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Research Article Free access | 10.1172/JCI116144
Department of Physiology and Cell Biology, Albany Medical College of Union University, New York 12208.
Find articles by Ge, M. in: JCI | PubMed | Google Scholar
Department of Physiology and Cell Biology, Albany Medical College of Union University, New York 12208.
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Department of Physiology and Cell Biology, Albany Medical College of Union University, New York 12208.
Find articles by Ryan, T. in: JCI | PubMed | Google Scholar
Department of Physiology and Cell Biology, Albany Medical College of Union University, New York 12208.
Find articles by Malik, A. in: JCI | PubMed | Google Scholar
Published December 1, 1992 - More info
We studied the effects of fibrinogen degradation product (FDP) fragment D on endothelial monolayer integrity and the mechanisms of fragment D-induced endothelial cell detachment from the substratum. Incubation of bovine pulmonary artery endothelial cells (BPAEC) with fragment D caused concentration- and time-dependent cell detachment from the substratum. The optimal response occurred at fragment D concentrations of 2 microM and required an incubation time of 24 h. BPAEC challenged with fragment D increased the concentration and activity of urokinase-type plasminogen activator (uPA) in the conditioned medium within 2 to 4 h of incubation. Fragment D also induced the release of tissue-type plasminogen activator, but to a lesser extent than uPA. Fragment D concurrently increased plasminogen activator (PA) activity in a concentration-dependent manner. Increased PA activity was followed by augmentation of cell-associated plasmin activity and subsequent increase in the degradation of 125I-fibrinogen and 125I-vitronectin precoated in the subendothelial matrix. Pretreatment of BPAEC with anti-uPA antibody, and inhibitors of uPA (dansyl-GGACK) and plasmin (aprotinin) prevented approximately 60% of the fragment D-induced endothelial cell detachment. We conclude that FDP fragment D increases secretion of endothelial PAs and enhances the generation of plasmin, thereby contributing to proteolysis of extracellular matrix and endothelial cell detachment. Fragment D may be a critical mediator linking activation of fibrinolysis to vascular endothelial injury in inflammatory disorders.
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