title: Relaxin decreases the severity of established hepatic fibrosis in mice.
abstract: OBJECTIVE
  Hepatic fibrosis is characterized by excess collagen deposition, decreased extracellular matrix degradation and activation of the hepatic stellate cells. 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 in vivo model after establishing hepatic fibrosis
  
  
  METHODS
  Male mice were made fibrotic by carbon tetrachloride treatment for 4 weeks, followed by treatment with two doses of relaxin (25 or 75 μg/kg/day) or vehicle for 4 weeks, with continued administration of carbon tetrachloride.
  
  
  RESULTS
  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 MMP13 and MMP3, decreased the expression of MMP2 and tissue inhibitor of metalloproteinase 2 (TIMP2) and increased the overall level of collagen-degrading activity. Relaxin decreased TGFβ-induced Smad2 nuclear localization in mouse hepatic stellate cells.
  
  
  CONCLUSIONS
  The results suggest that relaxin reduced collagen deposition and HSC activation in established hepatic fibrosis despite the presence of continued hepatic insult. This reduced fibrosis was associated with increased expression of the fibrillar collagen-degrading enzyme MMP13, decreased expression of TIMP2, and enhanced collagen-degrading activity, and impaired TGFβ 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.
authors.affiliation: Research Service, VA Nebraska-Western Iowa Health Care System, Omaha, NE, USA; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA; Department of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA; Department of Pharmacology & Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Bennett
authors.forename: Dean G
authors.initials: DG
authors.lastname: Heimann
authors.forename: Sudhir
authors.initials: S
authors.lastname: Singh
authors.forename: Ronda L
authors.initials: RL
authors.lastname: Simpson
authors.forename: Dean J
authors.initials: DJ
authors.lastname: Tuma
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002251:Carbon Tetrachloride / Q000633:toxicity; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D055166:Hepatic Stellate Cells / Q000187:drug effects*; D022781:Hepatocytes / Q000378:metabolism; D008099:Liver / Q000473:pathology*; D008103:Liver Cirrhosis / Q000188:drug therapy*; D008297:Male; D053505:Matrix Metalloproteinases, Secreted / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D012065:Relaxin / Q000627:therapeutic use*; D051899:Smad2 Protein / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D000199:Actins; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D016212:Transforming Growth Factor beta; C544013:alpha-smooth muscle actin, mouse; D019716:Tissue Inhibitor of Metalloproteinase-2; D012065:Relaxin; D003094:Collagen; D002251:Carbon Tetrachloride; D053505:Matrix Metalloproteinases, Secreted
keywords: cirrhosis; collagen; hepatic stellate cells; liver disease; relaxin family peptides