Blockade of C5a and C5b-9 generation inhibits leukocyte and platelet activation during extracorporeal circulation.
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.
Rinder
C S
CS
Department of Laboratory Medicine, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
Rinder
H M
HM
Smith
B R
BR
Fitch
J C
JC
Smith
M J
MJ
Tracey
J B
JB
Matis
L A
LA
Squinto
S P
SP
Rollins
S A
SA
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
D000911:Antibodies, Monoclonal; D018845:CD11 Antigens; D015938:Complement Membrane Attack Complex; D015936:Complement C5a