{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T08:45:11Z","timestamp":1791276311718,"version":"4.1.0"},"reference-count":43,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","license":[{"start":{"date-parts":[[2000,12,1]],"date-time":"2000-12-01T00:00:00Z","timestamp":975628800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"},{"start":{"date-parts":[[2003,12,30]],"date-time":"2003-12-30T00:00:00Z","timestamp":1072742400000},"content-version":"vor","delay-in-days":1124,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2000,12]]},"abstract":"<jats:sec>\n            <jats:title\/>\n            <jats:p>Tissue inhibitor of metalloproteinases\u20131 (TIMP\u20131) has been shown to be increased in liver fibrosis development both in murine experimental models and human samples. However, the direct role of TIMP\u20131 during liver fibrosis development has not been defined. To address this issue, we developed transgenic mice overexpressing human TIMP\u20131 (hTIMP\u20131) in the liver under control of the albumin promoter\/enhancer. A model of CCl<jats:sub>4<\/jats:sub>\u2013induced hepatic fibrosis was used to assess the extent of fibrosis development in TIMP\u20131 transgenic (TIMP\u2013Tg) mice and control hybrid (Cont) mice. Without any treatment, overexpression of TIMP\u20131 itself did not induce liver fibrosis. There were no significant differences of pro\u2013(\u03b11)\u2013collagen\u2013I, (\u03b12)\u2013collagen\u2013IV, and \u03b1\u2013smooth muscle actin (\u03b1\u2013SMA) mRNA expression in the liver between TIMP\u2013Tg and Cont\u2013mice, suggesting that overexpression of TIMP\u20131 itself did not cause hepatic stellate cell (HSC) activation. After 4\u2013week treatment with CCl<jats:sub>4<\/jats:sub>, however, densitometric analysis revealed that TIMP\u2013Tg\u2013mice had a seven\u2013fold increase in liver fibrosis compared with the Cont\u2013mice. The hepatic hydroxyproline content and serum hyaluronic acid were also significantly increased in TIMP\u2013Tg\u2013mice, whereas CCl<jats:sub>4<\/jats:sub>\u2013induced liver dysfunction was not altered. An active form of matrix metalloproteinases\u20132 (MMP\u20132) level in the liver of TIMP\u2013Tg\u2013mice was decreased relative to that in Cont\u2013mice because of the transgenic TIMP\u20131. Immunohistochemical analysis revealed that collagen\u2013I and collagen\u2013IV accumulation was markedly increased in the liver of CCl<jats:sub>4<\/jats:sub>\u2013treated TIMP\u2013Tg\u2013mice with a pattern similar to that of \u03b1\u2013SMA positive cells. These results suggest that TIMP\u20131 does not by itself result in liver fibrosis, but strongly promotes liver fibrosis development.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1053\/jhep.2000.20521","type":"journal-article","created":{"date-parts":[[2005,2,10]],"date-time":"2005-02-10T08:51:33Z","timestamp":1108025493000},"page":"1248-1254","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":220,"title":["Tissue Inhibitor of Metalloproteinases\u20131 Promotes Liver Fibrosis Development in A Transgenic Mouse 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