Urokinase mediates fibrinolysis in the pulmonary microvasculature.
The role of urokinase-type plasminogen activator (uPA) and its receptor (uPAR) in fibrinolysis remains unsettled. The contribution of uPA may depend on the vascular location, the physical properties of the clot, and its impact on tissue function. To study the contribution of urokinase within the pulmonary microvasculature, a model of pulmonary microembolism in the mouse was developed. Iodine 125 ((125)I)-labeled fibrin microparticles injected intravenously through the tail vein lodged preferentially in the lung, distributing homogeneously throughout the lobes. Clearance of (125)I-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 completely 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 uPA contributes to endogenous fibrinolysis in the pulmonary vasculature to the 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 properties of fibrin clots, including size, age, and cellular composition, as well as heterogeneity in endothelial cell function, may modify the participation of uPA in endogenous fibrinolysis. (Blood. 2000;96:1820-1826)
Bdeir
K
K
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Murciano
J C
JC
Tomaszewski
J
J
Koniaris
L
L
Martinez
J
J
Cines
D B
DB
Muzykantov
V R
VR
Higazi
A A
AA
D000818:Animals; D004195:Disease Models, Animal; D005337:Fibrin / Q000032:analysis; D005340:Fibrinogen / Q000008:administration & dosage / Q000493:pharmacokinetics; D005342:Fibrinolysis / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D008168:Lung / Q000737:chemistry / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008863:Microspheres; D010316:Particle Size; D011652:Pulmonary Circulation / Q000187:drug effects / Q000502:physiology*; D011655:Pulmonary Embolism / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D011956:Receptors, Cell Surface / Q000235:genetics; D055293:Receptors, Urokinase Plasminogen Activator; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology; D014018:Tissue Distribution; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000502:physiology*
C524898:PLAUR protein, human; C524899:Plaur protein, mouse; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D011994:Recombinant Proteins; D005337:Fibrin; D005340:Fibrinogen; D014568:Urokinase-Type Plasminogen Activator