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Blood, 15 February 2008, Vol. 111, No. 4, pp. 1999-2006. Prepublished online as a Blood First Edition Paper on November 28, 2007; DOI 10.1182/blood-2007-07-103002. This Article Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2007-07-103002v1 111/4/1999    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Ding, B.-S. Articles by Muzykantov, V. R. Search for Related Content PubMed PubMed Citation Articles by Ding, B.-S. Articles by Muzykantov, V. R. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted July 24, 2007 Accepted November 20, 2007 Prophylactic thrombolysis by thrombin-activated latent pro-urokinase targeted to PECAM-1 in the pulmonary vasculature Bi-Sen Ding, Nankang Hong, Juan-Carlos Murciano, Kumkum Ganguly, Claudia Gottstein, Melpo Christofidou-Solomidou, Steven M. Albelda, Aron B. Fisher, Douglas B. Cines, and Vladimir R. Muzykantov* Department of Pharmacology, Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, PA Institute for Environmental Medicine, University of Pennsylvania, Philadelphia, PA Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain Division of Biosciences, Los Alamos National Laboratory, Los Alamos, TX Department of Chemical Engineering, University of California Santa Barbara, Santa Barbara, CA Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pennsylvania, Philadelphia, PA Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA * Corresponding author; email: muzykant{at}mail.med.upenn.edu. A recombinant pro-drug, single-chain urokinase-type plasminogen activator (scuPA) fused to an anti-PECAM-1 antibody single-chain variable fragment (anti-PECAM scFv/scuPA) targets endothelium and augments thrombolysis in the pulmonary vasculature1. To avoid premature activation and inactivation and to limit systemic toxicity, we replaced the native plasmin activation site in scFv/low molecular weight (lmw)-scuPA with a thrombin activation site, generating anti-PECAM scFv/uPA-T that: i) is latent and activated by thrombin instead of plasmin, ii) binds to PECAM-1; iii) does not consume plasma fibrinogen; iv) accumulates in mouse lungs after IV injection; and, v) resists PA inhibitor PAI-1 until activated by thrombin. In mouse models of pulmonary thrombosis caused by thromboplastin and ischemia-reperfusion (I/R), scFv/uPA-T provided more potent thromboprophylaxis and greater lung protection than plasmin-sensitive scFv/uPA. Endothelium-targeted thromboprophylaxis triggered by a pro-thrombotic enzyme illustrates a novel approach to time- and site-specific regulation of proteolytic reactions that can be modulated for therapeutic benefit. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: B.-S. Ding, N. Hong, M. Christofidou-Solomidou, C. Gottstein, S. M. Albelda, D. B. Cines, A. B. Fisher, and V. R. Muzykantov Anchoring Fusion Thrombomodulin to the Endothelial Lumen Protects against Injury-induced Lung Thrombosis and Inflammation Am. J. Respir. Crit. Care Med., August 1, 2009; 180(3): 247 - 256. [Abstract] [Full Text] [PDF]

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