Molecular Mechanisms of Complement Activation during Ischemia and Reperfusion

  • C. L. F. Ciurana
  • C. E. Hack


Ischemia is a frequent clinical problem occurring, amongst others, in myocardial infarction, transplantation, vascular surgery, and thrombo-embolic disease. The obvious treatment of ischemia is reperfusion of the jeopardized organ or tissue. However, when ischemia is too severe, reperfusion may exacerbate rather than limit tissue damage, a phenomenon known as ischemia/reperfusion (I/R)-injury. A number of studies have been performed to unravel the pathophysiology of I/R-injury, and it is now clear that this condition is mainly due to an inflammatory process elicited by reperfusion. Hence, limiting I/R-induced inflammatory reactions is expected to improve the efficacy of reperfusion. Indeed, inhibition of inflammatory mediators improves the beneficial effects of reperfusion of ischemic tissues in animal models. In this chapter we will summarize the role of inflammation in the pathogenesis of I/R-injury, and discuss in more detail that of the complement system, as this plasma cascade system seems to be a key mediator in this condition.


Complement Activation Complement Inhibitor Complement Receptor Type Classical Complement Pathway Mannan Binding Lectin 
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  1. 1.
    Li C, Browder W, Kao RL (1999) Early activation of transcription factor NF-KB during ischemia in reperfused rat heart. Am J Physiol 276:H543–H552 (Abst)Google Scholar
  2. 2.
    Konturek PC, Duda A, Brzozowski T, et al (2000) Activation of genes for superoxide dismutase, interleukin-lß, tumor necrosis factor-alpha and intercellular adhesion molecule-1 during healing of ischemia-reperfusion-induced gastric injury. Scand J Gastroenterol 35: 452463Google Scholar
  3. 3.
    Seekamp A, Warren JS, Remick DG, Till GO, Ward PA (1993) Requirements for tumor necrosis factor-alpha and interleukin-1 in limb ischemia/reperfusion injury and associated lung injury. Am J Pathol 143: 453–463PubMedGoogle Scholar
  4. 4.
    Steinberg JB, Kapelanski DP, Olson JD, Weiler JM (1993) Cytokine and complement levels in patients undergoing cardiopulmonary bypass. J Thorac Cardiovasc Surg 106: 1008–1016PubMedGoogle Scholar
  5. 5.
    Yang Z, Zingarelli B, Szabo C (2000) Crucial role of endogenous IL-10 production in myocardial ischemia reperfusion injury. Circulation 101: 1019–1026PubMedCrossRefGoogle Scholar
  6. 6.
    Zund G, Nelson DP, Neufeld EJ et al (1996) Hypoxia enhances stimulus-dependent induction of E-selectin on aortic endothelial cells. Proc Natl Acad Sci USA 93: 7075–7080PubMedCrossRefGoogle Scholar
  7. 7.
    Lindsay TF, Hill J, Ortiz F et al (1992) Blockade of complement activation prevents local and pulmonary albumin leak after lower torso ischemia-reperfusion. Ann Surg 216: 677683Google Scholar
  8. 8.
    Seekamp A, Mulligan MS, Till GO, et al (1993) Role of ß2 integrins and ICAM-1 in lung injury following ischemia-reperfusion of rat hind limb. Am J Pathol 143: 464–472PubMedGoogle Scholar
  9. 9.
    Lucchesi BR, Kilgore KS (1997) Complement inhibitors in myocardial ischemia/reperfusion injury. Immunopharmacology 38: 27–42PubMedCrossRefGoogle Scholar
  10. 10.
    Entman ML, Michael L, Rossen RD, et al (1991) Inflammation in the course of early myocardial ischemia. Faseb J 5: 2529–2537PubMedGoogle Scholar
  11. 11.
    Cines DB, Pollak ES, Buck CA, et al (1998) Endothelial Cells in Physiology and in the Pathophysiology of vascular disorders. Blood 91: 3527–3561PubMedGoogle Scholar
  12. 12.
    Silverstein RL (1999) The vascular endothelium. In: Gallin JI, Snyderman R, Haynes BF (eds) Inflammation: Basic Principles and Clinical Correlates. 3rd edition, Lipincott Williams & Wilkins, Philadelphia, pp 207–225Google Scholar
  13. 13.
    Iwahori Y, Ishiguro N, Shimizu T, et al (1998) Selective neutrophils depletion with monoclonal antibody attenuates I/R injury in skeletal muscle. J Reconstr Microsurg 14: 109–116PubMedCrossRefGoogle Scholar
  14. 14.
    Zhao ZQ, Lefer DJ, Sato H, Hart KK, Jefforda PR, Vinten-Johansen J (1997) Monoclonal antibody to ICAM-1 preserves postischemic blood flow and reduces infarct size after ischemia-reperfusion in rabbit. J Leukoc Biol 62: 292–300PubMedGoogle Scholar
  15. 15.
    Cooper NL (1999) Biology of the complement system. In: Gallin JI, Snyderman R, Haynes BF (eds) Inflammation: Basic Principles and Clinical Correlates. 3rd edition, Lipincott Williams & Wilkins, Philadelphia, pp 281–307Google Scholar
  16. 16.
    Wolbink GJ, Brouwer MC, Buysmann S, Ten Berge IJM, Hack CE (1996) CRP-mediated activation of complement in vivo. I Immunol 157: 473–479Google Scholar
  17. 17.
    Vakeva AP, Agah A, Rollins SA, et al (1998) Myocardial infarction and apoptosis after myocardial ischemia and reperfusion. Role of the terminal complement components and inhibition by anti-05 therapy. Circulation 97: 2259–2267PubMedCrossRefGoogle Scholar
  18. 18.
    Tedesco F, Pausa M, Nardon E, Introna M, Mantovani A, Dobrina A (1997) The cytolytically inactive terminal complement complex activates endothelial cells to express adhesion molecules and tissue factor procoagulant activity. J Exp Med 185: 1619–1627PubMedCrossRefGoogle Scholar
  19. 19.
    Agostoni A, Gardinali M, Frangi D, et al (1994) Thrombolytic treatment and complement activation. Ann Ital Med Int 9: 178–179PubMedGoogle Scholar
  20. 20.
    Marks RM, Todd III RF, Ward PA (1989) Rapid induction of neutrophil-endothelial adhesion by endothelial complement fixation. Nature 339: 314–317PubMedCrossRefGoogle Scholar
  21. 21.
    Vakeva A, Meri S (1998) Complement activation and regulator expression after anoxic injury of human endothelial cells. APMIS 106: 1149–1156PubMedCrossRefGoogle Scholar
  22. 22.
    Chenoweth DE, Cooper SW. Hugli TE, Steward RW, Blackstone EH, Kirklin JW (1981) Complement activation during cardio-pulmonary bypass. Evidence for generation of C3a and C5a anaphylatoxins. N Engl J Med 304: 497–503PubMedCrossRefGoogle Scholar
  23. 23.
    Jones J, Morgan BP (1995) Apoptosis is associated with reduced expression of complement regulatory molecules, adhesion molecules and other receptors on polymorphonuclear leucocytes: functional and role in inflammation. Immunology 86: 651–660PubMedGoogle Scholar
  24. 24.
    Weisman HF, Bartow T, Leppo MK, et al (1990) Soluble human complement receptor type 1: in vivo inhibitor of complement suppressing post-ischemic myocardial inflammation and necrosis. Science 249: 146–151PubMedCrossRefGoogle Scholar
  25. 25.
    Soarzec JY, Delautier D, Moreau A, et al (1994) Expression of complement-regulatory proteins in normal and UW-preserved human liver. Gastroenterology 107: 505–516Google Scholar
  26. 26.
    Brooimans RA, Van der Ark AAJ, Tornita M, Van Es LA, Daha M (1992) CD59 expressed by human endothelial cells functions as a protective molecule against complement-mediated lysis. Eur J Immunol 22: 791–797PubMedCrossRefGoogle Scholar
  27. 27.
    Vakeva A, Morgan BP, Tikkanen I, Helin K, Laurila P, Meri S (1994) Time course of complement activation and inhibitor expression after ischemic injury of rat myocardium. Am J Pathol 144: 1357–1368PubMedGoogle Scholar
  28. 28.
    Vakeva A, Lehto T, Takala A, Meri S (2000) Detection of a soluble form of the complement membrane attack complex inhibitor CD59 in plasma after acute myocardial infarction. Scand J Immunol 52: 411–414PubMedCrossRefGoogle Scholar
  29. 29.
    Collard CD, Vakeva A, Bukusoglu C, et al (1997) Reoxygenation of hypoxic human umbilical vein endothelial cells activates the classic complement pathway. Circulation 96: 326–333PubMedCrossRefGoogle Scholar
  30. 30.
    Collard CD, Bukusoglu C, Agah A, et al (1999) Hypoxia-induced expression of complement receptor type 1 (CR1, CD35) in human vascular endothelial cells. Am J Physiol 276: C450 - C458PubMedGoogle Scholar
  31. 31.
    Hill JH, Ward PA (1971) The phlogistic role of C3 leukotactic fragments in myocardial infarcts of rats. J Exp Med 133: 885–900PubMedCrossRefGoogle Scholar
  32. 32.
    Horstick G, Heimann A, Götze O, et al (1997) Intracoronary application of cl esterase inhibitor improves cardiac function and reduces myocardial necrosis in an experimental model of ischemia and reperfusion. Circulation 95: 701–708PubMedCrossRefGoogle Scholar
  33. 33.
    Buerke M, Prüfer D, Dahm M, et al (1998) Blocking of classical complement pathway inhibits endothelial adhesion molecule expression and preserves ischemic myocardium from reperfusion injury. J Pharmacol Exp Ther 286: 429–438PubMedGoogle Scholar
  34. 34.
    Lehmann TG, Koeppel TA, Kirschfink M, et al (1998) Complement inhibition by soluble complement receptor type 1 improves microcirculation after rat liver transplantation. Transplantation 66: 717–722PubMedCrossRefGoogle Scholar
  35. 35.
    Eror AT, Stojadinovic A, Starnes BW, et al (1999) Antiinflammatory effects of soluble complement receptor type 1 promote rapid recovery of ischemia/reperfusion injury in rat small intestine. Clin Immunol 90: 266–275PubMedCrossRefGoogle Scholar
  36. 36.
    Lazar HL, Bao Y, Gaudiani J, et al (1999) Total complement inhibition: An effective strategy to limit ischemic injury during coronary revascularization on cardiopulmonary bypass. Circulation 100: 1438–1442Google Scholar
  37. 37.
    Maroko PR, Carpenter CB, Chariello M (1978) Reduction by cobra venom factor of myocardial necrosis after coronary artery occlusion. J Clin Invest 61: 661–670PubMedCrossRefGoogle Scholar
  38. 38.
    Ikai M, Itoh M, Joh T, et al (1996) Complement plays an essential role in shock following intestinal ischaemia in rats. Clin Exp Immunol 106: 156–159PubMedCrossRefGoogle Scholar
  39. 39.
    Kroshus TJ, Salerno CT, Yeh CG, et al (2000) A recombinant soluble chimeric complement inhibitor composed of human cd46 and cd55 reduces acute cardiac tissue injury in models of pig-human heart transplantation. Transplantation 69: 2282–2289PubMedCrossRefGoogle Scholar
  40. 40.
    Heller T, Hennecke M, Baumann U et al (1999) Selection of C5a receptor antagonist from phage libraries attenuating the inflammatory response in immune complex disease and ischemia/reperfusion injury. J Immunol 163: 985–994PubMedGoogle Scholar
  41. 41.
    Fitch JCK, Rollins S, Matis L, et al (1999) Pharmacology and biological efficacy of recombinant, humanized, single-chain antibody c5 complement inhibitor in patients undergoing coronary artery bypass graft surgery with cardiopulmonary bypass. Circulation 100: 24992506Google Scholar
  42. 42.
    Collard CD, Agah A, Reenstra W, Buras J, Stahl GL (1999) Endothelial nuclear factor-Kb translocation and vascular cell adhesion molecule-1 induction by complement: inhibition with anti-human C5 therapy or cGMP analogues. Arterioscler Thromb Vasc Biol 19: 26232629Google Scholar
  43. 43.
    Kyriakides C, Austen W, Wang Y, et al (1999) Skeletal muscle reperfusion injury is mediated by neutrophils and the complement membrane attack complex. Am J Physiol 277: 1263–1268Google Scholar
  44. 44.
    Collard CD, Lebowski R, Jordan JE, Agah A, Stahl GL (1999) Complement activation following oxidative stress. Mol Immunol 36: 941–948PubMedCrossRefGoogle Scholar
  45. 45.
    Weiser MR, Williams JP, Moore FD, et al (1996) Reperfusion injury of ischemic skeletal muscle is mediated by natural antibody and complement. J Exp Med 183: 2343–2348PubMedCrossRefGoogle Scholar
  46. 46.
    Williams JP, Pechet TTV, Weiser MR, et al (1999) Intestinal reperfusion injury is mediated by IgM and complement. J Appl Physiol 86: 938–942PubMedGoogle Scholar
  47. 47.
    Suankratay C, Mold C, Zhang Y, et al (1998) Complement regulation in innate immunity and the acute-phase response: inhibition of mannan-binding lectin-initiated complement cytolysis by C-reactive protein ( CRP ). Clin Exp Immunol 113: 353–359Google Scholar
  48. 48.
    Volanakis JE, Narkates AJ (1981) Interaction of C-reactive protein with artificial phosphatidylcholine bilayers and complement. J Immunol 126: 1820–1825PubMedGoogle Scholar
  49. 49.
    Lagrand WK, Visser CA, Hermens WT et al (1999) C-Reactive protein as a cardiovascular risk factor. More than epiphenomenon? Circulation 100: 96–102PubMedCrossRefGoogle Scholar
  50. 50.
    Lagrand WK, Niessen HWM, Wolbink GJ, et al (1997) C-Reactive protein colocalizes with complement in human hearts during acute myocardial infarction. Circulation 95 (1): 97–103PubMedCrossRefGoogle Scholar
  51. 51.
    Griselli M, Herbert J, Hutchinson WL, et al (1999) C-reactive protein and complement are important mediators of tissue damage in acute myocardial infarction. J Exp Med 190: 17331740Google Scholar
  52. 52.
    Pasceri V, Willerson JT, Yeh ETH (2000) Direct proinflammatory effect of c-reactive protein on human endothelial cells. Circulation 102: 2165–2168PubMedCrossRefGoogle Scholar
  53. 53.
    Kagiyama A, Savage HE, Michael LH, Hanson G, Entman ML, Rossen RD (1989) Molecular basis of complement activation in ischemic myocardium: identification of specific molecules of mitochondrial origin that bind human Clq and fix complement. Circ Res 64: 607615Google Scholar
  54. 54.
    Rossen RD, Michael LH, Hawkins HK, et al (1994) Cardiolipin-protein complexes and initiation of complement activation after coronary artery occlusion. Circ Res 75: 546–555PubMedCrossRefGoogle Scholar
  55. 55.
    Giclas PC, Pinckard RN, Olson MS (1979) In vitro activation of complement by isolated human heart subcellular membranes. J Immunol 122: 146–151PubMedGoogle Scholar
  56. 56.
    Collard CD, Vakeva A, Morrissey MA, et al (2000) Complement activation after oxidative stress: role of the lectin complement pathway. Am J Pathol 156: 1549–1556PubMedCrossRefGoogle Scholar
  57. 57.
    Collard CD, Montaldo MC, Reenstra WR, Buras JA, Stahl GL (2001) Endothelial oxidative stress activates the lectin complement pathway; role of cytokeratin 1. Am J Pathol 159: 1045–1054PubMedCrossRefGoogle Scholar
  58. 58.
    Jordan JE, Montaldo MC, Stahl GL (2001) Inhibition of mannose-binding lectin reduces postischemic myocardial reperfusion injury. Circulation 104: 1413–1418PubMedCrossRefGoogle Scholar
  59. 59.
    Salama A, Hugo FH, Heinrich D, et al (1988) Deposition of terminal C5b-9 complement complexes on erythrocytes and leukocytes during cardiopulmonary bypass. N Engl J Med 318: 408–414PubMedCrossRefGoogle Scholar
  60. 60.
    Hostetter MK, Johnson GM (1989) The erythrocytes as instigator of inflammation. J Clin Invest 84: 665–671PubMedCrossRefGoogle Scholar
  61. 61.
    Test ST, Mitsuyoshi J (1997) Activation of the alternative pathway of complement by calcium-loaded erythrocytes resulting from loss of membrane phospholipid asymmetry. J Lab Clin Med 130: 169–182PubMedCrossRefGoogle Scholar
  62. 62.
    Hindsmarsh EJ, Marks RM (1998) Complement activation occurs on subendothelial extra-cellular matrix in vitro and is initiated by retraction or removal of overlying endothelial cells. J Immunol 160: 6128–6136Google Scholar
  63. 63.
    Mold C, Morris CA (2001) Complement activation by apoptotic endothelial cells following hypoxia/reoxygenation. Immunology 102: 359–364PubMedCrossRefGoogle Scholar
  64. 64.
    Familian A, Zwart B, Huisman HG, et al (2001) Chromatin-independent binding of serum amyloid P component to apoptotic cells. J Immunol 167: 647–654PubMedGoogle Scholar

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© Springer Science+Business Media New York 2002

Authors and Affiliations

  • C. L. F. Ciurana
  • C. E. Hack

There are no affiliations available

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