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Blood, 1 September 2000, Vol. 96, No. 5, pp. 1820-1826
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Urokinase mediates fibrinolysis in the pulmonary
microvasculature
Khalil Bdeir,
Juan-Carlos Murciano,
John Tomaszewski,
Lauren Koniaris,
Jose Martinez,
Douglas B. Cines,
Vladimir
R. Muzykantov, and
Abd Al-Roof Higazi
From the Departments of Pathology and
Laboratory Medicine and Pharmacology, University of Pennsylvania School
of Medicine, Philadelphia, PA; the Department of Medicine, Thomas
Jefferson Medical College, Philadelphia, PA; and the Department of
Clinical Biochemistry, Hadassah Hospital, Hebrew University, Jerusalem,
Israel.
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 (125I)-labeled fibrin microparticles injected
intravenously through the tail vein lodged preferentially in the lung,
distributing homogeneously throughout the lobes. Clearance of
125I-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.
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