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PMID: 7657827 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Blockade of C5a and C5b-9 generation inhibits leukocyte and platelet activation during extracorporeal circulation.

The Journal of clinical investigation ·Vol. 96 ·No. 3 ·1995-09-00 ·Pages 1564-72

Rinder CS, Rinder HM, Smith BR, Fitch JC, Smith MJ, Tracey JB, Matis LA, Squinto SP, Rollins SA

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.

MeSH Terms
Antibodies, Monoclonal/pharmacology Blood Platelets/physiology CD11 Antigens/blood Cardiopulmonary Bypass Complement Activation Complement C5a/antagonists & inhibitors,immunology,physiology Complement Membrane Attack Complex/antagonists & inhibitors,immunology,physiology Extracorporeal Circulation Hemolysis Humans Kinetics Leukocytes/physiology Models, Biological Neutrophils/immunology,physiology Platelet Activation Reference Values Time Factors
Chemicals
Antibodies, Monoclonal CD11 Antigens Complement Membrane Attack Complex Complement C5a
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Rinder C S
Department of Laboratory Medicine, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
Rinder H M
Smith B R
Fitch J C
Smith M J
Tracey J B
Matis L A
Squinto S P
Rollins S A
References (69)
69 references, click to expand
  1. GMP-140 mediates adhesion of stimulated platelets to neutrophils.
    Blood. 1990 Feb 1;75(3):550-4 PMID: 1688717
  2. Complement proteins C5b-9 induce vesiculation of the endothelial plasma membrane and expose catalytic surface for assembly of the prothrombinase enzyme complex.
    J Biol Chem. 1990 Mar 5;265(7):3809-14 PMID: 2105954
  3. Rapid neutrophil adhesion to activated endothelium mediated by GMP-140.
    Nature. 1990 Feb 22;343(6260):757-60 PMID: 1689464
  4. Structure and function of the leukocyte adhesion molecules CD11/CD18.
    Blood. 1990 Mar 1;75(5):1037-50 PMID: 1968349
  5. Mac-1 (CD11b/CD18) mediates adherence-dependent hydrogen peroxide production by human and canine neutrophils.
    J Immunol. 1990 Apr 1;144(7):2702-11 PMID: 2181020
  6. Aprotinin protects platelets against the initial effect of cardiopulmonary bypass.
    J Thorac Cardiovasc Surg. 1990 May;99(5):788-96; discussion 796-7 PMID: 1691806
  7. Integrins and other cell adhesion molecules.
    FASEB J. 1990 Aug;4(11):2868-80 PMID: 2199285
  8. Stratton lecture 1989. Thrombosis and inflammation as multicellular processes: pathophysiologic significance of transcellular metabolism.
    Blood. 1990 Nov 15;76(10):1903-7 PMID: 2242418
  9. Progressive platelet activation with storage: evidence for shortened survival of activated platelets after transfusion.
    Transfusion. 1991 Jun;31(5):409-14 PMID: 1710840
  10. Platelet activation and aggregation during cardiopulmonary bypass.
    Anesthesiology. 1991 Sep;75(3):388-93 PMID: 1716077
  11. Activated and unactivated platelet adhesion to monocytes and neutrophils.
    Blood. 1991 Oct 1;78(7):1760-9 PMID: 1717070
  12. Modulation of platelet surface adhesion receptors during cardiopulmonary bypass.
    Anesthesiology. 1991 Oct;75(4):563-70 PMID: 1718190
  13. Role of leukocyte adhesion molecules in complement-induced lung injury.
    J Immunol. 1993 Mar 15;150(6):2401-6 PMID: 8095513
  14. Complement inhibition with soluble complement receptor type 1 in cardiopulmonary bypass.
    Ann Thorac Surg. 1993 Mar;55(3):619-24 PMID: 8383955
  15. Tissue factor is expressed on monocytes during simulated extracorporeal circulation.
    Circ Res. 1993 May;72(5):1075-81 PMID: 8097439
  16. Changes in serum complement and immunoglobulins following cardiopulmonary bypass.
    Surgery. 1972 Jun;71(6):824-7 PMID: 5030498
  17. Function of human platelets during extracorporeal circulation.
    Am J Physiol. 1977 Jun;232(6):H622-8 PMID: 18017
  18. Demonstration of specific C5a receptor on intact human polymorphonuclear leukocytes.
    Proc Natl Acad Sci U S A. 1978 Aug;75(8):3943-7 PMID: 279010
  19. Effects of prostacyclin and albumin on platelet loss during in vitro simulation of extracorporeal circulation.
    Blood. 1979 Jun;53(6):1033-42 PMID: 375998
  20. Thromboxane synthesis and platelet secretion during cardiopulmonary bypass with bubble oxygenator.
    J Thorac Cardiovasc Surg. 1980 Jan;79(1):91-6 PMID: 7350392
  21. Complement activation during cardiopulmonary bypass.
    Anaesthesia. 1980 Jan;35(1):22-6 PMID: 7396108
  22. Complement activation during cardiopulmonary bypass: evidence for generation of C3a and C5a anaphylatoxins.
    N Engl J Med. 1981 Feb 26;304(9):497-503 PMID: 7453783
  23. Monoclonal antibodies against platelet membrane glycoproteins. Characterization and effect on platelet function.
    Eur J Biochem. 1983 Mar 15;131(2):427-36 PMID: 6832159
  24. Complement and the damaging effects of cardiopulmonary bypass.
    J Thorac Cardiovasc Surg. 1983 Dec;86(6):845-57 PMID: 6606084
  25. Complement deficiency states and infection: epidemiology, pathogenesis and consequences of neisserial and other infections in an immune deficiency.
    Medicine (Baltimore). 1984 Sep;63(5):243-73 PMID: 6433145
  26. Neutrophil-endothelial cell interactions. Modulation of neutrophil adhesiveness induced by complement fragments C5a and C5a des arg and formyl-methionyl-leucyl-phenylalanine in vitro.
    J Clin Invest. 1984 Nov;74(5):1581-92 PMID: 6501563
  27. Plasmin effect on platelet glycoprotein Ib-von Willebrand factor interactions.
    Blood. 1985 Jan;65(1):32-40 PMID: 3155489
  28. Inherited deficiency of the Mac-1, LFA-1, p150,95 glycoprotein family and its molecular basis.
    J Exp Med. 1984 Dec 1;160(6):1901-18 PMID: 6096477
  29. Loss of fibrinogen receptors from the platelet surface during simulated extracorporeal circulation.
    J Lab Clin Med. 1985 Apr;105(4):514-22 PMID: 2984300
  30. Loss of platelet alpha 2-adrenergic receptors during simulated extracorporeal circulation: prevention with prostaglandin E1.
    J Lab Clin Med. 1985 May;105(5):601-7 PMID: 4039346
  31. The severe and moderate phenotypes of heritable Mac-1, LFA-1 deficiency: their quantitative definition and relation to leukocyte dysfunction and clinical features.
    J Infect Dis. 1985 Oct;152(4):668-89 PMID: 3900232
  32. A platelet alpha granule membrane protein that is associated with the plasma membrane after activation. Characterization and subcellular localization of platelet activation-dependent granule-external membrane protein.
    J Clin Invest. 1986 Jul;78(1):130-7 PMID: 2941452
  33. Platelet surface glycoproteins. Studies on resting and activated platelets and platelet membrane microparticles in normal subjects, and observations in patients during adult respiratory distress syndrome and cardiac surgery.
    J Clin Invest. 1986 Aug;78(2):340-8 PMID: 2942561
  34. A murine antiglycoprotein Ib complex monoclonal antibody, SZ 2, inhibits platelet aggregation induced by both ristocetin and collagen.
    Blood. 1987 Feb;69(2):570-7 PMID: 3801672
  35. Fibrinogen receptors in platelet adhesion to surfaces of extracorporeal circuit.
    Am J Physiol. 1987 Mar;252(3 Pt 2):H615-21 PMID: 2950774
  36. Detection of activated platelets in whole blood using activation-dependent monoclonal antibodies and flow cytometry.
    Blood. 1987 Jul;70(1):307-15 PMID: 3297204
  37. Stimulated mobilization of monocyte Mac-1 and p150,95 adhesion proteins from an intracellular vesicular compartment to the cell surface.
    J Clin Invest. 1987 Aug;80(2):535-44 PMID: 3038962
  38. Reduction of experimental canine myocardial reperfusion injury by a monoclonal antibody (anti-Mo1, anti-CD11b) that inhibits leukocyte adhesion.
    J Clin Invest. 1988 Feb;81(2):624-9 PMID: 3339135
  39. Deposition of terminal C5b-9 complement complexes on erythrocytes and leukocytes during cardiopulmonary bypass.
    N Engl J Med. 1988 Feb 18;318(7):408-14 PMID: 3340119
  40. Complement: function and clinical relevance.
    Ann Allergy. 1988 Apr;60(4):293-300 PMID: 3282455
  41. The saturable high affinity association of factor X to ADP-stimulated monocytes defines a novel function of the Mac-1 receptor.
    J Biol Chem. 1988 May 25;263(15):7007-15 PMID: 2835359
  42. The effects of complement activation during cardiopulmonary bypass. Attenuation by hypothermia, heparin, and hemodilution.
    Ann Surg. 1988 Jul;208(1):95-103 PMID: 3260474
  43. Generation of a monoclonal antibody to mouse C5 application in an ELISA assay for detection of anti-C5 antibodies.
    Mol Cell Probes. 1987 Jun;1(2):141-9 PMID: 3453897
  44. Adhesive receptor Mac-1 coordinates the activation of factor X on stimulated cells of monocytic and myeloid differentiation: an alternative initiation of the coagulation protease cascade.
    Proc Natl Acad Sci U S A. 1988 Oct;85(20):7462-6 PMID: 2971972
  45. Adherence of neutrophils to cultured human microvascular endothelial cells. Stimulation by chemotactic peptides and lipid mediators and dependence upon the Mac-1, LFA-1, p150,95 glycoprotein family.
    J Clin Invest. 1989 Feb;83(2):637-46 PMID: 2521491
  46. Loss of platelet fibrinogen receptors during clinical cardiopulmonary bypass.
    J Thorac Cardiovasc Surg. 1989 Feb;97(2):235-9 PMID: 2915559
  47. Formation of C1s-C1-inhibitor, kallikrein-C1-inhibitor, and plasmin-alpha 2-plasmin-inhibitor complexes during cardiopulmonary bypass.
    Blood. 1989 Feb;73(2):468-71 PMID: 2917186
  48. Complement proteins C5b-9 induce secretion of high molecular weight multimers of endothelial von Willebrand factor and translocation of granule membrane protein GMP-140 to the cell surface.
    J Biol Chem. 1989 May 25;264(15):9053-60 PMID: 2470750
  49. Cooperative interactions of LFA-1 and Mac-1 with intercellular adhesion molecule-1 in facilitating adherence and transendothelial migration of human neutrophils in vitro.
    J Clin Invest. 1989 Jun;83(6):2008-17 PMID: 2566624
  50. Correlated measurement of platelet release and aggregation in whole blood.
    Cytometry. 1989 Jul;10(4):448-55 PMID: 2475308
  51. Cytokine-induced respiratory burst of human neutrophils: dependence on extracellular matrix proteins and CD11/CD18 integrins.
    J Cell Biol. 1989 Sep;109(3):1341-9 PMID: 2475511
  52. Assembly of the platelet prothrombinase complex is linked to vesiculation of the platelet plasma membrane. Studies in Scott syndrome: an isolated defect in platelet procoagulant activity.
    J Biol Chem. 1989 Oct 15;264(29):17049-57 PMID: 2793843
  53. PADGEM protein: a receptor that mediates the interaction of activated platelets with neutrophils and monocytes.
    Cell. 1989 Oct 20;59(2):305-12 PMID: 2478294
  54. Participation of protein kinases in complement C5b-9-induced shedding of platelet plasma membrane vesicles.
    Blood. 1991 Dec 1;78(11):2880-6 PMID: 1659468
  55. Cardiopulmonary bypass induces leukocyte-platelet adhesion.
    Blood. 1992 Mar 1;79(5):1201-5 PMID: 1371416
  56. Inhibition of terminal complement complex formation and cell lysis by monoclonal antibodies.
    Complement Inflamm. 1991;8(5-6):328-40 PMID: 1724954
  57. Time for new concepts about measurement of complement activation by cardiopulmonary bypass?
    Ann Thorac Surg. 1992 Oct;54(4):725-31 PMID: 1417231
  58. Increased expression of neutrophil and monocyte adhesion molecules in unstable coronary artery disease.
    Circulation. 1993 Aug;88(2):358-63 PMID: 8101771
  59. Downregulation of human platelet reactivity by neutrophils. Participation of lipoxygenase derivatives and adhesive proteins.
    J Clin Invest. 1993 Sep;92(3):1357-65 PMID: 7690778
  60. C5a-induced myocardial ischemia: role for CD18-dependent PMN localization and PMN-platelet interactions.
    Am J Physiol. 1993 Nov;265(5 Pt 2):H1750-61 PMID: 7902015
  61. Cytokine and complement levels in patients undergoing cardiopulmonary bypass.
    J Thorac Cardiovasc Surg. 1993 Dec;106(6):1008-16 PMID: 8246532
  62. Complement activation during cardiopulmonary bypass in infants and children. Relation to postoperative multiple system organ failure.
    J Thorac Cardiovasc Surg. 1993 Dec;106(6):978-87 PMID: 8246580
  63. Humoral and cellular activation in a simulated extracorporeal circuit.
    Ann Thorac Surg. 1993 Dec;56(6):1509-14 PMID: 7505562
  64. Platelet dysfunction during cardiopulmonary bypass surgery. With special reference to platelet membrane glycoproteins.
    ASAIO J. 1993 Jul-Sep;39(3):M550-3 PMID: 8268596
  65. Platelet-leukocyte activation and modulation of adhesion receptors in pediatric patients with congenital heart disease undergoing cardiopulmonary bypass.
    J Thorac Cardiovasc Surg. 1994 Jan;107(1):280-8 PMID: 8283897
  66. Complement and neutrophil activation during cardiopulmonary bypass: a study in the complement-deficient dog.
    Ann Thorac Surg. 1994 Feb;57(2):345-52 PMID: 7906115
  67. Complement, leukocytes, and leukocyte elastase in full-term neonates undergoing cardiac operation.
    J Thorac Cardiovasc Surg. 1994 Jul;108(1):29-36 PMID: 8028376
  68. C5a-induced expression of P-selectin in endothelial cells.
    J Clin Invest. 1994 Sep;94(3):1147-55 PMID: 7521884
  69. P-selectin induces the expression of tissue factor on monocytes.
    Proc Natl Acad Sci U S A. 1994 Sep 13;91(19):8767-71 PMID: 7522321
Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI118195
Published
1995-09-00
Pages
1564-72
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC185782
Subset
IM
Grants
NHLBI NIH HHS · R01 HL047193 · United States
NHLBI NIH HHS · HL-02668 · United States
NHLBI NIH HHS · HL-47193 · United States
External Links
PubMed source DOI: 10.1172/JCI118195 PMC Full Text View journal details
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