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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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.
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Toll-like receptors (TLR) play a pivotal role in the innate immune response, and the expression levels of these receptors may reflect the sensitivity of immune cells to infections. The binding of lipopolysaccharide (LPS) to TLR-4 triggers human monocytes to produce cytokines, which play a dominant role in the inflammatory response, as can be observed during sepsis and after polytrauma. Here, we evaluated TLR-4 expression of isolated monocytes in the presence of tumor necrosis factor (TNF)-alpha, interleukin (IL) 6, IL-8, and IL-10, and we investigated cellular activation of this treatment. ⋯ Stimulation with IL-8 or IL-10 had no significant effects. We conclude that not only LPS but also TNF-alpha and IL-6 have the potency to regulate the immune response via TLR-4. Down-regulation of TLR-4 by TNF-alpha is associated with LPS hyporeactivity for NF-kappaB formation, whereas upregulation of TLR-4 via IL-6 can increase the responsiveness of mononuclear phagocytes.
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D-lactate is produced by indigenous bacteria in the gastrointestinal tract. Mammals do not have the enzyme systems to metabolize D-lactate rapidly. The present study was designed to determine the kinetics of circulating D-lactate levels and to examine whether the severity of shock affects circulating D-lactate levels in rats subjected to hemorrhagic/traumatic shock. ⋯ Our data suggest that hemorrhagic/traumatic shock is associated with mucosal damage and increased plasma D-lactate levels. The severity of shock affects D-lactate concentrations in plasma. Plasma D-lactate may be a useful marker of intestinal injury after hemorrhagic/traumatic shock.
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Because gut-derived factors carried in mesenteric lymph are implicated in multiple organ dysfunction syndrome and have been shown to injure endothelial cells, we investigated several cellular pathways by which this process could occur. To accomplish this, mesenteric lymph (5%, v/v) collected at 1 to 3 h postshock from male rats undergoing trauma (5-cm laparotomy) and hemorrhagic shock (90 min of mean arterial pressure [MAP] of 30 mmHg; T/HS) was tested for endothelial cell cytotoxicity on human umbilical vein endothelial cells (HUVECs). Over 30 pharmacologic agents that had been reported to inhibit endothelial cell death were tested for their ability to prevent T/HS lymph-induced HUVEC cell death. ⋯ These agents were equally effective when added simultaneously with lymph or preincubated with the HUVECs, suggesting an extracellular or membrane-bound process. In summary, the inhibitors that provided protection from toxic lymph appear to work at the membrane and are involved in limiting membrane peroxidation. Based on this study, it appears that an oxidant pathway is involved in T/HS lymph-induced endothelial cell injury and death.