title: Leukocyte effects of C5a-receptor blockade during simulated extracorporeal circulation.
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.
authors.affiliation: Department of Anesthesiology, Yale University School of Medicine, New Haven, Connecticut 06520-8051, USA. christine.rinder@yale.edu
authors.forename: Christine S
authors.initials: CS
authors.lastname: Rinder
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Smith
authors.forename: Henry M
authors.initials: HM
authors.lastname: Rinder
authors.forename: Daniel N
authors.initials: DN
authors.lastname: Cortright
authors.forename: Robbin M
authors.initials: RM
authors.lastname: Brodbeck
authors.forename: James E
authors.initials: JE
authors.lastname: Krause
authors.forename: Brian R
authors.initials: BR
authors.lastname: Smith
mesh_terms: D001792:Blood Platelets / Q000187:drug effects; D039481:CD11b Antigen / Q000032:analysis; D002315:Cardiopulmonary Bypass; D003167:Complement Activation / Q000187:drug effects; D006801:Humans; D016209:Interleukin-8 / Q000032:analysis; D019272:Leukocyte Elastase / Q000502:physiology; D007962:Leukocytes / Q000187:drug effects*; D009504:Neutrophils / Q000187:drug effects; D044087:Receptor, Anaphylatoxin C5a / Q000037:antagonists & inhibitors*
chemical_list: D039481:CD11b Antigen; D016209:Interleukin-8; D044087:Receptor, Anaphylatoxin C5a; D019272:Leukocyte Elastase