title: Blockade of C5a and C5b-9 generation inhibits leukocyte and platelet activation during extracorporeal circulation.
abstract: Complement activation contributes to the systemic inflammatory response induced by cardiopulmonary bypass. At the cellular level, cardiopulmonary bypass activates leukocytes and platelets; however the contribution of early (3a) versus late (C5a, soluble C5b-9) complement components to this activation is unclear. We used a model of simulated extracorporeal circulation that activates complement (C3a, C5a, and C5b-9 formation), platelets (increased percentages of P-selectin-positive platelets and leukocyte-platelet conjugates), and neutrophils (upregulated CD11b expression). to specifically target complement activation in this model, we added a blocking mAb directed at the human C5 complement component and assessed its effect on complement and cellular activation. Compared with a control mAB, the anti-human C5 mAb profoundly inhibited C5a and soluble C5b-9 generation and serum complement hemolytic activity but had no effect on C3a generation. Additionally, the anti-human C5 mAb significantly inhibited neutrophil CD11b upregulation and abolished the increase in P-selectin-positive platelets and leukocyte-platelet conjugate formation compared to experiments performed with the control mAb. This suggests that the terminal components C5a and C5b-9, but not C3a, directly contribute to platelet and neutrophil activation during extracorporeal circulation. Furthermore, these data identify the C5 component as a site for therapeutic intervention in cardiopulmonary bypass.
authors.affiliation: Department of Laboratory Medicine, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: C S
authors.initials: CS
authors.lastname: Rinder
authors.forename: H M
authors.initials: HM
authors.lastname: Rinder
authors.forename: B R
authors.initials: BR
authors.lastname: Smith
authors.forename: J C
authors.initials: JC
authors.lastname: Fitch
authors.forename: M J
authors.initials: MJ
authors.lastname: Smith
authors.forename: J B
authors.initials: JB
authors.lastname: Tracey
authors.forename: L A
authors.initials: LA
authors.lastname: Matis
authors.forename: S P
authors.initials: SP
authors.lastname: Squinto
authors.forename: S A
authors.initials: SA
authors.lastname: Rollins
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001792:Blood Platelets / Q000502:physiology*; D018845:CD11 Antigens / Q000097:blood; D002315:Cardiopulmonary Bypass; D003167:Complement Activation; D015936:Complement C5a / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*; D015938:Complement Membrane Attack Complex / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*; D005112:Extracorporeal Circulation; D006461:Hemolysis; D006801:Humans; D007700:Kinetics; D007962:Leukocytes / Q000502:physiology*; D008954:Models, Biological; D009504:Neutrophils / Q000276:immunology / Q000502:physiology; D015539:Platelet Activation; D012016:Reference Values; D013997:Time Factors
chemical_list: D000911:Antibodies, Monoclonal; D018845:CD11 Antigens; D015938:Complement Membrane Attack Complex; D015936:Complement C5a