Critical Role of Plasminogen Activator Inhibitor-1 in Cholestatic Liver Injury and Fibrosis

Abstract

Plasminogen activator inhibitor-1 (PAI-1) is an acute phase protein known to correlate with hepatic fibrosis. However, whether or not PAI-1 plays a causal role in this disease process had not been directly tested. Therefore, wild-type or PAI-1 knockout (PAI-1(-/-)) mice underwent bile duct ligation. Mice were sacrificed either 3 or 14 days after surgery for assessment of early (i.e., inflammation) and late (i.e., fibrosis) changes caused by bile duct ligation. Liver injury was determined by histopathology and plasma enzymes. Accumulation of extracellular matrix was evaluated by Sirius red staining and by measuring hydroxyproline content. Hepatic expression of PAI-1 was increased approximately 9-fold by bile duct ligation in wild-type mice. Furthermore, early liver injury and inflammation due to bile duct ligation was significantly blunted in PAI-1(-/-) mice in comparison with wild-type mice. Although PAI-1(-/-) mice were significantly protected against the accumulation of extracellular matrix caused by bile duct ligation, increases in expression of indices of stellate cell activation and collagen synthesis caused by bile duct ligation were not attenuated. Protection did, however, correlate with an elevation in hepatic activities of plasminogen activator and matrix metalloprotease activities. In contrast, the increase in tissue inhibitor of metalloproteases-1 protein, a major inhibitor of matrix metalloproteases, caused by bile duct ligation was not altered in PAI-1(-/-) mice compared with the wild-type strain. The increase in hepatic activity of urokinase-type plasminogen activator was also accompanied by more activation of the hepatocyte growth factor receptor c-Met. Taken together, these data suggest that PAI-1 plays a causal role in mediating fibrosis during cholestasis.