Expression of connective tissue growth factor in experimental rat and human liver fibrosis

Abstract

Connective tissue growth factor (CTGF) stimulates in vitro fibroblast proliferation and extracellular matrix synthesis. The aim of this study was to assess the role of CTGF in liver fibrogenesis. CTGF expression was investigated both at the protein and mRNA level in biopsies of chronic liver diseases, in experimental models of liver fibrosis, and in hepatic stellate cells in culture. CTGF immunostaining was observed in most human liver biopsies with significant fibrosis. An increase of CTGF immunostaining was associated with a higher score of fibrosis both in the group of chronic hepatitis C ( 2 ‫؍‬ 9.3; P F .01) and in the non-hepatitis C group ( 2 ‫؍‬ 7.2; P F .02). In situ hybridization showed CTGF mRNA expression in spindle cells in both the fibrous septa and sinusoidal lining. In experimental models of liver fibrosis, CTGF accumulated in parallel with the development of septal fibrosis and cirrhosis. Quantification of CTGF mRNA by a real-time reversetranscription polymerase chain reaction (RT-PCR) assay showed a significant increase of CTGF mRNA in both CCl 4 -induced and bile duct-ligated rat models of liver fibrosis. Expression of CTGF protein and mRNA was definitively assigned to hepatic stellate cells, because CTGF was detected by Western blot both in lysate and supernatant of a hepatic stellate cell line derived from rats. These cells also displayed CTGF protein and mRNA as shown by immunohistochemistry and in situ hybridization. In conclusion, this study shows that CTGF is strongly expressed during liver fibrogenesis, and hepatic stellate cells seem to be the major cellular sources of CTGF in the liver. (HEPATOL-OGY 1999;30:968-976.)

PAR1 antagonism protects against experimental liver fibrosis. Role of proteinase receptors in stellate cell activation

“…1,8 -10 Furthermore, thrombin-induced activation of PAR 1 stimulates the synthesis and shedding of profibrogenic factors such as heparin-binding epidermal growth factor, PDGF, connective tissue growth factor, fibroblast migration and proliferation, and extracellular matrix production, providing a system that detects tissue injury and triggers a set of cellular responses that contribute to inflammation and tissue repair and remodeling. 6,7,37 Thrombin has been involved in hepatic fibrogenesis in humans, as well in experimental models of liver injury. 5,38 Immunohistochemistry and in situ hybridization studies have demonstrated, that although PAR 1 is expressed in the normal liver in the endothelial lining of the hepatic sinusoids, its expression is up-regulated in response to acute or chronic liver injury.…”

MMP‐13 deletion decreases profibrogenic molecules and attenuates N‐nitrosodimethylamine‐induced liver injury and fibrosis in mice

“…CTGF plays a central role in the pathogenesis of hepatic fibrosis by triggering activation and transformation of quiescent hepatic stellate cells into myofibroblasts, and it also stimulates the production of CTGF itself 21, 22. Activated stellate cells over‐produce collagens, fibronectin and laminin under stimulation with CTGF 23.…”

Curcumin suppresses the expression of extracellular matrix genes in activated hepatic stellate cells by inhibiting gene expression of connective tissue growth factor

“…Accumulating evidence has suggested that upregulation of CTGF might be a central pathway during HSC activation and hepatic fibrogenesis by mediating many of the profibrotic effects of TGF-␤ (1,41,42,53). CTGF expression in HSCs is significantly enhanced during the process of activation in vitro and in vivo (41,53).…”

“…CTGF expression in HSCs is significantly enhanced during the process of activation in vitro and in vivo (41,53). HSCs are the major cellular source of CTGF in the liver during liver fibrogenesis (42). In response to exogenous CTGF, HSCs demonstrate increased migration, proliferation, adhesion, and expression of type I collagen (6,41).…”