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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STAT3-mediated IL-17 production by postseptic T cells exacerbates viral immunopathology of the lung.
Survivors of severe sepsis exhibit increased morbidity and mortality in response to secondary infections. Although bacterial secondary infections have been widely studied, there remains a paucity of data concerning viral infections after sepsis. In an experimental mouse model of severe sepsis (cecal ligation and puncture [CLP]) followed by respiratory syncytial virus (RSV) infection, exacerbated immunopathology was observed in the lungs of CLP mice compared with RSV-infected sham surgery mice. ⋯ This increased IL-17 production correlated with increased STAT3 transcription factor binding to the IL-17 promoter in CD4 T cells from CLP mice. Furthermore, in vivo neutralization of IL-17 before RSV infection led to a significant reduction in virus-induced mucus production and TH2 cytokines. Taken together, these data provide evidence that postseptic CD4 T cells are primed toward IL-17 production via increased STAT3-mediated gene transcription, which may contribute to the immunopathology of a secondary viral infection.
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Clinical Trial
Factors influencing compliance with early resuscitation bundle in the management of severe sepsis and septic shock.
The Surviving Sepsis Campaign guidelines recommend implementing a 6-h resuscitation bundle, which has been associated with reduced mortality of patients presenting with severe sepsis or septic shock. However, this resuscitation bundle has not yet become a widely implemented treatment protocol. It is still unclear what factors are associated with the rate of compliance with the resuscitation bundle. ⋯ Factors related with lower compliance were cryptic shock (adjusted OR, 0.26; 95% CI, 0.13-0.52) and higher serum lactate levels (adjusted OR, 0.90; 95% CI, 0.82-0.98). Furthermore, we found several potential factors that influence compliance with the sepsis resuscitation bundle. To improve the compliance with the resuscitation bundle, interventions focusing on those factors will be needed.
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The endogenous bacteria have been hypothesized to play a significant role in the pathophysiology of critical illness, although their role in sepsis is poorly understood. The purpose of this study was to determine how commensal bacteria alter the host response to sepsis. Conventional and germ-free (GF) C57Bl/6 mice were subjected to Pseudomonas aeruginosa pneumonia. ⋯ However, in a separate set of experiments, gut apoptosis was similar between septic GF Rag-1 mice and septic GF wild-type mice. These data demonstrate that the endogenous bacteria play a protective role in mediating mortality from pneumonia-induced sepsis, potentially mediated through altered intestinal apoptosis and the local proinflammatory response. In addition, sepsis-induced lymphocyte-dependent increases in gut epithelial apoptosis appear to be mediated by the endogenous bacteria.
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Sepsis-triggered immune paralysis including T-cell dysfunction increases susceptibility to infections. Statins exert beneficial effects in patients with sepsis, although the mechanisms remain elusive. Herein, we hypothesized that simvastatin may attenuate T-cell dysfunction in abdominal sepsis. ⋯ Lastly, it was found that simvastatin reduced CLP-induced bacteremia. In conclusion, these novel findings suggest that simvastatin is a powerful regulator of T-cell immune dysfunction in abdominal sepsis. Thus, these protective effects of simvastatin on T-cell functions help to explain the protective effect of statins in patients with sepsis.
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Neutrophils and non-muscle myosin light chain kinase (nmMLCK) have been implicated in intestinal microvascular leakage and mucosal hyperpermeability in inflammation and trauma. The aim of this study was to characterize the role of nmMLCK in neutrophil-dependent gut barrier dysfunction following thermal injury, a common form of trauma that typically induces inflammation in multiple organs. Histopathological examination of the small intestine in mice after a full-thickness burn revealed morphological evidence of mucosa inflammation characterized by neutrophil infiltration into the lamina propria, epithelial contraction, and narrow villi with blunt brush borders and loss of goblet cells. ⋯ Consistent with the in vivo observations, in vitro assays with Caco-2 epithelial cell monolayers revealed a decrease in transcellular electric resistance coupled with myosin light chain phosphorylation, actomyosin ring condensation, and claudin-1 internalization upon stimulation with fMLP (N-formyl-methionyl-leucyl-phenylalanine)-activated neutrophils. Pretreatment of the cells with the MLCK inhibitor ML-7 prevented the tight junction responses. Taken together, the results suggest that nmMLCK plays an important role in neutrophil-dependent intestinal barrier dysfunction during inflammatory injury.