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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Previous studies show that chronic alcohol abuse is an independent risk factor for acute lung injury (ALI) and impairs alveolar epithelial barrier function through glutathione depletion. However, the precise molecular structures that are damaged by chronic ethanol ingestion have not been identified. To test whether chronic ethanol ingestion impairs the alveolar epithelium barrier by tight junction protein deterioration and predisposes to ALI, this study determined the alterations in tight junction proteins occludin, zonula occludens (ZO)-1, and adherens junction protein E-cadherin in alveolar epithelium and observed the protective effect of glutamine (Gln) supplementation. ⋯ Moreover, Gln supplementation markedly attenuated the enhanced bronchoalveolar epithelial permeability and decreased messenger RNA and protein expression of those molecules induced by ethanol and ethanol plus LPS. These data suggest that chronic ethanol ingestion impairs the alveolar epithelial barrier function via occludin, ZO-1, and E-cadherin deterioration, and predisposes to ALI. Glutamine supplementation has protective effect.
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Mitochondrial dysfunction is thought to play an important role in the pathogenesis of many different disease states. It has been proposed that an acquired defect in oxidative phosphorylation prevents cells from using molecular oxygen for adenosine triphosphate production and potentially causes sepsis-induced organ dysfunction. This concept, termed cytopathic hypoxia, however, has been difficult to prove because impaired oxidative phosphorylation has never been shown to cause sepsis-induced organ failure or to be a reversible phenomenon. Presented here is are view of oxidative phosphorylation, evidence of defective electron-transport-chain function in the heart and other organ systems during sepsis, and support for a link between mitochondrial dysfunction and pathologic metabolic down-regulation.
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Transmigration of neutrophil polymorphonuclear leukocytes through the microvascular endothelium is a cardinal event of acute inflammation. In vitro, this process can be restricted by gap junctional intercellular communication, but whether it also occurs in vivo is unknown. Connexin 40 (Cx40) is a gap junctional protein abundantly present in the lung, notably in vascular endothelium. ⋯ The time points for studies with the knockout mice were chosen in such a manner that inflammation was clearly present and Cx40 still largely expressed in wild-type animals. In either model, the development of lung inflammation did not differ between wild-type and Cx40-deficient mice. In conclusion, the pulmonary expression of the Cx40 protein is progressively and markedly decreased in two different murine models of acute lung inflammation, but there is no causal relationship between this process and the pulmonary transmigration of neutrophils.
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Complement activation has been reported after major trauma. However, little is known about the clinical relevance and the mechanisms of complement activation early after trauma. Therefore, the aim of this study was to measure complement activation, to identify the roles of injury severity and hypoperfusion, to determine the predominant activated pathway, and to identify the clinical significance of early complement activation in trauma patients. ⋯ Finally, in patients with low C3a levels, C5b-9 levels correlated with plasma levels of prothrombin fragments 1 + 2, a marker of thrombin generation, suggesting additional C3-independent complement activation by thrombin after severe trauma. In summary, complement activation via its amplification by the alternative pathway is observed early after trauma and correlates with injury severity, tissue hypoperfusion, and worse clinical outcomes. Besides complement activation by the classical and/or lectin pathways, there is an independent association between thrombin generation and complement activation.
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Sepsis-associated myocardial depression is associated with calcium desensitization and adrenergic uncoupling. We conducted a prospective randomized investigation on the effects of the calcium sensitizer, levosimendan, on hemodynamics, myocardial blood flow, and myocardial lactate metabolism during porcine endotoxemia. Twelve pigs were studied. ⋯ Myocardial blood flow remained unchanged in both groups; however, 80 min after the start of levosimendan infusion, left ventricular myocardial hypoxia ensued, as evidenced by a negative myocardial lactate gradient (P = 0.01). Two control and five levosimendan animals died before the end of the study. Early administration of levosimendan during porcine endotoxemia increased heart rate, caused arterial vasodilation, and decreased coronary perfusion pressure, resulting in myocardial hypoxia.