The most common cause of death of septic surgical patients is now the multiple system organ failure syndrome (MSOF). Although renal failure and respiratory failure can be counteracted by external support systems, hepatic failure cannot. One hypothesis for the possible pathogenesis of hepatic failure in septic surgical patients deserves further study; The Kupffer cells, specialized macrophages within the liver sinusoids, receive and normally clear the bloodstream of circulating septic stimuli. In the process they become stimulated, which may lead in turn, to the production of mediators that alter the function of contiguous hepatocytes. We have obtained a significant body of preliminary data supporting this hypothesis. These data derive from direct co-cultivation of Kupffer cells (or macrophages) and hepatocytes. Septic stimuli (lipopolysaccharide or killed bacteria) added to co-culture resulted in a significant depression in protein synthesis of the hepatocytes. In contrast, co-culture in the absence of septic stimuli markedly enhanced hepatocyte protein synthesis. The same septic stimuli had no direct effect on protein synthesis of hepatocytes cultured alone (without Kupffer cells or macrophages). Subsequent experiments have indicated that Kupffer cells may modulate hepatocyte protein synthesis via soluble (? protein) monokines. The present grant proposal is designed: 1) to characterize the role of hepatocyte:Kupffer cell interactions in alterations of hepatocyte function in surgical sepsis, 2) to determine the mechanism(s) or mediator(s) through which Kupffer cells/macrophages alter hepatocyte function. Though the Kupffer cell mediated effects may represent a physiologic modulation of hepatocyte function, a continuum between physiologic alterations and pathologic injury may exist.
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