The long-term objective of this proposal is to elucidate the mechanisms underlying alcohol-induced liver disease. In spite of decades of effort in the field, the mechanisms whereby alcohol induces liver disease are not fully elucidated. Novel approaches have to be undertaken in an attempt to understand the mechanisms of the disease and to develop new therapeutical means. This project proposes to test two hypotheses: 1) alcohol-induced exacerbation of liver cells' apoptotic (programmed/physiological) death is an early component of alcoholic liver disease, and 2) one of the plausible mechanisms whereby alcohol exacerbates such a way of cell death is modulation of enzyme effectors involved in the initiation and execution phases of apoptosis. Accordingly, this proposal has three specific aims: 1) to determine the temporal relationship between the alcohol-exacerbated apoptosis and alcoholic hepatitis during chronic exposure of laboratory animals to alcohol; 2) to determine if exacerbation of apoptosis by chronic exposure to alcohol augments the liver response to pathogenic factors and progression to hepatitis, and 3) to determine if alcohol modulates the rate of apoptosis in various liver cells by altering the effectors ofenzymes involved in apoptosis - caspases. To achieve these goals, rats will be chronically exposed to alcohol by means of feeding an alcohol- containing liquid diet for various periods of time, in order to develop alcoholic hepatitis, followed by subsequent assessment of the apoptotic state and injury of the liver. In order to evaluate a potential deleterious effect of an exacerbated apoptosis on the liver, the liver propensity to suffer injury from factors such as Gram-negative bacterial lipopolysaccharide or D-galactosamine will be measured after apoptosis suppression using caspase inhibitors. Finally, by applying molecular biological, biochemical and cell physiological procedures, the project proposes to determine the effect of chronic alcohol exposure on the amount/expression of a number of pro- and anti- apoptotic factors in order to establish whether alcohol exacerbates apoptosis by altering these factors. The project will provide essential information which will: 1) bring novel elements in our understanding of the alcoholic liver disease, and 2) pave the way to novel therapeutical approaches to control the disease.
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