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Role of the Complement Cascade in Severe Sepsis

  • L. G. Thijs
  • C. E. Hack
Chapter
Part of the Update in Intensive Care and Emergency Medicine book series (UICM, volume 16)

Abstract

Activation of the complement system has been implicated as one of the possible mechanisms involved in the extremely complex pathophysiology of septic shock. Bacteria and their products like endotoxin can activate this system even in the absence of antibodies [1]. Complement activation results in the generation of several peptides which have strong biological properties and are called anaphylatoxins [2], Hypotension, leukopenia and increased pulmonary permeability are features of systemic complement activation which are also observed in human septic shock. In this chapter, we will review the available evidence for the role of activation of the complement system in severe sepsis, and some of its sequelae.

Keywords

Septic Shock Severe Sepsis Acute Lung Injury Complement Activation Septic Patient 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Morrison DC, Kline LF (1977) Activation of the classical and properdin pathways of complement by bacterial lipopolysaccharides (LPS). I Immunol 118:362–368Google Scholar
  2. 2.
    Vogt W (1986) Anaphylatoxins: Possible roles in disease. Complement 3:177–188PubMedGoogle Scholar
  3. 3.
    Yancey KB (1988) Biological properties of human C5a: Selected in vitro and in vivo studies. Clin Exp Immunol 71:207–210PubMedGoogle Scholar
  4. 4.
    Okusawa S, Yancey KB, Van der Meer JWM, et al. (1988) C5a stimulates secretion of tumor necrosis factor from human mononuclear cells in vitro. J Exp Med 168:443–448PubMedCrossRefGoogle Scholar
  5. 5.
    Cavaillon JM, Fitting C, Haeffner-Cavaillon N (1990) Recombinant C5a enhances interleu-kin-1 and tumor necrosis factor release by lipopolysaccharide-stimulated monocytes and macrophages. Eur J Immunol 20:253–257PubMedCrossRefGoogle Scholar
  6. 6.
    Scholz W, McClurg MR, Cardenas GJ, et al. (1990) C5a-mediated release of interleukin-6 by human monocytes. Clin Immunol Immunopathol 57:297–307PubMedCrossRefGoogle Scholar
  7. 7.
    Berger M, Wetzler EM, Wallis RS (1988) Tumor necrosis factor is the major monocyte product that increases complement receptor expression on mature human neutrophils. Blood 71:151–158PubMedGoogle Scholar
  8. 8.
    Bjork J, Hugli TE, Smedegard G (1985) Microvascular effects of anaphylatoxins C3a and C5a. J Immunol 134:1115–1119PubMedGoogle Scholar
  9. 9.
    Hamilton KK, Hattori R, Esmon CT, Sims PJ (1990) Complement proteins C5b-9 induce ve-siculation of the endothelial plasma membrane and expose catalytic surface of assembly of the prothrombinase enzyme complex. J Biol Chem 265:3809–3814PubMedGoogle Scholar
  10. 10.
    McCabe WR (1973) Serum complement levels in bacteremia due to gram-negative organisms. N Engl J Med 288:21–23PubMedCrossRefGoogle Scholar
  11. 11.
    Fearon DT, Ruddy S, Schur PH, McCabe WR (1975) Activation of the properdin pathway of complement in patients with gram-negative bacteremia. N Engl J Med 292:937–940PubMedCrossRefGoogle Scholar
  12. 12.
    Füst G, Petras G, Ujhelyi E (1976) Activation of the complement system during infections due to gram-negative bacteria. Clin Immunol Immunopathol 5:293–302PubMedCrossRefGoogle Scholar
  13. 13.
    León C, Rodrigo MJ, Tomasa A, et al. (1982) Complement activation in septic shock due to gram-negative and gram-positive bacteria. Crit Care Med 10:308–310PubMedCrossRefGoogle Scholar
  14. 14.
    Sprung CL, Schultz DR, Marcial E, et al. (1986) Complement activation in septic shock patients. Crit Care Med 14:525–528PubMedCrossRefGoogle Scholar
  15. 15.
    Whaley K, YeeKhong T, McCartney AG, et al. (1979) Complement activation and its control in gram-negative endotoxin shock. J Clin Lab Immunol 2:117–124Google Scholar
  16. 16.
    Witte J, Jochum M, Scherer R, Schramm W, Hochstrasser K, Fritz H (1982) Disturbances of selected plasma proteins in hyperdynamic septic shock. Intensive Care Med 8:215–222PubMedCrossRefGoogle Scholar
  17. 17.
    Shatney CH, Benner C (1985) Sequential serum complement (C3) and immunoglobulin levels in shock/trauma patients developing acute fulminant systemic sepsis. Circ Shock 16:9–17PubMedGoogle Scholar
  18. 18.
    Brandtzaeg P, Mollnes TE, Kierulf P (1989) Complement activation and endotoxin levels in systemic meningococcal disease. J Infect Dis 160:58–65PubMedCrossRefGoogle Scholar
  19. 19.
    Heideman M, Hugli TE (1984) Anaphylatoxin generation in multisystem organ failure. J Trauma 24:1038–1043PubMedCrossRefGoogle Scholar
  20. 20.
    Weinberg PF, Matthay MA, Webster RO, Roskos KV, Goldstein IM, Murray JF (1984) Biologically active products of complement and acute lung injury in patients with the sepsis syndrome. Am Rev Respir Dis 130:791–796PubMedGoogle Scholar
  21. 21.
    Slotman GJ, Burchard KW, Williams JJ, D’Arezzo A, Yellin SA (1986) Interaction of pro-staglandins, activated complement, and granulocytes in clinical sepsis and hypotension. Surgery 99:744–751PubMedGoogle Scholar
  22. 22.
    Ketai LH, Gram CM (1986) C3a and adult respiratory distress syndrome after massive transfusion. Crit Care Med 14:1001–1003PubMedCrossRefGoogle Scholar
  23. 23.
    Hällgren R, Samuelsson T. Modig J (1987) Complement activation and increased alveolar-capillary permeability after major surgery and in adult respiratory distress syndrome. Crit Care Med 15:189–193PubMedCrossRefGoogle Scholar
  24. 24.
    Tennenberg SD, Jacobs MP, Solomkin JS (1987) Complement-mediated neutrophil activation in sepsis — and trauma — related adult respiratory distress syndrome. Arch Surg 122:26–32PubMedCrossRefGoogle Scholar
  25. 25.
    Langlois PF, Gawryl MS (1988) Accentuated formation of the terminal C5b-9 complement complex in patient plasma precedes development of the adult respiratory distress syndrome. Am Rev Respir Dis 138:368–375PubMedGoogle Scholar
  26. 26.
    Bengtson A, Heideman M (1988) Anaphylatoxin formation in sepsis. Arch Surg 123:645–649PubMedCrossRefGoogle Scholar
  27. 27.
    Hack CE, Nuijens JH, Felt-Bersma RJF, et al. (1989) Elevated plasma levels of the anaphyla-toxins C3a and C4a are associated with a fatal outcome in sepsis. Am J Med 86:20–26PubMedCrossRefGoogle Scholar
  28. 28.
    Hammerschmidt DE, Weaver LJ, Hudson LD, Craddock PR, Jacob HS (1980) Association of complement activation and elevated plasma-C5a with adult respiratory distress syndrome. Lancet 1:947–949PubMedCrossRefGoogle Scholar
  29. 29.
    Ognibene FP, Parker MM, Burch-Whitman C, et al. (1988) Neutrophil aggregating activity and septic shock in humans: Neutrophil aggregation by C5a-like material occurs more frequently than complement component depletion and correlates with depression of systemic vascular resistance. J Crit Care 3:103–111CrossRefGoogle Scholar
  30. 30.
    Heideman, M, Norder-Hansson B, Bengtson A, Mollnes TE (1988) Terminal complement complexes and anaphylatoxins in septic and ischemic patients. Arch Surg 123:188–192PubMedCrossRefGoogle Scholar
  31. 31.
    Parsons PE, Giclas PC (1990) The terminal complement complex (sC5b-9) is not specifically associated with the development of the adult respiratory distress syndrome. Am Rev Respir Dis 141:98–103PubMedGoogle Scholar
  32. 32.
    George C, Carlet J, Sobel A, et al. (1980) Circulating immune complexes in patients with gram-negative septic shock. Intensive Care Med 6:123–127PubMedCrossRefGoogle Scholar
  33. 33.
    Kalter ES, Daha MR, ten Cate JW, Verhoef J, Bouma BN (1985) Activation and inhibition of Hageman factor-dependent pathways and the complement system in uncomplicated bactere-mia or bacterial shock. J Infect Dis 151:1019–1027PubMedCrossRefGoogle Scholar
  34. 34.
    Nuijens JH, Eerenberg-Belmer AJM, Huijbregts CCM, et al. (1989) Proteolytic inactivation of plasma C1 inhibitor in sepsis. J Clin Invest 84:443–450PubMedCrossRefGoogle Scholar
  35. 35.
    Nuijens JH, Huijbregts CCM, Eerenberg-Belmer AJM, et al. (1988) Quantification of plasma factor XIIa-C1-inhibitor and kallikrein-C1-inhibitor complexes in sepsis. Blood 72:1841–1848PubMedGoogle Scholar
  36. 36.
    Heideman M, Kaijser B, Gelin LE (1979) Complement activation early in endotoxin shock. J Surg Res 26:74–78PubMedCrossRefGoogle Scholar
  37. 37.
    Gilbert VE, Braude AI (1962) Reduction of serum complement in rabbits after injection of endotoxin. J Exp Med 116:477–490PubMedCrossRefGoogle Scholar
  38. 38.
    Garner R, Chater BV, Brown DL (1974) The role of complement in endotoxin shock and disseminated intravascular coagulation: Experimental observations in the dog. Brit J Haematol 28:393–401CrossRefGoogle Scholar
  39. 39.
    Fine DP (1985) Role of complement in endotoxin shock. In: Hinshaw LB (ed) Handbook of endotoxin, Vol 2, Elsevier Scientific Publishers, pp 129–144Google Scholar
  40. 40.
    Smedegard G, Cui L, Hugli TE (1989) Endotoxin-induced shock in the rat. A role for C5a. Am J Pathol 135:489–497PubMedGoogle Scholar
  41. 41.
    Wakabayashi G, Gelfand JA, Jung WK, Connolly RJ, Burke JF, Dinarello CA (1991) Staphy-lococcus epidermidis induces complement activation, tumor necrosis factor and interleukin-1, a shock-like state and tissue injury in rabbits without endotoxemia. J Clin Invest 87:1925–1935PubMedCrossRefGoogle Scholar
  42. 42.
    Bodammer G, Vogt W (1967) Actions of anaphylatoxin on circulation and respiration in the guinea pig. Int Arch Allergy 32:417–428PubMedCrossRefGoogle Scholar
  43. 43.
    Pavel K, Piper PJ, Smedegard G (1979) Anaphylatoxin-induced shock and two patterns of anaphylactic shock: Hemodynamics and mediators. Acta Physiol Scand 105:393–403CrossRefGoogle Scholar
  44. 44.
    Lundberg C, Marceau F, Hugli TE (1987) C5a-induced hemodynamic and hematologie changes in the rabbit. Role of cyclooxygenase products and polymorphonuclear leukocytes. Am J Pathol 128:471–483PubMedGoogle Scholar
  45. 45.
    Hsueh W, Sun X, Rioja LN, Gonzales-Crussi F (1990) The role of the complement system in shock and tissue injury induced by tumour necrosis factor and endotoxin. Immunology 70:309–314PubMedGoogle Scholar
  46. 46.
    Rampart M, Bull H, Herman AG (1983) Activated complement and anaphylatoxins increase the in vitro production of prostacyclin by rabbit aorta endothelium. Arch Pharmacol 322:158–165CrossRefGoogle Scholar
  47. 47.
    Hugli TE, Marceau F (1985) Effects of the C5a anaphylatoxin and its relationship to cyclooxygenase metabolites in rabbit vascular strips. Br J Pharmacol 84:725–733PubMedGoogle Scholar
  48. 48.
    Bult M, Herman, AG, Laekeman GM, Rampart M (1985) Formation of prostanoids during intravascular complement activation in rabbits. Br J Pharmacol 84:329–336PubMedGoogle Scholar
  49. 49.
    Schirmer WJ, Schirmer JM, Naff GB, Fry DE (1988) Systemic complement activation produces hemodynamic changes characteristic of sepsis. Arch Surg 123:316–321PubMedCrossRefGoogle Scholar
  50. 50.
    Thijs LG, Hack CE, Nuijens JH, Groeneveld ABJ (1989) Peripheral circulation in septic shock. In: Schlag G, Redl H (eds) Second Vienna Shock Forum, Alan R Liss Inc., pp 163–174Google Scholar
  51. 51.
    Hachfeld del Balzo U, Levi R, Polley MJ (1985) Cardiac dysfunction caused by purified human C3a anaphylatoxin. Proc Natl Acad Sci 82:886–890CrossRefGoogle Scholar
  52. 52.
    Stevens JH, O’Hanley P, Shapiro JM, et al. (1986) Effects of anti-C5a antibodies on the adult respiratory distress syndrome in septic primates. J Clin Invest 77:1812–1816PubMedCrossRefGoogle Scholar
  53. 53.
    Kaplan RL, Sahn SA, Petty TL (1979) Incidence and outcome of the respiratory distress sy-drome in gram-negative sepsis. Arch Intern Med 139:867–886PubMedCrossRefGoogle Scholar
  54. 54.
    Pepe PE, Potkin RT, Holtman Reus D, Hudson LD, Carrico CJ (1982) Clinical predictors of the adult respiratory distress syndrome. Am J Surg 144:124–130PubMedCrossRefGoogle Scholar
  55. 55.
    Craddock PR, Hammershmidt D, White JG, Dalmasso AP, Jacob HS (1977) Complement (C5a)-induced granulocyte aggregation in vitro. A possible mechanism of complement-mediated leukostasis and leukopenia. J Clin Invest 60:260–264PubMedCrossRefGoogle Scholar
  56. 56.
    Sacks T, Moldrow PR, Craddock PR, Bowers TK, Jacob HS (1978) Oxygen radicals mediate endothelial cell damage by complement-stimulated granulocytes. J Clin Invest 61:1161–1167PubMedCrossRefGoogle Scholar
  57. 57.
    Tate RM, Repine JE (1983) Neutrophils and the adult respiratory distress syndrome: State of the art. Am Rev Respir Dis 128:802–806Google Scholar
  58. 58.
    Tonnesen MG, Smedley LA, Henson PM (1984) Neutrophil-endothelial cell interactions: Modulation of neutrophil adhesiveness induced by complement fragments C5a and C5a-de-sArg and formyl-methionyl-leucyl phenylalanine in vitro. J Clin Invest 74:1581–1592PubMedCrossRefGoogle Scholar
  59. 59.
    Varani J, Ginsburg I, Schuger L, et al. (1989) Endothelial cell killing by neutrophils. Synergi-stic interaction of oxygen products and proteases. Am J Pathol 135:435–438PubMedGoogle Scholar
  60. 60.
    Craddock PR, Fehr J, Brigham KL, Kronenberg RS, Jacob HS (1977) Complement and leukocyte-mediated pulmonary dysfunction in hemodialysis. N Engl J Med 296:169–11ACrossRefGoogle Scholar
  61. 61.
    Thommasen HV, Rüssel JA, Boyko WJ, Hogg JC (1984) Transient leucopenia associated, with adult respiratory distress syndrome. Lancet 1:809–812PubMedCrossRefGoogle Scholar
  62. 62.
    Brigham KL, Woolverton WC, Blake LH, Staub NC (1974) Increased sheep lung permeability caused by Pseudomonas bacteria. J Clin Invest 54:792–804PubMedCrossRefGoogle Scholar
  63. 63.
    Brigham KL, Bowers R, Haynes L (1979) Increased sheep lung vascular permeability caused by E. coli endotoxin. Circ Res 45:292–297PubMedGoogle Scholar
  64. 64.
    Myrick BO, Brigham KL (1983) Acute effects of Escherichia coli endotoxin on the pulmonary microcirculation of anesthetized sheep. Structure-function relationships. Lab Invest 48:458–470Google Scholar
  65. 65.
    Heflin AG, Brigham KL (1981) Prevention by granulocyte depletion of increased vascular permeability of sheep lung following endotoxemia. J Clin Invest 68:1253–1260PubMedCrossRefGoogle Scholar
  66. 66.
    Hohn DC, Meyers AJ, Cherini ST, Beckmann A, Markinson RE, Churg AM (1980) Production of acute pulmonary injury by leukocytes and activated complement. Surgery 88:48–58PubMedGoogle Scholar
  67. 67.
    Webster RO, Larsen GL, Mitchell BC, Goins AJ, Henson PM (1982) Absence of inflammatory lung injury in rabbits challenged intravascularly with complement-derived chemotactic factors. Am Rev Respir Dis 125:335–340PubMedGoogle Scholar
  68. 68.
    Nuytinck JKS, Goris RJA, Weerts JGE, Schillings PHM, Schuurmans-Stekhoven JH (1986) Acute generalized microvascular injury by activated complement and hypoxia: The basis of the adult respiratory distress syndrome and multiple organ failure? Br J Exp Path 67:537–548Google Scholar
  69. 69.
    Till GO, Johnson KJ, Kunkel R, Ward PA (1982) Intravascular activation of complement and acute lung injury. J Clin Invest 69:1126–1135PubMedCrossRefGoogle Scholar
  70. 70.
    Hosea S, Brown E, Hammer C, Frank M (1980) Role of complement activation in a model of adult respiratory distress syndrome. J Clin Invest 66:375–382PubMedCrossRefGoogle Scholar
  71. 71.
    Hammerschmidt DE, Harris PD, Wayland JH, Craddock PR, Jacob HS (1981) Complement-induced granulocyte aggregation in vivo. Am J Pathol 102:146–150PubMedGoogle Scholar
  72. 72.
    Olson LM, Moss GS, Baukus O, DasGupta TK (1985) The role of C5 in septic lung injury. Ann Surg 202:771–776PubMedCrossRefGoogle Scholar
  73. 73.
    Hangen DH, Stevens JH, Satoh PS, Hall EW, O’Hanley PT, Raffin TA (1989) Complement levels in septic primates treated with anti-C5a antibodies. J Surg Res 46:195–199PubMedCrossRefGoogle Scholar
  74. 74.
    Haslett C, Worthen GS, Giclas PC, Morrison DC, Henson JE, Henson PM (1987) The pulmonary vascular sequestration of neutrophils in endotoxemia is initiated by an effect of endotoxin on the neutrophil in the rabbit. Am Rev Respir Dis 136:9–18PubMedCrossRefGoogle Scholar
  75. 75.
    Henson PM, Larsen GL, Webster RO, et al. (1982) Pulmonary vascular alteration and injury induced by complement fragments: Synergistic effect of complement activation, neutrophil sequestration, and prostaglandins. Ann NY Acad Sci 384:287–300PubMedCrossRefGoogle Scholar
  76. 76.
    Worthen GS, Haslett C, Rees AJ, Gumbay RS, Henson JE, Henson PM (1987) Neutrophil-mediated pulmonary vascular injury. Synergistic effect of trace amounts of lipopolysacchari-de and neutrophil stimuli on vascular permeability and neutrophil sequestration in the lung. Am Rev Respir Dis 136:19–28PubMedCrossRefGoogle Scholar
  77. 77.
    Smedly LA, Tonnesen MG, Sandhaus RA, et al. (1986) Neutrophil-mediated injury to endo-thelial cells: Enhancement by endotoxin and essential role of neutrophil elastase. J Clin Invest 77:1233–1242PubMedCrossRefGoogle Scholar
  78. 78.
    Duchateau J, Haas M, Schreyen H, et al. (1984) Complement activation in patients at risk of developing the adult respiratory distress syndrome. Am Rev Respir Dis 130:1058–1064PubMedGoogle Scholar
  79. 79.
    Solomkin JS, Cotta LA, Satoh PS, Hurst JM, Nelson RD (1985) Complement activation and clearance in acute illness and injury: Evidence for C5a as a cell-directed mediator of the adult respiratory distress syndrome in man. Surgery 97:668–678PubMedGoogle Scholar
  80. 80.
    Slotman GJ, Burchard KW, Yellin SA, Williams JJ (1986) Prostaglandin and complement interaction in clinical acute respiratory failure. Arch Surg 121:271–274PubMedCrossRefGoogle Scholar
  81. 81.
    Parsons PE, Wortehn GS, Moore EE, Tate RM, Henson PM (1989) The association of circulating endotoxin with the development of the adult respiratory distress syndrome. Am Rev Respir Dis 140:294–301PubMedCrossRefGoogle Scholar
  82. 82.
    Muller-Eberhard H (1986) The membrane attack complex of complement. Ann Rev Immunol 4:503–528CrossRefGoogle Scholar
  83. 83.
    Ognibene FP, Martin SE, Parker MM, et al. (1986) Adult respiratory distress syndrome in patients with severe neutropenia. N Engl J Med 315:547–551PubMedCrossRefGoogle Scholar
  84. 84.
    Laufe MD, Simon RH, Flint A, et al. (1986) Adult respiratory distress syndrome in neutrope-nic patients. Am J Med 80:1022–1026PubMedCrossRefGoogle Scholar
  85. 85.
    Maunder RJ, Hackman RC, Riff E, et al. (1986) Occurrence of the adult respiratory distress syndrome in neutropenic patients. Am Rev Respir Dis 133:313–316PubMedGoogle Scholar
  86. 86.
    Guthrie LA, McPhail LC, Henson PM, Johanston RB (1984) Priming of neutrophils for enhanced release of oxygen metabolites by bacterial lipopolysaccharide. J Exp Med 160:1656–1671PubMedCrossRefGoogle Scholar
  87. 87.
    Fittshen CF, Sandhaus RA, Worthen GS, Henson PM (1988) Bacterial lipopolysaccharide enhances chemoattractant induced elastase secretion by human neutrophils. J Leukocyte Biol 43:547–556Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1992

Authors and Affiliations

  • L. G. Thijs
  • C. E. Hack

There are no affiliations available

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