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Ann Thorac Surg 1994;57:126-133
© 1994 The Society of Thoracic Surgeons
a Department of Cardiac Surgery and Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions Baltimore, Maryland, USA
b Nova Pharmaceutical Corporation, Baltimore, Maryland, USA
Accepted for publication February 22, 1993.
* Address reprint requests to Dr Cameron, Department of Cardiac Surgery, The Johns Hopkins Hospital, 600 N Wolfe St, Blalock 61B, Baltimore, MD 21205.
Blood contact with synthetic surfaces during cardiopulmonary bypass (CPB) causes a diffuse inflammatory reaction that includes neutrophil activation. The purpose of this study was to determine if inhibition of neutrophil adhesion with a new antiinflammatory agent NPC 15669 (N-(9H-(2,7-dimethylfluorenyl-9-methoxy)-carbonyl)-L-leucine) could reduce pulmonary injury in a porcine model of CPB. NPC 15669 blocks adherence of activated neutrophils by inhibiting upregulation of the Mac-1 ( [equation]) adhesion molecule. Sixteen piglets underwent 2 hours of hypothermic CPB followed by 2 hours of observation; 8 received NPC 15669 (10 mg/kg intravenous bolus followed by 6 mg · kg–1 · h–1 intravenous infusion) and 8 received equal volumes of vehicle. After 90 minutes of CPB, expression of neutrophil adhesion molecule subunit CD18 increased 118% in control piglets but only 36% in piglets treated with NPC 15669 (p < 0.01). Although neutropenia developed in all animals during CPB, lung tissue myeloperoxidase content was significantly lower in treated than in control animals 2 hours after CPB (94.9 ± 10.4 versus 46.9 ± 5.5 µmol · 10 mg–1 · min–1; p < 0.002). Free radical-mediated lipid peroxidation (quantitated by spectrophotometric assay of plasma conjugated dienes) was significantly reduced by treatment with NPC 15669 during and after CPB. Pulmonary function was better in MPC 15669-treated animals: 2 hours after CPB, pulmonary vascular resistance increased 477% in control 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 interstitial and intraalveolar edema in control animals, but virtually normal lung architecture in animals that received NPC 15669. These results demonstrate that NPC 15669 reduced neutrophil adhesion molecule expression, pulmonary leukocyte sequestration, and free radical generation during CPB with a corresponding reduction in lung injury. These findings suggest that neutrophils are important mediators of CPB-associated pulmonary damage and that inhibition of neutrophil-endothelial adhesion is a promising new modality for reducing organ injury associated with CPB.
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