Thus, our results indicate that plasmin facilitates neutrophil extravasation in vivo via endogenous generation of lipid mediators. Consequently, in the early reperfusion phase, extravasated plasmin is suggested to induce the generation of leukotrienes and PAF which, in turn, directly activate XAV939 Wnt/beta-catenin inhibitor neutrophils and promote intravascular adherence as well as transmigration of these inflammatory cells in postischemic tissue. Since inhibition of leukotriene synthesis or blockade of the PAF receptor only partially reduced plasmin- as well as I/R-elicited activation of mast cells, the postischemic generation of lipid mediators is, at least in part, suggested to occur downstream of mast cell activation. In conclusion, our experimental data suggest that extravasated plasmin mediates firm adherence and transmigration of neutrophils to the reperfused tissue indirectly through activation of perivascular mast cells and a sequential generation of leukotrienes and PAF. The plasmin inhibitors tranexamic acid and e-aminocaproic acid as well as the broad-spectrum serine protease inhibitor aprotinin are thought to interfere with this inflammatory cascade and effectively prevent intravascular accumulation and transmigration of neutrophils to the reperfused tissue as well as protect the microvasculature from postischemic remodeling events. These findings provide novel insights into the mechanisms underlying the postischemic inflammatory response and highlight the use of plasmin inhibitors as a potential therapeutic approach for the prevention of I/R injury. The immunophilin-binding agents cyclosporine A, FK506 and rapamycin represent potent immunosuppressive agents that have revolutionized bone marrow and solid organ transplantation as well as treatment of autoimmune diseases. Sanglifehrin A is a novel immunophilin-binding immunosuppressive drug isolated from the actinomycetes strain Streptomyces A92-308110 exhibiting high affinity binding to Cyclophilin A, but unknown mechanism of action. SFA does not affect the calcineurin phosphatase or the mammalian target of rapamycin and it does not inhibit purine or pyrimidine de novo synthesis. Crystal structure analysis of SFA in complex with cyclophilin A indicated that the effector domain of SFA exhibits a chemical and threedimensional structure very different from CsA suggesting different immunosuppressive action. In contrast to CsA, the immunobiology of SFA is not well understood. Previous reports demonstrated that SFA is different from known immunosuppressive agent. SFA is approximately 15�C35-fold less potent than CsA at inhibiting T cell proliferation in 
mouse and human MLR cultures. In contrast to CsA and FK506, SFA does not inhibit TCR-induced anergy. Similarly to rapamycin, SFA blocks IL-2 dependent proliferation in T cells. Different groups have reported that SFA exerts suppressive effects on human and mouse DC. SFA suppresses antigen uptake, IL-12 and IL-18 production of DC in vitro and in vivo but it does not inhibit DC differentiation and surface costimulatory molecule expression. DCs are professional antigen presenting cells that play a central role in the initiation and modulation of innate and adaptive immunity. DC Silmitasertib attract effector cells through different chemokines that are critical for the coordination of the sequential interaction of immediate effector cells, such as neutrophils and natural killer cells and the delayed activation of antigen-specific B and T lymphocytes. Immunophilin-binding immunosuppressive agents, especially rapamycin, and to a lesser extent, CsA, have been reported to target key functions of DC.