PAI-1 deficiency reduces liver fibrosis after bile duct ligation in mice through activation of tPA

Abstract 

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-β1), 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.

Abbreviations: BDL, Bile duct ligation, HGF, hepatocyte growth factor, MMP, matrix metalloproteinase, PAI-1, plasminogen activator inhibitor-1, qRT-PCR, quantitative real time reverse transcriptase polymerase chain reaction, TGF-β1, transforming growth factor-beta 1, tPA, tissue-type plasminogen activator, uPA, urokinase plasminogen activator, WT, wild type

Keywords: Plasminogen activator inhibitor-1, Extrahepatic cholestasis, Liver fibrosis, Matrix metalloproteinase, Tissue-type plasminogen activator, Urokinase plasminogen activator, Hepatocyte growth factor