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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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. ⋯ 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.
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We have shown previously that bum trauma activates the stress responsive proteins, p38 mitogen-activated protein kinase (MAPK), c-jun NH2-terminal kinase (JNK), and NF-kappaB, and we have shown further that p38 MAPK is an important mediator of cardiomyocyte TNF-alpha secretion and cardiac dysfunction in burn trauma. Since burn trauma causes a rise in circulating catecholamine levels, we hypothesized that this increased sympathetic activity may function as an upstream activator of the p38 MARK pathway in burn trauma. This study determined whether the alpha1-adrenergic receptor ligand phenylephrine could mimic burn trauma activation of p38 MAPK, JNK, and NF-kappaB nuclear translocation; and the effect of the alpha1-adrenergic receptor antagonist prazosin on either phenylephrine or burn-mediated activation of the stress response pathway was examined. ⋯ Burn trauma activated cardiac p38 MAPK/JNK and NF-kappaB, increased TNF-alpha secretion by cardiomyocytes, and impaired cardiac function. Prazosin treatment in burns interrupted the burn-mediated signaling cascade, decreasing TNF-alpha secretion by cardiomyocytes and preventing post-burn cardiac contractile dysfunction. Thus, burn trauma-related sympathetic activity likely activates the stress-responsive cascade, which regulates myocardial TNF-alpha transcription/translation and culminates in cardiac contraction and relaxation defects.
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Comparative Study
Resuscitation from hemorrhagic shock with Ringer's ethyl pyruvate solution improves survival and ameliorates intestinal mucosal hyperpermeability in rats.
We previously showed that pretreatment with a solution of ethyl pyruvate in a calcium-containing balanced salt solution, Ringer's ethyl pyruvate solution (REPS), ameliorates gut mucosal damage in rats subjected to mesenteric ischemia/reperfusion. Herein, we sought to test the hypothesis that REPS would be beneficial as a post-treatment (i.e., resuscitation fluid) for hemorrhagic shock. Anesthetized Sprague-Dawley rats were bled to a mean arterial pressure (MAP) of 40 mmHg until 40% of shed blood was returned. ⋯ In Experiment 2, ileal FD4 clearances were 71 +/- 13* and 34 +/- 8 for rats treated with RLS and REPS (n = 5 each), respectively. Post-resuscitation levels of MDA in the ileum and liver were significantly lower in rats treated with REPS as compared with RLS. Resuscitation with REPS, a stable and nontoxic antioxidant solution, improves survival and ameliorates ileal mucosal permeability in a rat model of severe hemorrhagic shock.
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Although there are many reports of circadian variation in hormone secretion, there are only a few reports on the relationship between circadian rhythm and cytokine production. The aim of the present studies was to investigate whether there is a circadian effect on cytokine production of splenic lymphocytes and adherent splenocytes in mice after burn or sham injury. We selected day 7 after injury for our determinations because we have previously shown day 7 is the time of maximal suppression of T cell IL-2 and IFNgamma production and maximal increase in adherent cell proinflammatory cytokine secretion in this model. ⋯ IL-2 secretion was significantly decreased in burn compared to sham animals when splenocytes were harvested in the morning; the decrease was non-significant when splenocytes were harvested in the afternoon. TNFalpha secretion was significantly increased in burn vs. sham adherent cells only when injury took place in the morning. The observed circadian variations in cytokine production could have a significant effect on cytokine levels measured in clinical and animal studies of injury and may explain some of the reported discrepancies among these studies.
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Virtually of the all recent therapeutic interventions for treating sepsis have failed to improve survival. One potential explanation is that the heterogeneity of the immune response to the septic challenge is such that only a portion of the patients die as a result of excessive inflammation. The clinical trials lacked power because traditional measurements do not accurately identify these patients. ⋯ We tested the value of the IL-6 prediction by surgically resecting the cecum in those animals with IL-6 > 2000 pg/mL, which resulted in a significant improvement in survival. These data demonstrate that IL-6 measured 6 h after injury accurately predicts mortality resulting from experimental sepsis. This measurement may be determined quickly so that therapy may be targeted only to those individuals at significant risk of dying and initiated within sufficient time to be effective.