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 plasminogen activator (uPA) to its cell surface receptor (uPAR) greatly accelerates plasminogen activation. However, the role of uPAR in clearing abnormal fibrin deposits from the lung is uncertain. Knowing that uPA binding to uPAR is species specific, we used adenoviral vectors to transfer human or murine uPA genes into human or mouse epithelial cells in vitro and to mouse lungs in vivo. By measuring degradation of fluorescein-labeled fibrin, we found that uPA lysed fibrin matrices more efficiently when expressed in cells of the same species. A monoclonal antibody that blocks the binding of human uPA to human uPAR suppressed fibrin degradation by human cells expressing human uPA but not murine uPA. Importantly, 3 days after intratracheal delivery of the vectors, mice receiving murine uPA transgenes degraded fibrin matrices formed within their air spaces more efficiently than animals transduced with human uPA genes. These results show that uPA bound to uPAR increases the efficiency of fibrinolysis on epithelial cell surfaces in a biologically relevant fashion.
Hattori
N
N
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, Michigan 48109-0642, USA.
Sisson
T H
TH
Xu
Y
Y
Desai
T J
TJ
Simon
R H
RH
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002460:Cell Line; D005337:Fibrin / Q000378:metabolism*; D005342:Fibrinolysis; D005786:Gene Expression Regulation; D005822:Genetic Vectors; D006801:Humans; D008168:Lung / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D011956:Receptors, Cell Surface / Q000378:metabolism / Q000502:physiology*; D055293:Receptors, Urokinase Plasminogen Activator; D011994:Recombinant Proteins; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism
C524898:PLAUR protein, human; C524899:Plaur protein, mouse; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D011994:Recombinant Proteins; D005337:Fibrin; D014568:Urokinase-Type Plasminogen Activator