The cell and molecular biology of hepatic fibrogenesis. Clinical and therapeutic implications

Much has been learned in the past 2 decades about the cellular and molecular mechanisms underlying hepatic fibrogenesis and about potential therapeutic approaches in patients with liver disease. The central event in fibrogenesis seems to be the activation of hepatic stellate cells. Stellate cell activation is characterized by several important features, including enhanced matrix synthesis and a prominent contractile phenotype, processes that probably contribute to the physical distortion and dysfunction of the liver in advanced disease. It is important to emphasize that the factors controlling activation are multifactorial and complex. The extracellular matrix is a dynamic, active constituent of the fibrogenic response and undergoes active remodeling, including synthesis and degradation. Effective therapy for hepatic fibrogenesis will probably also be multifactorial, based on the basic mechanisms underlying the fibrogenic process. The most effective therapies will probably be directed at the stellate cell. Approaches that address matrix remodeling (i.e., by enhancing matrix degradation or by inhibiting factors that prevent matrix breakdown) may be effective.