INTERLEUKIN 6 ROLE IN ALCOHOLIC LIVER CIRRHOSIS

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DESCRIPTION: (Adapted from the Investigator's Abstract): Alcohol-induced liver cirrhosis is a leading cause of death worldwide and accounts for over 50 percent of all deaths due to cirrhosis. There is no proven therapy for this deadly disease and, therefore, multiple attempts are being made at developing novel anti-fibrogenic agents based on the current knowledge of the pathophysiology of the disease. Both local and systemic events play a key role in the development of liver cirrhosis. At a local level, are fibrogenic and induce the expression of type I collagen genes by hepatic stellate cells. These cells are in controlling portal blood flow, producing excess type I collagen and contracting the wound. Liver macrophages and inflammatory cells produce the cytokines and growth factors that play a key role in activating hepatic stellate cells to make scar tissue. At the systemic level, the general response of the organism to non-factor-alpha and inteleukin-6, which are produced during the acute phase, play a key role in priming hepatic stellate cells to proliferate and make type I collagen. The investigator's long-term goals are to define molecular mechanisms whereby ethanol induces liver fibrosis and to develop novel and more rational anti-fibrogenic therapies based on these findings. In this application they propose experiments to unravel basic molecular events whereby the acute phase in general, and tumor necrosis factor-alpha and interleukin-6 in particular, contribute to the fibrogenic process. Thus, the PI will use modern techniques in cell and molecular biology to unravel signal transduction pathways involved in the activation of hepatic stellate cells and in establishing pathways through which the acute phase cytokines enhance the fibrogenic actions of acetaldehyde. Moreover, the investigators will test whether colchicine, an anti-inflammatory drug with anti-fibrogenic potential that ameliorates live cirrhosis has an effect on the parameters to be investigated.