Pathogenesis of Liver Fibrosis

Abstract

1. Liver fibrosis is a common sequel to diverse liver injuries. It is characterized by an accumulation of interstitial collagens and other matrix components. The hepatic stellate cell is pivotal to the pathogenic process. Fibrotic liver injury results in activation of the hepatic stellate cell which undergoes a phenotypic change to a proliferative myofibroblast-like cell which synthesizes excess interstitial collagens and other matrix components. 2. The process of initiation of activation and its perpetuation result from complex, often interrelated series of signalling mechanisms which converge on this effector cell. Such mechanisms include alterations in matrix resulting in changed cell-matrix interactions and stimulation by cytokines released from damaged hepatocytes, infiltrating inflammatory cells, Kupffer cells and matrix. Foremost among the profibrotic cytokines is transforming growth factor beta 1. 3. Once the hepatic stellate cell is activated the preceding matrix changes and recurrent injurious stimuli will perpetuate the activated state. 4. Despite the accumulation of excess collagens, the liver retains a capacity for matrix degradation. This capacity may be overwhelmed and any secreted matrix remodelling enzymes may be inhibited by the concurrently secreted tissue inhibitors of metallo-proteinase-1 and alpha 2-macroglobulin. 5. Our understanding of the molecular pathogenesis of liver fibrosis is increasing. It is anticipated that this knowledge will provide novel therapeutic avenues to treat this disease process.

Matrix metalloproteinase-2 activation in human hepatic fibrosis regulation by cell-matrix interactions

“…4 It is suggested that, during fibrogenesis, alterations in subendothelial matrix composition promote activation of HSCs. 3 This assumption is strongly supported by cell culture experiments that show that the quiescent HSC phenotype is rapidly lost when the cells are cultivated on type I collagen or on plastic, whereas it is retained on a basement membrane-like matrix. 5,6 Elucidation of the mechanisms controlling the degradation of the normal perisinusoidal matrix is therefore of importance to better understand the early events that promote the development of liver fibrosis.…”

“…A number of studies have emphasized the profibrogenic functions of MMP-2 during the early phase of hepatic fibrogenesis. 3,20,21,51 It was suggested that MMP-2 might promote myofibroblastic transdifferentiation of quiescent HSC through remodeling of the normal subendothelial matrix. 3 However, the mechanisms leading to MMP-2 activation in the fibrotic liver have not been clearly delineated.…”

“…3,20,21,51 It was suggested that MMP-2 might promote myofibroblastic transdifferentiation of quiescent HSC through remodeling of the normal subendothelial matrix. 3 However, the mechanisms leading to MMP-2 activation in the fibrotic liver have not been clearly delineated. Although our results obtained with late passaged cells need to be confirmed in early activated transitional cells, we suggest the following sequence of events: (1) in response to a fibrogenic stimulus, HSC start to transdifferentiate into myofibroblastic cells, synthesize type I collagen and up-regulate pro-MMP-2 expression; (2) type I collagen deposited around transitional or fully transdifferentiated cells leads to increased expression of MT1-MMP protein in these cells, thereby stimulating pro-MMP-2 activation; (3) active MMP-2 degrades the normal perisinusoidal matrix, thereby amplifying the transdifferentiation process and promoting activation of nontransformed HSC.…”

“…This process is promoted by a variety of cytokines or soluble factors released by Kupffer cells, inflammatory cells, and injured hepatocytes, as well as by changes in the composition of the perisinusoidal matrix surrounding HSCs. 3 In normal liver, HSCs are embedded in a basement membrane-like matrix rich in type IV collagen. 4 It is suggested that, during fibrogenesis, alterations in subendothelial matrix composition promote activation of HSCs.…”

Halofuginone to Prevent and Treat Thioacetamide–Induced Liver Fibrosis in Rats

“…3 In the injured liver, the hepatic stellate cells (HSC) lying in the space of Disse beneath the endothelial cell layer, constitute the major source of the ECM proteins. 4,6,7 These cells are usually quiescent, with a low proliferation rate; on activation, probably because of hepatocyte injury, 8 they differentiate into myofibroblast-like cells, with high proliferative capacity. 7 The predominant ECM protein synthesized by the HSC in fibrosis is collagen type I, which increases from approximately 2% of total proteins in a normal human liver to 10% to 30% in a cirrhotic liver.…”