Increased expression of plasminogen activator and plasminogen activator inhibitor during liver fibrogenesis of rats: role of stellate cells

Background/Aims: Plasminogen activators and plasminogen activator inhibitor s are important regulators bf the balance between the proteolytic and antip roteolytic activities that determine extracellular matrix turnover. We exam ined the expression of plasminogen activator-plasmin system components in e xperimental liver fibrosis of rats. Methods: Liver fibrosis was produced in rats by injecting carbon tetrachlor ide for 6 to 12 weeks. Gene expression for plasminogen activator inhibitor- 1 (PAI-1), urokinase and tissue plasminogen activators (uPA and tPA), uroki nase plasminogen activator receptor (uPAR), and transforming growth factor- beta(1) (TGF-beta(1)) was examined by Northern analysis. Western analysis w as performed to detect protein expression of PAI-1, uPA and uPAR. An immuno histochemical study was performed to detect the localization of PAI-I. Addi tionally, primary cultured liver cells were examined by Northern and Wester n analyses for this protein with or without prior incubation with TGF-beta( 1). Results: At 6 weeks, when fibrosis had occurred, uPA and uPAR mRNAs had inc reased 2.8-fold and 1.8-fold, respectively; PAI-1 and tPA mRNA levels were unchanged. At the cirrhotic stage (9 to 12 weeks), mRNA levels for PAI-I, u PA, uPAR and tPA were all increased. Western analysis also showed increased uPA and uPAR expressions in fibrotic liver, and increased PAI-1, uPA and u PAR expressions in cirrhotic liver. PAI-1 protein was also demonstrated imm unohistochemically along sinusoids, vessels, and bile duct cells of normal and fibrotic liver. in liver cell cultures, Kupffer cells, hepatocytes, and especially stellate cells, expressed PAI-1. Expression was enhanced in ste llate cells cultured from fibrotic or cirrhotic liver or stimulated in vitr o with TGF-PI. Conclusion: Though increased uPA and uPAR may act on matrix degradation in fibrotic liver, increased PAI-1 together with uPA, uPAR and tPA are associa ted with overall inhibition of matrix degradation in cirrhotic liver. Hepat ic stellate cells are an important source of PAI-I during liver fibrosis.