The broad focus of the proposed research has been the cellular basis of hepatic fibrosis. It is postulated that hepatic lipocytes (a resident cell population also known as Ito cells or fat-storing cells) play the central role. Lipocytes respond to liver injury by proliferating and increasing their production of extracellular matrix (ECM) proteins, a process termed activation. The proposed work will be conducted with lipocytes in primary culture. During the past 2 years, it was shown that lipocytes in culture under appropriate conditions undergo changes that reproduce activation as seen in the intact liver. The process appears to occur in two stages: the first stage (initiation) is controlled by a factor released by Kupffer cells (hepatic macrophages and termed lipocyte Stimulating Factor (LSF). The second stage (perpetuation) encompasses the response of lipocytes to ECM, which has regulatory effects on its own. The future plans are to chemically characterize LSF and study its production; to investigate the mechanism of receptor induction by lsf; and to study the role of ECM in lipocyte activation. The results will have direct relevance to mechanisms of mesenchymal cell activation as well as implications for therapeutic intervention in the common and debilitating condition of hepatic cirrhosis.
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