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Ann Thorac Surg 2007;83:146-152
© 2007 The Society of Thoracic Surgeons

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Original Articles: Cardiovascular

Leukocyte Effects of C5a-Receptor Blockade During Simulated Extracorporeal Circulation

^a Department of Anesthesiology, Yale University School of Medicine, New Haven, Connecticut
^b Department of Laboratory Medicine, Yale University School of Medicine, New Haven, Connecticut
^c Department of Biomedical Sciences, Quinnipiac University, Hamden, Connecticut
^d Neurogen Corporation, Branford, Connecticut

Accepted for publication August 4, 2006.

^_* Address correspondence to Dr C.S. Rinder, Department of Anesthesiology, Yale University School of Medicine, 333 Cedar St, PO Box 208051, New Haven, CT 06520-8051. (Email: christine.rinder{at}yale.edu).

BACKGROUND: Distinct pathways of leukocyte activation during simulated cardiopulmonary bypass are mediated by the complement C5a anaphylatoxin. We hypothesized that a human C5a receptor antagonist would specifically inhibit the inflammatory response of neutrophils to simulated extracorporeal circulation, while preserving the C5b-9 pathway for innate immunity.

METHODS: An in vitro extracorporeal circuit recirculated fresh heparinized whole blood through a membrane oxygenator with and without addition of a small molecule human C5a receptor antagonist. Samples were periodically drawn over 90 minutes for complement and leukocyte activation studies.

RESULTS: Addition of the C5a receptor antagonist to simulated extracorporeal circulation abrogated both neutrophil CD11b upregulation and interleukin 8 release (p < 0.01 for both), despite full generation of C3a and C5b-9; however, elastase release from neutrophils was unaffected. Although C5a receptor blockade only trended toward inhibiting monocyte CD11b upregulation (p = 0.09), circuit clearance of both monocytes (p = 0.04) and neutrophils (p = 0.01) was significantly decreased. In addition, the C5a receptor antagonist completely blocked both neutrophil–platelet and monocyte–platelet conjugate formation (p < 0.001 for both), without affecting platelet P-selectin expression.

CONCLUSIONS: C5a receptor blockade during simulated extracorporeal circulation completely blocked neutrophil ß2 integrin upregulation and induction of plasma interleukin 8, suggesting an acute downregulatory effect on neutrophil chemotaxis-related pathways, while preserving terminal complement generation and neutrophil elastase release. Inhibition of leukocyte–platelet conjugate formation suggests a novel function for leukocyte adhesive receptors, possibly related to preservation of elastase generation.

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Invited commentary

Knut Tore Lappegard
Ann. Thorac. Surg. 2007 83: 152. [Extract] [Full Text] [PDF]

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				K. T. Lappegard Invited commentary Ann. Thorac. Surg., January 1, 2007; 83(1): 152 - 152. [Full Text] [PDF]