Cellular and molecular mechanisms in the pathogenesis of liver fibrosis: An update

Abstract

There have been considerable recent advances towards a better understanding of the complex cellular and molecular network underlying liver fibrogenesis. Recent data indicate that the termination of fibrogenic processes and the restoration of deficient fibrolytic pathways may allow the reversal of advanced fibrosis and even cirrhosis. Therefore, efforts have been made to better clarify the cellular and molecular mechanisms that are involved in liver fibrosis. Activation of hepatic stellate cells (HSCs) remains a central event in fibrosis, complemented by other sources of matrix-producing cells, including portal fibroblasts, fibrocytes and bone marrow-derived myofibroblasts. These cells converge in a complex interaction with neighboring cells to provoke scarring in response to persistent injury. Defining the interaction of different cell types, revealing the effects of cytokines on these cells and characterizing the regulatory mechanisms that control gene expression in activated HSCs will enable the discovery of new therapeutic targets. Moreover, the characterization of different pathways associated with different etiologies aid in the development of disease-specific therapies. This article outlines recent advances regarding the cellular and molecular mechanisms involved in liver fibrosis that may be translated into future therapies. The pathogenesis of liver fibrosis associated with alcoholic liver disease, non-alcoholic fatty liver disease and viral hepatitis are also discussed to emphasize the various mechanisms involved in liver fibrosis.

Keywords: Liver; Liver fibrosis; Cirrhosis; Fibrogenesis; Hepatic stellate cells; Myofibroblast; Extracellular matrix

Core tip: Liver fibrosis is a dynamic process that results from an imbalance between the production and dissolution of the extracellular matrix. Development of liver fibrosis is orchestrated by many cell types, including hepatic stellate cells (HSCs). The activation of HCSs is a complex process, leading to multiple potential sites for therapeutic interventions. Additionally, the differences between the pathogenesis of liver fibrosis associated with different etiologies may provide the determination of new therapeutic approaches. This review summarizes the most significant data that has contributed to the understanding of the cellular and molecular pathogenesis of liver fibrosis, which may be translated into future therapeutic strategies.