Inflammatory mediators and hepatocellular dysfunction

Hepatocellular dysfunction and multiple systems organ failure can occur after both sepsis and trauma without apparent infection; the unifying factor in all causes is an uncontrolled systemic inflammatory response. One hypothesis has been that the initiating event is activation or priming of polymorphonuclear cells by complement polypeptide C5a, gut-derived platelet activating factor, or lipopolysaccharide. Adhesion of these cells to hepatic endothelium occurs through selectins and intercellular adhesion molecules (ICAM-1), expression of which can be upregulated by other cytokines and platelet activating factor. Subsequent events may lead to generation of reactive oxygen species, cytokines, arachidonic acid derivatives, and nitric oxide (NO). Hepatic Kupffer cells may modulate this response and act as amplifiers, transmitting effects to sinusoidal lining cells and Ito cells controlling sinusoidal perfusion. Cytokines including IL-1, IL-6, and IL-8, which are liberated in large amounts during sepsis, have been implicated in many of the pathological processes occurring during endotoxemia, including alterations in hepatic protein synthesis. Tumor necrosis factor-a, released from neutrophils and endothelial cells by endotoxin, increases neutrophil activation, IL-1 production, and NO production by Kupffer cells. NO also depresses hepatic protein synthesis and, in turn, contributes to vascular hyporesponsiveness. The role of NO in modulating tissue injury is complex and may depend on the clinical context. Several studies have shown that it protects the liver from lipopolysaccharide-induced injury by acting as a vasodilator and partially reversing the effects of cytokines such as tumor necrosis factor-a. In contrast, during ischemia-reperfusion, NO production may contribute to hepatic injury by combining with oxygen free radicals to form peroxynitrite.

Healthy Fat Loss For A Longer Life

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