Alcoholic liver disease (ALD) is a serious consequence of alcohol abuse and results in a great deal of morbidity and mortality in the United States. The mechanisms that lead to ALD are poorly understood, and it is not known what factors are involved in the susceptibility for the development of ALD. The prevailing opinion is that some factor initiates an inflammatory response in the liver that is uncontrolled and ultimately results in the characteristic fibrosis associated with this process. Data from this laboratory have shown that a condition that resembles the sequence of events in ALD can be initiated in ethanol (ETOH)-fed C57Bl/6 mice after activation of T-lymphocytes by specific antigen or concanavalin A. These activation stimuli induce steatosis and hepatitis only in ETOH-fed mice, which ultimately result in liver damage evidenced by elevated serum levels of ALT and AST. These data support our suggestion that at least one factor involved in initiation and development of ALD is a specific immune response in the liver. To test this hypothesis we propose to use these murine models of ALD and a model of viral hepatitis to define the mechanisms responsible for this immune - mediated liver damage. It is our specific hypothesis that initiation of the inflammatory process is the result of specific T cell-mediated killing, either through direct cellular cytotoxicity or through the production of cytotoxic cytokines of the infected hepatocyte. Further, we hypothesize that corticosteroid production associated with ETOH consumption has a twofold effect in this system. First, the immune response is suppressed by corticosteroids to inhibit the ability to control the replication of the infectious agents, results in more inflammation. Second, corticosteroids sensitizes hepatocytes to enhance destruction of these cells by either direct T-cell-mediated lysis or lysis mediated by inflammatory cytokines such as tumor necrosis factor. The proposed research will also define the specific cells that initiate or mediate liver damage as well as the role of the inflammatory response and inflammatory cytokines in these models of experimental ALD.
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