INHIBITION OF NEUTROPHIL ADHESION DURING CARDIOPULMONARY BYPASS

Blood contact with synthetic surfaces during cardiopulmonary bypass (C PB) causes a diffuse inflammatory reaction that includes neutrophil ac tivation. The purpose of this study was to determine if inhibition of neutrophil adhesion with a new antiinflammatory agent NPC 15669 -dimet hylfluorenyl-9-methoxy)-carbonyl)-L-leucine) could reduce pulmonary in jury in a porcine model of CPB. NPC 15669 blocks adherence of activate d neutrophils by inhibiting upregulation of the Mac-1 (CD11b/CD18) adh esion molecule. Sixteen piglets underwent 2 hours of hypothermic CPB f ollowed by 2 hours of observation; 8 received NPC 15669 (10 mg/kg intr avenous bolus followed by 6 mg kg-l h-l intravenous infusion) and 8 re ceived equal volumes of vehicle. After 90 minutes of CPB, expression o f neutrophil adhesion molecule subunit CD18 increased 118% in control piglets but only 36% in piglets treated with NPC 15669 (p < 0.01). Alt hough neutropenia developed in all animals during CPB, lung tissue mye loperoxidase content was significantly lower in treated than in contro l animals 2 hours after CPB (94.9 +/- 10.4 versus 46.9 +/- 5.5 mu mol . 10 mg(-1) min(-1); p < 0.002). Free radical-mediated lipid peroxidat ion (quantitated by spectrophotometric assay of plasma conjugated dien es) was significantly reduced by treatment with NPC 15669 during and a fter CPB. Pulmonary function was better in NPC 15669-treated animals: 2 hours after CPB, pulmonary vascular resistance increased 477% in con trol piglets but only 140% in piglets receiving NPC 15669 (p < 0.03); arterial oxygen tension was significantly greater in piglets receiving NPC 15669 (428 +/- 33 mm Hg) than in controls (141 +/- 46; p < 0.0001 ). Histologic examination revealed neutrophil sequestration and inters titial and intraalveolar edema in control animals, but virtually norma l lung architecture in animals that received NPC 15669. These results demonstrate that NPC 15669 reduced neutrophil adhesion molecule expres sion, pulmonary leukocyte sequestration, and free radical generation d uring CPB with a corresponding reduction in lung injury. These finding s suggest that neutrophils are important mediators of CPB-associated p ulmonary damage and that inhibition of neutrophil-endothelial adhesion is a promising new modality for reducing organ injury associated with CPB.