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Ann Thorac Surg 2002;74:355-362
© 2002 The Society of Thoracic Surgeons
a Congenital Heart Surgery Service, Texas Children’s Hospital, Houston, Texas, USA
b Division of Congenital Heart Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas, USA
c Cullen Cardiovascular Surgical Research Laboratories, Texas Heart Institute, Houston, Texas, USA
d Tanox, Inc., Texas Heart Institute, Houston, Texas, USA
e Department of Biostatistics and Epidemiology, Texas Heart InstituteHouston, Texas, USA
f Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA
* Address reprint requests to Dr Ündar, Texas Children’s Hospital/Baylor College of Medicine, Congenital Heart Surgery Service, 6621 Fannin Street, Mail Code WT 19345-H, Houston, TX 77030-2399 USA
e-mail: aundar{at}bcm.tmc.edu
Presented at the Poster Session of the Thirty-eighth Annual Meeting of The Society of Thoracic Surgeons, Fort Lauderdale, FL, Jan 28–30, 2002.
Background. Adverse outcomes after cardiopulmonary bypass (CPB) are often related to systemic inflammation triggered by complement and leukocyte activation. To determine how inhibition of the alternative complement pathway affects systemic inflammation and tissue injury, we studied a novel monoclonal antibody (Mab), anti-human factor D murine Mab 166-32, in baboons.
Methods. Fourteen baboons (mean weight, 15 kg) underwent hypothermic CPB. The treatment group (n = 7) received a single injection of anti-factor D Mab 166–32 (5 mg/kg), and the control group (n = 7) was given saline solution. After initiation of CPB, all animals were subjected to 20 minutes of core cooling (rectal temperature, 27°C), followed by 60 minutes of aortic cross-clamping, 25 minutes of rewarming, and 30 minutes of normothermic CPB. Blood samples were collected before CPB, during CPB, and 1, 2, 3, 6, and 18 hours after CPB. To measure neutrophil and monocyte activation, we performed flow cytometry for CD11b expression, ELISA for complement activation (Bb, C3a, C4d, and sC5b-9) and interleukin-6 (IL-6) production, and tissue injury studies for creatine kinase MB isoenzymes (CK-MB), creatine kinase (CK), and lactic dehydrogenase (LDH) levels.
Results. Anti-factor D Mab almost completely inhibited plasma Bb, C3a, and sC5b-9 production during CPB (P < .001). CD11b expression on neutrophils (129 ± 5% vs. 210 ± 42%; P = .0006) and on monocytes (139 ± 14% vs. 245 ± 43%; P = .0002) was also lower in the treatment group during CPB. The treated animals had a significantly smaller increase in plasma IL-6 concentrations than did the control animals (71 ± 27 pg/mL vs. 104 ± 54 pg/mL; P = .0002). CK-MB levels were also lower in the treatment group 6 hours after the end of CPB (204 ± 30 vs. 335 ± 59 IU/L; P = .003) and 18 hours after the end of CPB (P < .05). Creatine kinase levels (6 and 18 hours after the end of CPB) and LDH levels (3 and 6 hours after the end of CPB) showed patterns similar to those of CK-MB (P < .05).
Conclusions. The alternative complement pathway plays a major role in systemic inflammation during CPB. Inhibition of complement activation via the alternative pathway by anti-factor D Mab 166–32 significantly reduces leukocyte activation and tissue injury in our baboon model.
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