PAI-1 deficiency reduces liver fibrosis after bile duct ligation in mice through activation of tPA.
Plasminogen activator inhibitor-1 (PAI-1) increases injury in several liver, lung and kidney disease models. The objective of this investigation was to assess the effect of PAI-1 deficiency on cholestatic liver fibrosis and determine PAI-1 influenced fibrogenic mechanisms. We found that PAI-1(-/-) mice had less fibrosis than wild type (WT) mice after bile duct ligation. This change correlated with increased tissue-type plasminogen activator (tPA) activity, and increased matrix metalloproteinase-9 (MMP-9), but not MMP-2 activity. Furthermore, there was increased activation of the tPA substrate hepatocyte growth factor (HGF), a known anti-fibrogenic protein. In contrast, there was no difference in hepatic urokinase plasminogen activator (uPA) or plasmin activities between PAI-1(-/-) and WT mice. There was also no difference in the level of transforming growth factor beta 1 (TGF-beta1), stellate cell activation or collagen production between WT and PAI-1(-/-) animals. In conclusion, PAI-1 deficiency reduces hepatic fibrosis after bile duct obstruction mainly through the activation of tPA and HGF.
Wang
Hongtao
H
Division of Gastroenterology and Nutrition, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.
Zhang
Yan
Y
Heuckeroth
Robert O
RO
D000818:Animals; D001652:Bile Ducts; D005341:Fibrinolysin / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D008026:Ligation; D008099:Liver / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics* / Q000378:metabolism; D010959:Tissue Plasminogen Activator / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism
D017395:Plasminogen Activator Inhibitor 1; D053773:Transforming Growth Factor beta1; D017228:Hepatocyte Growth Factor; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse