Profound changes in liver function accompany the host's response to severe infections (sepsis) or trauma. These responses can be physiologic, as in the acute phase response, or pathologic, as in the often-fatal liver failure associated with multiple organ failure. Even though the external signals (IL-6, IL-1, TNF) inducing the acute phase response are known, the intracellular second messengers and regulating process are not understood. Also unknown is the cause of the metabolic defect in hepatocytes which induce the liver failure associated with the organ failure syndrome. Work by the principal investigator has shown that liver cells (Kupffer cells and hepatocytes) exposed to septic stimuli produce significant quantities of nitric oxide, a highly reactive compound derived from L-arginine. Based on the known biologic functions of authentic nitric oxide in other systems and cell types, it is hypothesized in this proposal that hepatocyte-derived nitric oxide contributes to both the physiologic and pathologic responses of liver cells in sepsis. By activating enzymes involved in internal signal transduction, such as guanylate cyclase or ADP-ribosyltransferase, nitric oxide might play a role in regulating intracellular processes during the acute phase response. Nitric oxide released by liver cells into the extracellular space might protect the hepatocytes from adjacent activated Kupffer cells or infiltrating inflammatory cells by inhibiting cellular responses or detoxifying oxygen radicals. Through its action as a platelet disaggregating agent, hepatocyte-derived nitric oxide might function to prevent intrahepatic thrombosis. Larger quantities of nitric oxide can inactivate specific mitochondrial enzymes; therefore, excessive or prolonged nitric oxide production might have pathologic consequences by interfering with hepatocyte mitochondrial respiration. All of these possibilities will be thoroughly tested using cultured hepatocytes induced to synthesize nitric oxide endogenously or hepatocytes exposed to exogenous nitric oxide. To correlate in vitro and in vivo responses, hepatocytes will be stimulated to produce nitric oxide in vitro by exposing animals to inflammatory stimuli. Studies on hepatocytes isolated from these animals will seek to demonstrate the effects of in vivo nitric oxide production on hepatocytes. In addition the kinetics and specific signals of in vitro and in vivo hepatocyte nitric oxide production will be completely characterized.
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