TISSUE INHIBITOR OF METALLOPROTEINASE-1 AND METALLOPROTEINASE-2 RNA EXPRESSION IN RAT AND HUMAN LIVER FIBROSIS

The remodeling of extracellular matrix during chronic liver disease ma y partially be attributed to altered activity of matrix metalloprotein ases and their tissue inhibitors (TIMPs). Expression of TIMP-1 and -2 was studied by in situ hybridization combined with immunohistochemistr y in rat (acute and chronic carbon tetrachloride intoxication and seco ndary biliary fibrosis) and human livers and on isolated rat hepatic s tellate cells. TIMP-1 and -2 transcripts appeared in rat livers within 1 to 3 hours after intoxication, pointing to a role in the protection against accidental activation of matrix metalloproteinases, and were present at high levels in all fibrotic rat and human livers predominan tly in stellate cells. TIMP-2 RNA distribution largely matched with pr eviously reported patterns of matrix metalloproteinase-2 (72-kd gelati nase) expression, suggesting generation of a TIMP-2/matrix metalloprot einase-2 complex (large inhibitor of metalloproteinase). Isolated stel late cells expressed TIMP-1 and -2 RNA. Addition of transforming growt h factor-beta 1 enhanced TIMP-1 and matrix metalloproteinase-2 RNA lev els in vitro, whereas TIMP-2-specific signals were reduced, likely to result in a stoichiometric excess of matrix-metalloproteinase-2 over T IMP-2. In the context of previous demonstrations of transforming growt h factor-beta 1 and matrix metalloproteinase-2 in vivo, these patterns suggest an intrahepatic environment permitting only limited matrix de gradation, ultimately resulting in redistribution of extracellular mat rix with relative accumulation of collagen type I.