title: Plasminogen activator inhibitor-1 deficient mice are protected from angiotensin II-induced fibrosis.
abstract: PAI-1 has been shown to be both profibrotic and antifibrotic in animal models of hepatic fibrosis. Although these models have similarities to human fibrotic liver disease, no rodent model completely recapitulates the clinical situation; indeed, transaminase values in most models of hepatic fibrosis are much higher than in chronic liver diseases in humans. Here, wild-type and PAI-1(-/-) mice were administered AngII (500 ng/kg/min) for 4 weeks. ECM accumulation was evaluated by Sirius red staining, hydroxyproline content, and fibrin and collagen immunostaining. Induction of pro-fibrotic genes was assessed by real-time RT-PCR. Despite the absence of any significant liver damage, AngII infusion increased the deposition of hepatic collagen and fibrin ECM, with a perisinusoidal pattern. PAI-1(-/-) mice were protected from these ECM changes, indicating a causal role of PAI-1 in this fibrosis model. Protection in the knockout strain correlated with a blunted increase in αSMA, and elevated activities of matrix metalloproteinases (MMP2, MMP9). These data suggest that PAI-1 plays a critical role in mediating fibrosis caused by AngII and lends weight-of-evidence to a pro-fibrotic role of this protein in liver. Furthermore, the current study proposes a new model of 'pure' hepatic fibrosis in mice with little inflammation or hepatocyte death.
authors.affiliation: Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, KY 40292, USA. juliane.beier@louisville.edu
authors.forename: Juliane I
authors.initials: JI
authors.lastname: Beier
authors.forename: J Phillip
authors.initials: JP
authors.lastname: Kaiser
authors.forename: Luping
authors.initials: L
authors.lastname: Guo
authors.forename: Manuel
authors.initials: M
authors.lastname: Martínez-Maldonado
authors.forename: Gavin E
authors.initials: GE
authors.lastname: Arteel
mesh_terms: D000804:Angiotensin II / Q000008:administration & dosage / Q000276:immunology*; D000818:Animals; D003094:Collagen / Q000276:immunology; D005109:Extracellular Matrix / Q000276:immunology / Q000378:metabolism; D017353:Gene Deletion; D006801:Humans; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000235:genetics* / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics*
chemical_list: D017395:Plasminogen Activator Inhibitor 1; D000804:Angiotensin II; D003094:Collagen