• Bernd Uhl, Gabriele Zuchtriegel, Daniel Puhr-Westerheide, Marc Praetner, Markus Rehberg, Matthias Fabritius, Maximilian Hessenauer, Martin Holzer, Andrej Khandoga, Robert Fürst, Stefan Zahler, Fritz Krombach, and Christoph A Reichel.
• From the Walter Brendel Centre of Experimental Medicine (B.U., G.Z., D.P.-W., M.P., M.R., M.F., M. Hessenauer, M. Holzer, F.K., C.A.R.), Department of Otorhinolaryngology, Head and Neck Surgery (G.Z., M. Hessenauer, M. Holzer, C.A.R.), Department of Surgery, Klinikum der Universität München (A.K.), and Department of Pharmacy (R.F., S.Z.), Ludwig-Maximilians-Universität München, Munich, Germany; and Institute of Pharmaceutical Biology, Biocenter, Goethe-University Frankfurt/Main, Frankfurt am Main, Germany (R.F.).
• Arterioscler. Thromb. Vasc. Biol. 2014 Jul 1; 34 (7): 1495-504.

ObjectiveNeutrophil infiltration of the postischemic tissue considerably contributes to organ dysfunction on ischemia/reperfusion injury. Beyond its established role in fibrinolysis, tissue-type plasminogen activator (tPA) has recently been implicated in nonfibrinolytic processes. The role of this serine protease in the recruitment process of neutrophils remains largely obscure.Approach And ResultsUsing in vivo microscopy on the postischemic cremaster muscle, neutrophil recruitment and microvascular leakage, but not fibrinogen deposition at the vessel wall, were significantly diminished in tPA(-/-) mice. Using cell transfer techniques, leukocyte and nonleukocyte tPA were found to mediate ischemia/reperfusion-elicited neutrophil responses. Intrascrotal but not intra-arterial application of recombinant tPA induced a dose-dependent increase in the recruitment of neutrophils, which was significantly higher compared with stimulation with a tPA mutant lacking catalytic activity. Whereas tPA-dependent transmigration of neutrophils was selectively reduced on the inhibition of plasmin or gelatinases, neutrophil intravascular adherence was significantly diminished on the blockade of mast cell activation or lipid mediator synthesis. Moreover, stimulation with tPA caused a significant elevation in the leakage of fluorescein isothiocyanate dextran to the perivascular tissue, which was completely abolished on neutrophil depletion. In vitro, tPA-elicited macromolecular leakage of endothelial cell layers was abrogated on the inhibition of its proteolytic activity.ConclusionsEndogenously released tPA promotes neutrophil transmigration to reperfused tissue via proteolytic activation of plasmin and gelatinases. As a consequence, tPA on transmigrating neutrophils disrupts endothelial junctions allowing circulating tPA to extravasate to the perivascular tissue, which, in turn, amplifies neutrophil recruitment through the activation of mast cells and release of lipid mediators.© 2014 American Heart Association, Inc.

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