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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.
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“Some of these genes have been previously implicated in liver fibrosis (Serpine133, Tgm234), while role of others (Cd14, Marco, Csf1) have not been investigated to date.”
From Hepatocyte mitochondria-derived danger signals directly activate hepatic stellate cells and drive progression of liver fibrosis (2020) · cites this paper as [33]
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Metadata
- Authors
- Wang, H., Zhang, Y., & Heuckeroth, R. O.
- Affiliations
- Washington University in St. Louis (US)
- Sun Yat-sen University (CN)
- Corresponding author
- Heuckeroth, Robert O.
- Venue
- FEBS Letters
- Publisher
- Wiley
- Published
- 2007-05-29
- Volume
- 581
- Issue
- 16
- Pages
- 3098-3104
- ISSN
- 0014-5793 (ISSN-L)
- 1873-3468
- OpenAlex
- W1970138640
- Cited by
- 98
- References
- 35
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 4 · 2023: 2 · 2022: 4 · 2021: 7 · 2020: 2 · 2019: 4 · 2018: 4 · 2017: 8 · 2016: 4 · 2015: 3 · 2014: 7 · 2013: 9 · 2012: 5
- FWCI
- 3.65
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- FEBS Letters (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (1c06rr015502-01)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 068371, P30 DK-52574, R01DK064592, DK 64592, DK62452, R01DK057038, R21DK068371, DK57038, U01DK062452, P30DK056341, P30DK052574)
- National Center for Research Resources (C06-RR-015502)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Keywords
- plasminogen activator inhibitor-1, liver fibrosis, bile duct ligation, cholestasis, tissue plasminogen activator, hepatocyte growth factor, MMP-9, urokinase, plasmin, hepatic stellate cells, TGF-β1
- MeSH terms
- Animals, Bile Ducts, Fibrinolysin, Ligation, Liver, Liver Cirrhosis, Male, Mice, Inbred C57BL, Tissue Plasminogen Activator, Urokinase-Type Plasminogen Activator, Hepatocyte Growth Factor, Plasminogen Activator Inhibitor 1, Mice, Knockout, Matrix Metalloproteinase 9, Mice, Transforming Growth Factor beta1
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