Leukocyte effects of C5a-receptor blockade during simulated extracorporeal circulation

Ann Thorac Surg. 2007 Jan;83(1):146-52. doi: 10.1016/j.athoracsur.2006.08.019.

Abstract

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 beta2 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Blood Platelets / drug effects
  • CD11b Antigen / analysis
  • Cardiopulmonary Bypass*
  • Complement Activation / drug effects
  • Humans
  • Interleukin-8 / analysis
  • Leukocyte Elastase / physiology
  • Leukocytes / drug effects*
  • Neutrophils / drug effects
  • Receptor, Anaphylatoxin C5a / antagonists & inhibitors*

Substances

  • CD11b Antigen
  • Interleukin-8
  • Receptor, Anaphylatoxin C5a
  • Leukocyte Elastase