Elevated Expression of Urokinase-like Plasminogen Activator and Plasminogen Activator Inhibitor Type 1 During the Vascular Remodeling Associated With Pulmonary Thromboembolism

From the University of Vienna, Austria (I.M.L.); the Division of Pulmonary and Critical Care Medicine, University of California at San Diego (I.M.L., K.M.M.); and The Scripps Research Institute, La Jolla, California (I.M.L., R.R.S.).

Correspondence to Raymond R. Schleef, PhD, Department of Vascular Biology (VB-1), The Scripps Research Institute, 10550 N. Torrey Pines Rd, La Jolla, CA 92037. E-mail rschleef{at}riscsm.scripps.edu

Abstract—Information is lacking on the mechanisms involved in the organization, resolution, and repair of the vascular lumen after acute pulmonary thromboembolism. Because recent data suggest that the balance between plasminogen activators (PAs) and type 1 plasminogen activator inhibitor (PAI-1) plays a role in regulating cell migration within the extracellular matrix, we investigated the expression of these molecules by immunohistochemical and in situ hybridization analysis of pulmonary artery specimens from patients suffering fatal pulmonary embolism. The data were compared with the expression of these molecules in both patients' noninvolved pulmonary arteries and organ donor pulmonary arteries. Regions of initial organization and vascular remodeling were identified by a modified trichrome stain and by the presence of proliferating cell nuclear antigen (PCNA), a cell marker of proliferation. Staining for tissue-type PA antigen was low to undetectable in endothelial cells directly in contact with the fibrin-platelet thromboembolus and in areas in which the endothelial cell lining was replaced by cell growth into the thrombus. Urokinase-like PA (u-PA) expression was detected in mononuclear cells within the thrombus in the initial phase of thromboembolism and within cells migrating into the thrombus during the later stages of organization. PAI-1 expression was elevated in the monolayer of endothelial cells underlying the fresh platelet-fibrin thromboembolus and in a PCNA-positive cell population present between the pulmonary arterial intima and the thromboembolus that represents early organization. Increased expression of PAI-1 may play a role in inhibiting proteolysis and fostering the localization of the acute fibrin-platelet thrombus to the vascular wall, which is followed by the upregulation of u-PA in migrating cells during the reorganization process.

Key Words: thrombus organization • plasminogen activators • plasminogen activator inhibitor type 1 • pulmonary thromboembolism

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