Inhibition of neutrophil adhesion during cardiopulmonary bypass

A. Marc Gillinov, J. Mark Redmond, Kenton J. Zehr, Ian C. Wilson, William E. Curtis, Jenny M. Bator, Ronald M. Burch, Bruce A. Reitz, William A. Baumgartner, Ahvie Herskowitz, Duke E. Cameron

Research output: Contribution to journalArticlepeer-review

Abstract

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 ( CD11b CD18) 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.

Original languageEnglish (US)
Pages (from-to)126-133
Number of pages8
JournalThe Annals of thoracic surgery
Volume57
Issue number1
DOIs
StatePublished - Jan 1994

ASJC Scopus subject areas

  • Surgery
  • Pulmonary and Respiratory Medicine
  • Cardiology and Cardiovascular Medicine

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