Tissue inhibitor of metalloproteinases-1 attenuates spontaneous liver fibrosis resolution in the transgenic mouse.
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 CCl(4)-induced liver fibrosis. The extent of fibrosis resolution, MMP expression, alpha-smooth-muscle actin (alpha-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 alpha-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.
Yoshiji
Hitoshi
H
Third Department of Internal Medicine, Nara Medical University, Japan. yoshijih@naramed-u.ac.jp
Kuriyama
Shigeki
S
Yoshii
Junichi
J
Ikenaka
Yasuhide
Y
Noguchi
Ryuichi
R
Nakatani
Toshiya
T
Tsujinoue
Hirohisa
H
Yanase
Koji
K
Namisaki
Tadashi
T
Imazu
Hiroo
H
Fukui
Hiroshi
H
D000199:Actins / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D024042:Collagen Type I / Q000235:genetics; D017364:Collagenases / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006909:Hydroxyproline / Q000378:metabolism; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008103:Liver Cirrhosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053509:Matrix Metalloproteinase 13; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000032:analysis; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics* / Q000378:metabolism*
D000199:Actins; D024042:Collagen Type I; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D017364:Collagenases; D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse; D020778:Matrix Metalloproteinase 2; D006909:Hydroxyproline