin, have not only antimicrobial activities but also anti-inflammatory effects by inhibiting tumour necrosis factor-alpha(TNF-alpha) production. In the present study, we evaluated the lipopolysaccharide (LPS)-binding activities and the protective effects of these peptides on LPS-induced lethal shock in d-galactosamine (GalN)-sensitized mice. These peptides were shown to bind to erythrocytes coated with LPS and the binding activity of peptide A to LPS was significantly higher than those of peptide B and polymyxin B. Mice were injected intraperitoneally with peptide A or B at doses of 25, 50, 100 and 150 mg/kg before an injection of Salmonella abortusequi LPS (5 microg/kg) and GalN (1 g/kg) (LPS+GalN). All of wild-type mice died within 24 h after challenged with LPS+GalN. All of TNF-alpha-deficient mice challenged with LPS+GalN survived. An injection of peptide A immediately after challenge with LPS+GalN resulted in significantly improved survival rates in a dose dependent manner. Peptide B showed only minor protection. The levels of TNF-alpha in the ameliorated mice by peptide A were significantly lower than those of challenge control, suggesting a suppressive effect of peptide A on TNF-alpha production. Furthermore, peptide A-treated mice showed significantly lower levels of asparate aminotransferase and alanine aminotransferase when compared to challenge control. Concordantly, hemorrhage and necrosis in the liver of peptide A-treated mice were less apparent than those of untreated control mice. These results suggest that peptide A has a protective effect on LPS-induced mortality in this mouse model. |
| PMID: 16399628 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
Publication Types:
MeSH Terms:
Substances:
|
| 58. | Int Immunopharmacol. 2006 Feb;6(2):226-33. Epub 2005 Sep 12.Enantiomers of higenamine inhibit LPS-induced iNOS in a macrophage cell line and improve the survival of mice with experimental endotoxemia.Park JE, Kang YJ, Park MK, Lee YS, Kim HJ, Seo HG, Lee JH, Hye Sook YC, Shin JS, Lee HW, Ahn SK, Chang KC.Department of Pharmacology, School of Medicine and Institute of Health Sciences, Gyeongsang National University, Jinju, South Korea. The importance of development of single enantiomers (optically pure isomers) of chiral molecules has been recognized and manifested in countless pharmaceutical and biological advancement. (RS)-(+/-)-Higenamine (racemic mixture), an active ingredient of Aconite tuber, has been shown to have antioxidant activity along with inhibitory action of iNOS expression in various cells. In the present study, the effects of each enantiomer of higenamine [(S)-(-)-higenamine and (R)-(+)-higenamine] were investigated in comparison with the effects of racemic mixture [(RS)-(+/-)-higenamine] on iNOS expression and NO production in RAW 264.7 cells activated with LPS. In addition, the effects of higenamine enantiomers on the survival rates were also investigated using mice, in which each test compound was injected (i.p.) 90 min prior to LPS. All three forms of higenamine inhibited iNOS expression and reduced NO production with IC50 of 26.2, 86.3, and 53.4 microM, for (S)-, (R)-, and (RS)-higenamine, respectively. (S)-higenamine also significantly reduced serum NOx level and increased survival rates in LPS-treated mice. In contrast, (R)-isomer only showed tendency to increase the survival rates which was not statistically significant when compared to LPS-treated controls. Taken together, it was concluded that (S)-higenamine may be more beneficial than (R)-enantiomer in diseases associated with iNOS over-expression, such as septic shock. |
| PMID: 16399627 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
Publication Types:
MeSH Terms:
Substances:
|
| 59. | J Infect Dis. 2006 Jan 15;193(2):251-8. Epub 2005 Dec 13.The duration of hypotension before the initiation of antibiotic treatment is a critical determinant of survival in a murine model of Escherichia coli septic shock: association with serum lactate and inflammatory cytokine levels.Kumar A, Haery C, Paladugu B, Kumar A, Symeoneides S, Taiberg L, Osman J, Trenholme G, Opal SM, Goldfarb R, Parrillo JE.Division of Cardiovascular Diseases and Critical Care Medicine, Cooper Hospital/University Medical Center, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Camden, New Jersey. akumar61@yahoo.com BACKGROUND: This study was designed to examine the relationship between the timing of antibiotic treatment and both survival rates and hemodynamic/inflammatory correlates of survival in a murine model of Escherichia coli septic shock. METHODS: Surgical implantation of an E. coli (O18:K1:H7)-laced, gelatin capsule-encased fibrinogen clot was used to generate a bacteremic model of murine septic shock. Survival duration, hemodynamic responses, and circulating serum tumor necrosis factor (TNF)-alpha , interleukin (IL)-6, and lactate levels were assessed in relation to increasing delays in or absence of antibiotic treatment. RESULTS: A critical inflection point with respect to survival occurred between 12 and 15 h after implantation. When initiated at or before 12 h, antibiotic treatment resulted in < or = 20% mortality, but, when initiated at or after 15 h, it resulted in >85% mortality. Physiologically relevant hypotension developed in untreated septic mice by 12 h after implantation. Values for heart rate differed between untreated septic mice and sham-infected control mice by 6 h after implantation, whereas values for cardiac output and stroke volume did not differ until at least 18-24 h after implantation. Antibiotic treatment initiated > or = 12 h after implantation was associated with persistence of increased circulating serum lactate, TNF- alpha , and IL-6 levels. CONCLUSIONS: The timing of antibiotic treatment relative to hypotension is closely associated with survival in this murine model of septic shock. Delay in antibiotic treatment results in the persistence of inflammatory/stress markers even after antibiotic treatment is initiated. |
| PMID: 16362889 [PubMed - indexed for MEDLINE] | |
| Related articles | |
 | |
MeSH Terms:
Substances:
|
| 60. | Med Hypotheses. 2006;66(3):660-3. Epub 2005 Nov 2.More tea for septic patients?--Green tea may reduce endotoxin-induced release of high mobility group box 1 and other pro-inflammatory cytokines.Chen X, Li W, Wang H.Department of Emergency Medicine, North Shore University Hospital, New York University School of Medicine, 350 Community Drive, Manhasset, NY 11030, USA. Despite recent advances in antibiotic therapy and intensive care, sepsis remains widespread problems in critically ill patients. The high mortality of sepsis is in part mediated by bacterial endotoxin, which stimulates macrophages/monocytes to sequentially release early (e.g., TNF, IL-1, and IFN-gamma) and late (e.g., HMGB1) pro-inflammatory cytokines. In light of our recent discovery of HMGB1 as a late mediator of lethal systemic inflammation, and the observation that green tea (Camellia sinensis) dose-dependently attenuated bacterial endotoxin-induced HMGB1 release, we propose that regular tea intake might decrease the incidence of and mortality rates from lethal endotoxemia and sepsis. PMCID: PMC1447554 |
| PMID: 16266789 [PubMed - indexed for MEDLINE] | |
| Related articles Free article | |
| | |
Publication Types:
MeSH Terms:
Substances:
Grant Support:
|
| 61. | J Infect Dis. 2005 Nov 1;192(9):1613-20. Epub 2005 Sep 27.Temporin A alone and in combination with imipenem reduces lethality in a mouse model of staphylococcal sepsis.Cirioni O, Giacometti A, Ghiselli R, Kamysz W, Orlando F, Mocchegiani F, Silvestri C, Licci A, Łukasiak J, Saba V, Scalise G.Institute of Infectious Diseases and Public Health, Department of General Surgery, Polytechnic University of Marche, Ancona, Italy. BACKGROUND: Morbidity and mortality from staphylococcal toxic shock remain high, despite the availability of antibiotics to which the microorganism is sensitive. METHODS: In in vitro experiments, the ability of temporin A to inhibit lipoteichoic acid-induced production of tumor necrosis factor (TNF)- alpha and nitric oxide (NO) was determined. Also, mouse models of staphylococcal sepsis were used to evaluate the efficacy of temporin A alone and in combination with imipenem. BALB/c mice were injected intravenously with live Staphylococcus aureus or heat-killed cells and then received either isotonic sodium chloride solution, 2 mg/kg temporin A, 7 mg/kg imipenem, or 2 mg/kg temporin A in combination with 7 mg/kg imipenem immediately and 6 h after challenge. The main outcome measures were lethality rates, plasma bacterial counts, and plasma TNF- alpha and interleukin (IL)-6 levels. RESULTS: The in vitro experiments showed that temporin A did not cause TNF- alpha or NO release. In the in vivo experiments with live bacteria, both compounds reduced lethality rates and bacterial growth. Imipenem exhibited the highest efficacy. The combination-treated group had significantly lower bacterial counts than did the singly-treated groups and the lowest lethality rates. In the experiments with heat-killed cells, only temporin A demonstrated significant efficacy with respect to lethality and reduction of plasma TNF- alpha and IL-6 levels. DISCUSSION: This study shows that temporin A can reduce the stimulatory effects of bacterial cell components and suggests that it may be beneficial in the treatment of severe staphylococcal sepsis. |
| PMID: 16206076 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
Publication Types:
MeSH Terms:
Substances:
|
| 62. | FASEB J. 2005 Nov;19(13):1890-2. Epub 2005 Aug 29.Bilirubin decreases nos2 expression via inhibition of NAD(P)H oxidase: implications for protection against endotoxic shock in rats.Lanone S, Bloc S, Foresti R, Almolki A, Taillé C, Callebert J, Conti M, Goven D, Aubier M, Dureuil B, El-Benna J, Motterlini R, Boczkowski J.INSERM U 700 and U 683, Faculté de Médecine Xavier Bichat, Université Paris VII, Paris, France. We investigated a possible beneficial role for bilirubin, one of the products of heme degradation by the cytoprotective enzyme heme oxygenase-1 in counteracting Escherichia coli endotoxin-mediated toxicity. Homozygous jaundice Gunn rats, which display high plasma bilirubin levels due to deficiency of glucuronyl transferase activity, and Sprague-Dawley rats subjected to sustained exogenous bilirubin administration were more resistant to endotoxin (LPS)-induced hypotension and death compared with nonhyperbilirubinemic rats. LPS-stimulated production of nitric oxide (NO) was significantly decreased in hyperbilirubinemic rats compared with normal animals; this effect was associated with reduction of inducible NO synthase (NOS2) expression in renal, myocardial, and aortic tissues. Furthermore, NOS2 protein expression and activity were reduced in murine macrophages stimulated with LPS and preincubated with bilirubin at concentrations similar to that found in the serum of hyperbilirubinemic animals. This effect was secondary to inhibition of NAD(P)H oxidase since 1) inhibition of NAD(P)H oxidase attenuated NOS2 induction by LPS, 2) bilirubin decreased NAD(P)H oxidase activity in vivo and in vitro, and 3) down-regulation of NOS2 by bilirubin was reversed by addition of NAD(P)H. These findings indicate that bilirubin can act as an effective agent to reduce mortality and counteract hypotension elicited by endotoxin through mechanisms involving a decreased NOS2 induction secondary to inhibition of NAD(P)H oxidase. |
| PMID: 16129699 [PubMed - indexed for MEDLINE] | |
| Related articles Free article | |
 | |
Publication Types:
MeSH Terms:
Substances:
|
| 63. | Folia Microbiol (Praha). 2005;50(2):167-71.Antibiotic-induced release of inflammatory mediators from bacteria in experimental Klebsiella pneumoniae-induced sepsis.Toky V, Sharma S, Bramhne HG, Chhibber S.Department of Microbiology, Panjab University, 160 014 Chandigarh, India. kltoky@yahoo.com In a fibrin-clot model of sepsis, developed in mice, treatment with the antibiotics ceftazidime (Cfz) and ofloxacin (Ofl) caused significant (p < 0.01) release of endotoxin and TNF-alpha after 4.5 h when compared with control (untreated) and amikacin (Ami) treated group. Except for control group, the level of bacteremia declined in all three antibiotic-treated groups. The results suggest that antibiotic therapy, irrespective of the agent used, results in an increase in endotoxin levels in vivo. The amount of endotoxin liberated by Ami was much smaller than with Cfz and Ofl therapy, which makes it an appropriate agent for the treatment of sepsis. An increase in the level of TNF-alpha along with endotoxin is suggestive of increased inflammatory response. |
| PMID: 16110923 [PubMed - indexed for MEDLINE] | |
| Related articles | |
MeSH Terms:
Substances:
|
| 64. | Circulation. 2005 Jul 5;112(1):117-24.Statin treatment after onset of sepsis in a murine model improves survival.Merx MW, Liehn EA, Graf J, van de Sandt A, Schaltenbrand M, Schrader J, Hanrath P, Weber C.Medizinische Klinik I, RWTH Aachen, 52057 Aachen, Germany. mmerx@ukaachen.de BACKGROUND: HMG-CoA-reductase inhibitors have been shown to exhibit pronounced immunomodulatory effects independent of lipid lowering. We have recently demonstrated that pretreatment with simvastatin profoundly improves survival in a cecal ligation and perforation (CLP) model of sepsis. Here, we studied whether treatment with simvastatin after onset of sepsis-induced hemodynamic alterations is beneficial and whether prolonged survival can also be achieved with other statins. METHODS AND RESULTS: Mice were rendered septic by CLP. At 6 hours after sepsis induction, when profound hemodynamic alterations were manifest, treatment with atorvastatin, fluvastatin, pravastatin, simvastatin, or placebo was initiated. Except for fluvastatin (27+/-2.3 hours), survival time was extended from 23+/-1.2 hours for placebo-treated mice to 37+/-3.6 hours for simvastatin-treated, to 40+/-4.2 hours for atorvastatin-treated, and to 39+/-3.9 hours for pravastatin-treated mice. This profound improvement is based on the preservation of cardiac function and hemodynamic status in statin-treated animals, both of which are severely impaired in untreated CLP mice. As underlying mechanisms, improved susceptibility to endothelial nitric oxide synthase stimulation and reduced endothelial adhesion of leukocytes could be demonstrated after statin treatment. CONCLUSIONS: Well established in the treatment of lipid disorders and coronary artery disease, statins harbor the additional and novel potential of effective sepsis treatment. This benefit extends to several but not all statins tested. |
| PMID: 15998696 [PubMed - indexed for MEDLINE] | |
| Related articles Free article | |
 | |
Publication Types:
MeSH Terms:
Substances:
|
| 65. | Clin Infect Dis. 2005 Aug 1;41 Suppl 3:S213-7.Defective innate antibacterial host responses during murine Klebsiella pneumoniae bacteremia: tumor necrosis factor (TNF) receptor 1 deficiency versus therapy with anti-TNF-alpha.Moore TA, Lau HY, Cogen AL, Standiford TJ.Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan 48109-0642, USA. tmoore@umich.edu Klebsiella pneumoniae is a leading cause of pneumonia due to gram-negative bacteria. A significant clinical complication of pulmonary infection with K. pneumoniae is peripheral blood dissemination, which results in a systemic infection coincident with the localized pulmonary infection. This study describes the critical importance of tumor necrosis factor (TNF) receptor 1 (TNFR1)-mediated signaling during K. pneumoniae bacteremia. TNFR1-deficient mice displayed a significantly increased mortality rate after intravenous inoculation. Unexpectedly, this increased mortality occurred in the absence of either increased bacterial burden or increased liver injury. However, excessive production of proinflammatory cytokines, including TNF-alpha , was observed in TNFR1-deficient mice, compared with that observed in infected C57BL/6 mice, which suggests that production was dysregulated in the absence of TNFR1 signaling. In contrast, other experiments examined the effect of immunotherapy with anti-TNF-alpha during K. pneumoniae bacteremia. Administration of a neutralizing anti-TNF-alpha antibody completely ablated K. pneumoniae-induced liver injury. This reduction in liver injury failed to translate into an improved survival rate, because mice died of the infection as late as 10 days after infection. Bacterial clearance after neutralization of TNF-alpha was significantly impaired at later time points during infection. Diminished production of liver-associated cytokines and chemokines correlated with impaired bacterial clearance, which suggests that antibacterial immune responses were dampened. These data indicate that the antibacterial host response is dysregulated in mice lacking TNFR1 or TNF-alpha bioactivity. |
| PMID: 15983903 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
Publication Types:
MeSH Terms:
Substances:
Grant Support:
|
| 66. | Am J Physiol Regul Integr Comp Physiol. 2005 Oct;289(4):R1048-53. Epub 2005 Jun 9.Early antibiotic administration but not antibody therapy directed against IL-6 improves survival in septic mice predicted to die on basis of high IL-6 levels.Vyas D, Javadi P, Dipasco PJ, Buchman TG, Hotchkiss RS, Coopersmith CM.Washington University School of Medicine, 660 South Euclid Ave., Campus Box 8109, St. Louis, MO 63110, USA. Elevated interleukin (IL)-6 levels correlate with increased mortality following sepsis. IL-6 levels >14,000 pg/ml drawn 6 h after cecal ligation and puncture (CLP) are associated with 100% mortality in ND4 mice, even if antibiotic therapy is initiated 12 h after septic insult. Our first aim was to see whether earlier institution of antibiotic therapy could improve overall survival in septic mice and rescue the subset of animals predicted to die on the basis of high IL-6 levels. Mice (n = 184) were subjected to CLP, had IL-6 levels drawn 6 h later, and then were randomized to receive imipenem, a broad spectrum antimicrobial agent, beginning 6 or 12 h postoperatively. Overall 1-wk survival improved from 25.5 to 35.9% with earlier administration of antibiotics (P < 0.05). In mice with IL-6 levels >14,000 pg/ml, 25% survived if imipenem was started at 6 h, whereas none survived if antibiotics were started later (P < 0.05). On the basis of these results, we examined whether targeted antibody therapy could improve survival in mice with elevated IL-6 levels. A different cohort of mice (n = 54) had blood drawn 6 h after CLP, and then they were randomized to receive either monoclonal anti-IL-6 IgG or irrelevant rat IgG. Anti-IL-6 antibody failed to improve either overall survival or outcome in mice with IL-6 levels >14,000 pg/ml. These results demonstrate that earlier systemic therapy can improve outcome in a subset of mice predicted to die in sepsis, but we are unable to demonstrate any benefit in similar animals using targeted therapy directed at IL-6. PMCID: PMC1237117 |
| PMID: 15947070 [PubMed - indexed for MEDLINE] | |
| Related articles Free article | |
 | |
Publication Types:
MeSH Terms:
Substances:
Grant Support:
|
| 67. | J Pharm Pharm Sci. 2005 Apr 30;8(1):107-14.Anti-inflammatory effects of Podophyllum hexandrum (RP-1) against lipopolysaccharides induced inflammation in mice.Prakash H, Ali A, Bala M, Goel HC.Department of Radiation Biology, Institute of Nuclear Medicine and Allied Sciences, Brig. S. K. Mazumdar Marg, Delhi, India. PURPOSE: Down-regulation of lipopolysaccharide (LPS) induced hyper-inflammatory response by non-toxic pharmacological agents acquires paramount importance for countering bacterial sepsis. Anti-inflammatory potential of aqueous extract of Podophyllum hexandrum, a plant well documented in Ayurvedic literature for various therapeutic purposes, was investigated. METHODS: In vivo studies were performed on Balb/c mice pre-treated with supra-lethal dose of LPS endotoxin (E.coli 055:B5) with or without treatment with P. hexandrum extract (RP-1). Mouse peritoneal macrophage cultures were used to understand ex vivo effects of RP-1 on LPS generated nitric oxide (NO), secretion of IFN-gamma, IL-6 and TNF-alpha. Griess assay and sandwich ELISA method were used to quantify inducible NO and cytokines respectively. RESULTS: Minimal dose of LPS that rendered 100% mortality to mice was found to be 450 microg/kg b.w. Administration of RP-1 (200 mg/kg b.w., i.p.) one hour before lethal LPS treatment (0.5 mg/kg b.w.) rendered maximum (78%) survival. Ex vivo study revealed that RP-1 (50 microg/ml) treatment to peritoneal macrophages inhibited LPS (5 microg/ml) induced nitrite generation to 37%, IFN-gamma secretion to 5%, IL-6 secretion to 50% and TNF-alpha secretion to 50 % of LPS treated control values. CONCLUSION: This study has demonstrated anti-inflammatory potential of aqueous extract of P. hexandrum. |
| PMID: 15946604 [PubMed - indexed for MEDLINE] | |
| Related articles Free article | |
 | |
Publication Types:
MeSH Terms:
Substances:
|
| 68. | Am J Physiol Lung Cell Mol Physiol. 2005 Oct;289(4):L583-90. Epub 2005 Jun 3.Alpha-chemokine receptor blockade reduces high mobility group box 1 protein-induced lung inflammation and injury and improves survival in sepsis.Lin X, Yang H, Sakuragi T, Hu M, Mantell LL, Hayashi S, Al-Abed Y, Tracey KJ, Ulloa L, Miller EJ.Department of Surgery, North Shore University Hospital, Long Island Jewish Medical Center, Manhasset, NY 11030, USA. High mobility group box 1 (HMGB1) protein, a late mediator of lethality in sepsis, can induce acute inflammatory lung injury. Here, we identify the critical role of alpha-chemokine receptors in the HMGB1-induced inflammatory injury and show that alpha-chemokine receptor inhibition increases survival in sepsis, in a clinically relevant time frame. Intratracheal instillation of recombinant HMGB1 induces a neutrophilic leukocytosis, preceded by alveolar accumulation of the alpha-chemokine macrophage inflammatory protein-2 and accompanied by injury and increased inflammatory potential within the air spaces. To investigate the role of alpha-chemokine receptors in the injury, we instilled recombinant HMGB1 (0.5 microg) directly into the lungs and administered a subcutaneous alpha-chemokine receptor inhibitor, Antileukinate (200 microg). alpha-Chemokine receptor blockade reduced HMGB1-induced inflammatory injury (neutrophils: 2.9 +/- 3.2 vs. 8.1 +/- 2.4 x 10(4) cells; total protein: 120 +/- 48 vs. 311 +/- 129 microg/ml; reactive nitrogen species: 2.3 +/- 0.3 vs. 3.5 +/- 1.3 microM; and macrophage migration inhibitory factor: 6.4 +/- 4.2 vs. 37.4 +/- 15.9 ng/ml) within the bronchoalveolar lavage fluid, indicating that HMGB1-induced inflammation and injury are alpha-chemokine mediated. Because HMGB1 can mediate late septic lethality, we administered Antileukinate to septic mice and observed increased survival (from 58% in controls to 89%) even when the inhibitor treatment was initiated 24 h after the induction of sepsis. These data demonstrate that alpha-chemokine receptor inhibition can reduce HMGB1-induced lung injury and lethality in established sepsis and may provide a novel treatment in this devastating disease. |
| PMID: 15937067 [PubMed - indexed for MEDLINE] | |
| Related articles Free article | |
 | |
Publication Types:
MeSH Terms:
Substances:
Grant Support:
|
| 69. | Shock. 2005 Apr;23(4):365-70.The induction of super-resistance using synthetic lipopolysaccharide receptor agonist rescues fatal endotoxemia in rats without excessive immunosuppression.Hatao F, Hiki N, Mimura Y, Ogawa T, Kojima J, Mafune K, Hawkins LD, Muroi M, Tanamoto K, Kaminishi M.Department of Metabolic Care and Gastrointestinal Surgery, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan. Endotoxin tolerance provides protection against mortality under various conditions of stress. However, the induction of endotoxin tolerance thus far has no clinical application because of endotoxin toxicity and the excessive immune suppression that follows the tolerance induction. In this study, we examined whether a novel, synthetic lipopolysaccharide (LPS) receptor agonist, ER-803058 (ER) can induce endotoxin tolerance with accompanying low toxicity. The stimulative effects of ER on tumor necrosis factor (TNF)-alpha production from RAW264 cells were 50% to 70% lower than those of the corresponding quantities of LPS. ER pretreatment also diminished TNF-alpha secretion induced by a subsequent LPS shock. However, the degree of desensitization with ER pretreatment (10 ng/mL, 55.5% +/- 6.7%; 100 ng/mL, 42.3 +/- 4.9%) was modest in contrast with that measured for the corresponding LPS pretreatment (10 ng/mL, 36.7% +/- 3.7%; 100 ng/mL, 20.0% +/- 3.6%). The minimum in vivo dose (0.02 mg/kg/body weight) of ER-induced negligible production of TNF-alpha and interleukin (IL)-6 in rats, and resulted in a modest endotoxin tolerance with respect to TNF-alpha secretion. Although the plasma TNF-alpha level after ER pretreatment was decreased (48.2% +/- 1.1%), the suppression was not statistically significant. Interestingly, even this minimal quantity of ER pretreatment evoked a dramatic improvement in survival (90% survival) against administration of a lethal dose of LPS, which is inconsistent with the modest TNF-alpha suppression. Furthermore, ER pretreatment preserved normal plasma albumin levels and prevented the increase of plasma blood urea nitrogen levels seen with LPS. These results indicate that pretreatment with ER can effectively induce endotoxin tolerance, with a consequent improvement in mortality without toxicity and without subsequent excessive immunosuppression. |
| PMID: 15803061 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
MeSH Terms:
Substances:
|
| 70. | Bioorg Med Chem Lett. 2005 Mar 1;15(5):1295-8.Functionalized dendrimers as endotoxin sponges.Cromer JR, Wood SJ, Miller KA, Nguyen T, David SA.Department of Medicinal Chemistry, University of Kansas, Life Sciences Research Laboratories, 1501 Wakarusa Drive, Lawrence, KS 66049, USA. Lipopolysaccharides (LPS), otherwise termed 'endotoxins', are outer-membrane constituents of Gram-negative bacteria, and play a key role in the pathogenesis of 'Septic Shock', a major cause of mortality in the critically ill patient. We had previously defined the pharmacophore necessary for small molecules to specifically bind and neutralize LPS and, using animal models of sepsis, have shown that the sequestration of circulatory LPS by small molecules is a therapeutically viable strategy. Polyamidoamine dendrimers, with the surface amines substoichiometrically derivatized with alkyl groups bind LPS with high affinity, neutralize LPS-induced inflammatory responses in vitro, and afford protection in a murine model of endotoxic shock. Dendrimers represent a new class of potentially useful compounds for the therapy of Gram-negative sepsis. |
| PMID: 15713373 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
Publication Types:
MeSH Terms:
Substances:
Grant Support:
|
| 71. | Int J Antimicrob Agents. 2005 Feb;25(2):163-7.In vivo activity of gemifloxacin, moxifloxacin and levofloxacin against pneumococci with gyrA and parC point mutations in a sepsis mouse model measured with the all or nothing mortality end-point.Alkorta M, Giménez MJ, Vicente D, Aguilar L, Pérez-Trallero E.Servicio de Microbiología, Hospital Donostia, Po del Doctor Beguiristain s/n, 20014 San Sebastián, Spain. malkorta@hcru.osakidetza.net A dose-decreasing immunocompetent sepsis mouse model was used to evaluate the in vivo effect of levofloxacin, moxifloxacin and gemifloxacin, using a ciprofloxacin/levofloxacin susceptible serotype 6B strain (ciprofloxacin MIC: 1 mg/l) and two resistant serotype 14 and 19F strains with gyrA and parC point mutations (ciprofloxacin MICs of 32 and 64 mg/l, respectively). Significant higher in vivo activity was found for moxifloxacin and gemifloxacin than for levofloxacin against strains 1 and 2, and for gemifloxacin versus moxifloxacin or levofloxacin against strain 3. Gemifloxacin treatment resulted in 100% survival against strains 1 and 2(AUC0-24 h/MIC of 30 and 62) but against strain 3, survival was 60-80% (AUC0-24 h/MIC of 93). Similar AUC0-24 h/MIC values produced different therapeutic results suggesting that in vitro parameters other than the MIC could influence efficacy predictions based on in vitro susceptibility tests (MICs) or pharmacodynamic parameters (AUC0-24 h/MIC). |
| PMID: 15664487 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
Publication Types:
MeSH Terms:
Substances:
|
| 72. | Naunyn Schmiedebergs Arch Pharmacol. 2005 Jan;371(1):34-43. Epub 2005 Jan 15.Thaliporphine increases survival rate and attenuates multiple organ injury in LPS-induced endotoxaemia.Chiao CW, Lee SS, Wu CC, Su MJ.Institute of Pharmacology, College of Medicine, National Taiwan University, No. 1, Sec. 1, Jen-Ai Road, Taipei, 100, Taiwan. This study addressed the question of whether thaliporphine, a phenolic aporphine alkaloid obtained from Chinese herbs and possessing antioxidant and alpha-1 adrenoceptor antagonistic activity, has protective effects in endotoxaemic rats and we attempted to elucidate the mechanisms contributing to such protective effects. Injection of rats with endotoxin (E. coli lipopolysaccharide, LPS) induced severe hypotension and tachycardia as well as vascular hyporeactivity to noradrenaline. Pretreatment of LPS-treated rats with thaliporphine attenuated the delayed hypotension significantly whilst only a higher dose (1 mg/kg) of thaliporphine decreased LPS-induced tachycardia. LPS significantly increased nitric oxide (NO.) and superoxide anion (O(2).(-)) levels, a response that was reduced by pretreatment with 1 mg/kg thaliporphine. Endotoxaemia for 240 min resulted in a bell-shaped time course for the change of serum tumour necrosis factor-alpha (TNF-alpha) level with a peak at 60 min. Pretreatment of LPS-treated rats with 1 mg/kg thaliporphine significantly reduced the serum TNF-alpha level at 60 min. In addition, LPS caused a biphasic change in blood glucose and thaliporphine attenuated the late-phase decrease in blood glucose. Endotoxaemia induced multiple organ injury in the liver, kidney and heart, as indicated by increases of aspartate aminotransferase (GOT), alanine aminotransferase (GPT), creatinine (CRE), lactate dehydrogenase (LDH) and creatine phosphate kinase muscle-brain (CKMB) levels in serum. These increases of biochemical markers and inflammatory cell infiltration into injured tissues were reduced significantly by treatment with thaliporphine. In addition, thaliporphine increased the survival rate of LPS-treated mice dose-dependently. In conclusion, our results suggest that thaliporphine could be a novel agent for attenuating endotoxin-induced circulatory failure and multiple organ injury and may increase the survival rate. These beneficial effects of thaliporphine may be attributed to the suppression of TNF-alpha, NO. and O(2).(-) production. |
| PMID: 15654598 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
Publication Types:
MeSH Terms:
Substances:
|
| 73. | Peptides. 2005 Feb;26(2):169-75.RNAIII-inhibiting peptide improves efficacy of clinically used antibiotics in a murine model of staphylococcal sepsis.Giacometti A, Cirioni O, Ghiselli R, Dell'Acqua G, Orlando F, D'Amato G, Mocchegiani F, Silvestri C, Del Prete MS, Rocchi M, Balaban N, Saba V, Scalise G.Institute of Infectious Diseases and Public Health, Università Politecnica delle Marche, Ancona, Italy. RNAIII-inhibiting peptide (RIP, YSPWTNF-NH2) is a quorum-sensing peptide inhibitor that prevents Staphylococcus aureus toxin production and biofilm formation. A mouse sepsis model was used to test the efficacy of RIP alone or in combination with conventional antibiotics in suppressing S. aureus-induced sepsis. Mice were injected intravenously with 3.0x10(6)CFU of S. aureus ATCC 25923 or with 3.0x10(6)CFU of S. aureus strain Smith diffuse. All animals were randomized to receive intravenously isotonic sodium chloride solution as a control, or 20 mg/kg RIP alone or combined with 20 mg/kg cefazolin, 10 mg/kg imipenem, or 10 mg/kg vancomycin immediately or 6 h after bacterial challenge. Main outcome measures were bacteremia and lethality. All compounds reduced lethality when compared to controls. Although, in general combined-treated groups had significant lower bacterial counts when associated to singly-treated groups only the combination between RIP and vancomycin with respect to cefazolin gave a statistically significant decrease in the lethality rate. Lowest lethality rates (10%) and bacteremia (<10(2)CFU/ml) were obtained when RIP was administered in combination with vancomycin. Because RIP can be synergistic with current antibiotic therapies and help to reduce S. aureus exotoxins production, it can be considered a promising agent to associate with antibiotics for further clinical research into treatment of sepsis. |
| PMID: 15629527 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
Publication Types:
MeSH Terms:
Substances:
|
| 74. | Crit Care Med. 2004 Dec;32(12):2485-90.The antimicrobial peptide BMAP-28 reduces lethality in mouse models of staphylococcal sepsis.Giacometti A, Cirioni O, Ghiselli R, Bergnach C, Orlando F, D'Amato G, Mocchegiani F, Silvestri C, Del Prete MS, Skerlavaj B, Saba V, Zanetti M, Scalise G.Institute of Infectious Diseases and Public Health, Università Politecnica delle Marche, Ancona, Italy. Comment in: OBJECTIVE: A mouse model of staphylococcal sepsis was used to compare the efficacy of the bovine antimicrobial peptide BMAP-28, a compound of the cathelicidin family, with that of conventional antibiotics. DESIGN: Prospective, randomized, controlled animal study. SETTING: Research laboratory in a university hospital. SUBJECTS: BALB/c male mice. INTERVENTIONS: BALB/c mice were injected intravenously with 2.0 x 10(6) colony-forming units of live Staphylococcus aureus ATCC 25923 or with 5.0 x 10(8) heat-killed cells of the same strain. All animals were randomized to receive intravenously isotonic sodium chloride solution, 2 mg/kg BMAP-28, 7 mg/kg imipenem, 7 mg/kg vancomycin, 7 mg/kg clindamycin, and 7 mg/kg clarithromycin immediately and at 6 hrs after bacterial challenge. MEASUREMENTS AND MAIN RESULTS: Lethality, quantitative blood cultures, and detection of tumor necrosis factor-alpha and interleukin-6 plasma levels. In the experiments performed with live bacteria, all compounds reduced lethality rates and bacterial growth compared with controls. Imipenem and vancomycin exhibited the highest efficacy on these main outcome measures. In the experiments performed using heat-killed organisms, only BMAP-28 demonstrated significant efficacy on lethality rates, tumor necrosis factor-alpha, and interleukin-6 plasma levels compared with controls. CONCLUSION: These results highlight the capacity of BMAP-28 to reduce the effects of components of the bacterial cells and suggest that it may be beneficial in the treatment of severe staphylococcal infections in concert with other antimicrobial agents. |
| PMID: 15599155 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
Publication Types:
MeSH Terms:
Substances:
|
| 75. | J Pharmacol Exp Ther. 2005 Mar;312(3):1187-94. Epub 2004 Nov 10.Glabridin, an isoflavan from licorice root, inhibits inducible nitric-oxide synthase expression and improves survival of mice in experimental model of septic shock.Kang JS, Yoon YD, Cho IJ, Han MH, Lee CW, Park SK, Kim HM.Bioevaluation Center, Korea Research Institute of Bioscience and Biotechnology, Taejon, 305-333, Korea. (R)-4-(3,4-Dihydro-8,8-dimethyl)-2H,8H-benzo[1,2-b:3,4-b']dipyran-3yl)-1,3-benzenediol (glabridin), a flavonoid present in licorice extract, is known to have antimicrobial, anti-inflammatory, and cardiovascular protective activities. In the present study, we report the inhibitory effect of glabridin on nitric oxide (NO) production and inducible nitric oxide (iNOS) gene expression in murine macrophages. Glabridin attenuated lipopolysaccharide (LPS)-induced NO production in isolated mouse peritoneal macrophages and RAW 264.7 cells, a mouse macrophage-like cell line. Moreover, iNOS mRNA expression was also blocked by glabridin treatment in LPS-stimulated RAW 264.7 cells. Further study demonstrated that the LPS-induced nuclear factor (NF)-kappaB/Rel DNA binding activity and NF-kappaB/Rel-dependent reporter gene activity were significantly inhibited by glabridin in RAW 264.7 cells and that this effect was mediated through the inhibition of inhibitory factor-kappaB degradation and p65 nuclear translocation. Moreover, reactive oxygen species generation was also suppressed by glabridin treatment in RAW 264.7 cells. In contrast, the activity of mitogen-activated protein kinases was unaffected by glabridin treatment. In animal model, in vivo administration of glabridin increased the rate of survival of LPS-treated mice and inhibited LPS-induced increase in plasma concentrations of nitrite/nitrate and tumor necrosis factor-alpha. Collectively, these data suggest that glabridin inhibits NO production and iNOS gene expression by blocking NF-kappaB/Rel activation and that this effect was mediated, at least in part, by inhibiting reactive oxygen species generation. Furthermore, in vivo anti-inflammatory effect of glabridin suggests a possible therapeutic application of this agent in inflammatory diseases. |
| PMID: 15537821 [PubMed - indexed for MEDLINE] | |
| Related articles Free article | |
| | |
Publication Types:
MeSH Terms:
Substances:
|
| 76. | BMC Infect Dis. 2004 Oct 18;4:43.Effect of granulocyte colony-stimulating factor in experimental methicillin resistant Staphylococcus aureus sepsis.Alp E, Gozukucuk S, Canoz O, Kirmaci B, Doganay M.Department of Infectious Diseases, Faculty of Medicine, Erciyes University, Kayseri, Turkey. ealp@erciyes.edu.tr BACKGROUND: Methicillin resistant Staphylococcus aureus (MRSA) is the leading pathogenic cause of nosocomial infections, especially in bacteraemia and sepsis. The essential therapy for MRSA infection is glycopeptides. Therapeutic failure can be seen with this therapy and the mortality is still high. The aim of this study was to evaluate the additional effect of G-CSF on the traditional antibiotic treatment in an experimental MRSA sepsis. METHODS: Experimental sepsis was performed in mice by intraperitoneal injection of MRSA isolate. Inoculum dose was estimated as 6 x 10(9)ml. Mice were randomised for the study into four group; control group (not receive any therapy), G-CSF group (1000 ng/daily, subcutaneously for 3 d), antibiotic group (vancomycin 25 or 50 mg/kg intraperitoneally every 12 hours for 7 d), and vancomycin+G-CSF group (at the same concentrations and duration). Autopsy was done within one hour after mice died. If mice was still alive at the end of seventh day, they were sacrificed, and autopsy was done. In all groups, the effect of G-CSF therapy on the survival, the number of the MRSA colonies in the lung, liver, heart, spleen, and peritoneal cultures, the histopathology of the lung, liver, heart and spleen was investigated. RESULTS: One hundred and six mice were used. There were no significant differences in survival rates and bacterial eradication in G-CSF group compared with control group, and also in antibiotic +G-CSF group compared with antibiotic alone group. These parameters were all significantly different in antibiotic alone group compared with control group. Histopathologically, inflammation of the lung and liver were significantly reduced in vancomycin (25 mg/kg)+G-CSF and vancomycin (50 mg/kg)+G-CSF subgroups, respectively (p < 0.01). The histopathological inflammation of the other organs was not significantly different in antibiotic+G-CSF group compared with antibiotic group and, also G-CSF group compared with control group. CONCLUSION: G-CSF treatment had no additional effect on survival and bacterial eradication in MRSA sepsis in nonneutropenic mice; and only a little effect on histopathology. G-CSF treatment is very expensive, likewise glycopeptides. The more interest in infection control measures, and prevent the spread of MRSA infections is more rational. PMCID: PMC526191 |
| PMID: 15491501 [PubMed - indexed for MEDLINE] | |
| Related articles Free article | |
 | |
Publication Types:
MeSH Terms:
Substances:
|
| 77. | Free Radic Biol Med. 2004 Oct 15;37(8):1282-9.Ascorbate protects against impaired arteriolar constriction in sepsis by inhibiting inducible nitric oxide synthase expression.Wu F, Wilson JX, Tyml K.Lawson Health Research Institute, University of Western Ontario, London, Ontario, N6A 5C1, Canada. Compromised microvascular responsiveness is one of the key factors associated with mortality of septic patients. The present study addresses the mechanism of protection by ascorbate against impaired vasoconstriction in septic mice. Sepsis (i.e., cecal ligation and puncture (CLP) model) elevated both plasma protein carbonyl (i.e., an index of oxidative stress) and plasma nitrite/nitrate (NOx) levels, reduced baseline mean arterial blood pressure (MABP), and inhibited the MABP pressor response to angiotensin II (Ang II) at 6 h post-CLP. At the microvascular level, sepsis increased the inducible nitric oxide synthase (iNOS) mRNA level in cremaster muscle arterioles (18-25 microm diameter) at 3 h post-CLP, and impaired vasoconstriction to Ang II in these arterioles at 6 h post-CLP. At 24 h post-CLP, sepsis resulted in 9% survival. An intravenous bolus of ascorbate (200 mg/kg body wt) given 30 min prior to CLP prevented the protein carbonyl and NOx increases, partially restored the baseline arterial pressure, and completely protected against all arteriolar iNOS mRNA increases, arteriolar constriction hyporesponsiveness, and pressor response impairment. Survival increased to 65%. In septic mice, iNOS gene knockout resulted in protection of arteriolar constriction and pressor responses identical to that provided by ascorbate. Ascorbate bolus given 3 h post-CLP protected against the increase in plasma NOx concentration and against the pressor response impairment. We conclude that ascorbate may protect arteriolar vasoconstrictor responsiveness in sepsis by inhibiting excessive NO production. |
| PMID: 15451067 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
Publication Types:
MeSH Terms:
Substances:
|
| 78. | Anesthesiology. 2004 Oct;101(4):902-11.Local anesthetics reduce mortality and protect against renal and hepatic dysfunction in murine septic peritonitis.Gallos G, Jones DR, Nasr SH, Emala CW, Lee HT.Department of Anesthesiology, Columbia University, 630 West 168th Street, New York, NY 10032-3784, USA. BACKGROUND: Mortality from sepsis frequently results from multiple organ injury and dysfunction. Cecal ligation and puncture is an established murine model of septic peritonitis that produces septic shock characterized by an initial hyperinflammatory response. In addition to their anesthetic properties, local anesthetics have been shown to attenuate inflammatory responses both in vivo and in vitro. In the current study, the ability of local anesthetic infusions to protect against sepsis-induced mortality, as well as renal and hepatic dysfunction after cecal ligation and puncture, was investigated. METHODS: C57BL/6 mice received mini-osmotic pumps containing saline (vehicle), 10% lidocaine, or 1% bupivacaine and were subjected to cecal ligation and puncture. Twenty-four hours after cecal ligation and puncture, renal and hepatic functions were assessed as well as markers of inflammation (proinflammatory cytokine protein and mRNA concentrations and myeloperoxidase activity). Renal apoptosis and 7-day survival was also assessed. RESULTS: Mice treated with lidocaine or bupivacaine infusion showed improved survival and had significantly lower plasma creatinine, aspartate aminotransferase, and alanine aminotransferase concentrations compared with mice receiving vehicle alone. Significant reduction in plasma tumor necrosis factor-alpha and keratinocyte-derived chemokine, as well as reductions in myeloperoxidase activity, intracellular adhesion molecule-1 protein expression, mRNA concentrations of proinflammatory markers, and apoptosis were observed in renal cortices from both local anesthetic groups. CONCLUSIONS: The current data demonstrate that local anesthetic infusions confer a protective effect in mice from septic peritonitis by attenuating the hyperacute inflammatory response. This suppression resulted in improved mortality and less progression to acute kidney and liver injury and dysfunction. |
| PMID: 15448523 [PubMed - indexed for MEDLINE] | |
| Related articles Free article | |
 | |
MeSH Terms:
Substances:
|
| 79. | J Pharmacol Exp Ther. 2004 Dec;311(3):1256-63. Epub 2004 Jul 27.Comparative study of glucocorticoids, cyclosporine A, and JTE-607 [(-)-Ethyl-N[3,5-dichloro-2-hydroxy-4-[2-(4-methylpiperazin-1-yl)ethoxy]benzoyl]-L-phenylalaninate dihydrochloride] in a mouse septic shock model.Iwamura H, Sato M, Wakitani K.Japan Tobacco Inc., Central Pharmaceutical Research Institute, 1-1 Murasaki-Cho, Takatsuki, Osaka 569-1125, Japan. hiroyuki.iwamura@ims.jti.co.jp Actions of glucocorticoids, cyclosporine A, and JTE-607 [(-)-ethyl-N-[3,5-dichloro-2-hydroxy-4-[2-(4-methylpiperazin-1-yl)ethoxy]benzoyl]-L-phenylalaninate dihydrochloride], a proinflammatory cytokine inhibitor that does not inhibit interleukin (IL)-2 or interferon-gamma, were compared in a mouse septic shock model induced by cecal ligation and puncture (CLP). CLP caused elevation of macrophage inflammatory protein (MIP)-2 in lung, and MIP-2 and IL-6 in plasma and peritoneal fluid, reaching a peak 4 to 8 h after CLP. Myeloperoxidase (MPO) activity in lung increased and reached a peak 8 to 12 h after CLP. Acute treatment (subcutaneous injections 1 h before and 2 h after CLP) of mice with JTE-607 and methylprednisolone showed significant inhibition of elevated cytokine levels and MPO activity, plus increased survival rate. Similar treatment with cyclosporine A and prednisolone was ineffective. Chronic treatment (subcutaneous injection for seven consecutive days before CLP) of mice with JTE-607 also showed an inhibitory effect on cytokine production, MPO activity and mortality. In contrast, chronic treatment with cyclosporine A and prednisolone did not inhibit cytokine production or MPO activity, but rather exacerbated mortality. These results indicate that JTE-607 has protective effect on mouse mortality induced by CLP, correlating with inhibition of proinflammatory cytokines, whereas the immunosuppressants cyclosporine A and prednisolone do not. This suggests that JTE-607, a multiple cytokine inhibitor that does not cause adverse immunosuppression, is useful for treatment of septic shock. |
| PMID: 15280441 [PubMed - indexed for MEDLINE] | |
| Related articles Free article | |
| | |
Publication Types:
MeSH Terms:
Substances:
|
| 80. | Inflamm Res. 2004 Jul;53(7):292-6. Epub 2004 Jun 25.Protective effects of lactoferrin in Escherichia coli-induced bacteremia in mice: relationship to reduced serum TNF alpha level and increased turnover of neutrophils.Zimecki M, Artym J, Chodaczek G, Kocieba M, Kruzel ML.Department of Experimental Therapy, Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Weigla 12, 53-114, Wroclaw, Poland. OBJECTIVE AND DESIGN: Previous studies demonstrated that lactoferrin (LF), given intravenously (i.v.), 24 h before lethal Escherichia coli ( E. coli) infection, protects mice against mortality. The aim of this investigation was to determine whether downregulation of serum TNF alpha activity and increase of neutrophil number in the circulation and bone marrow by LF could contribute to the protective action of LF against E. coli-induced sepsis. MATERIAL AND SUBJECTS: CBA female mice, 10-12 week old, weight 20-22 g, were used. Treatment: Mice were given 10 mg LF i.v. either 2 h or 24 h before i.v. administration of lethal dose of E. coli (5 x 10(8)). METHODS: Serum activities of TNF alpha and IL-1 were determined by bioassays 2 h following E. coli or LF injection. The blood and bone marrow smears were stained with Giemsa and May-Grünwald reagents and reviewed histologically. RESULTS: LF given 24 h before E. coli caused a 60% reduction of TNF alpha released into circulation. However, pretreatment of mice with LF 2 h before bacterial challenge resulted in strong (15 fold) increase of TNF alpha serum level. Analysis of bone marrow cell composition revealed a significant increase in neutrophil lineage cell content (myelocytes, bands and mature neutrophils) following 24 h pretreatment with LF (51.8% of the total cell count), versus PBS control (32.7%) and 2 h LF pretreatment (35.8%). The percentage of neutrophils (bands and mature forms) in the peripheral blood rose to 47.4% versus 32% and 32%, respectively. Intravenous administration of LF increased also interleukin 1 (IL-1) concentration in the circulation of noninfected mice. CONCLUSIONS: This investigation has added more information regarding the mechanism of the protective action of LF in E. coli-induced bacteremia by revealing the phenomenon of accelerated neutrophil recruitment and down-regulation of E. coli-induced TNF alpha serum level. |
| PMID: 15241563 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
MeSH Terms:
Substances:
|
| 81. | Eur J Pharmacol. 2004 Jun 16;493(1-3):177-82.Potentiation by amino acid of the therapeutic effect of highly purified vitamin B2 in mice with lipopolysaccharide-induced shock.Toyosawa T, Suzuki M, Kodama K, Araki S.Tsukuba Research Laboratories, Eisai Co., Ltd., 5-1-3, Tokodai, Tsukuba 300-2635, Ibaraki, Japan. The aim of this experiment was to clarify whether an amino acid supplement could enhance the therapeutic effect of vitamin B2 (riboflavin 5'-sodium phosphate; purity > 97%) in mice with lipopolysaccharide-induced shock. Six hours after injection of a lethal dose of lipopolysaccharide, treatment (6-h i.v. infusion) was commenced. All mice died in the groups treated with saline or aminolevane (an amino acids mixture used to treat hepatopathy); however, the survival rates in the vitamin B2 (10 mg/kg/6 h) and vitamin B2 plus aminolevane groups were 45% (P < 0.05) and 80% (P < 0.05), respectively. Valine (200 mg/kg/6 h) alone had little effect on the survival rate (10%), but the combination of vitamin B2 (10 mg/k/g/6 h) and valine was highly effective (80%, P < 0.05). Clinical trials of vitamin B2 plus amino acids for the treatment of patients with sepsis would appear to be warranted. Copyright 2004 Elsevier B.V. |
| PMID: 15189780 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
MeSH Terms:
Substances:
|
| 82. | J Immunol. 2004 Jun 15;172(12):7583-91.Akt decreases lymphocyte apoptosis and improves survival in sepsis.Bommhardt U, Chang KC, Swanson PE, Wagner TH, Tinsley KW, Karl IE, Hotchkiss RS.Institute of Virology and Immunobiology, University of Würzburg, Würzburg, Germany. Sepsis induces extensive death of lymphocytes that may contribute to the immunosuppression and mortality of the disorder. The serine/threonine kinase Akt is a key regulator of cell proliferation and death. The purpose of this study was to determine whether overexpression of Akt would prevent lymphocyte apoptosis and improve survival in sepsis. In addition, given the important role of Akt in cell signaling, T cell Th1 and Th2 cytokine production was determined. Mice that overexpress a constitutively active Akt in lymphocytes were made septic, and survival was recorded. Lymphocyte apoptosis and cytokine production were determined at 24 h after surgery. Mice with overexpression of Akt had a marked improvement in survival compared with wild-type littermates, i.e., 94 and 47% survival, respectively, p < 0.01. In wild-type littermates, sepsis caused a marked decrease in IFN-gamma production, while increasing IL-4 production >2-fold. In contrast, T cells from Akt transgenic mice had an elevated production of IFN-gamma at baseline that was maintained during sepsis, while IL-4 had little change. Akt overexpression also decreased sepsis-induced lymphocyte apoptosis via a non-Bcl-2 mechanism. In conclusion, Akt overexpression in lymphocytes prevents sepsis-induced apoptosis, causes a Th1 cytokine propensity, and improves survival. Findings from this study strengthen the concept that a major defect in sepsis is impairment of the adaptive immune system, and suggest that strategies to prevent lymphocyte apoptosis represent a potential important new therapy. |
| PMID: 15187138 [PubMed - indexed for MEDLINE] | |
| Related articles Free article | |
 | |
Publication Types:
MeSH Terms:
Substances:
Grant Support:
|
| 83. | Eur J Pharmacol. 2004 May 25;492(2-3):273-80.Effects of intravenous infusion of highly purified vitamin B2 on lipopolysaccharide-induced shock and bacterial infection in mice.Toyosawa T, Suzuki M, Kodama K, Araki S.Tsukuba Research Laboratories, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan. We investigated the effect of an i.v. infusion of highly purified vitamin B(2) (riboflavin 5'-sodium phosphate: purity >97%) on lipopolysaccharide-induced shock and bacterial infection in mice. Six hours after lipopolysaccharide injection or 1 h after bacterial infection, vitamin B(2) or human activated protein C (APC) was administered by 6-h i.v. infusion. Vitamin B(2) at 10 mg/kg/6 h and up to 80 mg/kg/6 h significantly improved lipopolysaccharide-induced endotoxin shock. APC was also effective at low doses, but was deleterious at higher doses. Moreover, vitamin B(2) at 80 mg/kg/6 h significantly reduced the lethality of Escherichia coli and Staphylococcus aureus infection, whereas APC at up to 600 units/kg/6 h was ineffective. The i.v. infusion of vitamin B(2) reduced the elevations of proinflammatory cytokines and nitric oxide induced by lipopolysaccharide. These results suggest that i.v. infusion of vitamin B(2) represents a promising strategy for the treatment of sepsis and septic shock. |
| PMID: 15178375 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
Publication Types:
MeSH Terms:
Substances:
|
| 84. | Surg Infect (Larchmt). 2004 Spring;5(1):29-37.Inhibition of cyclooxygenase-2 by NS-398 following hemorrhage and subsequent sepsis: no beneficial effects in either gender.Kahlke V, Seidel M, Stapela S, Brötzmann K, Schafmayer C, Schröder J.Department of General Surgery, University of Schleswig-Holstein, Kiel, Germany. Vkahlke@surgery.uni0kiel.de BACKGROUND: Inhibition of cyclooxygenase-2 with a reduction of prostaglandin E(2)production by the specific antagonist NS-398 has been shown to have beneficial effects on immune function and survival in a trauma model. Immune function after experimental hemorrhagic shock and subsequent sepsis may be gender-related, with enhanced immunity and better survival in females. However, it remains unclear if the observed effect of NS-398 treatment is gender-related following hemorrhagic shock and subsequent sepsis. METHODS: Male and female CBA/J mice (age: 2-3 months) were subjected to hemorrhagic shock (35 +/- 5 mm Hg for 90 min and fluid resuscitation) or sham operation. At resuscitation and after 20 and 40 h each received either NS-398 10 mg/kg or placebo i.p. At 48 h after resuscitation, either splenocytes and peritoneal macrophages (pM phi) were harvested (n = 8 per group), or polymicrobial sepsis was induced by cecal ligation and puncture (CLP). Following CLP, either 10-day survival (n = 15 per group) was determined or pM phi and splenocytes were harvested 4 h after CLP (n = 8 per group). Cytokine release of pM phi, and splenocyte proliferation and responsiveness in vitro were assessed. RESULTS: Treatment with NS-398 led to lower PGE(2) levels as compared to placebo-treated animals, reaching significance (p < 0.05) in males. Placebo-treated males had significantly depressed proinflammatory immune response (IL-1, IL-6, IL-2, IFN-gamma) after hemorrhagic shock and experienced further suppression by CLP (all, p < 0.05). In contrast, young females displayed unchanged cytokine release after hemorrhagic shock, but a comparable suppression following CLP. Treatment with NS-398 did not influence cytokine release nor survival. CONCLUSIONS: Despite a significant reduction of PGE(2) concentration, NS-398 treatment has no beneficial effects on cytokine release and survival in this model of hemorrhage and subsequent sepsis. |
| PMID: 15142421 [PubMed - indexed for MEDLINE] | |
| Related articles | |
 | |
Publication Types:
MeSH Terms:
Substances:
|
| 85. | Crit Care Med. 2004 May;32(5 Suppl):S239-46.Effect of factor V Leiden polymorphism in severe sepsis and on treatment with recombinant human activated protein C.Yan SB, Nelson DR.Lilly Research Laboratories, Indianapolis, IN, USA. OBJECTIVE: Coagulation activation is part of the acute innate host response to infection that, when uncontrolled, may contribute to organ dysfunction and death. Activated protein C limits excessive coagulation activation by inactivating factors Va and VIIIa. The factor V Leiden mutation (R506Q), a prothrombotic gene polymorphism, disrupts the activity of this natural anticoagulant by rendering factor Va partially resistant to inactivation by activated protein C. Previous findings in the mouse factor V Leiden endotoxemia model and in patients with severe sepsis suggest that factor V Leiden constitutes a rare example of a balanced gene polymorphism that may provide a survival advantage for heterozygous carriers with severe sepsis. We sought to confirm that carriers of this prothrombotic factor V Leiden mutation do not have an increased risk of developing severe sepsis and that carriers with severe sepsis derive similar treatment benefit from recombinant human activated protein C (drotrecogin alfa [activated]) as non-factor V Leiden carriers. DESIGN: Prospective collection of factor V Leiden status from two clinical studies of severe sepsis (PROWESS and ENHANCE). SETTING:: A total of 447 clinical sites across 25 countries. PATIENTS: A total of 3894 adult patients with severe sepsis. INTERVENTION: Either 24 microg x kg x hr drotrecogin alfa (activated) (n = 3063) or placebo (n = 800) for 96 hrs or no exposure to the study drug (n = 31). MAIN RESULTS: The effect of the factor V Leiden carrier status in severe sepsis in the PROWESS study has been previously reported. The combined data on factor V Leiden status from 3894 adult patients with severe sepsis from the PROWESS and ENHANCE (a single-arm, open-label study of drotrecogin alfa [activated]) studies are reported here. At study entry, 3.9% of patients (150/3894) presenting with severe sepsis were heterozygous carriers. No homozygous factor V Leiden carriers were identified. The proportion of factor V Leiden carriers in patients with severe sepsis differs slightly from that predicted (allelic frequency of 2.5%) by the Hardy-Weinberg equation for the general white population (p =.05). There was no significant difference in baseline disease severity (Acute Physiology and Chronic Health Evaluation II score or number of organ dysfunctions) between heterozygous carriers and non-Leiden carriers. There was no significant difference in serious bleeding or thrombotic event rates with drotrecogin alfa (activated) treatment between heterozygous carriers and non-Leiden carriers. The 28-day mortality rates for heterozygous carriers and non-Leiden carriers with drotrecogin alfa (activated) treatment were 20.3% and 24.9%, respectively (risk ratio, 0.82; 95% confidence interval, 0.57-1.17). CONCLUSIONS:: Compared with non-Leiden carriers, factor V Leiden heterozygous carriers may have a slightly decreased risk of developing severe sepsis from infection, do not seem to have increased mortality in severe sepsis, and derive similar benefit and risk profiles from drotrecogin alfa (activated) treatment. Therefore, factor V Leiden carriers should not be excluded from this new sepsis therapy. |
| PMID: 15118525 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
MeSH Terms:
Substances:
|
| 86. | Peptides. 2003 Nov;24(11):1829-36.Treatment efficacy of the lead RNAIII-inhibiting peptide YSPWTNF-NH2 in acquired Staphylococcus aureus sepsis: a histopathological assessment.Ribeiro PD, Ribeiro OD, Marcolan AM, Medina-Acosta E.Laboratório de Biotecnologia, Universidade Estadual do Norte Fluminense Darcy Ribeiro, Avenida Alberto Lamego 2000, Parque Califórnia, Campos dos Goytacazes, RJ, CEP 28013-602, Brazil. enrique@medina-acosta.com The quorum-sensing interfering RNAIII-inhibiting peptide (RIP) YSPXTNF and its synthetic analogues YSPWTNF and YSPITNF have been shown to prevent and suppress diseases caused by Staphylococcus aureus at different body sites in different animal models. This study was designed to investigate histopathologically the therapeutic efficacy of lead peptide RIP YSPWTNF-NH(2) in the subcutaneous air sac murine model of acquired S. aureus sepsis. Two experimental protocols were evaluated: an infection/therapy protocol, for which twenty BALB/c mice per group were infected with a subcutaneous inoculum of S. aureus strain ATCC 25923 ( [Formula: see text] colony forming units) that were either pretreated or not with 150microg of peptide RIP, and a safety protocol, for which three uninfected mice per group received treatment with either 150microg of peptide RIP or saline. Therapeutic efficacy was assessed by clinical examination for a period of 20 days and histopathology at 12, 24, 36, 48, 96 and 168h after inoculation. Treatment safety was assessed histopathologically at 24, 48 and 264h after inoculation. Subcutaneous administration of uninfected control mice with a single dose of peptide RIP YSPWTNF caused no significant histopathology in most organs examined, except for slight to moderate lung and liver congestions. In contrast to the situation with the untreated infected control group mice that presented with histopathological alterations consistent with the diagnosis of rapidly progressive and highly erosive disease (100% mortality by day 3), treatment of infected animals with peptide RIP YSPWTNF had a profound therapeutic effect on survival rate (67% by day 20) and on disease progression. The histopathological examination confirmed the clinical findings showing that extensive tissue damage at the site of the infection and in organs were greatly suppressed in the peptide RIP-treated animals. |
| PMID: 15019216 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
Publication Types:
MeSH Terms:
Substances:
|
| 87. | Crit Care Med. 2004 Feb;32(2):489-94.Antibiotics delay but do not prevent bacteremia and lung injury in murine sepsis.Doerschug KC, Powers LS, Monick MM, Thorne PS, Hunninghake GW.Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, IA, USA. OBJECTIVES: To investigate the effect of antibiotics on infection, lung injury, and mortality rate in polymicrobial sepsis and to determine whether an association exists between infection and lung injury and mortality rate. To circumvent the effect of antibiotics on cultures, we used polymerase chain reaction to detect bacteria. DESIGN: Prospective, randomized, controlled laboratory trial. SETTING: University research laboratory. SUBJECTS: C57/BL6 mice. INTERVENTIONS: Mice underwent cecal ligation and puncture without antibiotics (CLP) or with imipenem (CLP + Abx). MEASUREMENTS AND MAIN RESULTS: CLP resulted in 50% mortality rate at 48 hrs and 100% mortality rate at 84 hrs. Antibiotics delayed these time points to 72 and 120 hrs, respectively. Lung injury occurred before mortality in both groups. Polymerase chain reaction detected bacteria in the blood and lungs of all CLP mice by 24 hrs. Antibiotics delayed but did not prevent infection in CLP + Abx mice. Serum tumor necrosis factor-alpha and lung endotoxin were elevated to similar concentrations in both CLP and CLP + Abx mice. CONCLUSIONS: In this model of sepsis, antibiotics delay but do not prevent acute lung injury and mortality. Even in the presence of antibiotics, acute lung injury is strongly associated with bacteremia and bacteria within the lungs. |
| PMID: 14758168 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
Publication Types:
MeSH Terms:
Substances:
Grant Support:
|
| 88. | Shock. 2004 Feb;21(2):121-5.Antibiotics improve survival in sepsis independent of injury severity but do not change mortality in mice with markedly elevated interleukin 6 levels.Turnbull IR, Javadi P, Buchman TG, Hotchkiss RS, Karl IE, Coopersmith CM.Department of Surgery, Washington University School of Medicine, St. Louis, Missouri 63110, USA. Genetically identical mice have a heterogeneous response to antibiotic therapy in sepsis, with only a subset deriving therapeutic benefit. We sought to determine whether the severity of a septic insult correlates with the survival benefit conferred by antibiotics. We also sought to determine whether antibiotics given 12 h after injury alter survival in animals predicted to die based upon high interleukin (IL)-6 levels drawn 6 h earlier. Adult male ND4 mice (n = 363) were subjected to double-puncture cecal ligation and puncture (CLP) with a 19-, 21-, or 23-gauge needle. Animals were randomized to receive imipenem or 0.9% NaCl every 12 h after CLP for 5 days. Ten-day survival was 16%, 26%, and 52%, respectively, for untreated animals. Antibiotics decreased the absolute risk of death 17% to 23% regardless of injury severity. In a separate cohort, mice (n = 37) were subjected to single or double-puncture CLP with a 21-gauge needle. IL-6 levels were assayed 6 h postoperatively and mice were followed for survival. Levels greater than 14,000 pg/mL were identified as predicting a 100% mortality (7/7 animals dead). A third set of mice (n = 94) then underwent double-puncture CLP with either 21-, 23-, or 25-gauge needle and had IL-6 levels measured in a similar fashion. Animals were randomized to receive imipenem or 0.9% NaCl beginning 12 h postoperatively (6 h after IL-6 levels were drawn) and continued for 5 days or until death. Although antibiotics decreased mortality overall, all animals with IL-6 levels greater than 14,000 pg/mL (n = 13) died, regardless of whether they received antibiotics or the gauge of needle used. These results indicate that antibiotics improve outcome in murine sepsis, regardless of injury severity. Furthermore, there is a threshold IL-6 level that can be identified 6 h after sepsis above which animals are destined to die, and antibiotic treatment does not alter their outcome. |
| PMID: 14752284 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
Publication Types:
MeSH Terms:
Substances:
Grant Support:
|
| 89. | Immunobiology. 2003;208(4):381-9.Treatment of experimental sepsis-induced immunoparalysis with TNF.Echtenacher B, Urbaschek R, Weigl K, Freudenberg MA, Männel DN.Institute for Pathology/Tumor Immunology, University of Regensburg, Regensburg, Germany. Following a severe septic abdominal infection induced by sublethal cecal ligation and puncture (CLP) in mice, a phase of depressed immune reactivity occurred two days after CLP characterized by a reduced capacity to produce TNF. To determine whether this reduced TNF production causes immunoparalysis as determined by increased susceptibility to bacterial infection and whether therapeutic TNF substitution can be beneficial during this phase, a super-infection with Salmonella enterica Serovar typhimurium or Listeria monocytogenes was induced two days after sublethal CLP. After CLP a state of true immunoparalysis developed during which Salmonella or Listeria super-infection led to increased lethality paralleled by increased bacterial numbers in spleens and livers. Injection of recombinant human TNF before or at the time of super-infection conferred protection to Salmonella but not to Listeria. In the latter case, the infection mortality was even enhanced. Thus, super-infection during the state of sepsis-induced immunoparalysis leads to increased lethality. TNF substitution during this state of immunoparalysis can be beneficial or deleterious, depending on the location of TNF activity in the animal, timing of TNF administration, or the type of super-infection. These results demonstrate that impaired TNF production capacity can account for some aspects of immunoparalysis, however, diagnostic parameters are required for a safe TNF substitution therapy. |
| PMID: 14748511 [PubMed - indexed for MEDLINE] | |
| Related articles | |
Publication Types:
MeSH Terms:
Substances:
|
| 90. | J Med Microbiol. 2004 Feb;53(Pt 2):97-102.Protective effect of ethyl-3-(3-dimethyl aminopropyl)urea dihydrochloride (EDU) against LPS-induced death in mice.Matsumoto T, Nieuwenhuis EE, Cisneros RL, Ruiz-Perez B, Yamaguchi K, Blumberg RS, Onderdonk AB.Channing Laboratory, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. Evaluation of anti-adhesive gels and bioresorbable films in animal models of intra-abdominal infection has shown that a product of the cross-linking reaction between hyaluronic acid (HA) and CM-cellulose, 1-ethyl-3-(3-dimethyl aminopropyl)urea dihydrochloride (EDU), has immunomodulatory properties. The effects of EDU were evaluated by using an endotoxin-induced shock mouse model. Pre-treatment of mice with EDU (50 mg kg(-1)) in DMSO resulted in a significant reduction in mortality following injection of LPS, compared to vehicle (DMSO) pre-treatment alone. Serum levels of TNF-alpha, IL1beta and IFN-gamma in EDU-treated mice were significantly lower than those in vehicle-treated mice. Nitric oxide (NO) concentrations in the sera of mice after inoculation with LPS were significantly lower in the EDU-treated group than in the vehicle-treated group at various time-points. In contrast, EDU pre-treatment was associated with an enhanced IL10 response after LPS injection, compared to vehicle pre-treatment alone. In vitro studies revealed that IL10 production by RAW 264.7 macrophages, elicited by LPS, was increased significantly when EDU was added to the culture medium. These results suggest that the protective effect of EDU during LPS-induced shock in mice is the result of inhibition of proinflammatory cytokines and NO production and an enhanced IL10 response. |
| PMID: 14729928 [PubMed - indexed for MEDLINE] | |
| Related articles Free article | |
 | |
Publication Types:
MeSH Terms:
Substances:
Grant Support:
|
| 91. | Nat Med. 2004 Feb;10(2):161-7. Epub 2004 Jan 11.Therapeutic effects of lysophosphatidylcholine in experimental sepsis.Yan JJ, Jung JS, Lee JE, Lee J, Huh SO, Kim HS, Jung KC, Cho JY, Nam JS, Suh HW, Kim YH, Song DK.Department of Pharmacology, College of Medicine, Institute of Natural Medicine, Hallym University, 1 Okchon-dong, Chunchon, Gangwon-do, 200-702, South Korea. Comment in: Sepsis represents a major cause of death in intensive care units. Here we show that administration of lysophosphatidylcholine (LPC), an endogenous lysophospholipid, protected mice against lethality after cecal ligation and puncture (CLP) or intraperitoneal injection of Escherichia coli. In vivo treatment with LPC markedly enhanced clearance of intraperitoneal bacteria and blocked CLP-induced deactivation of neutrophils. In vitro, LPC increased bactericidal activity of neutrophils, but not macrophages, by enhancing H(2)O(2) production in neutrophils that ingested E. coli. Incubation with an antibody to the LPC receptor, G2A, inhibited LPC-induced protection from CLP lethality and inhibited the effects of LPC in neutrophils. G2A-specific antibody also blocked the inhibitory effects of LPC on certain actions of lipopolysaccharides (LPS), including lethality and the release of tumor necrosis factor-alpha (TNF-alpha) from neutrophils. These results suggest that LPC can effectively prevent and treat sepsis and microbial infections. |
| PMID: 14716308 [PubMed - indexed for MEDLINE] | |
| Related articles | |
 | |
Publication Types:
MeSH Terms:
Substances:
|
| 92. | Free Radic Res. 2003 Sep;37(9):919-29.N-acetylcysteine protects mice from lethal endotoxemia by regulating the redox state of immune cells.Victor VM, Rocha M, De la Fuente M.Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Instituto de Biomedicina de Valencia (CSIC), C/Jaime Roig no. 11, 46010 Valencia, Spain. vmvictor@cnic.es The excessive production of reactive oxygen species (ROS) associated with inflammation leads to oxidative stress, which is involved with the high mortality from several diseases such as endotoxic shock and can be controlled to a certain degree by antioxidants. The immune cells use ROS in order to support their functions and, therefore, need adequate levels of antioxidant defenses in order to avoid the harmful effect of an excessive ROS production. In the present work, the effect of the administration of the antioxidant N-acetylcysteine (NAC) on the redox state of peritoneal macrophages and lymphocytes from mice with lethal endotoxic shock (100 mg/kg i.p. of lipopolysaccharide, LPS), was studied. In both types of immune cells at 0, 2, 4, 12 and 24 h after LPS injection, an increase of ROS, of the proinflammatory cytokine tumor necrosis factor alpha (TNFalpha), the lipid peroxidation (malonaldehyde levels, MDA), inducible nitric oxide synthase (iNOS) expression and the oxidized/reduced glutathione (GSSG/GSH) ratio, as well as a decrease of enzymatic antioxidant defenses, such as superoxide dismutase (SOD) and catalase (CAT) activity, was observed. The injection of NAC (150 mg/kg i.p. at 30 min after LPS injection) decreased the ROS, the TNFalpha the MDA levels, iNOS expression and the GSSG/GSH ratio, and increased the antioxidant defenses in both macrophages and lymphocytes. Moreover, the NAC treatment prevented the activation of nuclear translocation of the nuclear factor kappaB (NF-kappaB), which regulates ROS, inflammatory cytokines and antioxidant levels. Our present results provide evidence that both cell types have a relevant role in the pathogenesis of endotoxic shock, and that NAC, by improving the redox state of these immune cells, could increase mouse survival. Thus, antioxidants could offer an alternative treatment of human endotoxic shock. |
| PMID: 14669999 [PubMed - indexed for MEDLINE] | |
| Related articles | |
Publication Types:
MeSH Terms:
Substances:
|
| 93. | Infect Immun. 2003 Nov;71(11):6199-204.Phage lytic enzyme Cpl-1 as a novel antimicrobial for pneumococcal bacteremia.Loeffler JM, Djurkovic S, Fischetti VA.Laboratory of Bacterial Pathogenesis, The Rockefeller University, New York, New York 10021, USA. Streptococcus pneumoniae is becoming increasingly antibiotic resistant worldwide, and thus new antimicrobials are badly needed. We report the use of Cpl-1, the lytic enzyme of a pneumococcal bacteriophage, as an intravenous therapy for pneumococcal bacteremia in a mouse model. A 2000- microg dose of Cpl-1 reduced pneumococcal titers from a median of log(10) 4.70 CFU/ml to undetectable levels (<log(10) 2.00 CFU/ml) within 15 min. This dose given 1 h after intravenous infection led to 100% survival at 48 h, compared to the 20% survival of buffer-treated controls. In advanced bacteremia, treatment with two doses at 5 and 10 h still resulted in significantly longer survival (P < 0.0001) and a hazard ratio of 0.29 (95% confidence interval, 0.04 to 0.35). The enzyme is immunogenic, but the treatment efficacy was not significantly diminished after previous intravenous exposure of mice and hyperimmune rabbit serum did not neutralize the activity. Cpl-1 is also very effective as a topical nasal treatment against colonization by S. pneumoniae. In vitro, the enzyme is active against many serotypes of S. pneumoniae, independent of their penicillin resistance, and it is very specific for this species. Bacteriophage enzymes are unusual but extremely effective antimicrobials and represent a new weapon against infections with resistant bacteria. PMCID: PMC219578 |
| PMID: 14573637 [PubMed - indexed for MEDLINE] | |
| Related articles Free article | |
 | |
Publication Types:
MeSH Terms:
Substances:
|
| 94. | Shock. 2003 Oct;20(4):338-46.The importance of systemic cytokines in the pathogenesis of polymicrobial sepsis and dehydroepiandrosterone treatment in a rodent model.Hildebrand F, Pape HC, Hoevel P, Krettek C, van Griensven M.Trauma Department, Hannover Medical School, Germany. The pathogenesis of sepsis is still undetermined to a large extent. It is an established fact that female gender is associated with a lower mortality and that sex steroid hormones influence the immunologic response. Dehydroepiandrosterone (DHEA) seems to have a protective immunologic effect in sepsis. It is still unknown in which way DHEA influences the pathogenesis of sepsis. Therefore, the effect of DHEA application on cytokine concentrations in tumor necrosis factor (TNF) receptor (TNF-RI(-/-)) and interleukin-6 (IL-6(-/-)) knockout mice was determined. In a model of polymicrobial sepsis induced by coecal ligation and puncture (CLP), the effect of DHEA on survival and cytokine concentrations was examined. For clarification of the role of TNF-RI, CLP was performed in TNF-RI knockout mice (TNF-RI(-/-)). In addition, IL-6 knockout mice (IL-6(-/-)) were used to clarify the role of IL-6. Furthermore, experiments were performed in mice that were not genetically modified (wild type, WT). The protective effect of DHEA could be confirmed in this CLP model. DHEA application was associated with a reduction in mortality in WT animals. Moreover, DHEA-treated animals demonstrated a reduction in systemic inflammatory effects, as determined by proinflammatory cytokines TNF-alpha, IL-1beta, IL-6, and the antiinflammatory cytokine IL-10. In this work, it was shown that the TNF-RI is essential for survival after CLP. DHEA application was associated with a reduction of mortality of 100% in TNF-RI(-/-) mice after CLP to 50%. This result engages, that the effect of DHEA is TNF-RI independent. However, the application of DHEA had no influence on the mortality in IL-6-/- mice. It can be concluded that the protective effect of DHEA in polymicrobial sepsis is mediated IL-6 dependently. DHEA reduces the systemic inflammation, measurable via the proinflammatory cytokines TNF-alpha, IL-1beta, IL-6, and the antiinflammatory cytokine IL-10. IL-6 might be involved in the DHEA-mediated reduction of postseptic complications. In contrast, DHEA seems to be TNF-RI independent. Consequently, DHEA might be useful as an adjunct therapy for the immune modulation in sepsis. |
| PMID: 14501948 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
MeSH Terms:
Substances:
|
| 95. | Crit Care Med. 2003 Aug;31(8):2096-101.Inflammatory status in sepsis alters efficacy of interleukin-18 binding protein therapy.Remick DG, Bolgos GE, Siddiqui J.Department of Pathology, University of Michigan, Ann Arbor, 48109-0602, USA. remickd@umich.edu Comment in: OBJECTIVE: Sepsis remains a serious clinical problem, and multiple attempts at blocking inflammation have failed to decrease mortality rate. Interleukin-18 has been demonstrated to be an important component of the innate immune response to bacterial infections. DESIGN: Previous work demonstrated that elevated plasma concentrations of interleukin-6 obtained in the first 6 hrs of sepsis predict a worse outcome. Mice were subjected to cecal ligation and puncture and, on the basis of the plasma concentration of interleukin-6, were randomized to receive either interleukin-18 binding protein or vehicle approximately 8 hrs after the onset of sepsis. SETTING: University research laboratory. SUBJECTS: Adult, female BALB/c mice. INTERVENTIONS: We sought to determine the role of interleukin-18 in sepsis by blocking its biological activity with the interleukin-18 binding protein in the murine model of sepsis induced by cecal ligation and puncture. MEASUREMENTS AND MAIN RESULTS: In this study, elevated plasma concentrations of interleukin-6 were associated with a worse outcome. Treatment with interleukin-18 binding protein decreased inflammation as determined by lower concentrations of plasma interleukin-6 obtained 48 hrs after the onset of sepsis. In mice with increased risk of dying, interleukin-18 binding protein slightly decreased mortality rate. However, in those mice with a predicted low mortality rate, interleukin-18 binding protein significantly increased mortality rate. CONCLUSIONS: In this study, mice at low risk of death due to sepsis had decreased survival when treated with interleukin-18 binding protein. These results have potential implications for the use of interleukin-18 binding protein for treatment of chronic inflammatory conditions since it may place the host at increased risk of infectious complications. |
| PMID: 12973165 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
MeSH Terms:
Substances:
|
| 96. | Am J Physiol Heart Circ Physiol. 2003 Dec;285(6):H2524-30. Epub 2003 Aug 7.A selective inducible NOS dimerization inhibitor prevents systemic, cardiac, and pulmonary hemodynamic dysfunction in endotoxemic mice.Ichinose F, Hataishi R, Wu JC, Kawai N, Rodrigues AC, Mallari C, Post JM, Parkinson JF, Picard MH, Bloch KD, Zapol WM.Department of Anesthesia and Critical Care and Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114-2620, USA. ichinose@etherdome.mgh.harvard.edu Increased nitric oxide (NO) production by inducible NO synthase (NOS2), an obligate homodimer, is implicated in the cardiovascular sequelae of sepsis. We tested the ability of a highly selective NOS2 dimerization inhibitor (BBS-2) to prevent endotoxin-induced systemic hypotension, myocardial dysfunction, and impaired hypoxic pulmonary vasoconstriction (HPV) in mice. Mice were challenged with Escherichia coli endotoxin before treatment with BBS-2 or vehicle. Systemic blood pressure was measured before and 4 and 7 h after endotoxin challenge, and echocardiographic parameters of myocardial function were measured before and 7 h after endotoxin challenge. The pulmonary vasoconstrictor response to left mainstem bronchus occlusion, which is a measure of HPV, was studied 22 h after endotoxin challenge. BBS-2 treatment alone did not alter baseline hemodynamics. BBS-2 treatment blocked NOS2 dimerization and completely inhibited the endotoxin-induced increase of plasma nitrate and nitrite levels. Treatment with BBS-2 after endotoxin administration prevented systemic hypotension and attenuated myocardial dysfunction. BBS-2 also prevented endotoxin-induced impairment of HPV. In contrast, treatment with NG-nitro-l-arginine methyl ester, which is an inhibitor of all three NOS isoforms, prevented the systemic hypotension but further aggravated the myocardial dysfunction associated with endotoxin challenge. Treatment with BBS-2 prevented endotoxin from causing key features of cardiovascular dysfunction in endotoxemic mice. Selective inhibition of NOS2 dimerization with BBS-2, while sparing the activities of other NOS isoforms, may prove to be a useful treatment strategy in sepsis. |
| PMID: 12907425 [PubMed - indexed for MEDLINE] | |
| Related articles Free article | |
 | |
Publication Types:
MeSH Terms:
Substances:
Grant Support:
|
| 97. | Shock. 2003 May;19(5):408-14.Antibiotics improve survival and alter the inflammatory profile in a murine model of sepsis from Pseudomonas aeruginosa pneumonia.Coopersmith CM, Amiot DM 2nd, Stromberg PE, Dunne WM, Davis CG, Osborne DF, Husain KD, Turnbull IR, Karl IE, Hotchkiss RS, Buchman TG.Department of Surgery, Washington University School of Medicine, St. Louis, Missouri 63110, USA. Differing antibiotic regimens can influence both survival and the inflammatory state in sepsis. We investigated whether the addition and/or type of antimicrobial agent could effect mortality in a murine model of Pseudomonas aeruginosa pneumonia-induced sepsis and if antibiotics altered systemic levels of cytokines. FVB/N mice were subjected to intratracheal injection of pathogenic bacteria and were given gentamicin, imipenem, or 0.9% NaCl 2 h after surgery, which continued every 12 h for a total of six doses. Survival at 7 days (n = 24 in each group) was 100% for mice given gentamicin, 88% for mice given imipenem, and 8% for sham mice treated with 0.9% NaCl (P < 0.0001). Systemic interleukin (IL) 6 levels were assayed 6 h postoperatively on all mice to see if they were predictive of outcome. Plasma IL-6 levels above 3,600 pg/mL were associated with a 100% mortality, levels under 1,200 pg/mL were associated with a 100% survival, and levels between 1,200 and 3,600 pg/mL had no utility in predicting mortality. In a separate experiment, mice were sacrificed at 3, 6, 12 or 24 h after instillation of P. aeruginosa and were assayed for levels of TNF-alpha, IL-6, IL-10, and IL-12. Significant alterations in the proinflammatory cytokines TNF-alpha and IL-6 were present at all time points except 3 h between mice treated with antibiotics and sham controls. In contrast, statistically significant differences in the anti-inflammatory cytokine IL-10 were present between the groups only at 6 h, and levels of IL-12 were similar at all time points. These results indicate that both gentamicin and imipenem increase survival at least 10-fold in a model of pneumonia-induced monomicrobial sepsis, and this is predominantly associated with a down-regulation of proinflammatory cytokines. |
| PMID: 12744482 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
Publication Types:
MeSH Terms:
Substances:
Grant Support:
|
| 98. | Am J Respir Crit Care Med. 2003 Jul 1;168(1):85-91. Epub 2003 Apr 30.beta-Lapachone reduces endotoxin-induced macrophage activation and lung edema and mortality.Tzeng HP, Ho FM, Chao KF, Kuo ML, Lin-Shiau SY, Liu SH.Institute of Toxicology, College of Medicine, National Taiwan University, Number 1, Jen-Ai Road, Section 1, Taipei 10043, Taiwan. beta-Lapachone, a 1,2-naphthoquinone, is a novel chemotherapeutic agent. It has been shown to be capable of suppressing inducible nitric oxide synthase expression and function in rat alveolar macrophages. The authors further performed experiments to examine the molecular mechanism of beta-lapachone on LPS-induced responses in rat alveolar macrophages and to evaluate its in vivo antiinflammatory effect. A significant increase in nitrite production and inducible nitric oxide synthase expression was elicited in macrophages treated with LPS that was inhibited by coincubation with beta-lapachone. beta-Lapachone could also inhibit the production of tumor necrosis factor-alpha induced by LPS. LPS induces protein tyrosine phosphorylation and nuclear factor-kappaB binding activity by gel mobility shift assay in macrophages. These events were significantly inhibited by beta-lapachone. Furthermore, beta-lapachone in vivo protected against the induction of lung edema, lung-inducible nitric oxide synthase protein expression and nuclear factor-kappaB activation, lethality, and increased plasma nitrite and serum tumor necrosis factor-alpha levels induced by LPS. These results indicate that beta-lapachone suppresses inducible nitric oxide synthase induction and tumor necrosis factor-alpha production mediated by the inhibition of protein tyrosine phosphorylation and nuclear factor-kappaB activation caused by LPS. This results in a beneficial effect in an animal model of sepsis. |
| PMID: 12724123 [PubMed - indexed for MEDLINE] | |
| Related articles Free article | |
 | |
Publication Types:
MeSH Terms:
Substances:
|
| 99. | Shock. 2003 Apr;19(4):310-3.Effects of age on mortality and antibiotic efficacy in cecal ligation and puncture.Turnbull IR, Wlzorek JJ, Osborne D, Hotchkiss RS, Coopersmith CM, Buchman TG.Department of Surgery, Washington University School of Medicine, St. Louis, Missouri 63110-1093, USA. The incidence and mortality of sepsis increase with age, consequently, 80% of the clinical mortality from sepsis occurs in patients over age 65. Despite this aged clinical population, most research models of sepsis use 6- to 16-week-old mice as patient surrogates. This age range of mice corresponds to human ages 10 to 17 years. To assess the influence of age on rodent CLP and on antibiotic therapy, we studied young (4 month), mature (12 month), and aged (24 month) mice. Male C57BL/6 mice (n = 27-30 in each age group) were subjected to cecal ligation and puncture (CLP), two punctures with a 25-gauge needle. Mice were observed untreated for 10 days. Young mice had 20% mortality, mature mice had 70% mortality (P = 0.0013 vs. young), and aged mice had 75% mortality (P = 0.0001 vs. young). To assess the effects of age on antibiotic therapy, mice were subjected to CLP as above (n = 38-40 in each age group). Mice were then randomized to treatment with intraperitoneal injections of ceftriaxone and metronidazole or normal saline. Therapy was initiated 12 h after CLP, and injections were repeated every 12 h for 7 days. Young mice saw a 56% decrease in mortality from CLP with antibiotic therapy (P = 0.001), and mature mice had a 30% decrease in mortality (P = 0.06). Aged mice saw no benefit from antibiotic therapy. We also compared plasma cytokine levels between young and aged mice after CLP. When compared with young mice, aged mice had higher levels of IL-6 and TNF-alpha 24 h after CLP. However, high IL-6 was predictive of mortality at any age. Mice appear to have age-dependent responses to intra-abdominal sepsis and to appropriate therapy. |
| PMID: 12688540 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
Publication Types:
MeSH Terms:
Substances:
Grant Support:
|
| 100. | Crit Care Med. 2003 Jan;31(1 Suppl):S57-64.Endotoxin as a drug target.Opal SM, Glück T.Infectious Disease Division, Brown Medical School, Providence, RI, USA. OBJECTIVE: To review the preclinical and clinical evidence that antiendotoxin therapeutic strategies are potentially useful in the prevention and treatment of septic shock. STUDY DESIGN: A critical review of the literature over the past 30 yrs relating basic and clinical research on the therapeutic value of endotoxin as a target for the prevention and treatment of severe sepsis and septic shock. MAIN RESULTS: Bacterial endotoxin is a potent and predominant microbial mediator that induces an intense inflammatory and procoagulant response by elements of the innate immune response. This macromolecule is capable of inducing lethal septic shock in experimental animals, and a large number of preclinical studies consistently demonstrate the survival advantage of endotoxin inhibition in experimental models of sepsis. Clinical studies indicate that endotoxin may be found in the systemic circulation in the majority of humans with septic shock. Endotoxemia is largely independent of the nature of the infecting microorganism despite the fact that this molecule is specifically found in the outer membrane of Gram-negative bacteria only. Antiendotoxin strategies studied thus far have not provided reproducible survival benefits in clinical trials in septic patients. CONCLUSIONS: Despite compelling evidence of the critical importance of endotoxin in the pathogenesis of Gram-negative bacterial sepsis in preclinical investigations and numerous clinical interventional trials, the utility of antiendotoxin approaches to significantly reduce the mortality rate in human septic shock remains unproven. Ongoing clinical trials with specific endotoxin inhibitors should determine the potential value of this therapeutic approach to the management of septic shock. |
| PMID: 12544978 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
Publication Types:
MeSH Terms:
Substances:
|
| 101. | Shock. 2002 Nov;18(5):445-9.Dehydroepiandrosterone (DHEA) modulates the activity and the expression of lymphocyte subpopulations induced by cecal ligation and puncture.van Griensven M, Dahlweid FM, Giannoudis PV, Wittwer T, Böttcher F, Breddin M, Pape HC.Department of Trauma Surgery, Hannover Medical School, Germany. Griensven.Martijn.van@MH-Hannover.DE Dehydroepiandrosterone (DHEA) exerts a variety of positive effects on the immunologic alterations after trauma and sepsis. We therefore measured the therapeutic efficacy of DHEA after cecal ligation and puncture (CLP) on the expression of lymphocyte subpopulations and on the delayed type hypersensitivity (DTH) reaction. Male NMRI-mice were randomly assigned to four different treatment groups. Treatment consisted of DHEA or saline (S) administration after CLP or laparotomy only. Flow cytometry was performed (CD4+, CD8+, and CD56 lymphocytes) after 96 hours. DTH-reaction, activity and mortality rate were documented. The CLP-induced reduction in activity and survival (mortality: 34/40) was significantly (p < 0.03) less sustained in CLP-DHEA (mortality: 22/40). The DTH-ratio (before vs. after secondary challenge) was significantly lowered in CLP-S (1.01 +/- 0.15) compared to CLP-DHEA (1.35 +/- 0.1) after 48 hours (p < 0.01). CLP-DHEA (22.2 +/- 7.9%) was associated with a statistically significant less sustained increase of CD56+ cells (p < 0.01) compared with CLP-S (49.0 +/- 6.9%). DHEA-treatment after CLP was associated with less reduction in the CD8+ T-lymphocyte subsets (p < 0.01 vs. all other groups). DHEA treatment after CLP was associated with fewer alterations in the changes of CD8+ and CD56, cells, and the DTH reaction compared with animals submitted to CLP without any treatment. This difference was associated with improved outcome (reactivity, mortality). These results suggest a modulation at specific immune reactions by DHEA treatment. |
| PMID: 12412624 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
Publication Types:
MeSH Terms:
Substances:
|
| 102. | J Infect. 2002 Jul;45(1):32-8.Anti-septicaemic effect of polysaccharide from Panax ginseng by macrophage activation.Lim DS, Bae KG, Jung IS, Kim CH, Yun YS, Song JY.Laboratory of Immunology, Korea Cancer Center Hospital, KAERI, Seoul 139-706, Republic of Korea. The aim of the present research was conducted to elucidate anti-septicaemic effect of a polysaccharide (PS) isolated from Panax ginseng C.A. Meyer (Araliaceae) by nitric oxide production from stimulated macrophage. In vitro assays for the activity measurement of PS, NO production test with Greiss reagent, phagocytic activity test using zymosan and cytokines production test using ELISA kit were also conducted. In vivo anti-septicaemic activity was assessed by using C57BL/6J mice. This was done with Staphylococcus aureus infection test. PS used at 0.025 mg/kg concentration showed a potent anti-septicaemic activity (80%, survival). However, it did not directly inhibit S. aureus in a minimum inhibitory concentration (MIC) test, conducted in vitro (data not shown). Nitric oxide production via macrophage activation showed the highest value of 5.5 nmol/ml at 1 microg/ml PS. In in vitro phagocytic activity test, PS at 10 microg/ml concentration showed a potent phagocytic activity for zymosan with 167% of the control. Production of TNF-alpha by macrophage activation at 10 microg/ml of PS was 96% lysis of L929. Also production of IL-1 and IL-6 by stimulation of macrophage with 100 microg/ml PS dose increased to 235 pg/ml and 0.47 ng/ml, respectively. The low mortality of PS treated (0.025 mg/kg) infected mice was concurrent with decreased bacterial content in the blood. Nitric oxide production in S. aureus infected mice whose macrophage was stimulated by PS (0.025 mg/kg) increased approximately 4 times than the untreated S. aureus infected group at 24 and 48 h incubation. In the PS treated (0.025 mg/kg) group, the intracellular concentration of S. aureus in macrophages decreased approximately by 50%, compared with the untreated group. Combine treatment with PS (0.025 mg/kg body weight) and vancomycin (10 mg/kg B.W.) resulted in 100% survival of the animals, whereas only 67% or 50% of the animals survived, respectively, when treated with PS or vancomycin alone. These results suggest that PS from Panax ginseng possess a potent anti-septicaemic activity by stimulating macrophage and a potentiality as an immunomodulator against sepsis occurred by Staphylococcus aureus. Copyright 2002 The British Infection Society |
| PMID: 12217729 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
MeSH Terms:
Substances:
|
| 103. | Crit Care Med. 2002 Jul;30(7):1560-4.Protein synthesis inhibiting clindamycin improves outcome in a mouse model of Staphylococcus aureus sepsis compared with the cell wall active ceftriaxone.Azeh I, Gerber J, Wellmer A, Wellhausen M, Koenig B, Eiffert H, Nau R.Department of Neurology, Georg-August-University, Goettingen, Germany. OBJECTIVE: The release of proinflammatory components from bacteria depends on the mode of action of the antibacterial therapy used. We studied whether this influences mortality in experimental sepsis. DESIGN: In a lethal murine model of Staphylococcus aureus sepsis, animals were randomly assigned to receive the protein synthesis inhibitor clindamycin (CLI) or the beta-lactam ceftriaxone (CRO). SETTING: Therapy was introduced subcutaneously 5 hrs after intraperitoneal injection of 10 colony forming units of S. aureus American Type Culture Collection 29213 and was continued every 8 hrs for 3 days. MEASUREMENTS AND RESULTS: Survival was higher in mice receiving CLI (29/50 animals [58%]) than in mice receiving CRO (16/50 animals [32%]; p =.015). Mice treated with CRO died earlier than mice receiving CLI (p =.002). Eight hours after the first antibiotic dose, the motor performance of mice receiving CRO had deteriorated more than it did for mice receiving CLI (p =.009). Higher levels of tumor necrosis factor-alpha were measured in serum (p =.027) and peritoneal fluid (p =.001) of CRO-treated mice. In vitro, CLI released smaller amounts of staphylococcal enterotoxin A than CRO. CONCLUSIONS: Antibiotic treatment of Gram-positive sepsis with a protein synthesis inhibitor decreases morbidity and mortality compared with a bacteriolytic compound. This may be caused by a reduction of the concentrations of proinflammatory/toxic bacterial components and cytokines. |
| PMID: 12130979 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
Publication Types:
MeSH Terms:
Substances:
|
| 104. | Shock. 2002 Jul;18(1):24-8.Early interleukin-10 treatment improves survival and enhances immune function only in males after hemorrhage and subsequent sepsis.Kahlke V, Dohm C, Mees T, Brötzmann K, Schreiber S, Schröder J.Department of General Surgery, University of Kiel, Germany. Recent studies have demonstrated gender differences in the immune response following hemorrhagic shock with an enhanced immune function and lower mortality following subsequent sepsis in females. Early interleukin-10 (IL-10) treatment has been shown to have beneficial effects on the depressed immune function in males, but not in females following shock. However, it remains unclear if the observed gender-related effect of IL-10 treatment results in an advantage following subsequent polymicrobial sepsis. To study this, male and female CBA/J mice (age 2-3 months) were subjected to hemorrhage (35 +/- 5 mmHg for 90 min and fluid resuscitation). At resuscitation, each received either 10 microg of recombinant murine IL-10 or placebo i.p.. At 48 h after resuscitation, either peritoneal macrophages (pMphi) and plasma were harvested, or polymicrobial sepsis was induced by cecal ligation and puncture (CLP). Following CLP, either survival over 10 days was measured, or pMphi and plasma were harvested 4 h after CLP to assess TNF-alpha, IL-6, IL-10, and prostaglandin E2 (PGE2) release of pMphi and plasma levels of IL-10, free testosteron, and 17-beta estradiol. Early IL-10 treatment restored depressed proinflammatory immune response in males (TNF-alpha and PGE2), which was associated with an enhanced survival (P < 0.05) following subsequent sepsis as compared with placebo-treated mice (8/20 and 1/20, respectively). In contrast, the immune response and survival in females receiving IL-10 was not significantly changed, although females treated with IL-10 had a trend towards higher mortality (7/15 and 2/15, respectively; P = 0.08). Thus, early IL-10 anti-inflammatory treatment following hemorrhage has potential beneficial effects only in males associated with enhanced survival following subsequent sepsis. |
| PMID: 12095129 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
MeSH Terms:
Substances:
|
| 105. | Antimicrob Agents Chemother. 2002 May;46(5):1340-4.Effects of specific antibodies against Streptococcus pneumoniae on pharmacodynamic parameters of beta-lactams in a mouse sepsis model.Casal J, Aguilar L, Jado I, Yuste J, Giménez MJ, Prieto J, Fenoll A.Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain. jcasal@isciii.es A dose-ranging study to investigate the in vivo effects of the presence of specific antibodies on the efficacy of beta-lactam treatment of sepsis caused by Streptococcus pneumoniae (non-beta-lactam-susceptible serotype 6B isolate) was performed with a BALB/c mouse model. Hyperimmune serum was obtained from mice immunized with the heat-inactivated strain. The rate of mortality was 100% in nontreated animals in the absence of specific antibodies. A single injection of a one-half or one-quarter dilution of hyperimmune serum produced 60 to 40% survival rates. In the absence of specific antibodies, the minimal effective doses of amoxicillin and cefotaxime that produced survival rates of 100 and 80% were 25 and 50 mg/kg of body weight (three times a day for up to six doses), respectively. These doses produced times that the levels in serum remained above the MIC (deltaT > MICs) approximately 30% of the dosing interval. When specific antibodies were present (by administration of a one-half or one-quarter dilution of hyperimmune serum), the minimal effective doses of the antibiotics were 3.12 and 6.25 mg/kg ( approximately 8 times lower), with the deltaT > MICs being approximately 3 and 5% of the dosing interval for amoxicillin and cefotaxime, respectively. This in vivo combined pharmacodynamic effect offers possibilities that can be used to address penicillin resistance. PMCID: PMC127147 |
| PMID: 11959566 [PubMed - indexed for MEDLINE] | |
| Related articles Free article | |
 | |
Publication Types:
MeSH Terms:
Substances:
|
| 106. | Am J Respir Crit Care Med. 2002 Mar 15;165(6):818-23.Luteolin reduces lipopolysaccharide-induced lethal toxicity and expression of proinflammatory molecules in mice.Kotanidou A, Xagorari A, Bagli E, Kitsanta P, Fotsis T, Papapetropoulos A, Roussos C.George P. Livanos Laboratory, Evangelismos Hospital, Department of Critical Care and Pulmonary Services, University of Athens, Athens, Greece. Luteolin is a flavonoid that has been shown to reduce proinflammatory molecule expression in vitro. In the present study, we have tested the ability of luteolin to inhibit lipopolysaccharide (LPS)- induced lethal toxicity and proinflammatory molecule expression in vivo. Mice receiving LPS (Salmonella enteriditis LPS, 32 mg/kg, intraperitoneally) exhibited high mortality with only 4.1% of the animals surviving seven days after the LPS challenge. On the contrary, mice that had received luteolin (0.2 mg/kg, intraperitoneally) before LPS showed an increased survival rate with 48% remaining alive on Day 7. To investigate the mechanism by which luteolin affords protection against LPS toxicity we measured intercellular adhesion molecule-1 (ICAM-1) and tumor necrosis factor-alpha (TNF-alpha) production in response to LPS in the presence or absence of luteolin pretreatment. Treatment of animals with LPS increased serum TNF-alpha levels in a time-dependent manner. The increase in peak serum TNF-alpha levels was sensitive to luteolin pretreatment. Luteolin pretreatment also reduced LPS-stimulated ICAM-1 expression in the liver and abolished leukocyte infiltration in the liver and lung. We conclude that luteolin protects against LPS-induced lethal toxicity, possibly by inhibiting proinflammatory molecule (TNF-alpha, ICAM-1) expression in vivo and reducing leukocyte infiltration in tissues. |
| PMID: 11897650 [PubMed - indexed for MEDLINE] | |
| Related articles Free article | |
| | |
Publication Types:
MeSH Terms:
Substances:
|
| 107. | J Antimicrob Chemother. 2002 Feb;49(2):331-5.Beta-lactam modification of the bacteraemic profile and its relationship with mortality in a pneumococcal mouse sepsis model.Yuste J, Jado I, Fenoll A, Aguilar L, Giménez MJ, Casal J.Centro Nacional de Microbiología, Instituto de Salud Carlos III, Ctra. Majadahonda-Pozuelo, Km. 2, 28220 Majadahonda, Madrid, Spain. A sepsis BALB/c mice model was used to investigate the relationship between mortality and the bacteraemic profile produced by a serotype 6B Streptococcus pneumoniae clinical isolate (MIC/MBC of amoxicillin 4/4 mg/L and of cefotaxime 2/4 mg/L). Animals were treated subcutaneously with doses of amoxicillin or cefotaxime ranging from 6.25 to 50 mg/kg tds for 48 h, starting 1 h after intraperitoneal inoculation (2 x 10(7) cfu/mouse). Blood cultures were carried out daily over 15 days. A survival rate of 100% was obtained with amoxicillin 25 mg/kg and of 60% with cefotaxime 50 mg/kg. A statistically significant (P = 0.012) relationship was found between the maximum cfu/mL in blood and mortality. A maximum log cfu/mL of 6.5 was associated with an 84% probability of death. |
| PMID: 11815576 [PubMed - indexed for MEDLINE] | |
| Related articles Free article | |
| | |
Publication Types:
MeSH Terms:
Substances:
|
| 108. | Transfus Med Rev. 2002 Jan;16(1):11-24.Myeloid hematopoietic growth factors and their role in prevention and/or treatment of neonatal sepsis.Parravicini E, van de Ven C, Anderson L, Cairo MS.Divisions of Pediatric Oncology and Neonatology, Department of Pediatrics, Columbia University, New York, NY, USA. Sepsis continues to be an important cause of morbidity and mortality among both full-term and preterm infants, secondary to an immaturity in neonatal host defense. The incidence of neonatal sepsis ranges from 30% in very low birth weight infants to 0.4% in preterm neonates and 0.1% in term neonates. The dysregulation of the expression and production of hematopoietic cytokines in the neonate contributes to quantitative and qualitative deficiencies in neonatal myeloid progenitor activity and decreased availability and function of mature effector neutrophils. These abnormalities contribute in large part to the increased incidence and mortality associated with neonatal sepsis. In this review, we have summarized and analyzed the studies investigating the dysregulation, expression and production of myelopoietic growth factors in neonates, the preclinical in vivo effects of myelopoietic growth factors in neonatal animals, the preclinical in vivo effects of myelopoietic growth factors during experimental sepsis in neonatal animals, the in vitro effects of growth factors on human neonatal phagocytic immunity, and clinical results of myelopoietic growth factors in human neonates. Future studies should be focused on investigating other abnormalities of neonatal host defense and multiple and simultaneous approaches to circumvent identified defects to attempt to reduce both the incidence and severity of neonatal host defense. Copyright 2002 by W.B. Saunders Company |
| PMID: 11788926 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
Publication Types:
MeSH Terms:
Substances:
|
| 109. | Clin Microbiol Rev. 2002 Jan;15(1):95-110.Modulation of release of proinflammatory bacterial compounds by antibacterials: potential impact on course of inflammation and outcome in sepsis and meningitis.Nau R, Eiffert H.Department of Neurology, University of Goettingen, Goettingen, Germany. rnau@gwdg.de Several bacterial components (endotoxin, teichoic and lipoteichoic acids, peptidoglycan, DNA, and others) can induce or enhance inflammation and may be directly toxic for eukaryotic cells. Bactericidal antibiotics which inhibit bacterial protein synthesis release smaller quantities of proinflammatory/toxic bacterial compounds than B-lactams and other cell wall-active drugs. Among the B-lactams, compounds binding to penicillin-binding protein 2 (PBP-2) release smaller amounts of bacterial substances than antibacterials inhibiting PBP-3. Generally, high antibiotic concentrations (more than 10 times the MIC) induce the release of fewer bacterial proinflammatory/toxic compounds than concentrations close to the MIC. In several in vitro and in vivo systems, bacteria treated with protein synthesis inhibitors or B-lactams inhibiting PBP-2 induce less inflammation than bacteria treated with PBP-3-active B-lactams. In mouse models of Escherichia coli peritonitis sepsis and of Streptococcus pneumoniae meningitis, lower release of proinflammatory bacterial compounds was associated with reduced mortality. In conclusion, sufficient evidence for the validity of the concept of modulating the release of proinflammatory bacterial compounds by antibacterials has been accumulated in vitro and in animal experiments to justify clinical trials in sepsis and meningitis. A properly conducted study addressing the potential benefit of bacterial protein synthesis inhibitors versus B-lactam antibiotics will require both strict selection and inclusion of a large number of patients. The benefit of this approach should be greatest in patients with a high bacterial load. PMCID: PMC118062 |
| PMID: 11781269 [PubMed - indexed for MEDLINE] | |
| Related articles Free article | |
 | |
Publication Types:
MeSH Terms:
Substances:
|
| 110. | Pharmacol Ther. 2001 Sep;91(3):179-213.Is nitric oxide overproduction the target of choice for the management of septic shock?Feihl F, Waeber B, Liaudet L.Division of Pathophysiology and Medical Teaching, Department of Internal Medicine, University Hospital, PPA, BH19-317, CHUV, CH 1011 Lausanne, Switzerland. Francois.Feihl@chuv.hospvd.ch Sepsis is a heterogeneous class of syndromes caused by a systemic inflammatory response to infection. Septic shock, a severe form of sepsis, is associated with the development of progressive damage in multiple organs, and is a leading cause of patient mortality in intensive care units. Despite important advances in understanding its pathophysiology, therapy remains largely symptomatic and supportive. A decade ago, the overproduction of nitric oxide (NO) had been discovered as a potentially important event in this condition. As a result, great hopes arose that the pharmacological inhibition of NO synthesis could be developed into an efficient, mechanism-based therapeutic approach. Since then, an extraordinary effort by the scientific community has brought a deeper insight regarding the feasibility of this goal. Here we present in summary form the present state of knowledge of the biological chemistry and physiology of NO. We then proceed to a systematic review of experimental and clinical data, indicating an up-regulation of NO production in septic shock; information on the role of NO in septic shock, as provided by experiments in transgenic mice that lack the ability to up-regulate NO production; effects of pharmacological inhibitors of NO production in various experimental models of septic shock; and relevant clinical experience. The accrued evidence suggests that the contribution of NO to the pathophysiology of septic shock is highly heterogeneous and, therefore, difficult to target therapeutically without appropriate monitoring tools, which do not exist at present. |
| PMID: 11744067 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
Publication Types:
MeSH Terms:
Substances:
|
| 111. | Am J Respir Crit Care Med. 2001 Oct 1;164(7):1213-20.Inosine reduces systemic inflammation and improves survival in septic shock induced by cecal ligation and puncture.Liaudet L, Mabley JG, Soriano FG, Pacher P, Marton A, Haskó G, Szabó C.Inotek Corporation, Beverly, Massachusetts 01915, USA. Inosine is a naturally occurring purine formed from the breakdown of adenosine. Here we have evaluated the effects of inosine in a murine model of polymicrobial sepsis induced by cecal ligation and puncture (CLP). Mice subjected to CLP were treated with either inosine (100 mg/kg, intraperitoneally) or vehicle 1 h before and 6 h after CLP. After 12 h tumor necrosis factor alpha, interleukin 6 (IL-6), and IL-10 were measured in plasma. Biochemical markers of organ damage, liver NAD+/NADH (indicator of the mitochondrial redox state), plasma nitrate, tissue myeloperoxidase (MPO, indicator of neutrophil accumulation) and malondialdehyde (MDA, indicator of lipid peroxidation), liver and lung chemokines (macrophage inflammatory protein 1alpha [MIP-1alpha] and MIP-2), and ex vivo vascular reactivity in aortic rings were also measured. Mice treated with inosine had significantly lower levels of circulating cytokines. Organ damage was significantly reduced by inosine treatment, which was associated at the tissue level with an increased hepatic NAD+/NADH ratio, decreased MPO activity in the lung, reduced MDA formation in the gut and liver, and decreased MIP-1alpha and MIP-2 in the lung and liver. Furthermore, inosine significantly improved endothelium-dependent relaxant responses of aortic rings. These effects were associated with significant improvement of the survival of CLP mice treated with inosine, an effect that was still observed when inosine treatment was delayed 1 h after CLP, especially when it was associated with appropriate antibiotic treatment. Thus, inosine reduced systemic inflammation, organ damage, tissue dysoxia, and vascular dysfunction, resulting in improved survival in septic shock. |
| PMID: 11673212 [PubMed - indexed for MEDLINE] | |
| Related articles Free article | |
| | |
Publication Types:
MeSH Terms:
Substances:
Grant Support:
|
| 112. | Am J Physiol Lung Cell Mol Physiol. 2001 Sep;281(3):L537-43.Selective inhibition of COX-2 improves early survival in murine endotoxemia but not in bacterial peritonitis.Reddy RC, Chen GH, Tateda K, Tsai WC, Phare SM, Mancuso P, Peters-Golden M, Standiford TJ.Division of Pulmonary and Critical Care Medicine, Department of Medicine, The University of Michigan Medical School, Ann Arbor, Michigan 48109-0360, USA. Comment in: Prostaglandins of the E series are believed to act as important mediators of several pathophysiological events that occur in sepsis. Studies were performed to evaluate the effect of cyclooxygenase (COX)-2-specific inhibition on the outcome in murine endotoxemia and cecal ligation and puncture (CLP). We observed a significant time-dependent upregulation of PGE(2) production in both blood and lung homogenates of mice administered lipopolysaccharide intraperitoneally, which was nearly completely suppressed by the administration of the COX-2 inhibitor NS-398. Treatment with NS-398 significantly improved early but not late survival in lipopolysaccharide-challenged mice. On the contrary, elevated PGE(2) levels were found in bronchoalveolar lavage fluid but not in plasma of mice subjected to CLP (21 gauge). Pretreatment with NS-398 failed to significantly improve survival in CLP mice. No significant differences were noted in plasma or lung homogenate proinflammatory cytokine levels or lung neutrophil sequestration between the NS-398-treated and control groups. These results demonstrate that selective COX-2 inhibition confers early but not long-term benefits without affecting the expression of proinflammatory cytokines or the development of lung inflammation. |
| PMID: 11504678 [PubMed - indexed for MEDLINE] | |
| Related articles Free article | |
| | |
Publication Types:
MeSH Terms:
Substances:
Grant Support:
|
| 113. | Microbes Infect. 2001 Jun;3(7):527-34.Impact of transcription factors AP-1 and NF-kappaB on the outcome of experimental Staphylococcus aureus arthritis and sepsis.Gjertsson I, Hultgren OH, Collins LV, Pettersson S, Tarkowski A.Department of Rheumatology, University of Göteborg, Guldhedsgatan 10A, S-413 46 Göteborg, Sweden. inger.gjertsson@rheuma.gu.se Staphylococcus aureus infection is, despite adequate antibiotic treatment, a disease characterized by high mortality. The bacterium triggers an exaggerated immune response in the host, which on the one hand acts as an efficient defense, but on the other hand gives rise to tissue damage. In this study we have modulated the hosts response to S. aureus by inhibition of nuclear factor kappaB (NF-kappaB) and activator protein-1 (AP-1)-triggered release of pro-inflammatory cytokines and tissue-destructive proteins, respectively. Mice were administered with antisense oligonucleotides (ODN) to the p65 subunit of NF-kappaB and/or a double-stranded oligonucleotide (mCoAP-1) with homology to the murine AP-1 binding site of collagenase IV gene (metalloproteinase-9; MMP-9), solely or in combination with antibiotics. In mice systemically treated with antisense ODN to NF-kappaB p65 alone, the bacterial burden in the kidneys was significantly increased (P = 0.04) The same tendency was seen when mCoAP-1 was administered either alone or in combination with antibiotics. We also found significantly (P = 0.04) elevated levels of IL-6 in p65 antisense treated mice. Surprisingly, this p65 antisense therapy approach, which has turned out to be highly efficient in amelioration of aseptic arthritis and colitis, failed to change the clinical course of either septic arthritis or sepsis. We suggest that interaction with transcription factors leads to increased bacterial burden in vivo, abrogating the potential benefits of the anti-inflammatory properties exerted by these compounds. |
| PMID: 11418326 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
Publication Types:
MeSH Terms:
Substances:
|
| 114. | Acta Med Okayama. 2001 Apr;55(2):105-15.Protection of mice from LPS-induced shock by CD14 antisense oligonucleotide.Furusako S, Takahashi T, Mori S, Takahashi Y, Tsuda T, Namba M, Mochizuki H.Research Center, Mochida Pharmaceutical Co., Ltd., Shizuoka 412-8524, Japan. CD14 is a pattern recognition receptor on myeloid cells and plays a pivotal role in an innate immune system that is responsible for Gram-negative and Gram-positive bacteria infection. Lipopolysaccharide (LPS), a cell wall component of Gram-negative bacteria, can induce production of a large quantity of proinflammatory cytokines into the circulation mediated by CD14-mediated macrophages and monocytes. These cytokines eventually cause septic shock. Several in vitro and in vivo studies have shown that suppression of a CD14 function by a CD14 antibody led to an inhibition of the production of proinflammatory cytokines such as TNF-alpha, IL-1 beta, and IL-8. In the present study, we found that CD14 antisense oligonucleotide (ODN) can prevent lethal LPS shock in D-galactosamine-sensitized mice. This ODN inhibited CD14 expression in a mouse macrophage cell line, RAW264.7, and suppressed production of TNF-alpha in LPS-stimulated RAW264.7 cells. Furthermore, we designed a consensus antisense ODN that could hybridize human and mouse CD14 RNA, and we evaluated its efficacy. The consensus antisense ODN rescued mice primed with Mycobacterium bovis bacillus Calmette-Guerin (BCG) from the LPS-induced lethal shock. In this model, the CD14 antisense ODN down-regulated LPS-elicited CD14 expression in the liver, resulting in a decrease in LPS-induced TNF-alpha production. These findings suggest that the CD14 antisense ODN is distributed in the liver and efficiently suppresses LPS-induced TNF-alpha production by reducing CD14 expression on Kupffer cells. This CD14 antisense ODN may be useful for the development of a therapeutic agent against sepsis and septic shock. |
| PMID: 11332197 [PubMed - indexed for MEDLINE] | |
| Related articles Free article | |
 | |
MeSH Terms:
Substances:
|
| 115. | Crit Care Med. 2001 Feb;29(2):380-4.Dehydroepiandrosterone decreases mortality rate and improves cellular immune function during polymicrobial sepsis.Oberbeck R, Dahlweid M, Koch R, van Griensven M, Emmendörfer A, Tscherne H, Pape HC.Department of Trauma Surgery, University Hospital of Essen, Essen, Germany. Comment in: OBJECTIVE: Sepsis is associated with a marked depression of cellular immune function. The steroid hormone dehydroepiandrosterone (DHEA) is proposed to have immunoenhancing activities. We, therefore, investigated the effect of DHEA on the mortality rate and cellular immune functions in an experimental model of sepsis. DESIGN: Randomized animal study. SETTING: Level I trauma center, university research laboratory. SUBJECTS: Male NMRI mice. INTERVENTIONS: Mice were subjected to laparotomy (sham) or cecal ligation and puncture (CLP). Mice were treated with (sham/DHEA; CLP/DHEA) or without (sham; CLP) the steroid hormone DHEA (30 mg/kg sc). Animals were killed 48 hrs after the onset of sepsis. MEASUREMENTS AND MAIN RESULTS: The survival rate of septic mice was determined 24 and 48 hrs after onset of sepsis. Forty-eight hours after the septic challenge, a white blood cell count was performed and serum tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta concentrations were monitored using ELISA. Furthermore, the delayed type of hypersensitivity (DTH) reaction was evaluated on the basis of ear pinna swelling after dinitrofluorobenzene (DNFB) administration, and clinical variables (body weight, temperature, heart rate, fluid input/output, food intake) were monitored using metabolic cages. DHEA administration improved the survival rate (87% vs. 53% after 48 hrs; p <.001). This was accompanied by a restoration of the depressed DTH reaction and a reduction in TNF-alpha serum concentrations (20.7 +/- 1.4 pg/mL vs. 32.4 +/- 6.6 pg/mL). CONCLUSIONS: These results demonstrate that DHEA administration leads to an increased survival following a septic challenge. The immunoenhancing effect of DHEA is accompanied by a reduction of TNF-alpha release and an improved activity of T-cellular immunity. DHEA administration may, therefore, be beneficial in systemic inflammation. |
| PMID: 11246320 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
Publication Types:
MeSH Terms:
Substances:
|
| 116. | Crit Care Med. 2001 Jan;29(1):13-7.The activity of tissue factor pathway inhibitor in experimental models of superantigen-induced shock and polymicrobial intra-abdominal sepsis.Opal SM, Palardy JE, Parejo NA, Creasey AA.Brown University School of Medicine, Providence, RI, USA. steven_opal@brown.edu Comment in: OBJECTIVES: To study recombinant human tissue factor pathway inhibitor (rhTFPI) in a superantigen-induced shock model and in a cecal ligation and puncture (CLP) model of peritonitis in mice. DESIGN: Prospective, randomized, experimental study. SETTING: An experimental animal research laboratory. SUBJECTS: Eighty BALB/c mice for the superantigen model, and 56 BALB/c mice for the CLP model. INTERVENTIONS: In the superantigen-induced shock model, animals received rhTFPI (350 mg/kg) subcutaneously every 12 hrs (n = 30) or saline control (n = 30) for 60 hrs after staphylococcal enterotoxin B (SEB; 10 microg iv) and a sublethal dose of E. coli 0111:B4 lipopolysaccharide (LPS; 75 microg ip). Control groups received SEB alone (n = 10) and LPS alone (n = 10). In the CLP model, rhTFPI or saline was given every 8 hrs for 48 hrs by using a 21-gauge needle (n = 9) or 23-gauge needle (n = 14) for CLP. A sham surgery control group (n = 10) was also included. MEASUREMENTS AND MAIN RESULTS: There was 0% mortality in the SEB and LPS control groups. The mortality rate was 64% in the saline control group that received both SEB and LPS (19 of 30), whereas the rhTFPI- treated animals had a mortality rate of 20% (6 of 30; p < .01). The rhTFPI-treated group had significantly lower interleukin-6 levels (61.8 +/- 41 pg/mL vs. 285 +/- 63 pg/mL; p < .05) than the control group but no differences in tumor necrosis factor-alpha or interferon-gamma levels. In the CLP experiment, rhTFPI-treated animals did not have any survival advantage over the control group after the large-bore (21-gauge) needle puncture. The rhTFPI group had significantly improved 7-day mortality rate after CLP with the small-bore needle (23-gauge; 21.4% [rhTFPI] vs. 71.4% [control], p < .01). Plasma LPS, interleukin-6, interferon-gamma, and tumor necrosis factor-alpha levels were unchanged by rhTFPI treatment, but significantly reduced LPS (p = .006) and IFNgamma (p = .001) levels were found in the peritoneal fluid. CONCLUSIONS: Tissue factor pathway inhibitor significantly improves the mortality rate in models of superantigen-induced shock and polymicrobial intra-abdominal infection, supporting its potential use in clinical trials for septic shock. |
| PMID: 11176151 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
Publication Types:
MeSH Terms:
Substances:
|
| 117. | J Lab Clin Med. 2001 Jan;137(1):28-37.Effects of zinc acetate on splenocytes of endotoxemic mice: enhanced immune response, reduced apoptosis, and increased expression of heat shock protein 70.Unoshima M, Nishizono A, Takita-Sonoda Y, Iwasaka H, Noguchi T.Departments of Anesthesiology and Microbiology, Oita Medical University, Japan. Immune function is markedly attenuated in endotoxemia. Zinc is involved in the regulation of cellular functions and maintenance of immune function, and its level in the serum is low in endotoxemia. We mainly investigated the effects of zinc acetate (ZA) on splenocytes in mice with endotoxemia. After we confirmed increased plasma zinc level by ZA treatment, C57BL/6 mice were randomly divided into four groups: 10 control mice received 500 microL saline solution as vehicle; 10 control mice received ZA at 3 mg/kg body weight; 20 endotoxemic mice received a 40 mg/kg lethal dose of lipopolysaccharide (LPS); 20 mice received ZA followed by LPS as the above dose. In vivo, we confirmed that ZA pretreatment did not significantly affect the plasma cytokine level in endotoxemic mice. In vitro, splenocytes from ZA-plus-LPS mice showed drastic effects, in that ZA abrogated LPS-induced suppression of cellular proliferation and production of interleukin-2 and interferon-gamma. The percentage of apoptotic splenocytes was significantly reduced in ZA-plus-LPS mice (23.4%) as compared with LPS mice (41.6%). Furthermore, the expression of HSP-70 mRNA in splenocytes was strongly enhanced in both ZA and ZA-plus-LPS mice, especially in the latter group. Finally, studies monitoring survival rates for 6 days showed that LPS caused 100% mortality while ZA-plus-LPS mice showed 75% survival. Our results suggest that zinc normalized the immune response and reduced apoptosis of splenocytes. These changes were probably caused by increased synthesis of HSP-70 by splenocytes, which might enhance survival of mice with LPS-induced endotoxemia. |
| PMID: 11150021 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
MeSH Terms:
Substances:
|
| 118. | J Pharmacol Exp Ther. 2000 Sep;294(3):1043-6.Cerivastatin improves survival of mice with lipopolysaccharide-induced sepsis.Ando H, Takamura T, Ota T, Nagai Y, Kobayashi K.The First Department of Internal Medicine, School of Medicine, Kanazawa University, Japan. Development of severe sepsis is thought to result from the overproduction of cytokines, such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta), and nitric oxide. Recently, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, which are antihypercholesterolemic agents, have been reported to inhibit lipopolysaccharide (LPS)-induced production of cytokines and nitric oxide in vitro. In this study, we tested these effects in vivo. After LPS administration (15 mg/kg i.p.) to CD-1 mice, serum levels of both TNF-alpha and IL-1beta transiently increased, and peaked at 2 h. After the peak responses of TNF-alpha and IL-1beta, serum levels of nitrite and nitrate increased until at least 8 h. Pretreatment of the mice with cerivastatin (20 mg/kg i.p. 12 and 1 h before LPS injection) reduced serum levels of TNF-alpha and IL-1beta at 2 h, and nitrite and nitrate at 8 h, by 93, 60, and 44%, respectively. In this model of sepsis, cerivastatin significantly (P =.016) improved the rate of 7-day survival from 26.7 to 73.3%. These results cast new light on the usefulness of cerivastatin in preventing severe sepsis. |
| PMID: 10945857 [PubMed - indexed for MEDLINE] | |
| Related articles Free article | |
| | |
MeSH Terms:
Substances:
|
| 119. | Shock. 2000 Jul;14(1):60-7.Terbutaline prevents circulatory failure and mitigates mortality in rodents with endotoxemia.Wu CC, Liao MH, Chen SJ, Chou TC, Chen A, Yen MH.Department of Pharmacology, National Defense Medical Center, Taipei, ROC, Taiwan. Septic shock is characterized by a decrease in systemic vascular resistance. Nevertheless, regional increases in vascular resistance can occur that may predispose mammals to organ dysfunction, including the acute respiratory distress syndrome. In the host infected by endotoxin (lipopolysaccharide, LPS), the expression and release of proinflammatory tumor necrosis factor-alpha (TNFalpha) rapidly increases, and this cytokine production is regulated by agents elevating cyclic AMP. In this report, we present evidence that terbutaline, a beta2-agonist, inhibits TNFalpha production and enhances interleukin-10 (IL-10) release in the anesthetized rat treated with LPS. In addition, an overproduction of nitric oxide (NO, examined by its metabolites nitrite/nitrate) by inducible NO synthase (iNOS, examined by western blot analysis) is attenuated by pretreatment of LPS rats with terbutaline. Overall, pretreatment of rats with terbutaline attenuates the delayed hypotension and prevents vascular hyporeactivity to norepinephrine. In addition, pretreatment of mice with terbutaline also improves the survival in a model of severe endotoxemia. The infiltration of polymorphonuclear neutrophils into organs (e.g., lung and liver) from the surviving LPS mice treated with terbutaline was reduced almost to that seen in the normal controls. These findings suggest that the inhibition of TNFalpha and NO (via iNOS) production as well as the increment of IL-10 production contribute to the beneficial effect of terbutaline in animals with endotoxic shock. |
| PMID: 10909895 [PubMed - indexed for MEDLINE] | |
| Related articles | |
Publication Types:
MeSH Terms:
Substances:
|
| 120. | Int J Immunopharmacol. 2000 Jan;22(1):83-90.Influence of pyrrolidine dithiocarbamate on the inflammatory response in macrophages and mouse endotoxin shock.Meisner M, Schmidt J, Schywalsky M, Tschaikowsky K.Department of Anesthesiology, University of Jena, Bachstr. 18, D-07743, Jena, Germany. meisner@anae1.med.uni-jena.de To analyze the immunomodulatory effect of pyrrolidine dithiocarbamate (PDTC) on the endotoxin (LPS) stimulated inflammatory response, we measured the LPS-stimulated cytokine and NO production in murine peritoneal macrophages, J774A.1 cells and human whole blood in the presence of PDTC (60 microM). PDTC significantly inhibited the production of nitrite, IL-1beta and IL-6 in these cells. TNFalpha release was stimulated in murine cells, but suppressed in human whole blood. We further investigated the influence of PDTC on mortality and cytokine release in mouse endotoxin shock. PDTC was i.p. injected 30 min prior to the induction of endotoxin shock in female NMRI-mice and survival was significantly improved as compared to controls (48% vs 20%, n=25 per group). Plasma concentrations of TNFalpha were slightly augmented while IL-6 levels were decreased in PDTC-treated animals as compared to controls, however, without reaching significance. We conclude that PDTC is a potent immunomodulatory substance that modulates the inflammatory response in vitro and reduces mortality in mouse endotoxin shock. The pathophysiological mechanisms of the protective effect of PDTC in vivo, however, appears to be pluripotent, comprising both antioxidative properties and the inhibition of NF-kB. |
| PMID: 10684991 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
Publication Types:
MeSH Terms:
Substances:
|
| 121. | Shock. 2000 Feb;13(2):160-5.Suppression of lethal toxicity of endotoxin by biscoclaurine alkaloid cepharanthin.Maruyama H, Kikuchi S, Kawaguchi K, Hasunuma R, Ono M, Ohbu M, Kumazawa Y.Department of Pathology, School of Allied Health Sciences, School of Pharmaceutical Sciences, Kitasato University, Sagamihara, Japan. Suppressive effects of Cepharanthin (CE) on lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNFalpha) production followed by liver injury were investigated. Pretreatment with CE reduced limulus activity of LPS. Intraperitoneal treatment with CE 10 min before an i.v. challenge of LPS resulted in protection from LPS lethality in D-galactosamine (GalN)-sensitized BALB/c but not in C57BL/6 and C57BL/10ScSn mice. Treatment with CE before the LPS challenge significantly reduced serum TNF levels in a dose-dependent manner. The suppression was most effective when CE was administered 10 min before the LPS challenge. Increased levels of enzymes released from hepatocytes into the circulation, as a result of LPS-induced liver injury, were reduced by CE administration. Histological evaluation demonstrated that massive cell infiltration after severe injury developed in liver of mice injected with LPS plus D-GalN unless they were pretreated with CE. Apoptotic cells decreased by treatment with CE. Treatment with CE retarded lethal shock induced by an infection with 10(8) CFU Salmonella typhimurium deltaaroA mutant. These results suggest that action of CE is initiated through suppression of LPS-induced TNF production. |
| PMID: 10670847 [PubMed - indexed for MEDLINE] | |
| Related articles | |
MeSH Terms:
Substances:
|
| 122. | Immunopharmacology. 2000 Jan;46(1):89-101.Ascorbic acid modulates in vitro the function of macrophages from mice with endotoxic shock.Victor VV, Guayerbas N, Puerto M, Medina S, De la Fuente M.Department of Animal Physiology, Faculty of Biological Sciences, Complutense University, Madrid, Spain. The toxic effects of oxygen radicals produced by immune cells can be controlled to certain degree by endogenous antioxidants because of their scavenger action. This control is specially important in a type of immune cell, i.e., the phagocyte, which produces oxygen-free radicals and uses antioxidants in order to support its functions. Antioxidants, such as ascorbic acid (AA), are free radical scavengers and improve the immune response. In the pathogenesis of endotoxic shock, a disease with high mortality caused by gram-negative bacterial endotoxin, the reactive oxygen species (ROS) produced by phagocytes have been implicated. In a previous study, we observed in peritoneal macrophages from BALB/c mice suffering lethal endotoxic shock caused by intraperitoneal (i.p.) injection of Escherichia coli lipopolysaccharide (LPS; 100 mg/kg) a high production of superoxide anion. Therefore, in the present work, we have studied the in vitro effect of AA, at different concentrations (0.001, 0.01, 0.1, 1 and 2.5 mM), on the various steps of the phagocytic process, i.e., adherence to substrate, chemotaxis, ingestion of particles and superoxide anion production of murine peritoneal macrophages obtained from BALB/c mice with that of endotoxic shock, at 2, 4, 12 and 24 h after LPS injection. The increased adherence, ingestion and superoxide anion production by macrophages from animals with endotoxic shock were lower in the presence of AA, reaching similar values to those of the control animals. The most effective AA concentration in cells from mice with endotoxic shock was 0.01 mM. These data suggest that AA can regulate the phagocytic process in endotoxic shock, principally decreasing free radical production and thus it could reduce endotoxic shock severity. |
| PMID: 10665783 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
Publication Types:
MeSH Terms:
Substances:
|
| 123. | Mol Med. 1999 Sep;5(9):585-94.Peptidomimetic fluoromethylketone rescues mice from lethal endotoxic shock.Grobmyer SR, Armstrong RC, Nicholson SC, Gabay C, Arend WP, Potter SH, Melchior M, Fritz LC, Nathan CF.Department of Surgery, Weill Medical College of Cornell University, New York, New York 10021, USA. BACKGROUND: Septic shock is a leading cause of mortality in intensive care units. No new interventions in the last 20 years have made a substantial impact on the outcome of patients with septic shock. Identification of inhibitable pathways that mediate death in shock is an important goal. MATERIALS AND METHODS: Two novel caspase inhibitors, (2-indolyl)-carbonyl-Ala-Asp-fluoromethylketone (IDN 1529) and (1-methyl-3-methyl-2-indolyl)-carbonyl-Val-Asp-fluoromethylketone (IDN 1965), were studied in a murine model of endotoxic shock. RESULTS: IDN 1529 prolonged survival when given before or up to 3 hr after high-dose LPS (p < 0.01) and increased by 2.2-fold the number of animals surviving longterm after a lower dose of LPS (p < 0.01). Despite its similar chemical structure, IDN 1965 lacked these protective effects. Both compounds inhibited caspases 1, 2, 3, 6, 8, and 9, and both afforded comparable reduction in Fas- and LPS-induced caspase 3-like activity and apoptosis. Paradoxically, administration of IDN 1529 but not IDN 1965 led to an increase in the LPS-induced elevation of serum cytokines related directly (IL-1beta, IL-18) or indirectly (IL-1alpha, IL-1Ra) to the action of caspase 1. CONCLUSIONS: A process that appears to be distinct from both apoptosis and the release of inflammatory cytokines is a late-acting requirement for lethality in endotoxic shock. Inhibition of this process can rescue mice even when therapy is initiated after LPS has made the mice severely ill. PMCID: PMC2230465 |
| PMID: 10551900 [PubMed - indexed for MEDLINE] | |
| Related articles Free article | |
| | |
Publication Types:
MeSH Terms:
Substances:
Grant Support:
|
| 124. | Surgery. 1999 Jul;126(1):54-65.Inhibiting early activation of tissue nuclear factor-kappa B and nuclear factor interleukin 6 with (1-->3)-beta-D-glucan increases long-term survival in polymicrobial sepsis.Williams DL, Ha T, Li C, Kalbfleisch JH, Laffan JJ, Ferguson DA.Department of Surgery, James H. Quillen College of Medicine, East Tennessee State University, Johnson City 37604-0575, USA. BACKGROUND: Recent data implicate the activation of nuclear factor-kappa B (NF-kappa B) and nuclear factor interleukin 6 (NF-IL6) as important steps in the pathophysiologic mechanisms of adult respiratory distress syndrome and systemic inflammatory response syndrome. METHODS: This study evaluated the effect of immunomodulating polysaccharides on transcription factor activation, cytokine expression, and mortality in a murine cecal ligation and puncture (CLP) model. ICR/HSD mice were treated with glucan (50 mg/kg) 1 hour before or 15 minutes after CLP. Liver and lung tissue were harvested at 3 hours and mortality trends were observed for 20 days. RESULTS: CLP increased liver and lung NF-kappa B and NF-IL6 nuclear binding activity as well as tumor necrosis factor-alpha and interleukin 6 messenger RNA levels at 3 hours. Pretreatment or posttreatment with glucans inhibited tissue NF-kappa B and NF-IL6 nuclear binding activity and tissue cytokine messenger RNA levels. Prophylaxis with glucan phosphate or scleroglucan increased (P < .001) long-term survival (20% CLP vs 65% glucan phosphate, 75% scleroglucan). Posttreatment with glucan phosphate also increased (P < .05) long-term survival (20% vs 65%). CONCLUSIONS: Pretreatment or posttreatment with biologic response modifiers decreased tissue transcription factor nuclear binding activity and cytokine message in liver and lung of septic mice. Inhibiting early transcription factor activation and cytokine message expression correlates with improved outcome in polymicrobial sepsis as denoted by increased long-term survival. |
| PMID: 10418593 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
Publication Types:
MeSH Terms:
Substances:
Grant Support:
|
| 125. | Cytokine. 1999 May;11(5):366-72.Paradoxical synergistic effects of tumour necrosis factor and interleukin 1 in murine gut-derived sepsis with Pseudomonas aeruginosa.Matsumoto T, Tateda K, Miyazaki S, Furuya N, Ohno A, Ishii Y, Hirakata Y, Yamaguchi K.Department of Microbiology, Toho University School of Medicine, Omori-Nishi, Ota-ku, Tokyo, Japan. tetsu@med.toho-u.ac.jp The authors evaluated the synergistic effect of tumour necrosis factor (TNF) and interleukin 1 (IL-1) in gut-derived sepsis in mice. After colonization of Pseudomonas aeruginosa strain D4 in the gastrointestinal tract, cyclophosphamide was administered to induce bacterial translocation of the P. aeruginosa and thereby to cause gut-derived sepsis. In this model, treatment either with 8 microg/kg of recombinant human TNF-alpha (rhTNF-alpha) or 2 microg/kg of recombinant human interleukin 1alpha (rhIL-1alpha) solely did not affect the mortality, whereas combined administration of the same doses of rhTNF-alpha and rhIL-1alpha significantly increased the mortality rate in comparison with saline-treated mice. Bacterial counts in liver and blood were significantly higher in rhTNF-alpha and rhIL-1alpha treated mice than in saline-treated mice. Endogenous TNF-alpha and IL-1beta productions were stimulated after combined treatment with rhTNF-alpha and rhIL-1alpha. On the contrary to these adverse effects, combined treatment with 500 microg/kg of rhTNF-alpha and 50 microg/kg of rhIL-1alpha on the day before the administration of cyclophosphamide significantly reduced the mortality from septic infection. We conclude that TNF and IL-1 synergistically affect the mortality of mice after gut-derived sepsis due to P. aeruginosa in mice and the timing of treatment with these cytokines causes both extremes in their effects. Copyright 1999 Academic Press. |
| PMID: 10328876 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
Publication Types:
MeSH Terms:
Substances:
|
| 126. | Shock. 1999 Apr;11(4):264-8.Diethyldithiocarbamate prolongs survival of mice in a lipopolysaccharide-induced endotoxic shock model: evidence for multiple mechanisms.Kishnani NS, Tabrizi-Fard MA, Fung HL.Department of Pharmaceutics, School of Pharmacy, State University of New York at Buffalo, 14260-1200, USA. Comment in: It is now known that overproduction of nitric oxide (NO) by nitric oxide synthase (NOS) is an important contributing factor for the development of cardiovascular collapse and subsequent death in endotoxic shock. Diethyldithiocarbamate (DETC) is a molecular scavenger of NO and can inhibit overexpression of a number of cytokines during shock through inactivation of transcription factors such as nuclear factor (NF)-kappaB. Thus, DETC may be a useful adjunct in the therapy of endotoxic shock. In our study, we examined the effect of DETC on survival time in a murine model of severe endotoxic shock. Our results indicated that selected in vivo dosage regimens of DETC (intraperitoneal: at -2, -1, 3, 6, and 10 h or at -2, -1, 3, 6, 9, 12, 15, and 18 h relative to lipopolysaccharide administration, 180 mg/kg, at t = 0) in endotoxic mice were effective in increasing survival time when compared with untreated animals and DETC pretreatment was more effective than methylprednisolone (p<.05). DETC was shown to exert multiple beneficial mechanisms, including 1) a decrease in circulating NO, as determined by plasma nitrite/nitrate levels, 2) a reduction in plasma tumor necrosis factor-alpha after lipopolysaccharide induction, and 3) decreased expressions of metalloproteinases such as gelatinase A and B which may be responsible for cellular release of cytokines. These results indicate that DETC and its analogs may be useful in the treatment of endotoxic shock. |
| PMID: 10220303 [PubMed - indexed for MEDLINE] | |
| Related articles | |
Publication Types:
MeSH Terms:
Substances:
Grant Support:
|
| 127. | Antimicrob Agents Chemother. 1999 Apr;43(4):912-9.Lipopolyamines: novel antiendotoxin compounds that reduce mortality in experimental sepsis caused by gram-negative bacteria.David SA, Silverstein R, Amura CR, Kielian T, Morrison DC.Department of Microbiology, Molecular Genetics and Immunology, University of Kansas Medical Center, Kansas City 66160, USA. sdavid@kumc.edu The interactions of lipopolyamines, a class of structurally unique compounds currently being used as transfection (lipofection) agents, with lipopolysaccharide (LPS) have been characterized. Our studies have demonstrated that 1,3-di-oleoyloxy-2-(6-carboxyspermyl)-propylamide), available commercially as DOSPER, binds to purified LPS with an affinity of about 1/10 that of polymyxin B. This essentially nontoxic compound inhibits, in a dose-dependent manner, LPS-induced activation of the Limulus clotting cascade and the production of tumor necrosis factor alpha (TNF-alpha) interleukin-6 (IL-6), and nitric oxide from LPS-stimulated J774.A1 cells, a murine macrophage-like cell line. Cytokine inhibition is paralleled by decreased steady-state levels of TNF-alpha and IL-6 mRNA and inhibits the nuclear translocation of nuclear factor kappa B. These findings suggest that the lipopolyamine compound sequesters LPS, thereby blocking downstream cellular activation events that lead to the production of proinflammatory mediators. Administration of DOSPER to D-galactosamine-sensitized mice challenged either with LPS or with Escherichia coli organisms provided significant protection against lethality both with and without antibiotic chemotherapy. Partial protection is evident in LPS-challenged mice treated with DOSPER as late as 2 to 4 h following the endotoxin challenge. A greater degree of protection is observed in E. coli-challenged animals receiving ceftazidime than in those receiving imipenem, which is probably attributable to the higher levels of LPS released in vivo by the former antibiotic. Potent antiendotoxic activity, low toxicity, and ease of synthesis render the lipopolyamines candidate endotoxin-sequestering agents of potential significant therapeutic value. PMCID: PMC89225 |
| PMID: 10103199 [PubMed - indexed for MEDLINE] | |
| Related articles Free article | |
| | |
Publication Types:
MeSH Terms:
Substances:
Grant Support:
|
| 128. | Biosci Biotechnol Biochem. 1998 Nov;62(11):2177-81.N2733, 1-[3-(3-pyridyl)-acryloyl]-2-pyrrolidinone hydrochloride inhibits LPS-induced TNF-alpha production and improves survival in endotoxemic mice.Katsuyama K, Kojima R, Yokoyama S, Yanai M, Sueda N, Sugita M, Momose K, Yamada H.Pharmaceutical Research Center, Nisshin Flour Milling Co., Ltd., Saitama, Japan. N2733, 1-[3-(3-pyridyl)-acryloyl]-2-pyrrolidinone hydrochloride, was examined for its effect on TNF-alpha production by human myeloid THP-1 cells stimulated with lipopolysaccharide (LPS). N2733 inhibited LPS-induced release of TNF-alpha from THP-1 cells with an IC50 of 11 microM. N2733 did not affect the cell viability at the concentration of 50 microM or 100 microM. This indicates that N2733 is a potent inhibitor for TNF-alpha production without severe cytotoxicity. N2733 was also studied in two murine endotoxin shock models induced with LPS. One model was DBA/2 mice injected with LPS (5.6 mg/kg, i.v.), which increased the serum level of TNF-alpha within 1 hr. Treatment of these mice with N2733 (100 mg/kg x 2, i.p.) decreased the serum level of TNF-alpha significantly. Another model was DBA/2 mice induced with LPS (30 mg/kg, i.v.), which reduced the survival rate to 30% during 7 days. Administrations of 30 mg/kg and 100 mg/kg N2733 (i.v.) restored the survival rates to 60% and 90% respectively. Our data demonstrate that N2733 inhibits LPS-induced TNF-alpha production, and this response is associated with an improvement in the survival rate of endotoxemic mice. |
| PMID: 9972238 [PubMed - indexed for MEDLINE] | |
| Related articles Free article | |
| | |
MeSH Terms:
Substances:
|
| 129. | J Parasitol. 1998 Dec;84(6):1274-7.Beneficial effect of selenium supplementation during murine infection with Trypanosoma cruzi.Davis CD, Brooks L, Calisi C, Bennett BJ, McElroy DM.Department of Biology, Western Kentucky University, Bowling Green 42101, USA. Selenium (Se) has been shown to function as an antioxidant that may enhance immunity during microbial infection. To investigate the effect of elevated levels of Se on the course of experimental Chagas' disease, 5 groups of C3HeB/FeJ mice were infected with 10(3) bloodform trypomastigotes of a Brazil strain of Trypanosoma cruzi while receiving supplements of 0 ppm, 2 ppm, 4 ppm, 8 ppm, or 16 ppm Se as sodium selenate in drinking water. After 64 days of infection, survival ranged from 0 to 60%, with groups receiving 4 ppm and 8 ppm Se exhibiting 60% survival and the group without Se exhibiting 0% survival. In addition, parasitemia levels of mice supplemented with Se were significantly lower (P<0.01) than in nonsupplemented mice. The results of the present study suggest that Se supplementation does have a beneficial effect during murine infection with T. cruzi, resulting in decreased parasitemias and increased longevity. |
| PMID: 9920329 [PubMed - indexed for MEDLINE] | |
| Related articles | |
Publication Types:
MeSH Terms:
Substances:
|
| 130. | Arch Surg. 1998 Dec;133(12):1281-8.Dehydroepiandrosterone: an inexpensive steroid hormone that decreases the mortality due to sepsis following trauma-induced hemorrhage.Angele MK, Catania RA, Ayala A, Cioffi WG, Bland KI, Chaudry IH.Center for Surgical Research, Department of Surgery, Brown University School of Medicine, Rhode Island Hospital, Providence 02903, USA. BACKGROUND: Recent studies suggest that male sex steroids play a role in producing immunodepression following trauma-hemorrhage. This notion is supported by studies showing that castration of male mice before trauma-hemorrhage or the administration of the androgen receptor blocker flutamide following trauma-hemorrhage in noncastrated animals prevents immunodepression and improves the survival rate of animals subjected to subsequent sepsis. However, it remains unknown whether the most abundant steroid hormone, dehydroepiandrosterone (DHEA), protects or depresses immune functions following trauma-hemorrhage. In this regard, DHEA has been reported to have estrogenic and androgenic properties, depending on the hormonal milieu. OBJECTIVE: To determine whether administration of DHEA after trauma-hemorrhage has any salutary or deleterious effects on immune responses, and whether it improves the survival of animals subjected to subsequent sepsis. DESIGN: Male C3H/HeN mice underwent laparotomy (ie, trauma-induced) and hemorrhagic shock (blood pressure, 35+/-5 mm Hg for 90 minutes) followed by fluid resuscitation, or sham operation. The animals then received 100 mg of DHEA (4 mg/kg) or propylene glycol (hereafter referred to as vehicle). At 24 hours after trauma-hemorrhage and resuscitation, the animals were killed and blood, spleens, and peritoneal macrophages were harvested. Splenocyte proliferation and interleukin (IL) 2 release and splenic and peritoneal macrophage IL-1 and IL-6 release were determined. In a separate set of experiments, sepsis was induced by cecal ligation and puncture at 48 hours after trauma-hemorrhage and resuscitation. For those studies, the animals received vehicle, a single 100-microg dose of DHEA, or 100 microg/d DHEA for 3 days following hemorrhage and resuscitation. Survival was monitored for 10 days after the induction of sepsis. RESULTS: Administration of DHEA restored the depressed splenocyte and macrophage functions at 24 hours after trauma-hemorrhage. Moreover, daily administration of DHEA for 3 days significantly increased the survival of animals subjected to subsequent sepsis (P=.01). CONCLUSION: The finding that DHEA markedly improves the depressed immune functions and survival of animals subjected to subsequent sepsis suggests that short-term treatment with DHEA after trauma-hemorrhage is a safe and novel approach for preventing immunodepression and for decreasing the mortality rate due to subsequent sepsis. |
| PMID: 9865644 [PubMed - indexed for MEDLINE] | |
| Related articles Free article | |
 | |
Publication Types:
MeSH Terms:
Substances:
Grant Support:
|
| 131. | Pharmacol Res. 1998 Nov;38(5):405-11.Effects of nitric oxide synthase inhibition in lipopolysaccharide-induced sepsis in mice.Tunçtan B, Uludag O, Altug S, Abacioglu N.Department of Pharmacology, Faculty of Pharmacy, Gazi University, Ankara, Turkey. In the present study, we have investigated the effects of nitric oxide (NO) synthase inhibition on mortality in lipopolysaccharide (LPS)-induced sepsis in mice. Serum nitrite levels peaked at 15 h after an injection of LPS (10 mg kg-1, i.p.). Aminoguanidine, a selective inducible NO synthase (iNOS) inhibitor, at a dose of 100 mg kg-1 significantly reduced the LPS-induced increase in nitrite levels and improved mortality. Econazole, iNOS inhibitor, calmodulin antagonist, 5-lipoxygenase and a specific thromboxane synthase inhibitor, at a 1 mg kg-1 dose significantly decreased the LPS-induced increase in nitrite levels, but increased mortality 4. 9-fold when compared to the LPS group (control). Indomethacin, a putative iNOS and non-selective cyclo-oxygenase (COX) inhibitor, of 1, 10 and 100 mg kg-1, dose dependently decreased the LPS-induced increase in nitrite levels. This decrease was significantly different from the control at 10 and 100 mg kg-1 dose levels. When indomethacin (100 mg kg-1) was combined with aminoguanidine (100 mg kg-1), LPS-induced nitrite levels were significantly attenuated. NO precursor, L-arginine, was added to this combination in order to test the inhibition of iNOS activity which resulted in no change in nitrite levels. An indomethacin and aminoguanidine combination increased mortality twofold when compared to the control. The addition of L-arginine to the combination enhanced the mortality rate to 1.5-fold. These results suggest that NO appears to play a role in the LPS-induced septic shock model in mice. The improvement in sepsis-induced mortality enhanced by aminoguanidine by the inhibition of iNOS but not with the other agents or combinations should be re-evaluated in order to make an appropriate choice of the therapeutic target. In addition, it may also suggest that other mediators, such as arachidonic acid products and cytokines play a role in septic shock pathogenesis as well. (c) 1998 The Italian Pharmacological Society. |
| PMID: 9806822 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
Publication Types:
MeSH Terms:
Substances:
|
| 132. | Shock. 1998 Aug;10(2):110-7.Antibiotic treatment influences outcome in murine sepsis: mediators of increased morbidity.Newcomb D, Bolgos G, Green L, Remick DG.Department of Pathology, University of Michigan Medical School, Ann Arbor 48109-0602, USA. Different antibiotic treatments may affect the survival and physiological responses of Balb/c mice following cecal ligation and puncture (CLP). The broad spectrum imipenem (IMP) was compared with a triple antibiotic mixture of gentamicin, clindamycin, and ciprofloxacin (3AB). Control mice received injections of 5% dextrose (D5W). After CLP with a 25 gauge needle, Mini-Mitters were implanted to measure temperature and activity. Therapy began with 1 mL injections of antibiotics or D5W 2 h post-CLP and continued every 12 h for 3 days. Survival was higher in IMP mice than in 3AB or D5W mice. Starting with the injection 12 h after CLP, 3AB always induced a profound hypothermic response not observed with D5W or IMP. Nocturnal activity levels were higher in IMP mice compared with 3AB or D5W mice during the first night following CLP. To determine the cause of this hypothermic response and to further investigate the acute effects that antibiotic choice may have on murine physiology, the kinetic appearance of IL-1, IL-6, TNF, and KC as well as lipopolysaccharide (LPS), were measured in the plasma and peritoneum of mice sacrificed at 0, .5, and 1.5 h after antibiotic injection at 24 h post-CLP. Cytokine and LPS concentrations in 3AB mice were not significantly different at any of the three time points when compared with IMP or D5W mice. Our data demonstrate that antibiotic therapy consisting of 3AB produces greater morbidity and mortality compared with therapy consisting of IMP. However, the mechanism of these alterations is not due to elevated systemic levels of cytokines or LPS. |
| PMID: 9721977 [PubMed - indexed for MEDLINE] | |
| Related articles | |
Publication Types:
MeSH Terms:
Substances:
Grant Support:
|
| 133. | Shock. 1998 Jul;10(1):49-53.Pyrrolidine dithiocarbamate augments IL-10, inhibits TNF-alpha, MIP-1alpha, IL-12, and nitric oxide production and protects from the lethal effect of endotoxin.Németh ZH, Haskó G, Vizi ES.Department of Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest. During endotoxemia, immune cells activated by lipopolysaccharide (LPS) produce various inflammatory mediators, including cytokines and nitric oxide (NO). The genes of several mediators are activated in part by the rapid binding of the transcription factor nuclear factor-kappa B (NF-kappaB) to its promoter. The induction of this transcription factor can be blocked by a wide range of antioxidants, including pyrrolidine dithiocarbamate (PDTC). Here we investigated in mice the effect of this compound on the plasma tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), interleukin-1alpha (IL-1alpha), interleukin-6 (IL-6), interleukin-10 (IL-10), interleukin-12 (IL-12), macrophage inflammatory protein-1alpha (MIP-1alpha), and nitric oxide (NO) response to intraperitoneal (i.p.) injection of LPS. Pretreatment of animals with PDTC (10-100 mg/kg) 30 min prior to LPS challenge (4 mg/kg, i.p.) decreased plasma TNF-alpha, IL-12, MIP-1alpha, and nitrite/nitrate (breakdown products of NO) concentrations, but enhanced plasma levels of IL-10. Moreover, pretreatment of mice with PDTC (10-100 mg/kg, i.p.) did not alter LPS-induced (4 mg/kg) production of IL-1alpha, IL-6, and IFN-gamma. Finally, PDTC (100 mg/kg) protected the mice against LPS (100 mg/kg)-induced lethality. These results indicate that blockade of the NF-kappaB pathway by PDTC has potent anti-inflammatory action in systemic inflammatory processes. |
| PMID: 9688091 [PubMed - indexed for MEDLINE] | |
| Related articles | |
Publication Types:
MeSH Terms:
Substances:
|
| 134. | Acta Trop. 1998 Jun;69(3):205-11.Activity of N,N-dimethy-1-2-propen-1-amine derivatives in mice experimentally infected with Trypanosoma cruzi.Pereira DG, de Castro SL, Durán N.Instituto de Química, Universidade Estadual de Campinas, São Paulo, Brazil. Propenamine derivatives 3-(4'-bromo-[1,1'-biphenyl]-4-yl)-3-(4-X-phenyl)-N,N-dimethyl-2-prope n-1-amine (where X = H or Br) were tested in experimentally infected mice with Trypanosoma cruzi (Y strain). When a daily dose of 20 mg kg-1 of the bromo (X = Br) derivative for 9 consecutive days was used, no parasite by optical microscopy was found. Significant parasitemic decrease was also observed with a single dose (100 mg kg-1) of this compound. Moreover, both treatment schemes displayed a strong protective effect characterized by decreased of mortality. On the other hand, similar treatment schedules using the unsubstituted (X = H) derivative led to parasitemic and mortality curves similar to the control group. These results indicate that the bromo derivative has a remarkable activity against T. cruzi infection. Due to the potentiality of this derivative, further investigation of this class of compounds as chemotherapeutic agents for Chagas' disease is of prime importance. |
| PMID: 9638273 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
Publication Types:
MeSH Terms:
Substances:
|
| 135. | Crit Care Med. 1998 May;26(5):895-904.Exogenous interleukin-10 fails to decrease the mortality or morbidity of sepsis.Remick DG, Garg SJ, Newcomb DE, Wollenberg G, Huie TK, Bolgos GL.Department of Pathology, University of Michigan, Ann Arbor 48109-0602, USA. Comment in: OBJECTIVE: To determine if exogenous interleukin (IL)-10 will decrease the morbidity or mortality of sepsis induced by cecal ligation and puncture. DESIGN: Prospective, randomized, controlled study. SETTING: University research laboratory. SUBJECTS: Adult, female, Balb¿c mice. INTERVENTIONS: Balb¿c mice were subjected to cecal ligation and puncture with an 18- or 23-gauge needle and treated with triple antibiotics. Mice were injected subcutaneously with recombinant human IL-10 (diluted in normal saline with 0.1% mouse serum albumin) and followed until death. In a separate experiment, IL-10 was also injected subcutaneously and lipopolysaccharide (LPS) injected intraperitoneally and plasma tumor necrosis factor concentrations measured 90 mins later. MEASUREMENTS AND MAIN RESULTS: In the LPS experiments, IL-10 decreased tumor necrosis factor (TNF) production by nearly 90%. For the cecal ligation and puncture experiments, temperature and movement were recorded continuously via implanted transmitters. Studies on mortality indicated that exogenous IL-10 given at 0, +6 and +12 hrs after surgery failed to increase survival when using an 18-gauge needle (alive:total cecal ligation and puncture alone 4:21; IL-10 10 microg/mouse 2:12; 1 microg/mouse 8:25; 0.1 microg/mouse 1:12) or a 23-gauge needle (cecal ligation and puncture alone 13:29; IL-10 1 microg 18:30). There was no difference in the number of hours to death between the groups. IL-10 did not prevent the hypothermia after cecal ligation and puncture or increase the animals' activity. To examine parameters of inflammation, mice were killed 8 hrs after 18-gauge cecal ligation and puncture. IL-10 (1 microg/mL) failed to reduce pulmonary neutrophil sequestration (lung myeloperoxidase, cecal ligation and puncture 107 +/- 10 [SEM], IL-10 107 +/- 5) or recruitment of neutrophils to the peritoneum (neutrophils x 10(6), cecal ligation and puncture 3.72 +/- 0.62; IL-10 3.49 +/- 0.37). IL-10 also failed to reduce the appearance of TNF or IL-6 in the plasma or peritoneal fluid. The chemokine KC was reduced in the peritoneal fluid but not the plasma and endogenous IL-10 production was not reduced in the peritoneum. CONCLUSION: Our data indicate that exogenous IL-10 fails to improve morbidity or mortality in the clinically relevant cecal ligation and puncture model of sepsis. |
| PMID: 9590320 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
Publication Types:
MeSH Terms:
Substances:
Grant Support:
|
| 136. | Fundam Clin Pharmacol. 1998;12(2):173-81.Effects of alpha 1-acid glycoprotein in different rodent models of shock.Muchitsch EM, Auer W, Pichler L.Department of Pharmacology and Toxicology, Immuno AG, Vienna, Austria. It was the aim of the present study to investigate the effects of the acute phase protein alpha 1-acid glycoprotein in different models of shock. The human plasma preparation used was without effect on mortality in lipopolysaccharide-injected mice when administered in two different doses (1 or 0.33 g/kg i.v.) and according to different treatment schedules. The same preparation significantly increased survival rate (48 h) in rats with septic peritonitis. This effect was seen when alpha 1-acid glycoprotein (200 mg/kg i.v.) was given 15 min prior to and 24 h after cecal puncture. All other dose regimes tested were without significant effect on survival rate. A hemorrhagic/hypovolemic shock model (including a defined trauma) in rats resuscitated with 200 mg/kg alpha 1-acid glycoprotein resulted in significantly higher values of mean arterial blood pressure, cardiac output and stroke volume when compared to corresponding values obtained after resuscitation with Ringer's solution or 200 mg/kg albumin i.v. (free of alpha 1-acid glycoprotein; placebo formulation). Taking all other possible mechanisms of alpha 1-acid glycoprotein into consideration, the partially protective effects of the preparation are explained by enhancing the capillary barrier function and thereby maintaining perfusion of vital organs. |
| PMID: 9565771 [PubMed - indexed for MEDLINE] | |
| Related articles | |
Publication Types:
MeSH Terms:
Substances:
|
| 137. | Shock. 1998 Mar;9(3):193-8.Soluble glucan protects against endotoxin shock in the rat: the role of the scavenger receptor.Vereschagin EI, van Lambalgen AA, Dushkin MI, Schwartz YS, Polyakov L, Heemskerk A, Huisman E, Thijs LG, van den Bos GC.Medical Institute, Novosibirsk, Russia. Soluble carboxymethyl-b-1,3-glucan (CMG), a possible ligand for scavenger receptors, has macrophage-activating action but lacks the granulomatose inflammatory side effect: it is a promising immunomodulator that may mitigate the severity of sepsis. This motivated us to study in rats the effect of CMG (25 mg/kg), injected into the tail vein at 48 and 24 h prior to the administration of 5 mg/kg Escherichia coli 0127.B8 endotoxin on survival, hemodynamic condition, and, in vitro, on the chemiluminescence of PMNs and macrophages, and on macrophagal tumor necrosis factor (TNF) production. Acetylated low density lipoprotein (AcLDL) clearance in vivo and in vitro binding to macrophages was used to study scavenger receptor function. In the nonpretreated group 9 of 10 rats died during the first 24 h after endotoxin, but all CMG-pretreated rats survived. CMG-pretreatment prevented severe decreases in cardiac output and blood pressure after endotoxin. Chemiluminescence of macrophages and PMNs from CMG-pretreated rats was about two times less (p < .05) than that from nonpretreated ones; the endotoxin induced TNF production by macrophages also decreased. Pretreatment with CMG increased, but coinjection of CMG and AcLDL decreased the AcLDL clearance, while coinjection of endotoxin and AcLDL decreased the survival rate. In vitro AcLDL uptake by macrophages decreased after coinjection with CMG. Our results thus showed that CMG was protective in rat endotoxin shock, which seemed partly connected with enhancement of endotoxin clearance through scavenger receptors and to decreased TNF production. |
| PMID: 9525326 [PubMed - indexed for MEDLINE] | |
| Related articles | |
MeSH Terms:
Substances:
|
| 138. | J Infect Dis. 1998 Feb;177(2):489-92.Doxycycline reduces mortality to lethal endotoxemia by reducing nitric oxide synthesis via an interleukin-10-independent mechanism.D'Agostino P, La Rosa M, Barbera C, Arcoleo F, Di Bella G, Milano S, Cillari E.Institute of General Pathology, University of Palermo, Italy. Erratum in:
It was demonstrated that doxycycline protected BALB/c mice injected intraperitoneally with bacterial lipopolysaccharide (LPS) against lethal septic shock. Doxycycline (at 1.5 mg/kg) exerted its protective effect by inhibiting nitrate production by an interleukin-10-independent mechanism. Experiments carried out in vitro also indicated that doxycycline inhibited NO synthesis by LPS-activated macrophages without inducing any significant modification in interleukin-10 release. These data suggest that the direct inhibition of nitrate release is the main mechanism of the antiinflammatory activity of doxycycline in septic shock. |
| PMID: 9466545 [PubMed - indexed for MEDLINE] | |
| Related articles | |
Publication Types:
MeSH Terms:
Substances:
|
| 139. | J Infect Dis. 1998 Feb;177(2):388-94.Limulus antilipopolysaccharide factor prevents mortality late in the course of endotoxemia.Roth RI, Su D, Child AH, Wainwright NR, Levin J.Department of Pathology, University of California School of Medicine, Department of Veterans Affairs Medical Center, San Francisco 94121, USA. Limulus antilipopolysaccharide factor (LALF) can neutralize bacterial endotoxin, but its ability to prevent mortality following prolonged endotoxemia is unknown. Mice were challenged with an LD50 dose of intraperitoneal E. coli lipopolysaccharide (LPS) and then received LALF at various times after administration of LPS. Survival at 72 h was significantly improved by the administration of LALF at 4, 10, and even 24 h after LPS (73%, 78%, and 65% survival, respectively, vs. 15% survival in controls). Following intravenous administration of LALF at either 10 or 24 h after LPS, plasma levels of biologically active LPS abruptly fell (> 1000-fold lower than pre-LALF levels). Plasma LALF concentrations fell much more gradually in LPS-treated mice (t1/2 = 120 min) than in control mice (t1/2 = 2.5 min). In conclusion, LALF markedly decreased plasma concentrations of biologically active LPS and protected mice from lethality even when LALF was not administered until long after the onset of continuous endotoxemia. |
| PMID: 9466526 [PubMed - indexed for MEDLINE] | |
| Related articles | |
Publication Types:
MeSH Terms:
Substances:
|
| 140. | J Infect Dis. 1998 Jan;177(1):127-32.Nonselective versus selective inhibition of inducible nitric oxide synthase in experimental endotoxic shock.Liaudet L, Rosselet A, Schaller MD, Markert M, Perret C, Feihl F.Institute of Pathophysiology, Department of Internal Medicine, University Hospital, Lausanne, Switzerland. The effects of two nitric oxide synthase (NOS) inhibitors with different isoform selectivity were compared in a murine model of endotoxemia. Mice challenged with 70 mg/kg intraperitoneal (ip) lipopolysaccharide (LPS) were treated 6 h after LPS with either NG-gamma-L-arginine methyl ester (L-NAME, nonselective NOS inhibitor, 10-60 mg/kg), L-canavanine (selective inhibitor of inducible NOS, 50-300 mg/kg), or saline (0.2 mL) given ip. In a subset of mice, plasma concentrations of nitrate (NO breakdown product), lipase (pancreas injury), lactate dehydrogenase, and transaminases (liver injury) were measured 16 h after LPS. Although both inhibitors reduced plasma nitrate, they produced contrasting effects on survival and organ injury. L-NAME enhanced liver damage and tended to accelerate the time of death, while L-canavanine significantly reduced mortality and had no deleterious effects in terms of organ damage. These results indicate that nonselective NOS inhibitors are detrimental in endotoxic shock and support the potential usefulness of selective inducible NOS inhibitors in this setting. |
| PMID: 9419179 [PubMed - indexed for MEDLINE] | |
| Related articles | |
Publication Types:
MeSH Terms:
Substances:
|
| 141. | Arch Surg. 1997 Nov;132(11):1207-14.Testosterone receptor blockade after hemorrhage in males. Restoration of the depressed immune functions and improved survival following subsequent sepsis.Angele MK, Wichmann MW, Ayala A, Cioffi WG, Chaudry IH.Center for Surgical Research, Brown University School of Medicine, Providence, USA. BACKGROUND: Recent studies suggest that androgen depletion by castration before hemorrhage has protective effects on cell-mediated immunity in male mice after soft tissue trauma and hemorrhagic shock. OBJECTIVE: To determine whether treatment with an androgen receptor blocker (eg, flutamide) after trauma-hemorrhage and sepsis has any salutary effects on cell-mediated immunity and on the survival of male animals under those conditions. DESIGN: Male C3H/HeN mice were either sham operated or subjected to hemorrhagic shock (mean [+/- SEM] blood pressure, 35 +/- 5 mm Hg for 90 minutes) followed by adequate fluid resuscitation (with shed blood and lactated Ringer solution). The animals then received either vehicle or 25-mg/kg body weight flutamide subcutaneously immediately after the resuscitation as well as 24 and 48 hours thereafter. At 48 hours after shock, sepsis was induced by cecal ligation and puncture. Sham-operated animals underwent laparotomy only. At 24 hours after cecal ligation and puncture, the animals were killed, blood was collected, and splenocytes and splenic macrophages were harvested to produce nonadherent and adherent cultures. Splenocytes were evaluated for splenocyte proliferation and interleukin 2 release, while interleukin 1 and interleukin 6 release were assayed in splenic macrophages. Plasma testosterone and corticosterone levels were also measured by radioimmunoassay. In a separate set of experiments, survival was measured over a period of 9 days after the induction of sepsis. RESULTS: Hemorrhage followed by sepsis produced a significant (P < .05) depression of splenocyte and macrophage functions in vehicle-treated animals. In contrast, animals treated with flutamide showed markedly improved immune functions, as evidenced by restoration of splenocyte proliferation, interleukin 2 release, splenic macrophage interleukin 1 release, and improvement of splenic macrophage interleukin 6 release. Plasma corticosterone levels were notably elevated while testosterone levels were depressed after hemorrhage and the induction of sepsis. The survival rate of the animals in the flutamide-treated group was also notably higher than the survival rate of animals in the vehicle-treated group subjected to hemorrhage and sepsis. CONCLUSION: The findings that flutamide not only markedly improves the depressed immune functions but also the survival of animals after hemorrhage and the induction of sepsis suggest that the short-term administration of androgen receptor blocker in males after trauma represents a safe and novel approach for preventing immune deficiency and decreasing the mortality rate from subsequent sepsis. |
| PMID: 9366714 [PubMed - indexed for MEDLINE] | |
| Related articles | |
 | |
Publication Types:
MeSH Terms:
Substances:
Grant Support:
|
| 142. | Clin Diagn Lab Immunol. 1997 Sep;4(5):607-10.Endotoxin-induced lethality in neonatal mice is counteracted by interleukin-10 (IL-10) and exacerbated by anti-IL-10.Nicoletti F, Mancuso G, Ciliberti FA, Beninati C, Carbone M, Franco S, Cusumano V.Institute of Microbiology, University of Milan, Italy. The lethal effects occurring in neonatal (<24-h-old) BALB/c mice after challenge with 25 mg of lipopolysaccharide (LPS) per kg of body weight were significantly counteracted by pretreatment with recombinant interleukin-10 (rIL-10; 25 or 50 ng/mouse). Concordantly, blockage of endogenous IL-10 with the SXC1 monoclonal antibody increased LPS-induced mortality. Both IL-10 and SXC1 modulated the release of tumor necrosis factor alpha (TNF-alpha) so that, relative to controls, peak TNF-alpha values after LPS challenge were decreased by rIL-10 and increased by anti-IL-10. PMCID: PMC170607 |
| PMID: 9302214 [PubMed - indexed for MEDLINE] | |
| Related articles Free article | |
 | |
Publication Types:
MeSH Terms:
Substances:
|
| 143. | Shock. 1997 Jun;7(6):427-31.A matrix metalloproteinase inhibitor prevents processing of tumor necrosis factor alpha (TNF alpha) and abrogates endotoxin-induced lethality.Solorzano CC, Ksontini R, Pruitt JH, Auffenberg T, Tannahill C, Galardy RE, Schultz GP, MacKay SL, Copeland EM 3rd, Moldawer LL.Department of Surgery, University of Florida College of Medicine, Gainesville 32610, USA. Excessive tumor necrosis factor alpha (TNF alpha) production in response to Gram-negative bacteremia or endotoxemia can often lead to hypotension, shock, and increased mortality. Current approaches used to block the deleterious effects of exaggerated TNF alpha production rely on monoclonal antibodies or immunoadhesins that bind TNF alpha and thus prevent the interaction with its cellular receptors. This report examines whether a previously described inhibitor of matrix metalloproteinases, GM-6001, can inhibit TNF alpha processing and release and attenuate endotoxin-induced mortality. In human peripheral blood mononuclear cells stimulated in vitro with 1 microgram/mL endotoxin, GM-6001 at concentrations > 5 micrograms/mL blocked release of TNF alpha, but did not affect the release of either IL-1 beta or IL-6. GM-6001 also inhibited the release of soluble TNF receptor (p75) from peripheral blood mononuclear cells stimulated with endotoxin and/or TNF alpha. To confirm the role of secreted TNF alpha in endotoxic shock-induced mortality, C57BL/6 mice were challenged with either endotoxin alone (500 micrograms/mouse) or endotoxin (100 ng/mouse) plus D-galactosamine (8 mg/mouse). GM-6001 pretreatment (100 mg/kg) significantly attenuated the 90-minute plasma TNF alpha response in both models and improved survival in mice treated with low-dose endotoxin plus D-galactosamine. However, plasma IL-1 beta and IL-6 concentrations at 90 min after endotoxin treatment were unaffected by GM-6001 following lethal endotoxin challenge, confirming the in vivo specificity of this matrix metalloproteinase inhibitor for TNF alpha processing. These findings demonstrate that a novel inhibitor of matrix metalloproteinases can prevent the release of TNF alpha both in vitro and in vivo, and can abrogate the harmful sequelae of endotoxemic shock. |
| PMID: 9185243 [PubMed - indexed for MEDLINE] | |
| Related articles | |
Publication Types:
MeSH Terms:
Substances:
Grant Support:
|
| 144. | J Surg Res. 1997 Feb 1;67(2):199-204.Differential effects of IL-1 beta and ibuprofen after endotoxic challenge in mice.Mansilla-Roselló A, Ferrón-Orihuela JA, Ruiz-Cabello F, Garrote-Lara D, Fernández-Mondéjar E, Delgado-Carrasco ML.Experimental Surgery Unit, Virgen de las Nieves Foundation, Granada, Spain. Interleukin-1 (IL-1) and ibuprofen modulate the host response in different models after endotoxic challenge. A comparative study was made between the two drugs, as they were jointly administered, to explore a potentiation of their therapeutic effects. Endotoxic challenge was provoked in CBA/H mice with lipopolysaccharide (LPS) from Escherichia coli (125 mg/kg), with administration of recombinant murine IL-1 beta (80 ng/mouse) 24 hr pre-LPS. Two doses of ibuprofen (1 mg/kg) were administered 1 hr before and 30 min after the septic challenge. Serum levels of IL-1 alpha, tumor necrosis factor-alpha (TNF alpha), and interleukin-6 (IL-6) were determined 1,2, and 4 hr, post-LPS, and prostaglandin E2 (PGE2) urine levels 4,8, and 12 hr post-LPS, and a comparative mortality study was performed. IL-1 beta treatment provoked a reduction of IL-1 alpha, TNF alpha, and IL-6 without affecting PGE2, while ibuprofen provoked a later increase of IL-1 alpha, TNF alpha, and IL-6, with a decrease of PGE2. Both drugs caused a notable enhancement of survival, with no difference between them, but their combined administration caused no improvement. We conclude that both drugs exert a similar therapeutic effect in endotoxic shock by different mechanisms. |
| PMID: 9073568 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
Publication Types:
MeSH Terms:
Substances:
|
| 145. | J Interferon Cytokine Res. 1996 Dec;16(12):995-1000.Injection time of interleukin-6 determines fatal outcome in experimental endotoxin shock.Yoshizawa K, Naruto M, Ida N.Basic Research Laboratories, Toray Industries Inc., Kanagawa, Japan. Circulating interleukin-6 (IL-6) levels are directly correlated to fatal outcome in both patients and animal models with endotoxin shock. However, whether IL-6 is deleterious or protective in regard to survival is obscure. We investigated the action of IL-6 in the pathogenic progress of endotoxin shock. C3H/HeN mice received 10 micrograms of natural human IL-6 (Hu-IL-6) s.c. at various times before or after challenge with Escherichia coli lipopolysaccharide (LPS) at a lethal dose. Pretreatment with Hu-IL-6 0, 1, and 4 h before LPS administration improved the survival rate of the mice. However, no protection was observed when Hu-IL-6 was administered 24 h before or 1 h after the LPS injection. The protective mechanism of Hu-IL-6 pretreatment was not explained on the changes in the circulating levels of tumor necrosis factor and endogenous murine IL-6 (Mu-IL-6). The induction of fibrinogen and immunosuppressive acidic protein, a type of acute-phase proteins, may have contributed to the protection. The results show that the order and the time interval in which the administered Hu-IL-6 and the Mu-IL-6 induced by LPS act are the key to the determination of fatal outcome. |
| PMID: 8974000 [PubMed - indexed for MEDLINE] | |
| Related articles | |
MeSH Terms:
Substances:
|
| 146. | Immunopharmacol Immunotoxicol. 1996 Nov;18(4):477-95.A lipid A analog inhibits LPS-induced cytokine expression and improves survival in endotoxemic mice.Someya K, Tsutomi Y, Soga T, Akahane K.New Product Research Laboratories I, Daiichi Pharmaceutical Co., Tokyo, Japan. It has recently been shown that inactive disaccharidic analogs of lipid A, an essential structure of lipopolysaccharide (LPS), may act as LPS antagonists which would be effective against septic shock induced by gram-negative bacteria endotoxin. In the present study we examined the inhibitory effect of DY-9973, a synthetic monosaccharidic lipid A analog, on LPS-induced cytokine expression in macrophages and lethal toxicity in mice. DY-9973 inhibited TNF-alpha production induced by LPS in human monocytes and monoblastic U937 cells. Expression of cytokine mRNAs such as TNF-alpha and IL-1 beta induced by LPS was inhibited by treatment with DY-9973 in U937 cells. Meanwhile, DY-9973 did not inhibit IL-1 beta-induced TNF-alpha production in U937 cells. TNF-alpha production induced by LPS or IL-1 beta was similarly inhibited by treatment with herbimycin, a tyrosine kinase inhibitor. Pretreatment with DY-9973 inhibited the elevation of serum TNF-alpha activity induced by the injection of LPS and reduced the lethal toxicity of LPS in BCG-primed mice. These results suggest that monosaccharidic lipid A analog such as DY-9973 can inhibit LPS-induced activation of macrophages and that it reduces lethal toxicity of LPS. |
| PMID: 8933165 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
MeSH Terms:
Substances:
|
| 147. | Proc Natl Acad Sci U S A. 1996 Aug 20;93(17):9138-41.Iron chelates bind nitric oxide and decrease mortality in an experimental model of septic shock.Kazmierski WM, Wolberg G, Wilson JG, Smith SR, Williams DS, Thorp HH, Molina L.Division of Organic Chemistry, Burroughs Wellcome, Research Triangle Park, NC 27709, USA. The hydroxamic acid siderophore ferrioxamine B [FeIII(HDFB)+] and the iron complex of diethylenetri-aminepentaacetic acid [FeIII(DTPA)2-] protected mice against death by septic shock induced by Corynebacterium parvum + lipopolysaccharide. Although FeIII(DTPA)2- was somewhat more effective than FeIII(HDFB)+, the iron-free ligand H4DFB+ was significantly more effective than DTPA. The hydroxamic acid chelator has a much higher iron affinity than the amine carboxylate, allowing for more efficient formation of the FeIII(HDFB)+ complex upon administration of the iron-free ligand. Electrochemical studies show that FeIII(DTPA)2- binds NO stoichiometrically upon reduction to iron(II) at biologically relevant potentials to form a stable NO adduct. In contrast, FeIII(HDFB)+ is a stable and efficient electrocatalyst for the reduction of NO to N2O at biologically relevant potentials. These results suggest that the mechanism of protection against death by septic shock involves NO scavenging and that particularly effective drugs that operate a low dosages may be designed based on the principle of redox catalysis. These complexes constitute a new family of drugs that rely on the special ability of transition metals to activate small molecules. In addition, the wealth of information available on siderophore chemistry and biology provides an intellectual platform for further development. PMCID: PMC38608 |
| PMID: 8799167 [PubMed - indexed for MEDLINE] | |
| Related articles Free article | |
| | |
Publication Types:
MeSH Terms:
Substances:
|
| 148. | Infect Immun. 1996 Aug;64(8):3429-34.Granulocyte-macrophage colony-stimulating factor: involvement in control of Trypanosoma cruzi infection in mice.Olivares Fontt E, Heirman C, Thielemans K, Vray B.Laboratoire d'Immunologie Expérimentale, Faculté de Médecine, Université Libre de Bruxelles, Belgium. Several cytokines play crucial roles in Trypanosoma cruzi infection in mice, but the involvement of endogenous granulocyte-macrophage colony-stimulating factor (GM-CSF) is poorly documented. This report shows that T. cruzi infection of mice triggered an early and sharp increase in plasma GM-CSF during the ascending phase of parasitemia. The plasma GM-CSF concentration remained stable at the peak of parasitemia and subsequently increased in those mice that survived to the acute phase. GM-CSF level increased again sharply, while parasitemia was rapidly decreasing. Finally, GM-CSF was undetectable, soon after the disappearance of circulating parasites. Injection of T. cruzi-infected mice with neutralizing anti-GM-CSF monoclonal antibodies induced the early appearance of parasitemia and aggravated cumulative mortality. In contrast, recombinant mouse GM-CSF (rmGM-CSF) caused sharp decreases in both parasitemia and cumulative mortality in T. cruzi-infected mice. Peritoneal macrophages from rmGM-CSF-treated and infected or uninfected mice were less infected ex vivo than those from control mice. Taken together these data demonstrate the protective action of endogenous GM-CSF in T. cruzi infection. Neutralization of endogenous GM-CSF aggravates infection, while exogenous rmGM-CSF decreases both parasitemia and host mortality. PMCID: PMC174243 |
| PMID: 8757888 [PubMed - indexed for MEDLINE] | |
| Related articles Free article | |
 | |
Publication Types:
MeSH Terms:
Substances:
|
| 149. | J Med Microbiol. 1996 Mar;44(3):211-4.Experimental endogenous septicaemia caused by Klebsiella pneumoniae and Escherichia coli in mice.Hirakata Y, Furuya N, Matsumoto T, Tateda K, Yamaguchi K.Department of Laboratory Medicine, Nagasaki University School of Medicine, Japan. Multi-resistant Klebsiella pneumoniae have recently occurred in several nosocomial outbreaks of septicaemia. An animal model resembling the pathophysiology of these infections in man would be very useful. A new model of endogenous septicaemia caused by K. pneumoniae and Escherichia coli strains in mice has been established. The mortality rate of conventional ddY mice given cyclophosphamide (CY) or fluorouracil (5-FU), each 200 mg/kg intraperitoneally, every other day was 70 and 100%, respectively. Pseudomonas aeruginosa septicaemia was observed in all dead mice treated with CY, whereas Enterobacteriaceae, including K. pneumoniae, were isolated from 90% of mice given 5-FU. Specific-pathogen-free mice, decontaminated with ampicillin and ceftazidime, were given multi-resistant K. pneumoniae CF504, CF514 or E. coli CF604, or CF614 carrying CAZ-1/TEM-5 plasmid by oral inoculation. Subsequent dosing with 5-FU induced lethal septicaemia caused by the inoculated strains in most of these mice, whereas CY did not regularly induce septicaemia. This model with 5-FU is considered to resemble closely the situation observed in man and to be beneficial for investigating pathophysiology and therapeutic strategies. |
| PMID: 8636939 [PubMed - indexed for MEDLINE] | |
| Related articles Free article | |
| | |
Publication Types:
MeSH Terms:
Substances:
|
| 150. | Burns. 1996 Mar;22(2):120-4.Experimental gut-derived endotoxaemia and bacteraemia are reduced by systemic administration of monoclonal anti-LPS antibodies.Gianotti L, Braga M, Vaiani R, Almondo F, Di Carlo V.Department of Surgery, Scientific Institute San Raffaele Hospital, University of Milan, Italy. This study aimed to investigate the effects and mechanisms of action of systemic administration of monoclonal antibodies, anti-endotoxin (HA-1A), in an animal model of gut-origin sepsis. In the first experiment, Balb/c mice were transfused with allogeneic blood (C3H/HeJ mice). Five days post-transfusion the animals were gavaged with 1 x 10(9) Escherichia coli and randomized into three groups (n = 22 each) to receive a sham burn (SB group) or a 20 per cent TBSA thermal injury, immediately followed by the systemic administration of monoclonal antibodies (3 mg/kg) (HA-1A group) or aliquots of sterile saline (Control group). The animal survival rate was observed for 10 days postburn. In the second experiment transfusion and burn injury were reproduced but the mice (n = 8/group) were gavaged with 10(9) E.coli labelled with 111indium oxine. Four hours after the burn the mesenteric lymph nodes, liver, lungs and blood were harvested to determine plasma endotoxin levels and the magnitude of translocation of labelled bacteria measured by the residual radioactivity in the organs. Circulating endotoxin levels were determined by limulus assay. The mortality rate of the HA-1A group (9 per cent) was similar to the SB group (0 per cent) and significantly lower than the control group (59 per cent) (P < 0.05). Both plasma endotoxin levels and degree of bacterial translocation in all extraintestinal tissues were significantly lower (by approximately 50 per cent) in the HA-1A group than in the control group (P < 0.05). Systemic administration of HA-1A exerts a beneficial effect by reducing the circulating levels of endotoxin and by increasing the gut barrier function to translocating microorganisms. |
| PMID: 8634118 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
MeSH Terms:
Substances:
|
| 151. | Toxicology. 1996 Jan 22;107(1):69-81.Protective effects of niacinamide in staphylococcal enterotoxin-B-induced toxicity.LeClaire RD, Kell W, Bavari S, Smith TJ, Hunt RE.United States Army Medical Research Institute of Infectious Diseases, Toxicology Divsion, Frederick, MD, USA. Staphylococcal enterotoxins (SE) interact with major histocompatibility complex (MHC) class II cell-surface receptors, eliciting signal transduction in antigen-presenting cells (APC). Subsequent toxin-class II complex interaction with specific T-cell receptors induces T-cell activation. We investigated the effect of niacinamide and interleukin (IL)-10 on SEB-induced responses. In a macrophage cell line, niacinamide (ED50--2mM) and IL-10 (ED50--7U/ml) inhibited interferon (IFN)-gamma-induced MHC class II expression in a dose-dependent manner. Also, niacinamide was a potent inhibitor of T-cell proliferation induced by SEB (ED50-- 1 mM) while IL-10 has minimal effects. In mice, the temporal responses of IL-1alpha, tumor necrosis factor (TNF)-alpha, IL-2, and IFN-gamma evoked by SEB were synergistically potentiated by lipopolysaccharide (LPS). Lethality occurred only when SEB was potentiated by LPS. Niacinamide or IL-10 improved survival of mice after lethal SEB challenge. Niacinamide reduced cytokine serum levels, although the pattern differed from that of IL-10. Niacinamide primarily reduced IL-2 and IFN-gamma, while IL-10 predominantly reduced IL-1alpha and TNF-alpha. The immunomodulatory effects of niacinamide observed on SEB-induced activation of APC and T-cells in vitro and in the LPS potentiated murine model for SEB-induced toxicity suggest it may have therapeutic value. |
| PMID: 8597033 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
MeSH Terms:
Substances:
|
| 152. | Eur J Pharmacol. 1995 Dec 27;294(1):353-5.Quinine inhibits release of tumor necrosis factor, apoptosis, necrosis and mortality in a murine model of septic liver failure.Gantner F, Uhlig S, Wendel A.Department of Biochemical Pharmacology, University of Konstanz, Germany. We investigated the effect of quinine on liver injury induced by lipopolysaccharide in mice sensitized with D-galactosamine. This model is characterized by high systemic release of tumor necrosis factor, which mediates hepatic apoptosis and necrosis. Pretreatment with quinine, a K+ channel blocker, prevented formation of tumor necrosis factor (TNF) as well as the subsequent hepatic DNA fragmentation and liver enzyme leakage. Thus, inhibition of K+ channels may be a novel therapeutic approach in cytokine-related organ damage. |
| PMID: 8788453 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
Publication Types:
MeSH Terms:
Substances:
|
| 153. | J Parasitol. 1995 Dec;81(6):974-8.Activity of lytic peptides against intracellular Trypanosoma cruzi amastigotes in vitro and parasitemias in mice.Barr SC, Rose D, Jaynes JM.Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853, USA. Three cecropin-like lytic peptides (DC-1, DC-2, and DC-2R) were synthesized with virtually no sequence homology with the natural compound (cecropin B) while retaining the charge distribution, amphipathic, and hydrophobic properties of the natural compound. A fourth analog (alpha-Pi) without these later properties, but a similar molecular weight, was also synthesized as a nonlytic peptide control. The 3 lytic peptides were examined for their ability to kill Trypanosoma cruzi trypomastigotes in vitro, intracellular amastigotes in vitro, and their toxicity to a mammalian cell line. DC-2 at 5 microM and DC-1 and DC-2R at 10 microM were 100% effective in killing T. cruzi trypomastigotes in vitro, suggesting at least a 10-fold increase in lytic activity over previous tested lytic peptide analogues, SB-37 and Shiva-1. When T. cruzi-infected Vero cells were treated with a single or double exposure of low concentrations (2.5 microM) of DC-1, DC-2, and DC-2R there was a significant (P < 0.05) reduction in amastigote numbers/cell when compared to untreated and alpha-Pi-treated T. cruzi-infected cells. Vero cells alone treated with the lytic peptides showed no reduction in number or toxicity. One of the peptides (DC-1) was tested for its toxicity in AJ mice and its ability to reduce parasitemias in T. cruzi-infected AJ mice. No untoward effects were seen in AJ mice injected intravenously with 50 micrograms/mouse daily for 10 days. There was a significant (P < 0.05) reduction in parasitemia and mortality by day 14 postinoculation (from 100% to 0%) in T. cruzi-infected AJ mice given 25 micrograms of DC-1/mouse on days 2, 4, 6, 8, and 10 postinoculation. |
| PMID: 8544074 [PubMed - indexed for MEDLINE] | |
| Related articles | |
Publication Types:
MeSH Terms:
Substances:
|
| 154. | Arch Surg. 1995 Apr;130(4):410-4.Detrimental effects of a nitric oxide synthase inhibitor (N-omega-nitro-L-arginine-methyl-ester) in a murine sepsis model.Fukatsu K, Saito H, Fukushima R, Inoue T, Lin MT, Inaba T, Muto T.Department of Surgery, University of Tokyo, Japan. OBJECTIVE: To examine the effects of a nitric oxide synthase inhibitor on host elimination of bacteria, tumor necrosis factor (TNF) production, and survival in a murine sepsis model. DESIGN: Prospective randomized experimental trials. SETTING: Laboratory. MATERIALS: Female Balb/c mice. INTERVENTIONS: Balb/c mice were injected with Escherichia coli (10(8) colony-forming units per body) into the peritoneal cavity. N-omega-Nitro-L-arginine-methyl-ester (L-NAME), an inhibitor of nitric oxide synthase, was given intraperitoneally at 10 mg/kg (N10 group) or 100 mg/kg (N100 group) 1 hour before bacterial challenge. MAIN OUTCOME MEASURES: Thirty animals were observed for survival. Samples of peritoneal lavaged fluid (PLF), blood, liver, and lungs were obtained at 4 and 6 hours after bacterial challenge (n = 60). The peritoneal exudative cells were counted. Viable bacterial counts were determined in PLF, blood, and organs. The TNF levels also were determined in plasma, PLF, and supernatant samples of cultured peritoneal exudative cells. RESULTS: Survival times after E coli challenge were significantly reduced by pretreatment with L-NAME (100 mg/kg intraperitoneally). Numbers of viable bacteria in the peritoneal cavity and plasma TNF level 4 hours after E coli challenge were higher in both L-NAME-treated groups than in the control group. The number of bacteria in the blood and the plasma TNF level 6 hours after E coli challenge were higher in the L-NAME-treated group (N100 group) than in the control group. Conversely, the number of hepatic bacteria in the control group was significantly higher than in the L-NAME-treated groups. Plasma TNF level showed significant positive correlations with numbers of bacteria in the PLF and in the blood 4 hours after challenge. No significant differences were noted in TNF levels in PLF and peritoneal exudative cell cultured supernatants. CONCLUSION: Inhibition of nitric oxide production is detrimental in this gram-negative sepsis model. |
| PMID: 7710342 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
MeSH Terms:
Substances:
|
| 155. | Shock. 1995 Mar;3(3):210-5.Pentoxifylline improves survival and reduces tumor necrosis factor, interleukin-6, and endothelin-1 in fulminant intra-abdominal sepsis in rats.Lundblad R, Ekstrøm P, Giercksky KE.Department of Surgery, Norwegian Radium Hospital, Oslo. The influence of pentoxifylline (PTX) on mortality and some important mediators was studied in a model of cecal perforation with fulminant intra-abdominal sepsis in rats. Cumulative mortality was registered in three groups of animals: untreated sepsis (n = 36), sepsis + PTX 20 mg/kg/24 h (n = 24), and sepsis + PTX 80 mg/kg/24 h (n = 24). PTX therapy was started at sepsis induction or after 4 h, and mortality was reduced from 89% in untreated sepsis to 60-66% in the PTX groups. Levels of sepsis mediators were studied in two groups: untreated sepsis and sepsis + PTX 40 mg/kg started 1 h after sepsis induction. In both groups 6-10 animals were sacrificed at 4 and 8 h to measure blood levels of bacteria, endotoxin, tumor necrosis factor (TNF), interleukin-6 (IL-6), endothelin-1, lactate, neutrophils, and packed cell volume. Cecal perforation gave high levels of bacteria, endotoxin, TNF, IL-6, and endothelin-1, leading to dehydration, lactacidosis, neutropenia, and death. Treatment with PTX did not modify dehydration, neutropenia, or concentrations of bacteria and endotoxin. Release of endothelin-1 was delayed, TNF burst was nearly abolished, and levels of IL-6 and lactate were substantially suppressed. In summary, PTX improves survival and reduces blood concentrations of TNF, IL-6, lactate, and endothelin-1 in fulminant intra-abdominal sepsis in rats. The primary effect of PTX in this sequence is probably reduction of TNF. |
| PMID: 7773801 [PubMed - indexed for MEDLINE] | |
| Related articles | |
Publication Types:
MeSH Terms:
Substances:
|
| 156. | J Infect Dis. 1995 Feb;171(2):393-9.Pharmacologic inhibitors of tumor necrosis factor production exert differential effects in lethal endotoxemia and in infection with live microorganisms in mice.Netea MG, Blok WL, Kullberg BJ, Bemelmans M, Vogels MT, Buurman WA, van der Meer JW.Department of Internal Medicine, University Hospital Nijmegen, Netherlands. Tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) are principal mediators of septic shock; inhibition of TNF-alpha production may ameliorate outcome in severe infections. Pentoxifylline, chlorpromazine, and thalidomide inhibit TNF-alpha production. Their effects were tested in lethal endotoxemia in sensitized mice. Only chlorpromazine significantly improved survival. Chlorpromazine and pentoxifylline significantly reduced postendotoxin circulating TNF-alpha, by 89% and 76%, respectively. Chlorpromazine also significantly reduced IL-1 beta and soluble TNF receptor-P75. No drug improved survival in Klebsiella pneumoniae-infected mice despite significantly lower circulating TNF-alpha concentrations in chlorpromazine- or pentoxifylline-treated animals. The three compounds decreased circulating TNF-alpha in Candida albicans-infected mice, but survival was not influenced. In neutropenic mice, chlorpromazine had no influence on candida in organs, but in normal mice, Candida counts in kidneys were higher in chlorpromazine-treated mice. Thus, inhibition of TNF-alpha production was of no benefit in K. pneumoniae infection and worsened outcome in C. albicans infection. |
| PMID: 7844376 [PubMed - indexed for MEDLINE] | |
| Related articles | |
Publication Types:
MeSH Terms:
Substances:
|
| 157. | J Infect Dis. 1995 Feb;171(2):385-92.Modulation of nonspecific antimicrobial resistance of mice to Klebsiella pneumoniae septicemia by liposome-encapsulated muramyl tripeptide phosphatidylethanolamine and interferon-gamma alone or combined.ten Hagen TL, van Vianen W, Bakker-Woudenberg IA.Department of Clinical Microbiology and Antimicrobial Therapy, Erasmus University, Rotterdam, Netherlands. Activation of the host defense system in a nonspecific way might provide tools to support failing antibiotic treatment in certain infectious diseases. The antimicrobial effect was investigated of liposome-encapsulated muramyl tripeptide phosphatidylethanolamine (MTPPE) and interferon (IFN)-gamma and liposome-coencapsulated MTPPE and IFN-gamma on Klebsiella pneumoniae septicemia in mice. Prophylactic treatment of mice with five doses of liposomal MTPPE or IFN-gamma increased survival from 0 to 65%. Administration of MTPPE and IFN-gamma coencapsulated in liposome resulted in 100% survival. In vitro, peritoneal macrophages by themselves were stimulated by these agents but were unable to kill K. pneumoniae. However, production of both oxygen and nitrogen intermediates increased when immunomodulators were added to macrophages. These results indicate that effective prophylactic treatment of septicemia due to K. pneumoniae with coencapsulated MTPPE and IFN-gamma is not solely due to activation of the resident macrophages. |
| PMID: 7844375 [PubMed - indexed for MEDLINE] | |
| Related articles | |
MeSH Terms:
Substances:
|
| 158. | Am Surg. 1995 Jan;61(1):11-5.Second place winner of the Conrad Jobst Award in the gold medal paper competition. Increased antibiotic effectiveness in a model of surgical infection through continuous infusion.Naziri W, Cheadle WG, Trachtenberg LS, Montgomery WD, Polk HC Jr.Price Institute for Surgical Research, Department of Surgery, University of Louisville School of Medicine, KY. As long as infection remains the most common cause of morbidity and mortality in severely ill patients, there exists the need for more effective anti-infective therapy. The current study was undertaken to determine whether continuous infusion (CONT) is superior to intermittent administration (INT) of an equal amount of cefazolin (CEF) in a model of surgical infection. The thigh suture model consists of the surgical placement of 1 cm of cotton suture with absorbed K. pneumoniae into the thigh muscle of mice. The experimental groups were: 1) controls (n = 20) with thigh suture inoculation and treatment with intraperitoneal (IP) sterile saline; 2) CONT infusion group that received CEF at 60 mg/kg IP 30 minutes before inoculation followed by CONT IP infusion at 180 mg/kg/day (n = 22) for 3 days; and 3) INT injection group that received CEF at 60 mg/kg IP 30 minutes before inoculation followed by INT IP injections every 8 hours at 180 mg/kg/day (n = 20) for 3 days. All CEF treated animals received identical quantities of total CEF, and all groups were followed for 10 days. The control and INT CEF groups had 20% survival, whereas the CONT CEF group had 81% survival, (P < 0.001). Continuous CEF yielded constant serum levels of 19 +/- 1 micrograms/mL, whereas INT injections resulted in peak serum level of 74 +/- 12 micrograms/mL at one minute but declined to 3.9 +/- 0.9 micrograms/mL in 2 hours. Although there was statistically significant tissue bacterial growth in the INT injection group, there was extensive tissue bacterial clearance in the CONT infusion group.(ABSTRACT TRUNCATED AT 250 WORDS) |
| PMID: 7832374 [PubMed - indexed for MEDLINE] | |
| Related articles | |
Publication Types:
MeSH Terms:
Substances:
|
| 159. | Shock. 1994 Oct;2(4):275-80.Beneficial effects of a novel platelet-activating factor receptor antagonist, ST 899, on endotoxin-induced shock in mice.Ruggiero V, Chiapparino C, Manganello S, Pacello L, Foresta P, Martelli EA.Sigma Tau Industrie Farmaceutiche Riunite SpA, Department of Microbiology and Immunology, Pomezia, Italy. The effect of ST 899, a novel platelet-activating factor (PAF) receptor antagonist, on serum tumor necrosis factor (TNF), interleukin-6 (IL-6), and interferon-gamma (IFN-gamma) production as well as on lethality in an experimental endotoxin shock model was investigated in C57BL/6 mice. In this model, animals receiving 40 mg/kg lipopolysaccharide (LPS) (Escherichia coli 055:B5) intraperitoneally were pretreated with ST 899 administered according to two different schedules. ST 899 pretreatment dose dependently reduced the mortality induced by LPS injection. The PAF receptor antagonist was also able to reduce significantly the LPS-induced increase in serum TNF. Although serum IL-6 levels were not affected, we found that ST 899, when administered intraperitoneally 60 min and intravenously 10 min prior to LPS challenge, had a tendency (at higher doses) to decrease circulating IFN-gamma levels. It is suggested that ST 899 may be beneficial, in combination with current therapies, in the treatment of diseases that involve overproduction of PAF, TNF, and IFN-gamma such as septic shock. |
| PMID: 7757521 [PubMed - indexed for MEDLINE] | |
| Related articles | |
MeSH Terms:
Substances:
|
| 160. | Br J Surg. 1994 Sep;81(9):1309-11.Improved survival in simulated surgical infection with combined cytokine, antibiotic and immunostimulant therapy.Gaar E, Naziri W, Cheadle WG, Pietsch JD, Johnson M, Polk HC Jr.Price Institute of Surgical Research, University of Louisville School of Medicine, Kentucky 40292. A study was performed to find an ideal combination and sequence of cytokines, antibiotics and immunorestorative agents to enhance survival from serious infection. The effects of combinations of granulocyte-macrophage colony-stimulating factor (GM-CSF), tumour necrosis factor (TNF) alpha, the immune adjuvant muramyl dipeptide (MDP) and two systemic antibiotics were studied in a validated murine model of surgical infection. A single cotton suture containing absorbed Klebsiella pneumoniae was placed into the thighs of mice to produce local and systemic infection. Control mice received a volume of subcutaneous saline equal to that of the therapeutic agent; only 18 per cent survived 9 days after infection. The survival time of mice treated with any single agent was similar to that of controls. The group given maximal combined therapy (65 mice) received GM-CSF, TNF-alpha, MDP, and ampicillin-sulbactam or cefoxitin for 6 days. The survival rate in this group 9 days after the introduction of infection was 84-90 per cent (P < 0.0001), suggesting that specific combinations of cytokines, immunostimulants and antibiotics may be useful in combating lethal infection. |
| PMID: 7953394 [PubMed - indexed for MEDLINE] | |
| Related articles | |
Publication Types:
MeSH Terms:
Substances:
|
| 161. | Crit Care Med. 1994 Apr;22(4):553-8.Human neutrophil bactericidal/permeability-increasing protein reduces mortality rate from endotoxin challenge: a placebo-controlled study.Fisher CJ Jr, Marra MN, Palardy JE, Marchbanks CR, Scott RW, Opal SM.Cleveland Clinic Foundation, OH. Comment in: OBJECTIVES: To study the toxicology and pharmacology of the endotoxin-neutralizing agent, bactericidal/permeability-increasing protein. DESIGN: Prospective, randomized, placebo-controlled laboratory study. SETTING: Academic research laboratory. SUBJECTS: CD-1 mice (n = 259); Sprague Dawley rats (n = 26); New Zealand White rabbits (n = 19). INTERVENTIONS: Pharmacokinetics of intravenously injected bactericidal/permeability-increasing protein was assessed in mice. Toxicology was tested in mice and rats. Efficacy of intravenously administered bactericidal/permeability-increasing protein as an endotoxin-neutralizing agent was tested in mice, rats, and rabbits. MEASUREMENTS AND MAIN RESULTS: Administration of a single 10-mg/kg bolus injection of bactericidal/permeability-increasing protein resulted in no alterations in hematologic, renal, or hepatic function, activity level, or weight gain in animals observed over a 7-day study period. A single bolus injection (10 mg/kg) of bactericidal/permeability-increasing protein protected 15 of 16 mice from a lethal endotoxin challenge (mortality rate 1/16 [6.25%]) compared with a 100% (16/16) mortality rate in the saline-treated controls (p < .001). Bactericidal/permeability-increasing protein administered up to 1 hr after endotoxin provided significant protection against lethal endotoxin challenge. Furthermore, bactericidal/permeability-increasing protein reduced the induration and dermal necrosis observed in the localized dermal Shwartzman reaction. CONCLUSIONS: Bactericidal/permeability-increasing protein is a potent antiendotoxin that neutralizes endotoxin in vivo and prevents mortality in animal models of lethal endotoxemia. |
| PMID: 8143463 [PubMed - indexed for MEDLINE] | |
| Related articles | |
Publication Types:
MeSH Terms:
Substances:
|
| 162. | J Immunol. 1993 Aug 1;151(3):1548-61.Soluble tumor necrosis factor (TNF) receptors are effective therapeutic agents in lethal endotoxemia and function simultaneously as both TNF carriers and TNF antagonists.Mohler KM, Torrance DS, Smith CA, Goodwin RG, Stremler KE, Fung VP, Madani H, Widmer MB.Department of Immunology, Immunex Corporation, Seattle, WA 98101. Two forms (monomeric or dimeric) of the extracellular, ligand-binding portion of the human p80 cell-surface receptor for TNF were used to antagonize TNF activity in vitro and in vivo. The dimeric sTNFR:Fc molecule was a more potent inhibitor of TNF than the monomeric sTNFR (50 to 1000x), as assessed in vitro by inhibition of TNF binding or bioactivity and in vivo by protection of mice from an otherwise lethal injection of LPS. Surprisingly, the dimeric sTNFR:Fc construct demonstrated a beneficial effect even when administered 3 h after a lethal LPS injection (i.e., after serum TNF levels had peaked and receded). To study the mechanism by which the soluble TNFR functions in vivo, serum TNF levels were examined in mice given LPS in the presence or absence of soluble receptor. Administration of a mortality-reducing dose of sTNFR:Fc ablated the rise in serum TNF bioactivity that normally occurs in response to LPS. However, TNF bioactivity was revealed in these "TNF-negative" serum samples when the L929 bioassay was modified by inclusion of a mAb that blocks the binding of murine TNF to the human soluble TNFReceptor. These results indicate that the absence of direct cytolytic activity in the L929 assay was caused by neutralization of TNF, rather than to an absence of TNF in the serum. Moreover, administration of either monomeric sTNFR or low doses of dimeric sTNFR:Fc actually resulted in increased serum TNF levels compared to mice given LPS but no soluble receptor. However, these "agonistic" doses of soluble receptor did not lead to increased mortality when an LD60 dose of LPS was given. Thus, dimeric sTNFR are effective inhibitors of TNF and under some circumstances function simultaneously as both TNF "carriers" and antagonists of TNF biologic activity. |
| PMID: 8393046 [PubMed - indexed for MEDLINE] | |
| Related articles | |
 | |
MeSH Terms:
Substances:
|
| 163. | Infect Immun. 1993 Apr;61(4):1496-9.Protective role of interleukin 6 in the lipopolysaccharide-galactosamine septic shock model.Barton BE, Jackson JV.Schering-Plough Research Institute, Kenilworth, New Jersey 07033. C57BL/6J mice given low doses of lipopolysaccharide (LPS) (100 ng per mouse) plus D-galactosamine (8 mg per mouse) die within 24 h following LPS administration. We used this septic shock model to confirm the role of tumor necrosis factor in mortality using a monoclonal antibody to tumor necrosis factor to prevent lethality. Furthermore, we demonstrated that interleukin 6, rather than playing a lethal role, protected mice against death in this septic shock model. Antibody to interleukin 6 did not affect the fatal outcome in this low-LPS-dose model. However, pretreatment with antibody to tumor necrosis factor did protect the mice against death, in a dose-dependent manner. Moreover, mortality was enhanced by pretreatment with antibody to interleukin 6 when tumor necrosis factor was partly limited by anti-tumor necrosis factor treatment. Mortality was significantly reduced by pretreatment with both recombinant interleukin 6 and low doses of antibody to tumor necrosis factor; in the absence of the low dose of antibody to tumor necrosis factor, interleukin 6 alone did not confer any protection. These data demonstrate in vivo antagonistic activities of tumor necrosis factor and interleukin 6 and show that interleukin 6 can play a protective role against death from septic shock. PMCID: PMC281391 |
| PMID: 8454355 [PubMed - indexed for MEDLINE] | |
| Related articles Free article | |
| | |
MeSH Terms:
Substances:
|
| 164. | Agents Actions. 1993;39 Spec No:C125-7.Additive effects of a bradykinin antagonist, NPC 17761, and a leumedin, NPC 15669, on survival in animal models of sepsis.Otterbein L, Lowe VC, Kyle DJ, Noronha-Blob L.Scios Nova Inc., Baltimore, MD 21224. The effects of coadministration of NPC 17761 (D-Arg-Arg-Pro-Hyp-Gly-Phe-Ser-D-Hype (transthiophenyl)-Oic-Arg), a potent bradykinin antagonist, and NPC 15669 (N-[9H-(2,7-dimethylfluoren-9-yl-methoxy)carbonyl]-L-leucine), a leukocyte recruitment inhibitor, were examined in rodent models of experimental shock. In mice, ED50 doses of NPC 17761 (0.12 mg/kg) and NPC 15669 (4 mg/kg), administered together, increased survival (83%) and inhibited leukopenia (60% at 4 h) in response to a lethal dose of endotoxin. In rats, independent administration of NPC 15669 (10 mg/kg, i.v. bolus) or NPC 17761 (0.1 mg/kg/h, 4 h) did not significantly increase survival (36 +/- 4 and 46 +/- 9 h, respectively) versus controls (27 +/- 1 h). However, co-treatment essentially "cured" (survival > 1 week) all septic animals, suggesting synergistic effects of the two agents. |
| PMID: 8273550 [PubMed - indexed for MEDLINE] | |
| Related articles | |
MeSH Terms:
Substances:
|
| 165. | Infection. 1992 May-Jun;20(3):168-70.Comparison of the efficacy of cilofungin, fluconazole and amphotericin B in the treatment of systemic Candida albicans infection in the neutropenic mouse.Bannatyne RM, Cheng PC, Fong IW.Dept. of Microbiology, St. Micheal's Hospital, Toronto, Canada. The relative efficacies of cilofungin, amphotericin B and fluconazole were compared in the treatment of systemic Candida albicans infection in neutropenic mice. Thirty-one day survival rates were lowest for cilofungin (14.6%), intermediate for amphotericin B (37.6%) and highest for fluconazole (50.5%). Residual tissue infection in surviving animals was observed with all agents, but was heaviest with fluconazole, especially in the kidneys. |
| PMID: 1644494 [PubMed - indexed for MEDLINE] | |
| Related articles | |
Publication Types:
MeSH Terms:
Substances:
|
| 166. | J Pharmacol Exp Ther. 1992 Feb;260(2):748-55.Beneficial effects of TCV-309, a novel potent and selective platelet activating factor antagonist in endotoxin and anaphylactic shock in rodents.Terashita Z, Kawamura M, Takatani M, Tsushima S, Imura Y, Nishikawa K.Biology Research Laboratory, Takeda Chemical Industries, Ltd, Osaka, Japan. Pharmacological profiles of a novel specific platelet activating factor (PAF) antagonist, TCV-309 (3-bromo-5-[N-phenyl-N-[2-[2- (1,2,3,4-tetrahydro-2-isoquinolycarbonyloxy)ethyl] carbamoyl]ethyl] carbamoyl]-1-propylpyridinium nitrate] and its beneficial effects in shock were examined. TCV-309 specifically inhibited PAF-induced aggregation of rabbit and human platelets, and [3H]PAF binding to rabbit platelet microsomes with IC50 values of 33, 58 and 27 nM, respectively. It was as potent as WEB 2086 and more potent than CV-6209 and CV-3988. TCV-309 did not cause hemolysis in human or rat blood due to a detergent-like action. In rats, TCV-309 selectively inhibited the PAF-induced hypotension, hemoconcentration and death with ED50 values of 2.7, 6.4 and 1.7 micrograms/kg (i.v.), respectively. TCV-309 most potently protected mice from death induced by PAF and due to anaphylactic shock with ED50 values of 2.1 and 2.6 micrograms/kg (i.v.), respectively, when compared with CV-3988, CV-6209, WEB 2086 (i.v.) and L-652731 (p.o.). TCV-309 also reversed PAF-induced hypotension and endotoxin-induced hypotension in rats with ED50 values of 3.3 and 1.2 micrograms/kg (i.v.), respectively. There was a significant linear relationship between the ability (ED50 value) of these PAF antagonists to prevent death induced by PAF and death due to anaphylactic shock in mice, and between their reversing ability (ED50 value) for the hypotension induced by PAF and endotoxin in rats. TCV-309 (100 micrograms/kg i.v.) protected rats from death induced by endotoxin. Thus, PAF may be a lethal mediator in anaphylactic shock and a hypotensive mediator in endotoxin shock in rodents. |
| PMID: 1738121 [PubMed - indexed for MEDLINE] | |
| Related articles | |
 | |
MeSH Terms:
Substances:
|
| 167. | Arch Surg. 1992 Feb;127(2):152-7; discussion 157-8.Modulation of macrophage hyperactivity improves survival in a burn-sepsis model.O'Riordain MG, Collins KH, Pilz M, Saporoschetz IB, Mannick JA, Rodrick ML.Department of Surgery, Brigham & Women's Hospital, Harvard Medical School, Boston, Mass. 02115. Macrophage hyperactivity with increased production of tumor necrosis factor, interleukin 6, interleukin 1, and prostaglandins has been demonstrated in the injured patient, but the effect of this on the clinical outcome is unclear. We studied the effect of combination interleukin 1 beta and indomethacin sodium therapy on macrophage hyperactivity and survival after sepsis in a murine burn model. Macrophage interleukin 1, interleukin 6, and tumor necrosis factor alpha production were all significantly increased 10 days after thermal injury. Treatment with recombinant human interleukin 1 beta in combination with indomethacin significantly reduced this overproduction of cytokines to normal levels, and this was associated with an improvement in survival after septic challenge (52% survival in interleukin 1 beta-indomethacin-treated group compared with 22% in burned vehicle control mice). Burned mice that received either interleukin 1 beta or indomethacin alone demonstrated tumor necrosis factor and interleukin 6 production and survival intermediate between the interleukin 1 beta-indomethacin-treated group and the vehicle control group. Control of macrophage hyperactivity is associated with improved survival from subsequent sepsis and offers a potential new strategy for the treatment of immune dysfunction in thermally injured patients. |
| PMID: 1540091 [PubMed - indexed for MEDLINE] | |
| Related articles | |
| | |
Publication Types:
MeSH Terms:
Substances:
Grant Support:
|
| 168. | Ann Surg. 1991 Oct;214(4):502-8; discussion 508-9.Inhibition of macrophage-activating cytokines is beneficial in the acute septic response.Redmond HP, Chavin KD, Bromberg JS, Daly JM.Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia. Interferon-gamma and other cytokines enhance macrophage (M phi) antimicrobial function and have been considered for therapeutic use in sepsis. Systemic sequelae of macrophage activation, however, are unclear. This study examined the effects of M phi activating cytokines (interferon-gamma [IFN-gamma] and interleukin-4 [IL-4]) and monoclonal antibodies directed against these cytokines in modulating the acute septic response. CFW/Swiss Webster mice (n = 345) received endotoxin (lipopolysaccharide [LPS]: 60 mg/kg body weight intraperitoneally) and were randomized to five treatment groups: IFN-gamma (10(4) units), IL-4 (10(4) units), IgG1 isotype antibody (TRFK5: 200 micrograms), anti-IFN-gamma (200 micrograms), or anti-IL-4 (200 micrograms) monoclonal antibodies (MAbs) given simultaneously or 2 hours after LPS. Animals were divided into two groups and studied for mortality or measurement of peritoneal M phi superoxide anion release (O2-), tumor necrosis factor (TNF), and IL-6 production 6 hours after administration of LPS +/- experimental regimens. Serum TNF and IL-6 also were assessed at 2 and 4 hours after LPS, respectively. Administration of LPS resulted in a 27% survival compared with 10% in the IFN-gamma and 13% in the IL-4 groups. Treatment with anti-IFN-gamma offered protection against LPS lethality (93%-100% survival, p less than 0.001 vs. other groups) when given either simultaneously or 2 hours after LPS. Anti-IFN-gamma also significantly decreased PM phi O-2 and TNF release. Thus anti-IFN-gamma may have an important role in the modulation of the acute septic response. PMCID: PMC1358556 |
| PMID: 1659339 [PubMed - indexed for MEDLINE] | |
| Related articles Free article | |
| | |
Publication Types:
MeSH Terms:
Substances:
|
| 169. | Surg Gynecol Obstet. 1989 Apr;168(4):323-31.New approach to endotoxic and septic shock by means of polymyxin B immobilized fiber.Hanasawa K, Tani T, Kodama M.Department of Surgery, Shiga University of Medical Science, Japan. Endotoxin shock therapy has not been successfully dealt with pharmacologically. Circulation of endotoxins in the blood is an important factor in the pathogenesis and clinical symptoms of endotoxic shock. We have recently developed polymyxin immobilized fiber (PMX-F) as a biomaterial for selectively detoxifying endotoxins. In ex vivo experiments, direct hemoperfusion (DHP) by PMX-F was performed on dogs injected with purified endotoxin. Only one of eight survived in the control group, but ten of 12 survived in the group receiving DHP with PMX-F. Mortality in the treated group decreased remarkably. Thus, the results indicate the efficacy of PMX-F in neutralizing endotoxins. By the same method as already mentioned, DHP with PMX-F was carried out on live dogs with Escherichia coli induced sepsis. All of the dogs in the control group died within 18 hours after bacterial infusion. All of the dogs in the treated group, however, survived for more than three days. Two of the five dogs are still alive. One of the remaining two survived for seven days and the other, 14. We found that PMX-F treatment prolonged or increased the survival rate in the endotoxic and septic dogs. |
| PMID: 2538938 [PubMed - indexed for MEDLINE] | |
| Related articles | |
Publication Types:
MeSH Terms:
Substances:
|
| 170. | Crit Care Med. 1988 Sep;16(9):848-51.Effect of scavengers of oxygen-derived free radicals on mortality in endotoxin-challenged mice.Broner CW, Shenep JL, Stidham GL, Stokes DC, Hildner WK.Department of Pediatrics, University of Tennessee-Memphis. Oxygen-derived free radicals have been implicated as mediators of cellular injury in several model systems. Recently, a role for free radicals has been proposed in the mortality associated with Gram-negative bacterial sepsis. To determine if pretreatment with free radical scavengers can prevent endotoxin-induced mortality, mice rendered sensitive to endotoxin with actinomycin D were treated with either superoxide dismutase (SOD), N-acetylcysteine (NAC) or saline and were then challenged with a dose of endotoxin calculated to cause a mortality of greater than 80%. Mortality was assessed at 12-h intervals after challenge. Increased survival was seen in the SOD-treated group compared to the control group (p less than or equal to .05). In contrast, survival in mice treated with NAC, another potential scavenger, was not significantly different from the control group. These results support the hypothesis that superoxide and hydroxyl radicals contribute to mortality in Gram-negative bacterial sepsis. |
| PMID: 3042286 [PubMed - indexed for MEDLINE] | |
| Related articles | |
Publication Types:
MeSH Terms:
Substances:
|
| 171. | Biomed Biochim Acta. 1988;47(10-11):S289-92.Influence of inhibitors of the eicosanoid metabolism, of antagonists of the eicosanoids and of PAF on mortality assayed in three biochemically characterized shock models.Bahr T, Schaper U, Becker K, Lueddeckens G, Förster W, Scheuch DW, Grupe R, Göres E.Institute of Pharmacological Research - VEB of Pharmaceutical Combine GERMED, Berlin-Friedrichsfelde, GDR. Experiments were carried out to lower the mortality (LD70-90) of rats in ovalbumin-induced anaphylactic (DA) shock and in endotoxin-induced (ET) shock, and of mice after injection of Platelet-activating Factor (PAF shock) comparing the effects of the cyclooxygenase (COX)-inhibitors aspirin (ASA), indomethacin, of the COX-/lipoxygenase (LOX)-inhibitors nordihydroguajaretic acid (NDGA), phenidone and X 86 (analogue of BW 755c), of the inhibitor of thromboxane (TX) synthesis HOE 944, of the TX-antagonist BM 13177, of the PAF-antagonist BN 52021 and of ketotifen. Ketotifen was strongly effective in DA shock, COX- and LOX-inhibitors only slightly. Combined COX- and LOX-inhibitors and BN 52021 showed good effects in the ET shock. Ketotifen was inefficacious. All the used substances influenced the PAF shock. The shock syndromes were biochemically characterized by determination of isocitratedehydrogenase (ICDH) activity, lactate, glucose, haematocrit, numbers of thrombocytes and leucocytes, TXB2 and 6-keto-Prostaglandin(PG)F1 alpha. |
| PMID: 3150272 [PubMed - indexed for MEDLINE] | |
| Related articles | |
Publication Types:
MeSH Terms:
Substances:
|
| 172. | Biull Eksp Biol Med. 1987 Oct;104(10):428-30.[Effect of verapamil, cromoglycate and dimedrol on the survivability of mice in endotoxic shock][Article in Russian] Shenkman BZ.The trial has been performed on blocking the potentiation of the lethal action of Sh. Sonnei endotoxin isolated using the agents possessing antiaggregation and antimediator properties--verapamil, cromoglycate and diphenhydramine. It was shown that LD50 of endotoxin increased 2-2.5-fold, provided there were 3 drug injection 1, 4 and 9 hours after endotoxin administration. The survival of mice at 100% level of mortality was also increased 2-2.5-fold. With endotoxin administered together with the first drug injection, the drugs were ineffective. In case endotoxin was administered 3 times at a 4-hour interval prophylactic and therapeutic effects of the drugs and their combinations have been observed. |
| PMID: 3118985 [PubMed - indexed for MEDLINE] | |
| Related articles | |
Publication Types:
MeSH Terms:
Substances:
|
| 173. | Circ Shock. 1986;19(1):69-74.Increased survival with calcium antagonists in antibiotic-treated bacteremia.Bosson S, Kuenzig M, Schwartz SI.This study was done to test the effectiveness of calcium antagonists on survival in a bacteremic model. Swiss albino mice were injected intraperitoneally with live Escherichia coli at an LD90 dose. When antibiotic treatment was delayed for 3 hr after E coli challenge, there was a mortality range of 30-50% for the gentamicin-treated mice and 40-60% for the cefoxitin-treated mice. A calcium antagonist, either nifedipine or verapamil, was added to this model in different dosages and at different time intervals. Nifedipine yielded a significantly lower mortality both with gentamicin and with cefoxitin. Verapamil did not affect mortality with cefoxitin but did improve survival with gentamicin. Effective dosages occur within a narrow range. The results are encouraging and call for further studies with calcium antagonists to ascertain their prospective usefulness as additives to septic shock treatment. |
| PMID: 3521931 [PubMed - indexed for MEDLINE] | |
| Related articles | |
Publication Types:
MeSH Terms:
Substances:
Grant Support:
|
| 174. | Arzneimittelforschung. 1981;31(9):1453-6.[Studies on the effects of a modified immunoglobulin and beta-lactam antibiotics in the experimental mouse septicemia (author's transl)][Article in German] Klesel N, Limbert M.A new gamma-globulin preparation obtained by partial enzymatic cleavage of Fc-regions (Gamma-Venin), was effective in i.v. monotherapy in mice, infected with Streptococcus Aronson B, Pneumococcus mucosus and Salmonella typhimurium. These septicemias are characterized by protracted mortality. There was no measurable effect of the gamma-globulin preparation monotherapy in infections with acute course (Staphylococcus aureus 108, E. coli 078). But in all five experimental septicemias the additional administration of the gamma-globulin formulation enhanced the effectivity of cefotaxime or ampicillin. In those animals both antibiotics were effective in lower doses than in animals having obtained only chemotherapy. |
| PMID: 6171294 [PubMed - indexed for MEDLINE] | |
| Related articles | |
Publication Types:
MeSH Terms:
Substances:
|
| 175. | Am J Clin Nutr. 1977 Aug;30(8):1364-8.Biochemically assisted antibiotic treatment of lethal murine Staphylococcus aureus septic shock.Smith IM, Burmeister LF.Evidence has been sought for life-prolonging effects of a variety of chemicals given subcutaneously 1 hr after intraperitoneal challenge of mice with 10(9) Staphylococcus aureus cells. The chemicals were chosen to replace chemicals found to be missing in the blood or carcass at death or to treat biochemical or visible abnormalities in sick mice near death from infection. Nafcillin given subcutaneously in adequate amounts cure S. aureus infection. In these experiments nafcillin treatment was delayed until 40% of the time from challenge to death in the controls. Chemicals were given in addition to nafcillin subcutaneously 20% of the time from challenge to death. Cortisol, Dilantic, epsilon-aminocaproic acid, glucose, nicotinamide, olive oil, phentolamine-propanalol, sodium bicarbonate, sodium lactate, and reserpine each prolonged life compared to saline treatment. When nafcillin was added, only cortisol, Dilantin, nicotinamide and reserpine were found to prolong life significantly compared to nafcillin-saline treatment Fatality rates were significantly reduced with cortisol and Dilantin when they were given in association with nafcillin compared to nafcillin-saline treatment. |
| PMID: 142426 [PubMed - indexed for MEDLINE] | |
| Related articles Free article | |
 | |
MeSH Terms:
Substances:
|
| 176. | Jpn Circ J. 1977 Jun;41(6):609-14.Protective action of estrogen in endotoxin shock.Imai T, Sakuraya N, Fujita T.Protective action of conjugated equine estrogen (CEE) against endotoxin shock was admitted in mice. Male DDN strain mice pretreated intraperitoneally with 2 mg of CEE showed various survival rates according to the interval between administration of CEE and endotoxin injection. Survival rates of the control were 20.4%, but in the group pretreated with CEE they were 0% at 0 hour, 26.3% at 1 hour, 33.3% at 12 hours, 55.7% at 24 hours (p less than 0.001), 10.5% at 36 hours, and 31.2% at 48 hours respectively. Mice pretreated with 2 mg of CEE before 24 hours exhibited excellent resistance to 0.5 mg endotoxin. On the other hand, the hemodynamic effect of CEE was examined in six mongrel dogs, which showed little hemodynamic changes following administration of 10 mg/kg CEE for three hours observation. We speculated that the anti-shock action of CEE was due to the modification of vascular response to vasoactive substances, on the one hand it augmented the vascular contractile response to vasopressors and on the other hand it lessened the hypersensitive vasoconstriction under shock state. |
| PMID: 196120 [PubMed - indexed for MEDLINE] | |
| Related articles | |
MeSH Terms:
Substances:
|
| 177. | Infect Immun. 1976 Mar;13(3):998-1000.Inhibition of lethality in endotoxin-challenged mice treated with zinc chloride.Snyder SL, Walker RI.Zinc chloride protected against lethality in mice undergoing endotoxin shock. PMCID: PMC420707 |
| PMID: 1270141 [PubMed - indexed for MEDLINE] | |
| Related articles Free article | |
| | |
Publication Types:
MeSH Terms:
Substances:
|
posted by JKB @ 05:35
0 Comments
0 Comments:
Post a Comment
Subscribe to Post Comments [Atom]
<< Home