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.
Highlights
Ischemia-reperfusion (I/R) injury is still the most common cause for organ dysfunction and failure after myocardial infarction, hemorrhagic shock, and transplantation
After 30 min of ischemia and 60 min of reperfusion, there was a significant increase in numbers of rolling leukocytes as compared to shamoperated animals which returned to baseline values after 120 min of reperfusion
E-aminocaproic acid, or aprotinin did not significantly alter leukocyte rolling during the entire reperfusion phase (Fig. 1B)
Summary
Ischemia-reperfusion (I/R) injury is still the most common cause for organ dysfunction and failure after myocardial infarction, hemorrhagic shock, and transplantation. Neutrophil recruitment from the microvasculature to the perivascular tissue is a hallmark in the pathogenesis of I/R injury [1] In this process, a variety of adhesion molecules, chemokines, and proteases have been implicated strictly controlling the single steps of leukocyte extravasation including rolling, firm adherence, and transendothelial migration [2,3]. In addition to its well-known fibrinolytic properties, this protease has been reported to play a critical role in various other physiological and pathophysiological processes including angiogenesis, wound healing, and inflammation. In this context, plasmin is suggested to initiate intracellular signaling pathways as well as to activate extracellular matrix (ECM) degrading enzymes facilitating cell adhesion and migration [4,5,6]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
