J Trauma
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Supporting its therapeutic application in sepsis, p38 mitogen-activated protein kinase (MAPK) inhibition decreases cardiopulmonary injury and lethality with lipopolysaccharide challenge. However, only one preclinical study has reported the survival effects of a p38 inhibitor (SB203580, 100 mg/kg) during infection. We therefore tested SB203580 in mice (n = 763) challenged with intratracheal Escherichia coli and treated with antibiotics and fluids. ⋯ Thus, SB203580 had divergent effects on cardiac and lung function in E. coli challenged mice. Furthermore, high dose worsened survival and low dose did not improve it. Altogether, these findings suggest that clearly defining the risks and benefits of p38 MAPK inhibition is important before such treatment is applied in patients with or at risk of serious infection.
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Severe injury can cause intestinal permeability through decreased expression of tight junction proteins, resulting in systemic inflammation. Activation of the parasympathetic nervous system after shock through vagal nerve stimulation is known to have potent anti-inflammatory effects; however, its effects on modulating intestinal barrier function are not fully understood. We postulated that vagal nerve stimulation improves intestinal barrier integrity after severe burn through an efferent signaling pathway, and is associated with improved expression and localization of the intestinal tight junction protein occludin. ⋯ Vagal nerve stimulation performed before injury improves intestinal barrier integrity after severe burn through an efferent signaling pathway and is associated with improved tight junction protein expression.
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Tissue injury from mechanical trauma modulates innate immunity. The resultant systemic inflammatory response syndrome (SIRS) closely mimics clinical sepsis, and bacterial n-formyl peptides are septic mediators. Similar formyl peptides exist in mitochondria but little is known about their actions on human neutrophils (PMN). ⋯ Formylated mitochondrial proteins are potent immune activators. Acting through the FPR-1 receptor on professional phagocytes, MDP elicits [Ca]i release responses and Ca entry via G-protein-coupled pathways. MDP activates chemotaxis and respiratory burst. Our findings suggest a novel paradigm wherein one root cause of SIRS after trauma may be the release of mitochondrial fragments from mechanically damaged tissues. In this paradigm, mitochondrial debris "alarmins" alter host PMN phenotype, activating or suppressing immunity, predisposing to SIRS, sepsis or organ failure.
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Erythropoietin (EPO) can exert acute hemodynamic and anti-inflammatory effects in addition to erythropoiesis. We tested the hypothesis that EPO given at resuscitation with saline will improve capillary perfusion and tissue oxygenation in the gut using a hemorrhagic shock model. ⋯ Our results suggest that the addition of rHuEPO at the time of saline resuscitation may have beneficial effects in hemorrhagic shock by improving tissue perfusion and decreasing dysoxia in the gut.