Participation of urokinase-type plasminogen activator receptor in the clearance of fibrin from the lung

In vitro studies have demonstrated that the binding of urokinase-type plasm inogen activator (uPA) to its cell surface receptor (uPAR) greatly accelera tes plasminogen activation. However, the role of uPAR in clearing abnormal fibrin deposits from the lung is uncertain. Knowing that uPA binding to uPA R is species specific, we used adenoviral vectors to transfer human or muri ne uPA genes into human or mouse epithelial cells in vitro and to mouse lun gs in vivo. By measuring degradation of fluorescein-labeled fibrin, we foun d that uPA lysed fibrin matrices more efficiently when expressed in cells o f the same species. A monoclonal antibody that blocks the binding of human uPA to human uPAR suppressed fibrin degradation by human cells expressing h uman uPA but not murine uPA. Importantly, 3 days after intratracheal delive ry of the vectors, mice receiving murine uPA transgenes degraded fibrin mat rices formed within their air spaces more efficiently than animals transduc ed with human uPA genes. These results show that uPA bound to uPAR increase s the efficiency of fibrinolysis on epithelial cell surfaces in a biologica lly relevant fashion.