Liver fibrogenesis and the role of hepatic stellate cells: New insights and prospects for therapy

Abstract

cation of apoptotic mediators in stellate cells and exploration of their role in clearance of activated stellate cells during the resolution of liver injury.A more comprehensive picture of liver fibrogenesis is thus emerging. This review will emphasize areas of recent progress in understanding liver fibrosis and how these exciting insights will contribute to the generation of effective therapies in the future. EXTRACELLULAR MATRIX: THE MICROENVIRONMENT OF HEPATIC FIBROSIS Extracellular matrix in normal and fibrotic liverThe extracellular matrix refers to the array of macromolecules that comprise the scaffolding of normal and INTRODUCTIONHepatic fibrosis is a wound healing or scarring process which arises in response to liver damage. This response is an attempt to encapsulate injury, but in doing so, liver function is ultimately impaired.The hepatic response to injury represents a paradigm for wound healing in other tissues including skin, lung and kidney, as it involves many of the same cell types and mediators. 1 There has been exciting progress in understanding hepatic fibrosis. Advances have occurred in the following areas: (i) characterization of components of the extracellular matrix (ECM) in normal and fibrotic liver; Department of Medicine and Liver Diseases, Mount Sinai School of Medicine, New York, USAAbstract Hepatic fibrosis is a wound-healing response to chronic liver injury, which if persistent leads to cirrhosis and liver failure. Exciting progress has been made in understanding the mechanisms of hepatic fibrosis. Major advances include: (i) characterization of the components of extracellular matrix (ECM) in normal and fibrotic liver; (ii) identification of hepatic stellate cells as the primary source of ECM in liver fibrosis; (iii) elucidation of key cytokines, their cellular sources, modes of regulation, and signalling pathways involved in liver fibrogenesis; (iv) characterization of key matrix proteases and their inhibitors; (v) identification of apoptotic mediators in stellate cells and exploration of their roles during the resolution of liver injury. These advances have helped delineate a more comprehensive picture of liver fibrosis in which the central event is the activation of stellate cells, a transformation from quiescent vitamin A-rich cells to proliferative, fibrogenic and contractile myofibroblasts. The progress in understanding fibrogenic mechanisms brings the development of effective therapies closer to reality. In the future, targeting of stellate cells and fibrogenic mediators will be a mainstay of antifibrotic therapy. Points of therapeutic intervention may include: (i) removing the injurious stimuli; (ii) suppressing hepatic inflammation; (iii) down-regulating stellate cell activation; and (iv) promoting matrix degradation. The future prospects for effective antifibrotic treatment are more promising than ever for the millions of patients with chronic liver disease worldwide.

Halofuginone upregulates the expression of heparanase in thioacetamide-induced liver fibrosis in rats

“…Several studies of either human patients or animal models have shown that recovery and remodeling of fibrotic liver is possible. 5,33,34 We have used TAA to induce liver fibrosis in rats. Based on histology and hydroxyproline concentration, 6 weeks of TAA administration twice weekly inflicted liver damage graded as advanced fibrosis according to the Ishak scoring system.…”

The role of P2X7 receptors in tissue fibrosis: a brief review

“…Liver fibrosis refers to the accumulation of fibrous scar tissue caused by the excessive accumulation of ECM [63,64] by activated hepatic stellate cells (HSCs) [65][66][67] induced by fibrogenic cytokines such as TGF-β1 [68]. Studies using models of hepatic fibrosis in transgenic mice have revealed IL-1β and TGF-β1 as key players mediating liver fibrogenesis [69,70].…”

Immortalization of pancreatic stellate cells as an in vitro model of pancreatic fibrosis: deactivation is induced by matrigel and N-acetylcysteine

“…[1][2][3][4] In liver cirrhosis, hepatic stellate cells (HSC) have been identified to be the main source of extracellular matrix (ECM) deposition. [5][6][7] Similarly, the recently identified pancreatic stellate cells (PSC) have been implicated in the development of fibrotic tissue in the pancreas in chronic pancreatitis and in pancreatic cancer. [8][9][10][11][12] Moreover, these cells seem to contribute to tissue regeneration after acute necrotizing pancreatitis.…”