TNF ALPHA AND RECOVERY FROM ALCOHOLIC LIVER INJURY

Johns Hopkins University, Baltimore MD

Investigators

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Abstract

DESCRIPTION: (Adapted from Investigator's Abstract) Ethanol produces liver disease by injuring the liver and by impairing the regenerative response. The investigator's goal is to identify mechanisms responsible for ethanol's anti-regenerative actions so that treatments can be designed to restore regeneration. Evidence obtained during the last grant indicates that tumor necrosis factor alpha (TNF) (an endotoxin-inducible cytokine involved in alcoholic liver injury) is a key mitogenic factor during liver regeneration. Ethanol-treated animals require TNF for liver regeneration after partial hepatectomy (PH), exhibiting almost no induction of hepatocyte DNA synthesis when treated with agents that neutralize TNF. Preliminary data suggest that specific TNF-dependent proliferative events are inhibited by chronic ethanol consumption although ethanol increases hepatic expression of TNF mRNA. This discrepancy between TNF expression and biological activity suggests that chronic ethanol exposure decreases biologically active TNF protein (despite increasing TNF mRNA) and/or changes hepatocyte sensitivity to TNF. Since both TNF expression and target cell sensitivity to TNF are regulated by other cytokines, this suggests that chronic ethanol exposure disturbs a network of interactive, endotoxin-inducible cytokines that regulate the regenerative response to liver injury. This project will test the hypothesis that PH permits endotoxemia which triggers a cascade of cytokines that cooperate to regulate hepatocyte proliferation. Chronic exposure to ethanol disturbs this cytokine network, resulting in a change in the hepatocyte phenotype that prevents proliferation despite enhanced local accumulation of TNF. Three specific aims are proposed: 1) To identify the TNF-related cytokines that are induced in the liver after PH, characterize the temporal pattern of their expression, and clarify the role of gut-derived endotoxin (LPS) in PH-induction of these genes; 2) To determine if acute or chronic consumption of ethanol alters expression of any of these cytokines before or after PH, and if so, whether this can be explained by increased portal or systemic endotoxemia; 3) To identify which TNF-regulated events in proliferative signaling are inhibited by ethanol, determine if inhibited proliferation predisposes hepatocytes to TNF toxicity, and assess whether proliferative signaling can be restored by "normalizing" the cytokine network.