Journal
FEBS LETTERS
Volume 581, Issue 16, Pages 3098-3104Publisher
WILEY
DOI: 10.1016/j.febslet.2007.05.049
Keywords
plasminogen activator inhibitor-1; extrahepatic; cholestasis; liver fibrosis; matrix metal loprotemase; tissue-type; plasminogen activator; urokinase plasminogen activator; hepatocyte growth factor
Funding
- NCRR NIH HHS [C06 RR015502] Funding Source: Medline
- NIDDK NIH HHS [DK57038, P30 DK056341, P30 DK056341-07, P30 DK056341-06, P30-DK52574, DK068371, DK62452, DK64592] Funding Source: Medline
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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-1-1(-/-) 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-beta 1), 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. (c) 2007 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
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