Anti-fibrogenic strategies and the regression of fibrosis

Abstract

Liver fibrosis is an outcome of many chronic diseases, and often results in cirrhosis, liver failure, and portal hypertension. Liver transplantation is the only treatment available for patients with advanced stage of fibrosis. Therefore, alternative methods are required to develop new strategies for anti-fibrotic therapy. Available treatments are designed to substitute for liver transplantation or bridge the patients, they include inhibitors of fibrogenic cytokines such as TGF-β1 and EGF, inhibitors of rennin angiotensin system, and blockers of TLR4 signalling. Development of liver fibrosis is orchestrated by many cell types. However, activated myofibroblasts remain the primary target for anti-fibrotic therapy. Hepatic stellate cells and portal fibroblasts are considered to play a major role in development of liver fibrosis. Here we discuss the origin of activated myofibroblasts and different aspects of their activation, differentiation and potential inactivation during regression of liver fibrosis.

Figure 1

Three sources of myofibroblasts have been proposed in fibrotic liver: resident cells (Hepatic stellate cells and portal fibroblasts); BM-derived cells (fibrocytes and mesenchymal cells), and cells originated by epithelial-to-mesenchymal transition (EMT or EndMT) and. Hence, recent studies suggested that EMT does not significantly contribute to liver fibrosis. Modified from .

Figure 2

The Renin Angiotensin pathway. The entire pathway is expressed in the fibrotic liver. ACE1 generates the fibrogenic Angiotensin II, which in turn binds to its receptor AT1 to activate NADPH oxidase (NOX). ACE2 has anti-fibrotic effects and degrades angiotensin II and apelin-12.