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Right arrow Extracorporeal circulation

J Thorac Cardiovasc Surg 2001;122:113-122
© 2001 The American Association for Thoracic Surgery

Cardiopulmonary Support and Physiology (CSP)

Inhibition of complement, neutrophil, and platelet activation by an anti-factor D monoclonal antibody in simulated cardiopulmonary bypass circuits

Michael Fung, PhDa, Paul G. Loubser, MDb*, Akif Ündar, PhDc,d,e, Maryann Mueller, CCPd, Cecily Sun, MSa, William N. Sun, PhDa, William K. Vaughn, PhDe, Charles D. Fraser, Jr, MDc,d,e

From Tanox, Inca; the Departments of Anesthesiologyb and Surgery,c Baylor College of Medicine; Texas Children's Hospitald; and Texas Heart Institute,e Houston, Tex.

This study was supported by Tanox, Inc, Houston, Tex.

Received for publication Sept 18, 2000. Revisions requested Dec 7, 2000; revisions received Jan 23, 2001. Accepted for publication Jan 29, 2001. Address for reprints: Michael Fung, PhD, Tanox, Inc, 10301 Stella Link, Houston, TX 77025 (E-mail: mfung{at}tanox.com).

Abstract

Objectives: Patients undergoing cardiopulmonary bypass frequently manifest generalized systemic inflammation and occasionally manifest serious multiorgan failure. Inflammatory responses of bypass are triggered by contact of blood with artificial surfaces of the bypass circuits, surgical trauma, and ischemia-reperfusion injury. We studied the effects of specific inhibition of the alternative complement cascade by using an anti-factor D monoclonal antibody (166-32) in extracorporeal circulation of human whole blood used as a simulated model of cardiopulmonary bypass.
Methods: Five healthy blood donors were used in the study. Monoclonal antibody 166-32 was added to freshly collected, heparinized human blood recirculated in a pediatric cardiopulmonary bypass circuit at a final concentration of 18 µg/mL. An irrelevant monoclonal antibody was used as a negative control with the same donor blood in a parallel bypass circuit on the same day. Blood samples were collected at different time points during recirculation for measurement of activation of complement, neutrophils, and platelets by immunofluorocytometric methods and enzyme-linked immunosorbent assays.
Results: Monoclonal antibody 166-32 inhibited the alternative complement activation and the production of Bb, C3a, sC5b-9, and C5a. Upregulation of CD11b on neutrophils and CD62P on platelets was also significantly inhibited by monoclonal antibody 166-32. This is consistent with the inhibition of the release of neutrophil-specific myeloperoxidase and elastase and platelet thrombospondin. The production of proinflammatory cytokine interleukin 8 was also suppressed by the antibody.
Conclusions: The alternative complement cascade is predominantly activated during extracorporeal circulation. Anti-factor D monoclonal antibody 166-32 is effective in inhibiting the activation of complement, neutrophils, and platelets. Inhibition of the alternative complement pathway by targeting factor D could be useful in reducing systemic inflammation in patients undergoing cardiopulmonary bypass.




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