title: Plasmin inhibitors prevent leukocyte accumulation and remodeling events in the postischemic microvasculature.
abstract: Clinical trials revealed beneficial effects of the broad-spectrum serine protease inhibitor aprotinin on the prevention of ischemia-reperfusion (I/R) injury. The underlying mechanisms remained largely unclear. Using in vivo microscopy on the cremaster muscle of male C57BL/6 mice, aprotinin as well as inhibitors of the serine protease plasmin including tranexamic acid and ε-aminocaproic acid were found to significantly diminish I/R-elicited intravascular firm adherence and (subsequent) transmigration of neutrophils. Remodeling of collagen IV within the postischemic perivenular basement membrane was almost completely abrogated in animals treated with plasmin inhibitors or aprotinin. In separate experiments, incubation with plasmin did not directly activate neutrophils. Extravascular, but not intravascular administration of plasmin caused a dose-dependent increase in numbers of firmly adherent and transmigrated neutrophils. Blockade of mast cell activation as well as inhibition of leukotriene synthesis or antagonism of the platelet-activating-factor receptor significantly reduced plasmin-dependent neutrophil responses. In conclusion, our data suggest that extravasated plasmin(ogen) mediates neutrophil recruitment in vivo via activation of perivascular mast cells and secondary generation of lipid mediators. Aprotinin as well as the plasmin inhibitors tranexamic acid and ε-aminocaproic acid interfere with this inflammatory cascade and effectively prevent postischemic neutrophil responses as well as remodeling events within the vessel wall.
authors.affiliation: Walter Brendel Centre of Experimental Medicine, Ludwig-Maximilians-Universität München, Munich, Germany. christoph.reichel@med.uni-muenchen.de
authors.forename: Christoph A
authors.initials: CA
authors.lastname: Reichel
authors.forename: Max
authors.initials: M
authors.lastname: Lerchenberger
authors.forename: Bernd
authors.initials: B
authors.lastname: Uhl
authors.forename: Markus
authors.initials: M
authors.lastname: Rehberg
authors.forename: Nina
authors.initials: N
authors.lastname: Berberich
authors.forename: Stefan
authors.initials: S
authors.lastname: Zahler
authors.forename: Matthias P
authors.initials: MP
authors.lastname: Wymann
authors.forename: Fritz
authors.initials: F
authors.lastname: Krombach
mesh_terms: D015119:Aminocaproic Acid / Q000494:pharmacology; D000818:Animals; D000933:Antifibrinolytic Agents / Q000494:pharmacology*; D007611:Aprotinin / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D007958:Leukocyte Count; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D055806:Microvessels / Q000187:drug effects* / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000097:blood / Q000276:immunology / Q000503:physiopathology* / Q000534:rehabilitation; D020556:Neutrophil Infiltration / Q000187:drug effects*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D014148:Tranexamic Acid / Q000494:pharmacology
chemical_list: D000933:Antifibrinolytic Agents; D015842:Serine Proteinase Inhibitors; D014148:Tranexamic Acid; D007611:Aprotinin; D015119:Aminocaproic Acid