The Respiratory Burst and Mechanisms of Oxygen Radical-Mediated Tissue Injury

  • Jeffrey S. Warren
  • Peter A. Ward
  • Kent J. Johnson


Although it has been recognized since the nineteenth century that the influx of phagocytic cells into sites of tissue injury is critical to the development of the inflammatory response, the recognition that neutrophils, monocytes, and macrophages are complex cells possessing diverse biological capabilities is relatively recent. Inflammatory cells are controlled by an extensive array of biochemical mediators. The concept that leukocytic proteases contribute to the tissue injury observed in acute inflammation has considerable supporting evidence but has been extensively broadened in recent years.1,2 Although numerous studies have demonstrated that lysosomal proteases can cause or enhance tissue injury, other studies have shown that tissue injury cannot be completely prevented by antiproteases.3,4 In addition, tissue injury still occurs in strains of mice whose leukocytes are deficient of proteases suggesting that other mechanisms are important in phagocyte-mediated tissue injury.5 Recent studies have provided compelling evidence that leukocyte-derived oxygen radicals and their metabolites are important mediators of inflammation and tissue injury.


Lung Injury Acute Lung Injury Phorbol Myristate Acetate Endothelial Cell Injury Human Neutrophil Elastase 
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.


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  1. 1.
    Senior RM, Tegner H, Kuhn C, et al: The induction of pulmonary emphysema with human leukocyte elastase. Am Rev Respir Dis 116: 469–475, 1977.PubMedGoogle Scholar
  2. 2.
    Janoff A, Sloan B, Weinbaum G, et al: Experimental emphysema produced by purified human neutrophil elastase: Tissue localization of the instilled protease. Am Rev Respir Dis 115: 461–478, 1977.PubMedGoogle Scholar
  3. 3.
    Johnson KJ, Ward PA: Role of oxygen metabolites in immune complex injury of lung. J Immunol 126: 1365–2369, 1981.Google Scholar
  4. 4.
    Cochrane CG, Janoff A: The Arthus reaction: A model of neutrophil, complement-mediated injury, in Zweifach B, Grant L, McClusky (eds): The Inflammatory Process, ed 2. New York, Academic, 1974, vol 3, p 85.Google Scholar
  5. 5.
    Johnson KJ, Varani J, Oliver J, et al: Immunologic vasculitis in beige mice with deficiency of leukocytic neutral protease. J Immunol 122: 1807–1812, 1979.PubMedGoogle Scholar
  6. 6.
    Babior BM: Oxygen-dependent microbial killing by phaogyctes. N Engl J Med 298:659–668, 721–725, 1978.Google Scholar
  7. 7.
    Klebanoff SJ: Oxygen metabolism and the toxic properties of phagocytes. Ann Intern Med 93:480– 490, 1980.Google Scholar
  8. 8.
    Fantone JC, Ward PA: Oxygen-Derived Radicals and Their Metabolites: Relationship to Tissue Injury. Kalamazoo, Michigan, The UpJohn Company, 1981.Google Scholar
  9. 9.
    Gabig TG, Lefker BA: Catalytic properties of the resolved flavoprotein and cytochrome B components of the NADPH dependent O2- generating oxidase from human neutrophils. Biochem Biophys Res Commun 118: 430–436, 1984.PubMedCrossRefGoogle Scholar
  10. 10.
    Crawford DR, Schneider DL: Ubiquinone content and respiratory burst activity of latex-filled phagolysosomes isolated from human neutrophils and evidence for the probable involvement of a third granule. J Biol Chem 258: 5363–5367, 1983.PubMedGoogle Scholar
  11. 11.
    Valentine JS: The chemical reactivity of superoxide anion in aprotic versus protic media: A review, in Caughey WS (ed): Biochemical and Clinical Aspects of oxygen. New York, Academic, 1979, p 659.Google Scholar
  12. 12.
    Fridovich I: Oxygen radicals, hydrogen peroxide and oxygen toxicity, in Pryor WA (ed): Free Radicals in Biology. New York, Academic, 1976, vol I, p 239.Google Scholar
  13. 13.
    Fridovich I: The biology of oxygen radicals. Science 201: 875–880, 1978.PubMedCrossRefGoogle Scholar
  14. 14.
    Root RK, Metcalf JA: H202 release from human granulocytes during phagocytosis: Relationship to superoxide anion formation and cellular catabolism of H202: Studies with normal and cytochalasin B treated cells. J Clin Invest 60: 1266–1279, 1977.PubMedCrossRefGoogle Scholar
  15. 15.
    Dahinden CA, Fehr J, Hugli T: Role of cell surface contact in the kinetics of superoxide production by granulocytes. J Clin Invest 72: 113–121, 1983.PubMedCrossRefGoogle Scholar
  16. 16.
    Nathan CF, Brukner LH, Silverstein SC, et al: Extracellular cytolysis by activated macrophages and granulocytes. I. Pharmacologic triggering of effector cells and the release of hydrogen peroxide. J Exp Med 149: 84–99, 1979.PubMedCrossRefGoogle Scholar
  17. 17.
    Koppenol WH: Reactions involving singlet oxygen and superoxide anion. Nature (Lond) 262:420– 421, 1976.Google Scholar
  18. 18.
    Foote CS: Detection of singlet oxygen in complex systems: A critique, in Caughey WS (ed): Biochemical and Clinical Aspects of Oxygen. New York, Academic, 1979, p 603.Google Scholar
  19. 19.
    Willson RL: Hydroxyl radicals and biological damage in vitro: What relevance in vivo?, in Oxygen Free Radicals and Tissue Damage, Ciba Foundation Symposium 65, Amsterdam, Excerpta Medica, 1979, p 19.Google Scholar
  20. 20.
    Beauchamp C, Fridovich I: A mechanism for the production of ethylene from methional. J Biol Chem 245: 4641–4646, 1970.PubMedGoogle Scholar
  21. 21.
    Halliwell B, Gutteridge JM: Formation of a thiobarbituric acid reactive substance from deoxyribose in the presence of iron salts. FEBS Lett 128: 347–352, 1981.PubMedCrossRefGoogle Scholar
  22. 22.
    Ambruso DR, Johnston RB: Lactoferrin enhances hydroxy 1 radical production by human neu-trophils, neutrophil particulate fractions, and an enzymatic generating system. J Clin Invest 67:352— 360, 1981.Google Scholar
  23. 23.
    Rosen H, Klebanoff SJ: Role of iron and ethylenediaminetetracetic acid in the bactericidal activity of a superoxide anion–generating system. Arch Biochem Biophys 208: 512–519, 1981.PubMedCrossRefGoogle Scholar
  24. 24.
    Weiss SJ, Rustagi PK, LoBuglio AF: Human granulocyte generation of hydroxyl radical. J Exp Med 147: 316–323, 1978.PubMedCrossRefGoogle Scholar
  25. 25.
    Repine JE, Eaton JW, Anders MW, et al: Generation of hydroxyl radical by enzymes, chemicals and human phagocytes in vitro. J Clin Invest 64: 1642–1651, 1979.PubMedCrossRefGoogle Scholar
  26. 26.
    Sagone AL, Decker MA, Wells RM, et al: A new method for the detection of hydroxyl radical production by phagocytic cells. Biochim Biophys Acta 628: 90–97, 1980.PubMedCrossRefGoogle Scholar
  27. 27.
    Klebanoff SJ, Rosen H: Ethylene formation by polymorphonuclear leukocytes: Role of myeloperox-idase. J Exp Med 148: 490–506, 1978.PubMedCrossRefGoogle Scholar
  28. 28.
    Green MR, Hill AD, Okolow-Zubkowska MJ, Et Al: The production of hydroxyl and superoxide radicals by stimulated human neutrophils-measurements by EPR spectroscopy. FEBS Lett 100:23– 26, 1979.Google Scholar
  29. 29.
    Rosen H, Klebanoff SJ: Hydroxyl radical generation by polymorphonuclear leukocytes measured by electron spin resonance spectroscopy. J Clin Invest 64: 1725–1729, 1979.PubMedCrossRefGoogle Scholar
  30. 30.
    Ramsey PG, Martin T, Chi E, et al: Arming of mononuclear phagoyctes by eosinophil peroxidase bound to Staphylococcus aureus. J Immunol 128: 415–420, 1982.PubMedGoogle Scholar
  31. 31.
    Stelmaszynska T, Zgliczynski JM: Myeloperoxidase of human neutrophilic granulocytes as color- inating enzyme. Eur J Biochem 45: 305–312, 1974.PubMedCrossRefGoogle Scholar
  32. 32.
    Mead JF: Free radical mechanisms of lipid damage and consequences for cellular membranes, in Pryor WA (ed): Free Radicals in Biology. New York, Academic, 1976, vol 1, p 51.Google Scholar
  33. 33.
    Fletcher BL, Dillard CJ, Tappel AL: Measurement of fluorescent lipid peroxidation products in biological systems and tissues. Anal Biochem 52: 1–9, 1973.PubMedCrossRefGoogle Scholar
  34. 34.
    Riley CA, Cohen G, Lieberman M: Ethane evolution: A new index of lipid peroxidation. Science 183: 208–210, 1974.CrossRefGoogle Scholar
  35. 35.
    Tappel AL, Dillard CJ: In vivo lipid peroxidation: Measurement via exhaled pentane and protection by vitamin E. Fed Proc 40: 174–178, 1981.Google Scholar
  36. 36.
    Roubul WT, Tappel AL: Polymerization of protein induced by free radical lipid peroxidation. Arch Biochem Biophys 173: 150–155, 1966.CrossRefGoogle Scholar
  37. 37.
    Roubul WT, Tappel AL: Damage to protein, enzymes and amino acids by peroxidizing lipids. Arch Biochem Biophys 113: 5–8, 1966.CrossRefGoogle Scholar
  38. 38.
    Fligiel SEG, Lee EC, McCoy JP, et al: Protein degradation following treatment with hydrogen peroxide. Am J Pathol 115: 418–425, 1984.PubMedGoogle Scholar
  39. 39.
    Gutteridge JM: thiobarbituric acid reactivity following iron dependent free radical damage to amino acids and carbohydrates. FEBS Lett 128:343–346, 1981.Google Scholar
  40. 40.
    Halliwell B: The biological effects of the superoxide radical and its products. Bull Eur Physiopathol Respir (suppl) 17: 21–28, 1981.Google Scholar
  41. 41.
    Doroshow JH, Locker GY, Myers CE: Enzymatic defenses of the mouse heart against reactive oxygen metabolites: Alterations produced by doxorubicin. J Clin Invest 65: 128–137, 1980.PubMedCrossRefGoogle Scholar
  42. 42.
    Lucy J A: Functional and structural aspects of biological membranes: A suggested structural role of vitamin E in the control of membrane permeability and stability. Ann NY Acad Sci 203: 4–21, 1972.Google Scholar
  43. 43.
    Denko CW: Protective role of ceruloplasmin in inflammation. Agents Actions 9: 333–341, 1979.PubMedCrossRefGoogle Scholar
  44. 44.
    Sacks T, Moldow CF, Craddock PR, et al: Oxygen radical mediated endothelial cell damage by complement-stimulated granulocytes: An in vitro model of immune vascular damage. J Clin Invest 50: 327–335, 1978.Google Scholar
  45. 45.
    Slivka A, LoBuglio AF, Weiss S: A potential role for hypochlorous acid in granulocyte mediated tumor cell cytotoxicity. Blood 55: 347–350, 1980.PubMedGoogle Scholar
  46. 46.
    Simon RH, Scoggin CH, Patterson D: Hydrogen peroxide causes the fatal injury to human fibro–blasts exposed to oxygen radicals. J Biol Chem 256: 7181–7186, 1981.PubMedGoogle Scholar
  47. 47.
    Nathan CF, Brukner L, Silverstein SC, et al: Extracellular cytolysis by activated macrophages and granulocytes. J Exp Med 149: 100–113, 1979.PubMedCrossRefGoogle Scholar
  48. 48.
    Weiss SJ: Neutrophil generated hydroxyl radicals destroy RBC targets. Clin Res 27: 466, 1979.Google Scholar
  49. 49.
    Klebanoff SJ, Clark RA: Hemolysis and iodination of erythrocyte components by a myeloperox- idase-mediated system. Blood 45: 699–101, 1975.PubMedGoogle Scholar
  50. 50.
    Hafeman DD, Lucas ZJ: Polymorphonuclear leukocyte mediated antibody dependent cellular cytotoxicity against tumor cells: Dependent on oxygen and the respiratory burst. J Immunol 123:55– 62, 1979.Google Scholar
  51. 51.
    Baehner RL, Boxer LA, Allen JM, et al: Autooxidation as a basis for altered function by polymorphonuclear leukocytes. Blood 50: 327–335, 1977.PubMedGoogle Scholar
  52. 52.
    Clark RA, Klebanoff SJ: Neutrophil-mediated tumor cell cytotoxicity: Role of the peroxidase system. J Exp Med 141: 1442–1447, 1975.PubMedCrossRefGoogle Scholar
  53. 53.
    Clark RA, Klebanoff SJ, Einstein AB, et al: Peroxidase-H2O2-halide system: Cytotoxic effect on mammalian tumor cells. Blood 45: 161–170, 1975.PubMedGoogle Scholar
  54. 54.
    Craddock PR, Fehr J, Brigham K, Et Al: complement and leukocyte mediated pulmonary dysfunction in hemodialysis. N Engl J Med 196: 769–774, 1977.CrossRefGoogle Scholar
  55. 55.
    Rinaldo JE, Rogers RM: Adult respiratory distress syndrome: Changing concepts of lung injury and repair. N Engl J Med 306: 900–909, 1982.PubMedCrossRefGoogle Scholar
  56. 56.
    Weiss SJ, Young J, LoBuglio AF, et al: Role of hydrogen peroxide in neutrophil-mediated destruction of cultured endothelial cells. J Clin Invest 68: 714–721, 1981.PubMedCrossRefGoogle Scholar
  57. 57.
    Varani J, Fligiel SEG, Till GO, et al: Pulmonary endothelial cell killing by human neutrophils. Possible involvement of hydroxyl radical. Lab Invest 53: 656–633, 1985.PubMedGoogle Scholar
  58. 58.
    Harlan JM, Killen PD, Harker LA, et al: Neutrophil-mediated endothelial injury in vitro: Mechanism of cell detachment. J Clin Invest 68: 1394–1403, 1981.PubMedCrossRefGoogle Scholar
  59. 59.
    Smedly LA, Tonnesen MG, Sandhaus RA, et al: Neutrophil-mediated injury to endothelial cells. Enhancement by endotoxin and essential role of neutrophil elastase. J Clin Invest 77: 1233–1243, 1986.PubMedCrossRefGoogle Scholar
  60. 60.
    Weiss SJ: Oxygen as a weapon in the phagocytic armamentarium, in Ward PA (ed): Immunology of Inflammation. New York, Elsevier, 1983, p 37.Google Scholar
  61. 61.
    Weiss SJ, Peppin G, Ortiz X, et al: Oxidative autoactivation of latent collagenase by human neutrophils. Science 227: 747–749, 1985.PubMedCrossRefGoogle Scholar
  62. 62.
    Peppin GJ, Weiss SJ: Activation of the endogenous metalloproteinase, gelatinase, by triggered human neutrophils. Proc Natl Acad Sei USA 83: 4322–4326, 1986.CrossRefGoogle Scholar
  63. 63.
    Schraufstätter IU, Hyslop PA, Jackson J, et al: Induction of DNA strand breaks by H202 and pMA. Fed Proc 45: 451, 1986.Google Scholar
  64. 64.
    Schraufstätter IU, Hinshaw DB, Hyslop PA, et al: Oxidant injury of cells. DNA strand-breaks activate polyadenosine diphosphate-ribose polymerase and lead to depletion of nicotinamide adenine dinucleotide. J Clin Invest 77: 1312–1320, 1986.PubMedCrossRefGoogle Scholar
  65. 65.
    Perez HD, Weksler BB, Goldstein I: Generation of a chemotactic lipid from arachidonic acid by exposure to a superoxide generating system. Inflammation 4: 313–328, 1980.PubMedCrossRefGoogle Scholar
  66. 66.
    Petrone WF, English DK, Wong K, et al: Free radicals and inflammation: the superoxide dependent activation of a neutrophil chemotactic factor in plasma. Proc Natl Acad Sei USA 77: 1159–1163, 1980.CrossRefGoogle Scholar
  67. 67.
    Matheson NR, Wong DS, Travis J: Enzymatic inactivation of human alpha-1-proteinase inhibitor by neutrophil myeloperoxidase. Biochem Biophys Res Commun 88: 402–409, 1979.PubMedCrossRefGoogle Scholar
  68. 68.
    Carp H, Janoff A: In vitro suppression of serum elastase inhibitory capacity by reactive oxygen species generated by phagocytosing polymorphonuclear leukocytes. J Clin Invest 63: 793–797, 1979.PubMedCrossRefGoogle Scholar
  69. 69.
    Oyanagui Y: Participation of superoxide anions at the prostaglandins phase of carrageenin foot edema. Biochem Pharmacol 25: 1465–1471, 1976.PubMedCrossRefGoogle Scholar
  70. 70.
    Huber W, Saifer MG: Orgotein. the drug version of bovine Cu-An superoxide dismutase. I. A summary account of safety and pharmacology in laboratory animals, in Michelson AM, McCord J, Fridovich I (eds): Superoxide and Superoxide Dismutases. New York, Academic, 1977, p 517.Google Scholar
  71. 71.
    Johnson KJ, Fantone JC, Kaplan J, Et Al: In vivo damage of rats lungs by oxygen metabolites. J Clin Invest 67: 983–993, 1981.CrossRefGoogle Scholar
  72. 72.
    Johnson KJ, Ward PA: Acute immunologic pulmonary alveolitis. J Clin Invest 54: 349–357, 1974.PubMedCrossRefGoogle Scholar
  73. 73.
    Till GO, Johnson KJ, Kunkel R, et al: Intravascular activation of complement and acute lung injury. Dependency on neutrophils and toxic oxygen metabolites. J Clin Invest 69: 1126–1135, 1982.PubMedCrossRefGoogle Scholar
  74. 74.
    Tvedten HW, Till GO, Ward PA: Mediators of lung injury in mice following systemic activation of complement. Am J Pathol 119: 92–100, 1985.PubMedGoogle Scholar
  75. 75.
    Ward PA, Till GO, Kunkel R, et al: Evidence for the role of hydroxy 1 radical in complement and neutrophil-dependent tissue injury. J Clin Invest 72: 789–801, 1983.PubMedCrossRefGoogle Scholar
  76. 76.
    Johnson KJ, Wilson BS, Till GO, et al: Acute lung injury in rat caused by immunoglobulin A immune complexes. J Clin Invest 74: 358–369, 1984.PubMedCrossRefGoogle Scholar
  77. 77.
    Johnson KJ, Ward PA, Kunkel RG, et al: Mediation of IgA induced lung injury in the rat. Role of macrophages and reactive oxygen products. Lab Invest 54: 499–508, 1986.PubMedGoogle Scholar

Copyright information

© Plenum Press, New York 1988

Authors and Affiliations

  • Jeffrey S. Warren
    • 1
  • Peter A. Ward
    • 1
  • Kent J. Johnson
    • 1
  1. 1.Department of PathologyUniversity of Michigan Medical SchoolAnn ArborUSA

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