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 recently reported that cerebral and cardiac injuries are mitigated in immature female piglets after severe hemorrhage with subsequent cardiac arrest. Female sex was also associated with a smaller increase in the cerebral expression of inducible nitric oxide synthase (iNOS) and neuronal nitric oxide synthase (nNOS). In the current study, we tested the hypothesis that exogenously administered 17β-estradiol (E₂) can improve neurological outcome by NOS modulation. ⋯ There was a significant correlation between nNOS and iNOS levels and neuronal injury. Interestingly, estradiol attenuated cerebral damage (including lower activation of nNOS and iNOS) both in male and female piglets. In conclusion, in our immature piglet model of hypovolemic cardiac arrest, E₂ downregulates iNOS and nNOS expression and results in decreased blood-brain-barrier permeability disruption and smaller neuronal injury.
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The influence of the gut-lung axis on the lung immunity, although appreciated, remains undefined mechanically. This study was designed to investigate whether commensal microflora in gut increase host defense against subsequent pneumonia through toll-like receptor (TLR) signaling and if oral TLR4 ligand supplementation enhances lung defense against bacterial challenge. We found that commensal gut depletion by antibiotic pretreatment before Escherichia coli pneumonia challenge induced a 15-fold and a 3-fold increase in bacterial counts in blood and lung, respectively, and a 30% increase of mortality when compared with the E. coli group. ⋯ Furthermore, LPS supplementation during antibiotic pretreatment reversed these effects. Commensal depletion also decreased bacterial killing activity of alveolar macrophages and increased IL-6 as well as IL-1β levels and keratinocyte-derived chemokine, macrophage inflammatory protein 2, and IL-1β expression of lung, and LPS supplementation reversed them. In conclusion, commensal gut microflora in the intestinal tract appear to be critical in inducing TLR4 expression as well as nuclear factor κB activation of intestine and lung innate defense against E. coli pneumonia.
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The reduction of neutrophil migration to an infectious focus is associated with a high mortality in severe sepsis. Previously, we showed that heme oxygenase (HO) products downregulate neutrophil recruitment in a noninfectious inflammatory model. The present study was designed to determine the role of HO in sepsis induced by cecal ligation and puncture (CLP) model. ⋯ Furthermore, hemin resulted in a reduction of neutrophil migration both in vivo and in vitro. Altogether, our results demonstrated that pretreatment with the HO inhibitor prevents the pathological findings in severe CLP. However, the combination of pretreatment plus posttreatment with ZnPP IX enhances sepsis severity because of an increase in circulating levels of heme, which is deleterious to the host tissues and also inhibits neutrophil migration.