Monoclonal Antibody toL-Selectin Attenuates Neutrophil Accumulation andProtects Ischemic Reperfused CatMyocardium

Background. Interaction ofCDii/CD18 located on neutrophil membranes withitsendothelial counterreceptor, intercellular adhesion molecule-1, plays a majorroleinpolymorphonuclear leukocyte (PMN)mediated endothelial dysfunction andmyocardial injury associated withischemia andreperfusion. However, PMN-derived L-selectin, whichisthought toplayan early roleinPMN rolling alongthe vascular endothelium, hasnotbeenstudied ina setting ofmyocardial ischemia andreperfusion. Methods andResults. Inthis study, weevaluated theeffects ofamonoclonal antibody against L-selectin, DREG-200, inafeline modelofmyocardial ischemia (1.5 hours) andreperfusion (4.5 hours). DREG-200 (1mg/kg) or an isotype-matched IgGlantibody, MAb R3.1, whichdoesnotcross-react incats, was administered asa bolus 10minutes before reperfusion. InMAb R3.1-treated cats, myocardial ischemia followed byreperfusion resulted insignificant coronaryvascular endothelial dysfunction, elevated cardiac myeloperoxidase activity indicative ofneutrophil accumulation intheischemic myocardium, andsevere myocardial injury. Incontrast, administration ofDREG-200at1 mg/kgsignificantly attenuated myocardial necrosis (14±4 versus32±3expressed aspercentage ofareaatrisk, P<.001) andattenuated coronaryendothelial dysfunction (P<.01) associated withischemia/reperfusion. Moreover, myeloperoxidaseactivity intheischemic myocardium was significantly lower thanMAb R3.1-treated cats(0.4±0.1 versus0.9±0.2 U/100 mg tissue, P<.05). Conclusions. Theseresults demonstrate thatblocking L-selectin withDREG-200exerts a significant cardioprotective effect inafeline modelofmyocardial ischemia andreperfusion, indicating thatL-selectin plays a significant roleinmediating PMN accumulation andPMN-induced endothelial andmyocardial injury after ischemia andreperfusion. (Circulation 1993;88:649-658)