Conventional treatment options for alcoholic liver disease have, in general, not been successful either in reversing liver injury or preventing progression in patients who continue to abuse alcohol. Current understanding of alcoholic liver injury revolves around the roles of endotoxin and oxidative stress. These stimuli acting in concert lead to upregulation of cyclooxygenase-2 (Cox-2). Based on studies in Cox-2 deficient mice and the intragastric feeding rat model for alcoholic liver disease, induction of Cox-2 appears to be a final common pathway for alcoholic liver injury. The studies proposed will evaluate the role of Cox-1 and Cox-2 in alcoholic liver injury and test the role of specific Cox inhibitors in preventing and reversing established alcohol-induced liver injury. A specific Cox-2 inhibitor and a non-specific Cox inhibitor (indomethacin) will be administered to rats fed ethanol intragastrically and their effects on the development of pathological changes, endotoxin levels, lipid peroxidation and cytokines will be evaluated. Based on our preliminary studies that show that Indomethacin aggravates liver injury, another drug with higher Cox-2 selectivity (Meloxicam) will be used in the prevention/treatment studies. Additionally, the effects of the drugs will be tested in a model (CCI4) in which extensive fibrosis is seen. The effect of the Cox inhibitors (Cox-2 and Meloxicam) in reversing established alcoholic liver injury will also be tested in rats by simulating an in-hospital alcoholic hepatitis setting and an outpatient alcoholic liver disease setting. In the first set of experiments (in-hospital model), rats will be fed a fish oil- ethanol diet for 6 weeks to induce liver injury. After discontinuing ethanol, the Cox-2 inhibitor or Meloxicam will be administered for two weeks with fish oil and dextrose. In the outpatient model, rats will be fed the fish oil-ethanol diet for 6 weeks followed by two weeks of treatment with the Cox-2 inhibitor or Meloxicam with continued ethanol administration. In both models, reversal of inflammatory and fibrotic changes will be evaluated. The prevention and treatment of alcoholic liver injury by Cox-2 inhibitors in these experiments should provide data for the testing of these drugs in patients with alcoholic liver disease.
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