Tissue inhibitors of metalloproteinases, hepatic stellate cells and liver fibrosis.

Hepatic stellate cells (HSC) play a central role in the pathogenesis of liver fibrosis. Following liver injury, these cells proliferate and are activated to a profibrogenic myofibroblastic phenotype. In addition to increased matrix protein synthesis, there is evidence to indicate that these cells are able to regulate matrix degradation. In the early phases of their cellular activation, HSC release matrix metalloproteinases with the ability to degrade the normal liver matrix. When HSC are fully activated, there is a net down-regulation of matrix degradation mediated by increased synthesis and extracellular release of tissue inhibitors of metalloproteinase (TIMP)-1 and -2. These studies in cell culture have been complemented by in vivo studies of hepatic TIMP-1 and TIMP-2 gene expression. In advanced human liver disease of various aetiologies, there is increased TIMP-1-mRNA and protein and increased TIMP-2-mRNA in fibrotic liver compared with control liver. Temporal studies of progressive rat liver fibrosis caused by bile duct ligation or by carbon tetrachloride, indicate an important role for increased TIMP-1 and TIMP-2 expression in pathogenesis. Moreover, in a rat model of reversible liver fibrosis, matrix remodelling and resolution of liver fibrosis is closely associated, temporally, with a marked decrease in TIMP-1 and TIMP-2 expression. These combined cell culture and in vivo findings have led us to investigate the mechanisms of regulation of TIMP-1 gene expression in hepatic stellate cells. Our recent data indicate that transcriptional regulation of TIMP-1 gene expression in HSC is mediated via a mechanism which differs considerably from that previously identified in skin fibroblasts. We conclude that increased TIMP-1 and TIMP-2 expression by HSC plays an important role in the pathogenesis of liver fibrosis. This may represent an important therapeutic target in the design of anti-fibrotic strategies for chronic liver disease.