The Role of Lipid Mediators in Oxygen-Induced Lung Injury

  • Ronald B. Holtzman
  • Joseph R. Hageman
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 314)


Oxygen therapy has been incorporated in the treatment of critically ill patients of all ages since the 1930’s. Although often life saving in this context, prolonged exposure to high concentrations of oxygen is toxic to all cells, particularly those comprising the alveolar-capillary unit of the lung. Pulmonary oxygen toxicity has been implicated in the pathogenesis of the adult respiratory distress syndrome, and among premature neonates oxygen injury is believed to play a central role in the development of bronchopulmonary dysplasia and retinopathy of prematurity.


Lung Injury Alveolar Macrophage Bronchoalveolar Lavage Fluid Lung Lavage Arachidonic Acid Metabolite 
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  1. 1.
    R. Gerschman, D.L. Gilbert, S.W. Nye, P. Dwyer, and W.O. Fenn. Oxygen poisoning and x-irradiation: a mechanism in common., Science., 119: 623 (1954).PubMedCrossRefGoogle Scholar
  2. 2.
    L. Frank and D. Massaro. Oxygen toxicity., Am. J. Med., 69: 117 (1980).PubMedCrossRefGoogle Scholar
  3. 3.
    J.M. Clark and C.J. Lambertson. Pulmonary oxygen toxicity: a review., Pharmacol. Rev., 23: 37 (1971).PubMedGoogle Scholar
  4. 4.
    J.R. Hageman, S. Babler, S.C. Lee, M. Cobb, L.M. Pachman, L.J. Smith, and C.E. Hunt. The early involvement of pulmonary prostaglandins in hyperoxic lung injury., Prostaglandins, Leukotrienes and Medicine., 25: 105 (1986).CrossRefGoogle Scholar
  5. 5.
    J.D. Crapo. Morphologic changes in pulmonary oxygen toxicity., Ann. Rev. Physiol., 48: 721 (1986).CrossRefGoogle Scholar
  6. 6.
    G. De Nucci, R. Astbury, N. Read, J.A. Salmon, and S. Moncada. Release of eicosanoids from isolated lungs of guinea-pigs exposed to pure oxygen: effect of dexamethasone., Eur. J. Pharmacol., 126: 11 (1986).PubMedCrossRefGoogle Scholar
  7. 7.
    P.H.S. Sporn, M. Peters-Golden, and R.H. Simon. Hydrogen-peroxide-induced arachidonic acid metabolism in the rat alveolar macrophage., Am. Rev. Respir. Dis., 137: 49 (1988).PubMedCrossRefGoogle Scholar
  8. 8.
    R.M. Tate, H.G. Morris, W.R. Schroeder, and J.E. Repine. Oxygen metabolites stimulate thromboxane production and vasoconstriction in isolated saline-perfused rabbit lungs., J. Clin. Invest., 74: 608 (1984).PubMedCrossRefGoogle Scholar
  9. 9.
    G.H. Gurtner, A. Knoblauch, P.L. Smith, H. Sies, and N. F. Adkinson. Oxidant-and lipid-induced pulmonary vasoconstriction mediated by arachidonic acid metabolites., J. Appl. Physiol., 55: 949 (1983).PubMedGoogle Scholar
  10. 10.
    J.R. Hageman, S.E. Lee, J. Zemaitis, L.J. Smith, and CE. Hunt. Prostaglandin E1 infusion fails to prevent hyperoxic lung injury in adult rabbits., Crit. Care Med., 17: 339 (1989).PubMedCrossRefGoogle Scholar
  11. 11.
    R. Jones, W.M. Zapol, and L. Reid. Pulmonary artery remodeling and pulmonary hypertension after exposure to hyperoxia for 7 days: a morphometric and hemodynamic study., Am. J. Pathol., 117: 273 (1984).PubMedGoogle Scholar
  12. 12.
    J.R. Hageman, K. McCulloch, P. Gora, E. Olsen, L. Pachman, and C.E. Hunt. Intralipid alterations in pulmonary prostaglandin metabolism and gas exchange., Crit. Care Med., 11: 794 (1983).PubMedCrossRefGoogle Scholar
  13. 13.
    D.W. Goldman and E.J. Goetzl. Specific binding of leukotriene B4 to receptors on human polymorphonuclear leukocytes., J. Immunol., 129: 1600 (1982).PubMedGoogle Scholar
  14. 14.
    A.W. Ford-Hutchinson, M.A. Bray, M.V. Doig, M.E. Shipley, and M.J. Smith. Leukotriene B4, a potent chemokinetic and aggregating substance released from polymorphonuclear leukocytes., Nature, 286: 264 (1980).PubMedCrossRefGoogle Scholar
  15. 15.
    S.E. Dahlen, P. Bjork, P. Hedqvist, K.E. Arfors, S. Hamarstrom, J. A. Lingren, and B. Samuelsson. Leukotrienes promote plasma leakage and leukocyte adhesion in postcapillary venules—in vitro effects with relevance to the acute inflammatory response., Proc. Natl. Acad. Sci. USA. 78: 3887 (1981).PubMedCrossRefGoogle Scholar
  16. 16.
    S.E. Dahlen, P. Hedqvist, S. Hammarstrom, and B. Samuelsson. Leukotrienes are potent constrictors of human bronchi., Nature, 288: 484 (1980).PubMedCrossRefGoogle Scholar
  17. 17.
    R.M. Jackson, D.B. Chandler, and J.D. Fulmer. Production of arachidonic acid metabolites by endothelial cells in hyperoxia., J. Appl. Physiol. 61: 584 (1986).PubMedGoogle Scholar
  18. 18.
    H. Taniguchi, F. Taki, K. Tagaki, T. Satake, S. Sugiyama, and T. Ozawa. The role of leukotriene B4 in the genesis of oxygen toxicity in the lung., Am. Rev. Respir. Dis., 133: 805 (1986).PubMedGoogle Scholar
  19. 19.
    T.R. Martin, L.C. Altman, R.K. Albert, and W.R. Henderson. Leukotriene B4 production by the human alveolar macrophage: a potential mechanism for amplifying inflammation in the lung., Am. Rev. Respir. Dis., 129: 108 (1984).Google Scholar
  20. 20.
    L.J. Smith, M. Shamsuddin, J. Anderson, and W. Hsueh. Hyperoxic lung damage in mice: appearance and bioconversion of peptide leukotrienes., J. Appl. Physiol., 64: 944 (1988).PubMedGoogle Scholar
  21. 21.
    K.R. Stenmark, M. Wyzaguirre, L. Remigio, J. Seccombe, and P.M. Henson. Recovery of platelet-activating factor and leukotrienes from infants with severe bronchopulmonary dysplasia: clinical improvement with cromolyn treatment., Am. Rev. Respir. Dis., 131: A236 (1985).Google Scholar
  22. 22.
    N.J. Kertesz, R.B. Holtzman, L. Adler, and J.R. Hageman. Evaluation of a leukotriene (LT) receptor antagonist in prevention of hyperoxic lung injury., Pediatr. Res.,25: 316A (1989).Google Scholar
  23. 23.
    O.C. Burghuber, R.J. Strife, J. Zirrolli, P.M. Henson, J.E. Henson, M.M. Mathias, J.T. Reeves, R.C. Murphy, and N.F. Voelkel. Leukotriene inhibitors attenuate rat lung injury induced by hydrogen peroxide., Am. Rev. Respir. Pis., 131: 778 (1985).Google Scholar
  24. 24.
    N. Suttorp and L.M. Simon. Lung cell oxidant injury: enhancement of polymorphonuclear leukocyte-mediated cytotoxicity in lung cells exposed to sustained in vitro hyperoxia., J. Clin. Invest., 70: 342 (1982).PubMedCrossRefGoogle Scholar
  25. 25.
    R.B. Fox, J.R. Hoidal, D.M. Brown, and J.E. Repine. Pulmonary inflammation due to oxygen toxicity: involvement of chemotactic factors and polymorphonuclear leukocytes., Am. Rev. Respir. Pis., 123: 521 (1981).Google Scholar
  26. 26.
    P.M. Shasby, R.B. Fox, R.N. Harada, and J.E. Repine. Reduction of the edema of acute hyperoxic lung injury by granulocyte depletion., J. Appl. Physiol., 52: 1237 (1982).PubMedGoogle Scholar
  27. 27.
    J.U. Raj and R.P. Bland. Neutrophil depletion does not prevent oxygen-induced lung injury in rabbits., Chest, 83: 20S (1983).Google Scholar
  28. 28.
    C.F. Nathan, H.W. Murray, and Z.A Conn. The macrophage as an effector cell., N Engl. J. Med., 303: 622 (1980).PubMedCrossRefGoogle Scholar
  29. 29.
    R.N. Harada, A.E. Vatter, and J.E. Repine. Macrophage effector function in pulmonary oxygen toxicity: hyperoxia damages and stimulates alveolar macrophages to make and release chemotaxins for polymorphonuclear leukocytes., J. Leukocyte Biol., 35: 373 (1984).PubMedGoogle Scholar
  30. 30.
    J.B. Chauncey, R.H. Simon, and M. Peters-Golden. Rat alveolar macrophages synthezize leukotriene B4 and 12-hydroxyeicosatetraenoic acid from alveolar epithelial cell-derived arachidonic acid., Am. Rev. Respir. Pis., 138: 928 (1988).CrossRefGoogle Scholar
  31. 31.
    J.R. Hageman, J. Zemaitia, R.B. Holtzman, S.E. Lee, L.J. Smith, and C.E. Hunt. Failure of nonselective inhibition of arachidonic acid metabolism to ameliorate hyperoxic lung injury., Prostaglandins, Leukotrienes, and Essential Fatty Acids, 32: 145 (1988).PubMedGoogle Scholar
  32. 32.
    L. Frank and E.E. Groseclose. Preparation for birth into an O2-rich environment: the antioxidant enzymes in the developing rabbit lung., Pediatr. Res., 18: 240 (1984).PubMedCrossRefGoogle Scholar
  33. 33.
    J. Yam, L. Frank, and R.J. Roberts. Oxygen toxicity: comparison of lung biochemical responses in neonatal and adult rats., Pediatr. Res., 12: 115 (1978).PubMedCrossRefGoogle Scholar
  34. 34.
    R.B. Holtzman, L. Adler, L.J. Smith, M. Shamsuddin, C.E. Hunt, and J.R. Hageman. Loss of oxygen tolerance in newborn rabbits: relationship to changes in eicosanoid and antioxidant levels., Pediatr. Pulmonol., 7: 200 (1989).PubMedCrossRefGoogle Scholar
  35. 35.
    R.B. Holtzman, J. Zemaitis, L. Adler, L.J. Smith, C.E. Hunt, and J.R. Hageman. Role of eicasanoids in relative oxygen tolerance of newborn rabbits., Prostaglandins, 37: 481 (1989).PubMedCrossRefGoogle Scholar
  36. 36.
    M.P. Mitchell Prostaglandins during pregnancy and the perinatal period., J. Reprod. Fertil., 62: 305 (1981).PubMedCrossRefGoogle Scholar
  37. 37.
    S. Cassin. Arachidonic acid metabolites and the pulmonary circulation of the fetus and newborn., In: S.M. MacLeod, A.B. Okey, and S.P. Speilberg (eds.). “Pevelopmental Pharmacology.” New York: Alan R. Liss, Inc., pp.227–250 (1983).Google Scholar
  38. 38.
    R.P. Goodman, A.P. Killam, A.R. Brash, and R.A Branch. Prostacyclin production during pregnancy: comparison of production during normal pregnancy and pregnancy complicated by hypertension., Am. J. Obstet. Gynecol., 142: 817 (1982).PubMedGoogle Scholar
  39. 39.
    M.L. Casey, S. Cutrer, and M.P. Mitchell. Origin of prostanoids in human amniotic fluid: The fetal kidney as a source of amniotic fluid prostanoids., Am. J. Obstet. Gynecol., 147: 547 (1983).PubMedGoogle Scholar
  40. 40.
    C.W. Leffler and J.R. Hessler. Perinatal pulmonary prostaglandin production., Am. J. Physiol., 24: H756 (1981).Google Scholar
  41. 41.
    C.W. Leffler, J.R. Hessler, and R.S. Green. Mechanism of stimulation of pulmonary prostacyclin synthesis at birth., Prostaglandins, 28: 877 (1984).PubMedCrossRefGoogle Scholar
  42. 42.
    R.H. Pemling. Role of prostaglandins in acute pulmonary microvascular injury., Ann. N.Y. Acad. Sci., 384: 517 (1982).CrossRefGoogle Scholar
  43. 43.
    J.E. Tateson, S. Moncada, and J.R. Vane. Effects of prostacyclin (PGX) on cyclic AMP concentrations in human platelets., Prostaglandins, 13: 389 (1977).PubMedCrossRefGoogle Scholar
  44. 44.
    M.L. Steer and E.W. Salzman. Cyclic nucleotides in hemostasis and thrombosis., Adv. Cyclic Nucleotide Res., 12: 71 (1980).PubMedGoogle Scholar
  45. 45.
    F.A. Kuehl, H.W. Dougherty, and E.A Ham. Interaction between prostaglandins and leuko-trienes., Biochem. Pharmacol., 33: 1 (1984).PubMedCrossRefGoogle Scholar
  46. 46.
    R.B. Holtzman, L. Adler, M. Shamsuddin, and J.R. Hageman. Iloprost infusion decreases mortality in fourteen day old rabbits exposed to hyperoxia for 96 hours., Pediatr. Res., 27: 307A (1990).Google Scholar
  47. 47.
    I.R.S. Sosenko, S.M. Innis, and L. Frank. Menhaden fish oil, n-3 polyunsaturated fatty acids, and protection of newborn rats from oxygen toxicity., Pediatr. Res., 25: 399 (1989).PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1991

Authors and Affiliations

  • Ronald B. Holtzman
    • 1
  • Joseph R. Hageman
    • 1
  1. 1.Evanston Hospital and Northwestern University Medical SchoolEvanstonUSA

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