title: PAI-1 plays a protective role in CCl4-induced hepatic fibrosis in mice: role of hepatocyte division.
abstract: Plasminogen activator inhibitor-1 (PAI-1) is an acute phase protein that has been shown to play a role in experimental fibrosis caused by bile duct ligation (BDL) in mice. However, its role in more severe models of hepatic fibrosis (e.g., carbon tetrachloride; CCl(4)) has not been determined and is important for extrapolation to human disease. Wild-type or PAI-1 knockout mice were administered CCl(4) (1 ml/kg body wt ip) 2x/wk for 4 wk. Plasma (e.g., transaminase activity) and histological (e.g., Sirius red staining) indexes of liver damage and fibrosis were evaluated. Proliferation and apoptosis were assessed by PCNA and TdT-mediated dUTP nick-end labeling (TUNEL) staining, respectively, as well as by indexes of cell cycle (e.g., p53, cyclin D1). In contrast to previous studies with BDL, hepatic fibrosis was enhanced in PAI-1(-/-) mice after chronic CCl(4) administration. Indeed, all indexes of liver damage were elevated in PAI-1(-/-) mice compared with wild-type mice. This enhanced liver damage correlated with impaired hepatocyte proliferation. A similar effect on proliferation was observed after one bolus dose of CCl(4), without concomitant increases in liver damage. Under these conditions, a decrease in phospho-p38, coupled with elevated p53 protein, was observed; these results suggest impaired proliferation and a potential G(1)/S cell cycle arrest in PAI-1(-/-) mice. These data suggest that PAI-1 may play multiple roles in chronic liver diseases, both protective and damaging, the latter mediated by its influence on inflammation and fibrosis and the former via helping maintain hepatocyte division after an injury.
authors.affiliation: Dept. of Pharmacology and Toxicology, Univ. of Louisville Health Sciences Center, Louisville, KY 40292, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: von Montfort
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: Swati
authors.initials: S
authors.lastname: Joshi-Barve
authors.forename: Michele T
authors.initials: MT
authors.lastname: Pritchard
authors.forename: J Christopher
authors.initials: JC
authors.lastname: States
authors.forename: Gavin E
authors.initials: GE
authors.lastname: Arteel
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002252:Carbon Tetrachloride Poisoning / Q000150:complications / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D008103:Liver Cirrhosis / Q000209:etiology / Q000517:prevention & control*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D017395:Plasminogen Activator Inhibitor 1 / Q000172:deficiency* / Q000502:physiology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D017395:Plasminogen Activator Inhibitor 1; D019715:Tissue Inhibitor of Metalloproteinase-1; D016159:Tumor Suppressor Protein p53; D019938:Cyclin D1; D020780:Matrix Metalloproteinase 9