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Abstract

Tissue inhibitor of metalloproteinases-1 (TIMP-1) has been shown to be increased in liver fibrosis development both in murine experimental models and human samples. However, the direct role of TIMP-1 during liver fibrosis development has not been defined. To address this issue, we developed transgenic mice overexpressing human TIMP-1 (hTIMP-1) in the liver under control of the albumin promoter/ enhancer. A model of CCl(4)-induced hepatic fibrosis was used to assess the extent of fibrosis development in TIMP-1 transgenic (TIMP-Tg) mice and control hybrid (Cont) mice. Without any treatment, overexpression of TIMP-1 itself did not induce liver fibrosis. There were no significant differences of pro-(alpha1)-collagen-I, (alpha2)-collagen-IV, and alpha-smooth muscle actin (alpha-SMA) mRNA expression in the liver between TIMP-Tg and Cont-mice, suggesting that overexpression of TIMP-1 itself did not cause hepatic stellate cell (HSC) activation. After 4-week treatment with CCl(4), however, densitometric analysis revealed that TIMP-Tg-mice had a seven-fold increase in liver fibrosis compared with the Cont-mice. The hepatic hydroxyproline content and serum hyaluronic acid were also significantly increased in TIMP-Tg-mice, whereas CCl(4)-induced liver dysfunction was not altered. An active form of matrix metalloproteinases-2 (MMP-2) level in the liver of TIMP-Tg-mice was decreased relative to that in Cont-mice because of the transgenic TIMP-1. Immunohistochemical analysis revealed that collagen-I and collagen-IV accumulation was markedly increased in the liver of CCl(4)-treated TIMP-Tg-mice with a pattern similar to that of alpha-SMA positive cells. These results suggest that TIMP-1 does not by itself result in liver fibrosis, but strongly promotes liver fibrosis development.

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PubMed ID:: 11093731

DOI:: 10.1053/jhep.2000.20521

ScienceOpen disciplines: Chemistry

Keywords: Actins,genetics,metabolism,Animals,Carbon Tetrachloride,pharmacology,Collagen,Humans,Immunohistochemistry,Liver,drug effects,enzymology,Liver Cirrhosis,chemically induced,Matrix Metalloproteinase 2,Mice,Mice, Inbred C57BL,Mice, Inbred CBA,Mice, Transgenic,Muscle, Smooth,RNA, Messenger,Reference Values,Tissue Inhibitor of Metalloproteinase-1

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ScienceOpen disciplines: Chemistry

Keywords: Actins, genetics, metabolism, Animals, Carbon Tetrachloride, pharmacology, Collagen, Humans, Immunohistochemistry, Liver, drug effects, enzymology, Liver Cirrhosis, chemically induced, Matrix Metalloproteinase 2, Mice, Mice, Inbred C57BL, Mice, Inbred CBA, Mice, Transgenic, Muscle, Smooth, RNA, Messenger, Reference Values, Tissue Inhibitor of Metalloproteinase-1

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