Inhibition of neutrophil adhesion during cardiopulmonary bypass.
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)
Gillinov
A M
AM
Department of Cardiac Surgery, Johns Hopkins Medical Institutions, Baltimore, Maryland.
Redmond
J M
JM
Zehr
K J
KJ
Wilson
I C
IC
Curtis
W E
WE
Bator
J M
JM
Burch
R M
RM
Reitz
B A
BA
Baumgartner
W A
WA
Herskowitz
A
A
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D015703:Antigens, CD / Q000378:metabolism; D018821:CD18 Antigens; D002448:Cell Adhesion / Q000187:drug effects; D001026:Coronary Artery Bypass; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D007958:Leukocyte Count / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology / Q000502:physiology; D010100:Oxygen / Q000097:blood; D013552:Swine; D014655:Vascular Resistance
D000894:Anti-Inflammatory Agents, Non-Steroidal; D015703:Antigens, CD; D018821:CD18 Antigens; C071244:N-(9H-(2,7-dimethylfluoren-9-ylmethoxy)carbonyl)leucine; D007930:Leucine; D010100:Oxygen