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Reichel, Christoph A.; Uhl, Bernd; Lerchenberger, Max; Puhr-Westerheide, Daniel; Rehberg, Markus; Liebl, Johanna; Khandoga, Andrej; Schmalix, Wolfgang; Zahler, Stefan; Deindl, Elisabeth; Lorenzl, Stefan; Declerck, Paul J.; Kanse, Sandip; Krombach, Fritz

Urokinase-Type Plasminogen Activator Promotes Paracellular Transmigration of Neutrophils Via Mac-1, But Independently of Urokinase-Type Plasminogen Activator Receptor

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  • Medientyp: E-Artikel
  • Titel: Urokinase-Type Plasminogen Activator Promotes Paracellular Transmigration of Neutrophils Via Mac-1, But Independently of Urokinase-Type Plasminogen Activator Receptor
  • Beteiligte: Reichel, Christoph A.; Uhl, Bernd; Lerchenberger, Max; Puhr-Westerheide, Daniel; Rehberg, Markus; Liebl, Johanna; Khandoga, Andrej; Schmalix, Wolfgang; Zahler, Stefan; Deindl, Elisabeth; Lorenzl, Stefan; Declerck, Paul J.; Kanse, Sandip; Krombach, Fritz
  • Erschienen: Ovid Technologies (Wolters Kluwer Health), 2011
  • Erschienen in: Circulation, 124 (2011) 17, Seite 1848-1859
  • Sprache: Englisch
  • DOI: 10.1161/circulationaha.110.017012
  • ISSN: 0009-7322; 1524-4539
  • Schlagwörter: Physiology (medical) ; Cardiology and Cardiovascular Medicine
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:sec> <jats:title>Background—</jats:title> <jats:p>Urokinase-type plasminogen activator (uPA) has recently been implicated in the pathogenesis of ischemia-reperfusion (I/R) injury. The underlying mechanisms remain largely unclear.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods and Results—</jats:title> <jats:p>Using in vivo microscopy on the mouse cremaster muscle, I/R-elicited firm adherence and transmigration of neutrophils were found to be significantly diminished in uPA-deficient mice and in mice treated with the uPA inhibitor WX-340, but not in uPA receptor (uPAR)–deficient mice. Interestingly, postischemic leukocyte responses were significantly reduced on blockade of the integrin CD11b/Mac-1, which also serves as uPAR receptor. Using a cell transfer technique, postischemic adherence and transmigration of wild-type leukocytes were significantly decreased in uPA-deficient animals, whereas uPA-deficient leukocytes exhibited a selectively reduced transmigration in wild-type animals. On I/R or stimulation with recombinant uPA, &gt;90% of firmly adherent leukocytes colocalized with CD31-immunoreactive endothelial junctions as detected by in vivo fluorescence microscopy. In a model of hepatic I/R, treatment with WX-340 significantly attenuated postischemic neutrophil infiltration and tissue injury.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions—</jats:title> <jats:p>Our data suggest that endothelial uPA promotes intravascular adherence, whereas leukocyte uPA facilitates the subsequent paracellular transmigration of neutrophils during I/R. This process is regulated via CD11b/Mac-1, and does not require uPAR. Pharmacological blockade of uPA interferes with these events and effectively attenuates postischemic tissue injury.</jats:p> </jats:sec>
  • Zugangsstatus: Freier Zugang