Tissue inhibitor of metalloproteinases-1 attenuates... : Hepatology (original) (raw)

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Tissue inhibitor of metalloproteinases-1 attenuates spontaneous liver fibrosis resolution in the transgenic mouse

Yoshiji, Hitoshi*,1; Kuriyama, Shigeki2; Yoshii, Junichi1; Ikenaka, Yasuhide1; Noguchi, Ryuichi1; Nakatani, Toshiya1; Tsujinoue, Hirohisa1; Yanase, Koji1; Namisaki, Tadashi1; Imazu, Hiroo1; Fukui, Hiroshi1

1Third Department of Internal Medicine, Nara Medical University, Nara

2Third Department of Internal Medicine, Kagawa Medical University, Kagawa, Japan

E-mail:[email protected]

*Address reprint requests to: Third Department of Internal Medicine, Nara Medical University, Shijo-cho 840, Kashihara, Nara 634-8522, Japan. fax: (81) 744-24-7122.

Received January 16, 2002; Accepted July 01, 2002; previously published online December 30, 2003

Abstract

It has been suggested that the tissue inhibitor of metalloproteinases-1 (TIMP-1) is involved in spontaneous resolution of liver fibrosis. The aim of this study was to investigate whether TIMP-1 altered spontaneous resolution of liver fibrosis in conjunction with matrix metalloproteinases (MMP) inhibition and hepatic stellate cell (HSC) activation. The livers of liver-targeted TIMP-1 transgenic (TIMP-Tg) and control hybrid (Cont) mice were harvested at 0, 3, 7, and 28 days following spontaneous recovery from CCl4-induced liver fibrosis. The extent of fibrosis resolution, MMP expression, α-smooth-muscle actin (α-SMA) positive cells, and procollagen-(I) messenger RNA (mRNA) in the liver were assessed at the respective periods in both groups. We also examined the effect of TIMP-1 on HSC apoptosis. The TIMP-Tg mice showed significantly attenuated resolution of spontaneous liver fibrosis compared with the Cont mice. The hydroxyproline content, number of α-SMA positive cells, and procollagen-(I) mRNA rapidly decreased with time in the Cont mice, whereas these markers were little changed in TIMP-Tg mice. The level of the active form of metalloproteinases-2 (MMP-2) in the TIMP-Tg mice was less than that in the Cont mice. TIMP-1 markedly decreased the nonparenchyma apoptotic cells in the liver fibrosis resolution model, and it also inhibited HSC apoptosis associated with suppression of caspase-3 activity in vitro. In conclusion, TIMP-1 significantly attenuated spontaneous resolution of liver fibrosis by the combination of a net reduction of the MMP activity and suppression of apoptosis in HSC.