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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Activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) has been shown to promote cellular energetic collapse and cellular necrosis in various forms of critical illness. Most of the evidence implicating the PARP pathway in disease processes is derived from preclinical studies. With respect to PARP and burns, studies in rodent and large animal models of burn injury have demonstrated the activation of PARP in various tissues and the beneficial effect of its pharmacological inhibition. ⋯ We conclude that human burn injury is associated with the activation of PARP. We hypothesize that this response may contribute to the inflammatory responses and cell dysfunction in burns. Some of the clinical benefit of propranolol in burns may be related to its inhibitory effect on PARP activation.
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We hypothesized that circulating levels of lipid peroxidation products in patients with severe sepsis are associated with the development of pulmonary, renal, hepatic, circulatory, and coagulation failure. Plasma levels of F2-isoprostanes and isofurans were measured by mass spectroscopy on intensive care unit day 2 in 50 critically ill patients with severe sepsis. Plasma F2-isoprostane levels were higher in patients who developed renal failure compared with those who did not (65 pg/mL [interquartile range {IQR} 44-112] vs. 44 pg/mL [IQR 29-54], P = 0.009) as were isofuran levels (1,223 pg/mL [IQR 348-2,531] vs. 329 pg/mL [IQR 156-1,127], P = 0.009). ⋯ Patients with isoprostane levels above the 25th percentile had higher mortality (42%) compared with patients with levels below the 25th percentile (8%, P = 0.03). Plasma levels of F2-isoprostanes and isofurans are associated with renal, hepatic, and coagulation failure, but not with circulatory or pulmonary failure in severe sepsis, suggesting that lipid peroxidation is a prominent feature of septic multisystem organ failure. Plasma isoprostanes and isofurans may be useful for monitoring oxidative stress in treatment trials of antioxidant therapies in severe sepsis.
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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.