Complement inhibitor Fut‐175 inhibits leukocyte‐endothelium interaction following ischemia and reperfusion

Fut‐175 has been shown to ameliorate ischemia/reperfusion (I/R) injury by inhibition of classical and alternative complement pathway. The effects of fut‐175 on leukocyte‐endothelial cell interactions were observed by intravital microscopy in the rat mesenteric microcirculation in vivo. Further, its effect on P‐selectin expression on the vasculature was analysed by immunohistochemical analysis. Leukocyte rolling, firm adherence and transmigration were studied in the microcirculation after hemorrhage (60 min) and reperfusion (90 min). Fut‐175 (1 and 5 mg/kg) was administrated as an i.v. bolus injection 5 minutes before reperfusion. Treatment with Fut‐175 significantly reduced leukocyte endothelium interaction in the rat mesenteric microcirculation. After hemorrhage followed by reperfusion leukocyte rolling was decreased from 58±5.2 to 5.2±1 cells/min (p< 0.01) and leukocyte adherence was decreased from 8.3±1.5 to 1.4±0.7 cells/100 μm (p< 0.01) following Fut‐175 treatment. Leukocyte extravasation was decreased 90 min after reperfusion. Immunhistochemical detection of P‐selectin showed a profound decrease in endothelial cell surface expression within the intestinal vasculature following Fut‐175 administration compared to vehicle treatment (38.5±4.3 v.s. 15.9±3,2% (p < 0.01)). Further, vascular leakage was significantly reduced by Fut‐175 treatment. Fut‐175 is a potent and effective vasculoprotective compound that inhibits leukocyte‐endothelial cell interaction after inflammatory activation. Further, reduction of endothelial P‐selectin expression may present a mechanism of Fut‐175 underlying its anti‐complement effect.