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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Studies have indicated that there is a development of generalized immune dysfunction after septic insult. However, the mechanisms responsible for these changes remain unclear. Recently, accumulating evidence shows that several lymphocyte subpopulations such as NKT-, CD4(+)-Th2-T-, CD8(+)-T-, gammadelta-T-, and CD4+ CD25+ T regulatory cells are capable of actively contributing to the induction of septic immune suppression. ⋯ Similarly, in vitro proliferation studies showed that proliferation index increased in CD4+ CD25+ cells from septic C57BL/6J and IL6 -/- mice, but it remained the same in IL-10 -/- mice. Surprisingly, depletion of CD25+ cells before inducing sepsis did not alter septic mortality. Together, these findings suggest that although CD4+ CD25+ T regulatory cells induced by IL-10 seem to contribute to aspects of sepsis-induced lymphoid immune suppression, the oblation of CD25+ cells does not provide a survival advantage or disadvantage.
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Although comprehension of postburn pathophysiology has grown in recent years, we are still unable to accurately identify burn patients who are at an increased risk of infectious complications and death. This unexplained variation is likely influenced by heritable factors; the genetic predisposition for death from infection has been estimated as greater than that for cardiovascular disease or cancer. Identify genetic variants associated with increased mortality after burn injury. ⋯ None of the other single nucleotide polymorphisms examined were significantly associated with mortality. These data provide strong evidence that a CD14 promoter allele that is known to impart lower baseline and induced CD14 transcription also affects mortality risk after burn injury. A potential (although untested) mechanism for our observation is that reduced signaling through CD14/toll-like receptor 4 in response to challenge by gram-negative bacteria after burns results in a blunted innate immune response and subsequent increased likelihood for systemic infection and death.
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Tumor necrosis factor (TNF)-alpha plays a major role in the immune system. Release of proinflammatory cytokines, such as TNF-alpha and interleukin 6, by macrophages and other cells occurs in response to bacterial products. It has been reported that the TNF-alpha -308 G/A polymorphism in the TNF-alpha gene determines basal TNF-alpha levels. ⋯ Basal and peak values of selected inflammatory and coagulation markers were not different between wild-type TNF-alpha -308 individuals (GG) and carriers of the TNF-alpha -308 mutant allele (GA and AA). The TNF-alpha -308 G/A polymorphism does not contribute significantly to the individual variability of systemic TNF-alpha plasma concentrations after endotoxin challenge. Thus, if any, the impact of the TNF-alpha -308 G/A polymorphism on systemic endotoxin-triggered inflammation seems to be limited.
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Tachyphylaxis against catecholamines often complicates hemodynamic support in patients with septic shock. Recent experimental and clinical research suggests that the hemodynamic response to exogenous arginine vasopressin (AVP) infusion may also be blunted. The purpose of the present study was therefore to clarify whether the efficacy of a continuous AVP infusion (0.04 U x min(-1)) decreases over time in ovine endotoxemia. ⋯ After 6 h of continuous AVP infusion, the vasopressor effect was significantly reduced. Interestingly, a bolus infusion of methylprednisolone (30 mg x kg(-1)) reestablished mean arterial pressure by increasing both cardiac index and systemic vascular resistance index. The present study demonstrates that in endotoxemia, (a) the vasopressor effect of AVP infusion may be reduced, (b) corticosteroids may potentially be useful to increase the efficacy of AVP infusion, and (c) even moderate AVP doses may potentially impair myocardial and hepatic function.
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Recent evidence indicates that shock is accompanied by a failure of the mucosal barrier in the intestine and entry of pancreatic digestive enzymes into the wall of the intestine. To investigate the formation of cytotoxic mediators produced by enzymatic digestion of the intestine, we applied homogenates of rat small intestinal wall to human neutrophils and used flow cytometry measurements of propidium iodide uptake to determine cytotoxicity. We show that homogenates of the small intestine after ischemia by occlusion of the superior mesenteric and celiac arteries for 3 h, but not without ischemia, are cytotoxic. ⋯ To test whether digested food can be cytotoxic, we homogenized rat food and digested it in vitro with chymotrypsin or endogenous enzymes in luminal fluid. Cytotoxicity was significantly increased after digestion of food by luminal fluid compared with luminal fluid or undigested food. These results indicate the presence of a previously unknown mechanism for hemorrhagic necrosis in shock.