Monoclonal antibody to ICAM-1 preserves postischemic blood flow and reduces infarct size after ischemia-reperfusion in rabbit.

Neutrophils are pivotal in the pathogenesis of reperfusion injury leading to myocardial infarction. Firm adhesion of PMN to endothelium may be initiated by the interaction between constitutively expressed intercellular adhesion molecule-1 (ICAM-1) on endothelium and beta2 integrin (CD11b/CD18) on neutrophils. We tested the hypothesis that a monoclonal antibody (mAb RR1/1) against ICAM-1 would preserve postischemic myocardial blood flow and attenuate myocardial injury in an anesthetized rabbit model of coronary occlusion and reperfusion. Either mAb RR1/1 or isotypematched control mAb (R3.1) was injected 10 min before reperfusion. Postischemic myocardial blood flow in the area at risk (Ar) and necrotic area was significantly improved with mAb RR1/1 treatment compared with vehicle and mAb R3.1 during the reperfusion period. RR1/1 had no effect on nonischemic zone blood flow. The Ar as a percent of left ventricle was comparable between groups. Infarct size (TTC) as a percent of Ar was significantly reduced by mAb RR1/1 compared with saline vehicle and mAb R3.1. Plasma creatine kinase activity confirmed the reduction of infarct size in mAb RR1/1 group. In in vitro studies, 40 microg/mL mAb RR1/l, which approximates the plasma concentration of 2 mg/kg mAb RR1/1, markedly inhibited platelet-activating factor-stimulated neutrophil adherence to rabbit aortic endothelium. We conclude that blockade of ICAM-1 during reperfusion reduces postischemic perfusion defects and attenuates the progression of myocardial injury leading to necrosis. This cardioprotection by mAb RR1/1 may be due to inhibition of neutrophil adhesion to the coronary endothelium.