Ethanol produces liver disease both in injuring the liver and by impairing the regenerative response to that injury. Our objective is to identify mechanisms responsible for ethanol's anti-regenerative actions so that treatments can be designed to restore effective regeneration. Tumor necrosis factor a (TNF) has been incriminated in the pathogenesis of alcoholic liver injury. Consequently, drugs which prevent TNF's actions have been suggested as therapies for this disease. However, we have evidence that TNF is important in inducing the regenerative response to liver injury. Hence, indiscriminate treatment with anti-cytokine agents could be harmful in patients with active alcoholic liver injury because it may further compromise liver regeneration. To clarify this dilemma, we will test the following HYPOTHESIS: a) Cytokines, including TNF, which are released locally during liver injury are necessary to initiate the regenerative response to injury. b) Although liver regeneration is impaired by ethanol, initiation of regeneration is preserved because ethanol enhances local accumulation of, sensitivity to, TNF. c) Elimination of TNF superimposes a block in proliferative cascades already compromised by ethanol. Together, these could cripple the regenerative response. By comparing regeneration post-partial hepatectomy (PH) in normal rats pretreated with antibodies to TNF or control IgG, we have discovered that TNF promotes induction of """"""""immediate-early"""""""" growth-related genes and stimulates liver regeneration after PH. Furthermore, antibodies to TNF virtually eliminate post-PH DNA synthesis in ethanol-fed rats. Therefore, we propose 5 SPECIFIC AIMS to determine if: 1) Focal liver injury (PH) induces hepatic or generalized accumulation of TNF 2) Accumulation of TNF initiates local or generalized induction of """"""""immediate-early"""""""" growth-related genes 3) Ethanol enhances hepatic accumulation of TNF or TNF induction of immediate early genes and 4) Ethanol prevents activation of """"""""downstream"""""""" effector molecules in the proliferative cascade.
In Specific Aim 5, primary hepatocyte cultures will be used to determine if TNF directly promotes, and ethanol inhibits, activation of immediate early genes or DNA synthesis and define the conditions in which these effects occur. This work will provide clinically relevant information about potential therapeutic limitations of anti-cytokine agents and further characterize the molecular mechanisms responsible for ethanol-associated growth inhibition.
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