title: Liver fibrosis protects mice from acute hepatocellular injury.
abstract: OBJECTIVE
  Development of fibrosis is part of the pathophysiologic process of chronic liver disease. Although it is considered deleterious, it also represents a form of tissue repair. Deposition of extracellular matrix changes the cellular environment of the liver; we investigated whether it increases resistance to noxious stimuli and the role of changes in intracellular signaling to hepatocytes in mediating this effect.
  
  
  METHODS
  Primary cultures of mouse hepatocytes were exposed to type I collagen (COL1); cell injury was assessed by morphologic and biochemical criteria. The expression of Bcl-2 family members was evaluated by immunoblot analyses. Activation of extracellular signal-regulated kinase (ERK) was assessed using phospho-specific antibodies. Liver fibrosis was induced by repeated administration of thioacetamide or carbon tetrachloride to mice; mice were then exposed to Fas antibodies.
  
  
  RESULTS
  Hepatocytes exposed to COL1 were more resistant to a variety of hepatotoxins, in a dose-dependent manner, and had lower levels of Bad, Bid, and Bax proapoptotic proteins compared with control hepatocytes. Activation of ERK1/2 was stronger and quicker in hepatocytes exposed to COL1. The MEK1/2 inhibitors U0126 and PD98059 reversed the protective effects of COL1 and the decrease in proapoptotic proteins. Hepatocytes isolated from ERK1(-/-) mice were insensitive to the protective effect of COL1. Fibrotic livers from wild-type mice had high levels of phospho-ERK1 and were resistant to Fas-induced cell death. ERK1(-/-) mice lost this effect.
  
  
  CONCLUSIONS
  Production of COL1 during liver fibrosis induces a hepatoprotective response that is mediated by activation of ERK1 signaling.
authors.affiliation: Laboratoire d'Hépatologie Cellulaire du Centre de Recherche du CHUM-Hôpital Saint-Luc, Montréal, Québec, Canada.
authors.forename: Eric
authors.initials: E
authors.lastname: Bourbonnais
authors.forename: Valérie-Ann
authors.initials: VA
authors.lastname: Raymond
authors.forename: Chantal
authors.initials: C
authors.lastname: Ethier
authors.forename: Bich N
authors.initials: BN
authors.lastname: Nguyen
authors.forename: Marc Saba
authors.initials: MS
authors.lastname: El-Leil
authors.forename: Sylvain
authors.initials: S
authors.lastname: Meloche
authors.forename: Marc
authors.initials: M
authors.lastname: Bilodeau
mesh_terms: D000208:Acute Disease; D000818:Animals; D017209:Apoptosis; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D015153:Blotting, Western; D002251:Carbon Tetrachloride; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D024042:Collagen Type I / Q000378:metabolism; D019610:Cytoprotection; D004789:Enzyme Activation; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction; D013853:Thioacetamide; D013997:Time Factors; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D051025:bcl-Associated Death Protein / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; C494820:Bad protein, mouse; C494827:Bax protein, mouse; C494815:Bid protein, mouse; D024042:Collagen Type I; D047428:Protein Kinase Inhibitors; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein; D019014:fas Receptor; D013853:Thioacetamide; D002251:Carbon Tetrachloride; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482127:Map2k1 protein, mouse; C482129:Map2k2 protein, mouse