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PAI‐1 deficiency reduces liver fibrosis after bile duct ligation in mice through activation of tPA
Author(s) -
Wang Hongtao,
Zhang Yan,
Heuckeroth Robert O.
Publication year - 2007
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2007.05.049
Subject(s) - plasminogen activator , medicine , hepatocyte growth factor , plasmin , endocrinology , fibrosis , ligation , chemistry , plasminogen activator inhibitor 1 , hepatic stellate cell , matrix metalloproteinase , hepatocyte , tissue plasminogen activator , enzyme , biochemistry , receptor , in vitro
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.