Liver cirrhosis is among the leading causes of death worldwide. Approximately 50% of the deaths attributable to liver cirrhosis recognize alcohol as the main ethiologic agent. Currently, there is no accepted treatment for this disease. The available treatment is directed primarily to complications of cirrhosis and not to inhibit the inflammatory or fibrogenic mechanisms. Close to 3 billion dollars were spent for the treatment of patients with liver cirrhosis in 1992. Therefore, the development of a treatment for this disease will relieve the suffering of hundreds of thousands and will save the USA government millions of dollars. Patients with alcoholic hepatitis have several of the manifestations of the acute-phase response (APR). They also have elevated levels of IL-1, IL-6 and TNF-alpha. These same cytokines are involved in cell injury and production of extracellular matrix by liver fat-storing cells. We have obtained evidence to suggest that IL-6 is a fibrogenic cytokine that induces the expression of alpha1(I) procollagen mRNA. In addition, TNF-alpha is a cytokine that mediates cell injury. Therefore, drugs that inhibit synthesis and/or secretion of cytokines or that prevent their biological activity could ameliorate liver cirrhosis. Colchicine is an orphan drug that has been used successfully for the treatment of cirrhosis. However, its mechanism of action remains to be elucidated. Recent evidence suggests that colchicine inhibits the release of cytokines and growth factors, prevents the cytotoxic effect of TNF-alpha and enhances the release of TNF-alpha soluble receptors. The long-term objectives of this proposal are to evaluate the contribution of the APR, and of IL-1, IL-6 and TNF-alpha in the development of liver cirrhosis and explore the anti-inflammatory and anti-fibrogenic potential of colchicine.
Our specific aims are: (1) To investigate the mechanisms by which the APR contributes to liver fibrosis and to determine the molecular mechanisms by which cytokines modulate type I collagen gene expression in fat-storing cells. The mechanisms by which colchicine prevents the APR will be explored. (2) To study the role of IL-1, IL-6 and TNF-alpha in inducing excess matrix deposition in a rat model of alcoholic cirrhosis, and evaluate the effectiveness of colchicine as a therapeutic agent for alcoholic liver cirrhosis. If we could better understand the mechanisms by which colchicine prevents liver fibrosis and improves liver function we could test the anti-inflammatory and anti-fibrogenic potential of many compounds, including a large number of colchicine derivatives currently available.
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