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The hormone relaxin has shown promise in the treatment of fibrosis in a number of tissues, but the effect of relaxin on established hepatic fibrosis is unknown. The aim of this study was to determine the effect of relaxin on an <jats:italic>in vivo<\/jats:italic> model after establishing hepatic fibrosis<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Male mice were made fibrotic by carbon tetrachloride treatment for 4\u00a0weeks, followed by treatment with two doses of relaxin (25 or 75\u00a0\u03bcg\/kg\/day) or vehicle for 4\u00a0weeks, with continued administration of carbon tetrachloride.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Relaxin significantly decreased total hepatic collagen and smooth muscle actin content at both doses, and suppressed collagen I expression at the higher dose. Relaxin increased the expression of the matrix metalloproteinases <jats:styled-content style=\"fixed-case\">MMP<\/jats:styled-content>13 and <jats:styled-content style=\"fixed-case\">MMP<\/jats:styled-content>3, decreased the expression of <jats:styled-content style=\"fixed-case\">MMP<\/jats:styled-content>2 and tissue inhibitor of metalloproteinase 2 (<jats:styled-content style=\"fixed-case\">TIMP<\/jats:styled-content>2) and increased the overall level of collagen\u2010degrading activity. Relaxin decreased <jats:styled-content style=\"fixed-case\">TGF<\/jats:styled-content>\u03b2\u2010induced Smad2 nuclear localization in mouse hepatic stellate cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The results suggest that relaxin reduced collagen deposition and <jats:styled-content style=\"fixed-case\">HSC<\/jats:styled-content> activation in established hepatic fibrosis despite the presence of continued hepatic insult. This reduced fibrosis was associated with increased expression of the fibrillar collagen\u2010degrading enzyme <jats:styled-content style=\"fixed-case\">MMP<\/jats:styled-content>13, decreased expression of <jats:styled-content style=\"fixed-case\">TIMP<\/jats:styled-content>2, and enhanced collagen\u2010degrading activity, and impaired <jats:styled-content style=\"fixed-case\">TGF<\/jats:styled-content>\u03b2 signalling, consistent with relaxin's effects on activated fibroblastic cells. The results suggest that relaxin may be an effective treatment for the treatment of established hepatic fibrosis.<\/jats:p><\/jats:sec>","DOI":"10.1111\/liv.12247","type":"journal-article","created":{"date-parts":[[2013,6,16]],"date-time":"2013-06-16T11:10:46Z","timestamp":1371381046000},"page":"416-426","source":"Crossref","is-referenced-by-count":55,"title":["Relaxin decreases the severity of established hepatic fibrosis in mice"],"prefix":"10.1111","volume":"34","author":[{"given":"Robert G.","family":"Bennett","sequence":"first","affiliation":[{"name":"Research Service VA Nebraska\u2010Western Iowa Health Care System Omaha NE USA"},{"name":"Department of Internal Medicine University of Nebraska Medical Center Omaha NE USA"},{"name":"Department of Biochemistry &amp; Molecular Biology University of Nebraska Medical Center Omaha NE USA"},{"name":"Department of Pharmacology &amp; Experimental Neuroscience University of Nebraska Medical Center Omaha NE 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