Blockade of CD18-Dependent Neutrophil Adhesion Limits Myocardial Infarct Size Following Coronary Artery Occlusion in Cynomolgus Monkeys

Neutrophil accumulation into ischemic myocardium is believed to underlie many of the deleterious sequelae observed with coronary artery occlusion and reperfusion. Excessive margination of and release of reactive and cytotoxic substances from activated neutrophils have been associated with the increased coronary vascular resistance, depressed ventricular wall function and myocardial necrosis resulting from ischemic and reperfusion injury. Neutrophil deposition in ischemic tissue is initiated by the attachment of these leukocytes to the vascular endothelium via various plasmalemmal adhesion macromolecules. These molecules include the lymphocyte function-associated antigen (LFA-1) family of glycoproteins located on the surface of neutrophils. We have initiated studies which attempt to elucidate the importance of the LFA-1 family of glycoproteins in mediating the possible deleterious effects of neutrophil infiltration in a primate model of myocardial ischemic and reperfusion injury. Male cynomolgus monkeys (5.0 to 6.7 kg) were anesthetized with Nembutal and implanted with catheters for monitoring hemodynamics (BP, HR, LVP, dP/dt, ECG) and administering radioactive microspheres for determining left ventricular area at risk (AAR) of ischemic injury. The left anterior descending coronary artery was occluded for 90 minutes followed by 4 hours of reperfusion. Animals received either saline or R15.7 (1.0 mg/kg i.v.), a monoclonal antibody (MAB) directed against the (primate) beta subunit (CD10) of LFA-1. Hearts were quickly removed following reperfusion, sectioned, and stained with triphenyletetrazolium chloride to image infarct size. Animals in both the saline (49 ± 3%, n=4) and R15.7 (49 ± 3%, n=5) treated groups had similar AAR (% of left ventricle).