Shock : molecular, cellular, and systemic pathobiological aspects and therapeutic approaches : the official journal the Shock Society, the European Shock Society, the Brazilian Shock Society, the International Federation of Shock Societies
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This study was conducted to demonstrate the burn-induced lung neutrophil deposition and damage in rats is affected by the nitric oxide (NO)-dependent downstream cGMP signaling. In experiment 1, 1H-[1,2,4] oxadiazolo [4,3-alpha] quinoxalin-1-one (ODQ) was given (20 mg/kg i.p.) to specific pathogen-free Sprague-Dawley rats immediately postburn to suppress the guanylate cyclase (GC) activity. At 8 h after burn, blood was assayed for the peroxynitrite-mediated dihydrorhodamine 123 (DHR 123) oxidation and lung tissues were harvested for myeloperoxidase (MPO) determination and histological studies. ⋯ Furthermore, ODQ decreased the burn or SNP-induced iNOS mRNA levels at 4 h after burn. These findings suggest that burn-induced lung dysfunction is mediated by the NO/cGMP system because it is abolished by application of either iNOS inhibitor or GC inhibitor. Also, the beneficial effect of ODQ is partly due to the attenuation of burn-induced iNOS expression by GC inhibition.
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Severe sepsis is common, frequently fatal, and expensive. Many factors related to the pathogenesis of severe sepsis have made it difficult to effectively design clinical trials for the management of this disease. Hence, multiple trials of compounds for the treatment of severe sepsis have yielded largely negative results, except in small subsets of patients. ⋯ Emphasis is placed on the difficulties in evaluating investigational agents in patients with severe sepsis because of the heterogeneity of the disorder, lack of correlation between animal and human models, the complexity of the insult and the host reaction, and the interaction between inflammation and coagulation in severe sepsis. Additionally, positive results from trials of steroids, intensive insulin therapy, and activated protein C (drotrecogin alfa [activated]) will be discussed. Because drotrecogin alfa (activated) is the only Food and Drug Administration-approved therapy for severe sepsis, the Phase 3 Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial results will be discussed in detail to help define a model for further clinical trials on severe sepsis.
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We tested the hypothesis that metalloendopeptidase inhibition using phosphoramidon during induction of endotoxemia 24 h later would down-regulate the protein expression of myocardial inducible nitric oxide synthase (iNOS) and phosphorylation of p38-mitogen-activated protein kinase (p38-MAPK). Male Sprague-Dawley rats (350-400 g) were randomly divided into sham-treated and LPS-treated groups (Escherichia. coli lipopolysaccharide [LPS] 2 mg/kg bolus + 2 mg/kg infusion for 30 min). The animals in each group were further subdivided into vehicle- and phosphoramidon (1 mg/kg bolus)-treated subgroups. ⋯ Phosphoramidon inhibited LPS-induced down-regulated expression of myocardial endothelial nitric oxide synthase and upregulated p38-MAPK phosphorylation. These results indicated that inhibition of metalloendopeptidase during induction of endotoxemia could regulate the phosphorylation of myocardial p38-MAPK and iNOS protein expression at 24-h post endotoxemia. We concluded that inhibition of metalloendopeptidases during early endotoxemia not only decreased the biosynthesis of ET-1 in heart locally but also simultaneously down-regulated myocardial protein expression of iNOS and p38-MAPK phosphorylation in the later stage of endotoxemia.
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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. ⋯ 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.