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Tissue Plasminogen Activator Promotes Postischemic Neutrophil Recruitment via Its Proteolytic and Nonproteolytic Properties

Tissue Plasminogen Activator Promotes Postischemic Neutrophil Recruitment via Its Proteolytic and... Tissue Plasminogen Activator Promotes Postischemic Neutrophil Recruitment via Its Proteolytic and Nonproteolytic Properties 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, Christoph A. Reichel Objective—Neutrophil 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 Results—Using 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 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Arteriosclerosis, Thrombosis, and Vascular Biology Wolters Kluwer Health

Tissue Plasminogen Activator Promotes Postischemic Neutrophil Recruitment via Its Proteolytic and Nonproteolytic Properties

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Copyright
© 2014 American Heart Association, Inc.
ISSN
1079-5642
eISSN
1524-4636
DOI
10.1161/ATVBAHA.114.303721
pmid
24764453
Publisher site
See Article on Publisher Site

Abstract

Tissue Plasminogen Activator Promotes Postischemic Neutrophil Recruitment via Its Proteolytic and Nonproteolytic Properties 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, Christoph A. Reichel Objective—Neutrophil 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 Results—Using 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

Journal

Arteriosclerosis, Thrombosis, and Vascular Biology – Wolters Kluwer Health

Published: Jul 1, 2014

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