Pathophysiological mechanisms of hepatic stellate cells activation in liver fibrosis

Abstract

Liver fibrosis is a complex pathological process controlled by a variety of cells, mediators and signaling pathways. Hepatic stellate cells play a central role in the development of liver fibrosis. In chronic liver disease, hepatic stellate cells undergo dramatic phenotypic activation and acquire fibrogenic properties. This review focuses on the pathophysiological mechanisms of hepatic stellate cells activation in liver fibrosis. They enter the cell cycle under the influence of various triggers. The “Initiation” phase of hepatic stellate cells activation overlaps and continues with the “Perpetuation” phase, which is characterized by a pronounced inflammatory and fibrogenic reaction. This is followed by a resolution phase if the injury subsides. Knowledge of these pathophysiological mechanisms paved the way for drugs aimed at preventing the development and progression of liver fibrosis. In this respect, impairments in intracellular signaling, epigenetic changes and cellular stress response can be the targets of therapy where the goal is to deactivate hepatic stellate cells. Potential antifibrotic therapy may focus on inducing hepatic stellate cells to return to an inactive state through cellular aging, apoptosis, and/or clearance by immune cells, and serve as potential antifibrotic therapy. It is especially important to prevent the formation of liver cirrhosis since the only radical approach to its treatment is liver transplantation which can be performed in only a limited number of countries.

Keywords: Chronic liver disease, Liver fibrosis, Pathogenesis, Hepatic stellate cells, Activation, Pathophysiological mechanisms

Core tip: This review focuses on the pathophysiological mechanisms of hepatic stellate cells activation in liver fibrosis. A better understanding of these pathophysiological mechanisms gave rise to drugs preventing liver fibrosis development and progression. In this respect, the disorder of the intracellular signaling regulation, epigenetic changes, and cellular stress response can be the target of an action aimed at hepatic stellate cells deactivation. This can be achieved by inducing their return to an inactive state, cellular aging, apoptosis, and/or clearance by immune cells, and may serve as potential antifibrotic therapy.