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 À/À 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 À/À and WT mice. There was also no difference in the level of transforming growth factor beta 1 (TGF-b1), stellate cell activation or collagen production between WT and PAI-1 À/À animals. In conclusion, PAI-1 deficiency reduces hepatic fibrosis after bile duct obstruction mainly through the activation of tPA and HGF.

Adenoviral Overexpression and Small Interfering RNA Suppression Demonstrate That Plasminogen Activator Inhibitor-1 Produces Elevated Collagen Accumulation in Normal and Keloid Fibroblasts

“…26 Although a balanced action between plasminogen activator and PAI-1 maintains the normal function of the protease system, altered plasminogen activator/PAI-1 has been implicated in the development of thrombotic diseases and metabolic disorders that are linked with the development of arteriosclerosis, 27 cancers, 28 and chronic wounds. 29 Increased PAI-1 activity has been a hallmark of fibrosis evident by a direct correlation between genetically determined level of PAI-1 and the extent of collagen accumulation that follows inflammation during injury repair in various organs such as liver, 30 lung, 31 kidney, 32 blood vessels, 33 and skin. 26 In addition to keloids, PAI-1 overexpression has been found in skin fibroblasts of Werner's fibrosis and scleroderma.…”

Epigenome-Wide Association (DNA Methylation) Study of Sex Differences in Normal Human Kidney

“…As a serine protease, PLAT, plays a fundamental role in regulating Extracellular Matrix (ECM) degradation and accumulation in the kidney. Conventionally, PLAT is beneficial in the pathogenesis of renal interstitial fibrotic lesions, where elevated levels of PLAT leads to increased degradation of the accumulation and deposition of ECM associated with renal interstitial fibrotic lesions [73,74]. Accumulation and deposition of ECM associated with renal interstitial fibrotic lesions are part of the common cascade of actions leading to chronic kidney disease [75,76].…”

The Antifibrinolytic Drug Tranexamic Acid Reduces Liver Injury and Fibrosis in a Mouse Model of Chronic Bile Duct Injury

“…However, the role of fibrin(ogen) in BDL-induced liver injury and fibrosis has not been described, with the reduction in hepatic fibrin in PAI-1 2/2 mice after BDL (Wang et al, 2005) likely a reflection of reduced liver injury. Indeed, PAI-1 deficiency did not affect plasmin activity in BDL mice (Wang et al, 2007b). Moreover, PAI-1 deficiency was shown to protect BDL mice by enhancing tPA-mediated activation of hepatocyte growth factor, a process not directly impacting fibrinolysis (Wang et al, 2007c).…”