REGULATION OF COLLAGEN EXPRESSION IN HEPATOCYTES

点击翻译按钮获取中文摘要

Hepatic fibrosis, a common sequela of toxic liver injury, is characterized by an accumulation of fibrous connective tissue, often resulting in a disruption of the normal lobular architecture of the liver. This pathologic process is often progressive, leading to cirrhosis, disordered hepatic function, and possibly death. The pathogenesis of hepatic fibrosis is unknown. The metabolism of the protein collagen, the major component of hepatic connective tissue, is undoubtedly of importance in this disease process. Current concepts of hepatic collagen metabolism, based largely on experiments in the living animal, indicate that both an increased rate of collagen synthesis and a decreased rate of collagen degradation may account for the increased collagen content in fibrotic liver. However, until recently, identification of all of the cells which synthesize or degrade collagen or of the factors which regulate these processes has not been accomplished. The lack of this essential information is largely due to methodologic limitations and the complexity of the intact animal as an experimental model of hepatic fibrosis. New developments have made liver cell culture an attractive technique to facilitate the study of hepatic collagen metabolism in vitro. Primary cultures of adult rat parenchymal cells in monolayer have proven useful to investigate collagen synthesis and degradation in the liver. Current studies from this laboratory have demonstrated that hepatocytes have the potential to synthesize multiple forms of collagen. Therefore, this cell culture system will be used to study the regulation of hepatocellular collagen synthesis by the extracellular matrix, glucocorticoid steroids, and soluble mediators from non-parenchymal liver cells. These interactions will be studied at the cellular and molecular level. Whole animal studies will also be performed using both molecular biology methods and physiologic procedures to begin relating in vitro findings to the intact liver. These basic studies of rat hepatocytes are directed toward the future understanding of hepatic collagen deposition and its regulation. The overall goal of this project is to provide in-depth information about hepatic collagen metabolism and to provide a basis for constructing a rational approach to the eventual treatment of human hepatic fibrosis.