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The Annals of Thoracic Surgery, Vol 57, 126-133, Copyright © 1994 by The Society of Thoracic Surgeons
AM Gillinov, JM Redmond, KJ Zehr, IC Wilson, WE Curtis, JM Bator, RM Burch, BA Reitz, WA Baumgartner and A Herskowitz
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 mumol.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 NPC 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).(ABSTRACT TRUNCATED
AT 250 WORDS)
ARTICLES
Inhibition of neutrophil adhesion during cardiopulmonary bypass
Department of Cardiac Surgery, Johns Hopkins Medical Institutions, Baltimore, Maryland.
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