Alcoholic hepatitis is a serious and potentially fatal complication of chronic alcohol abuse. The condition is marked by recruitment of inflammatory cells, in particular neutrophils, to the liver parenchyma. Once neutrophils invade the liver they can actively attack and destroy hepatocytes. The overall objectives of this research project are to determine how chronic alcohol consumption signal neutrophils to invade the liver, and how neutrophils and their chemoattractants cause liver damage. The main focus of the research will be on C-X-C chemokines. C-X-C chemokines are potent neutrophil chemoattractants and activators; when produced in the liver in vivo, they cause a severe neutrophilic hepatitis. In the setting of chronic ethanol abuse, C-X-C chemokines are induced in the liver and are believed to promote alcoholic hepatitis. However, the mechanism by which chronic ethanol consumption stimulates chemokine production is uncertain. Based on work to date, the investigators propose that ethanol alone is insufficient to induce hepatic chemokine production in vivo. The P.I. will explore the possibility that a cofactor, namely endotoxin, acts in conjunction with ethanol to stimulate C-X-C chemokine production by liver cells in intact rats. The investigators will address this question by administering low-dose endotoxin to ethanol-fed rats over a 4-wk interval, and by determining whether both insults induce C-X-C chemokines even if each alone does not. In separate studies they will investigate how C-X-C chemokines actually cause liver injury. Based on preliminary data, they propose that they induce liver damage by two independent mechanisms: one involving neutrophil recruitment and activation, and the other involving direct cytotoxicity toward hepatocytes. The investigators intend to explore this further by examining chemokine effects on liver cells in culture and in vivo. Cell culture studies will permit them to determine whether C-X-C chemokines cause death by apoptosis or necrosis, and whether they exert their effects intracellularly or by binding to cell-surface receptors. Studies in vivo will allow them to determine the extent to which neutrophils and direct cytotoxicity each contribute to chemokine-induced liver damage. Finally, they will investigate whether the adverse effects of chemokines are enhanced by chronic ethanol consumption.
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