title: Urokinase-type plasminogen activator promotes paracellular transmigration of neutrophils via Mac-1, but independently of urokinase-type plasminogen activator receptor.
abstract: BACKGROUND
  Urokinase-type plasminogen activator (uPA) has recently been implicated in the pathogenesis of ischemia-reperfusion (I/R) injury. The underlying mechanisms remain largely unclear.
  
  
  RESULTS
  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, >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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Walter Brendel Centre of Experimental Medicine, Munich, Germany. christoph.reichel@med.uni-muenchen.de
authors.forename: Christoph A
authors.initials: CA
authors.lastname: Reichel
authors.forename: Bernd
authors.initials: B
authors.lastname: Uhl
authors.forename: Max
authors.initials: M
authors.lastname: Lerchenberger
authors.forename: Daniel
authors.initials: D
authors.lastname: Puhr-Westerheide
authors.forename: Markus
authors.initials: M
authors.lastname: Rehberg
authors.forename: Johanna
authors.initials: J
authors.lastname: Liebl
authors.forename: Andrej
authors.initials: A
authors.lastname: Khandoga
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Schmalix
authors.forename: Stefan
authors.initials: S
authors.lastname: Zahler
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Deindl
authors.forename: Stefan
authors.initials: S
authors.lastname: Lorenzl
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Declerck
authors.forename: Sandip
authors.initials: S
authors.lastname: Kanse
authors.forename: Fritz
authors.initials: F
authors.lastname: Krombach
mesh_terms: D000818:Animals; D006801:Humans; D016177:Macrophage-1 Antigen / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000502:physiology; D009504:Neutrophils / Q000166:cytology* / Q000502:physiology*; D011897:Random Allocation; D055293:Receptors, Urokinase Plasminogen Activator / Q000502:physiology*; D057705:Transendothelial and Transepithelial Migration / Q000502:physiology*; D014568:Urokinase-Type Plasminogen Activator / Q000502:physiology*
chemical_list: D016177:Macrophage-1 Antigen; C524899:Plaur protein, mouse; D055293:Receptors, Urokinase Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator