Urokinase mediates fibrinolysis in the pulmonary microvasculature

The role of urokinase-type plasminogen activator (uPA) and its receptor (uP AR) in fibrinolysis remains unsettled. The contribution of uPA may depend o n the vascular location, the physical properties of the clot, and its impac t on tissue function. To study the contribution of urokinase within the pul monary microvasculature, a model of pulmonary microembolism in the mouse wa s developed, iodine 125 (I-125)-labeled fibrin microparticles injected intr avenously through the tail vein lodged preferentially in the lung, distribu ting homogeneously throughout the lobes. Clearance of I-125-microemboli in wild type mice was rapid and essentially complete by 5 hours. In contrast, uPA(-/-) and tissue-type plasminogen activator tPA(-/-) mice, but not uPAR( -/-) mice, showed a marked impairment in pulmonary fibrinolysis throughout the experimental period. The phenotype in the uPA-/- mouse was rescued comp letely by infusion of single chain uPA (scuPA), The increment in clot lysis was 4-fold greater in uPA(-/-) mice infused with the same concentration of scuPA complexed with soluble recombinant uPAR, These data indicate that uP A contributes to endogenous fibrinolysis in the pulmonary vasculature to th e same extent as tPA in this model system. Binding of scuPA to its receptor promotes fibrinolytic activity in vivo as well as in vitro. The physical p roperties of fibrin clots, including size, age, and cellular composition, a s well as heterogeneity in endothelial cell function, may modify the partic ipation of uPA in endogenous fibrinolysis. (C) 2000 by The American Society of Hematology.