(Circulation. 1999;100:553-558.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Role of C3 Cleavage in Monocyte Activation During Extracorporeal Circulation
From the Department of Laboratory Medicine (C.S.R., H.M.R., J.T., B.R.S.) and the Department of Anesthesiology, Yale University School of Medicine (C.S.R., D.L.L.), New Haven, Conn; Chiron Corp, Emeryville, Calif (K.J., G.P.); Quinnipiac College, Hamden, Conn (M.S.); and Cytomed, Inc, Cambridge, Mass (P.H., G.Y).
Correspondence to Christine S. Rinder, MD, Department of Laboratory Medicine, Fitkin 617, Yale University School of Medicine, 333 Cedar St, PO Box 208035, New Haven, CT 06520-8035. E-mail christine.rinder{at}yale.edu
Background—We previously demonstrated that inhibiting formation of terminal complement components (C5a and C5b-9) prevents platelet and neutrophil (PMN) but not monocyte activation during simulated extracorporeal circulation (SECC). This study examined whether earlier complement inhibition during SECC, blocking C3a formation, would additionally prevent monocyte activation.
Methods and Results—SECC was established by recirculating heparinized whole blood from human volunteers on a membrane oxygenator. CAB-2, a chimeric protein constructed from genes encoding the complement regulatory proteins CD46 and CD55, inactivates the C3/C5 convertases and blocks in vitro generation of C3a, C5a, and C5b-9. CAB-2 was used in 4 experiments at a final concentration of 300 µg/mL and 4 experiments at 30 µg/mL; 4 control runs used vehicle alone. Samples were assayed for C3a and C5b-9, monocyte activation (CD11b upregulation), PMN activation (CD11b upregulation and elastase release), and platelet activation (P-selectin expression and monocyte-platelet conjugate formation). CAB-2 at both doses significantly inhibited formation of C3a and C5b-9 during SECC. High-dose CAB-2 significantly blocked monocyte and PMN CD11b upregulation and PMN elastase release. CAB-2 also inhibited formation of platelet activation–dependent monocyte–platelet conjugates.
Conclusions—Blockade of complement activation early in the common pathway inhibited monocyte CD11b upregulation during SECC, suggesting that early complement components contribute most to monocyte activation during SECC. As expected, PMN and platelet activation were blocked by terminal complement inhibition. This investigation further elucidates the relation between complement and blood cell activation during simulated cardiopulmonary bypass.
Key Words: extracorporeal circulation • cell adhesion molecules • leukocytes • platelets
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