In addition to its well-known fibrinolytic properties, this protease has also 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 degrading enzymes ultimately facilitating cell adhesion and migration. Despite recent concerns about the safety of the broad-spectrum serine protease inhibitor aprotinin, clinical trials revealed beneficial effects of this naturally occurring substance for the prevention of postischemic organ dysfunction. Here, aprotinin has been suggested to suppress the transcription of genes which have been implicated in the evolution of the postischemic inflammatory response. The consequences for each single step of the leukocyte recruitment process during I/R, however, have not yet been studied. Previous studies have implicated the serine protease plasmin as well as plasminogen activators in the regulation of leukocyte migration to the site of inflammation. Interestingly, lysine analogues such as tranexamic acid or e-aminocaproic acid have recently been reported to effectively and safely inhibit plasmin activity. The effect of these synthetic plasmin inhibitors on postischemic leukocyte responses has not yet been evaluated. In the early reperfusion phase, remodeling processes within the perivenular basement membrane have been described which are thought to compromise microvascular integrity and to pave the way for the excessive leukocyte infiltration of reperfused tissue. Due to its capability to disintegrate components of the venular basement membrane as well as to activate other ECMdegrading proteases, plasmin has been implicated in these events. The effect of plasmin inhibitors and aprotinin on remodeling processes within the postischemic vessel wall has not yet been investigated. Restoration of blood flow is the overall goal for successful organ transplantation as well as for the treatment of myocardial infarction, hemorrhagic shock, and stroke. As a consequence of this inevitable approach, however, neutrophils accumulate within the postischemic microvasculature and compromise reperfusion of the affected organ. Subsequently, transmigrating neutrophils release reactive oxygen species, cytokines, and proteases, impairing microvascular integrity and promoting postischemic tissue injury. Notably, PF-04217903 extravasated neutrophils also contribute to tissue healing and regeneration collectively emphasizing neutrophil recruitment as a key event in the pathogenesis of I/R injury. Using different animal models, the serine protease plasmin as well as plasmin activators have been implicated particularly in the migration of monocytes, but also in the recruitment of neutrophils. Moreover, clinical trials revealed beneficial effects of the broad-spectrum serine protease inhibitor aprotinin for the prevention of postischemic organ dysfunction after coronary revascularization. In this context, aprotinin has been 
reported to suppress the transcription of genes which are supposed to play a major role in the postischemic inflammatory response. The resulting consequences for each single step of the leukocyte recruitment process, however, remained LDN-193189 ALK inhibitor unclear. Using near-infrared RLOT in vivo microscopy on the mouse cremaster muscle, we systematically analyzed the effects on postischemic rolling, firm adherence, and transmigration of leukocytes of the broad-spectrum serine protease inhibitor aprotinin, a naturally occurring bovine protein.