Arachidonic acid peroxidation in inflammation and its inhibition as a mechanism for anti-inflammatory activity

  • G. Higgs
  • K. Eakins
Part of the Inflammation: Mechanisms and Treatment book series (FTIN, volume 4)


It is 10 years since arachidonic acid metabolism was first associated with the development of the inflammatory response. The detection of prostaglandin release in experimental inflammation1 and anaphylaxis2 initiated a series of experiments in which arachidonic acid peroxidation was demonstrated in numerous inflammatory conditions in animals and man. In parallel with these studies, prostaglandins were shown to have potent inflammatory properties. It is now generally accepted that prostaglandins, along with vasoactive amines and kinins are the most likely chemical mediators of vascular responses in acute and chronic inflammation3. An important stimulus to this area of research came with the discovery that aspirin and other non-steroid anti-inflammatory drugs selectively inhibit prostaglandin symthesis4–6. This led Vane to propose his now famous theory that inhibition of prostaglandin biosynthesis explains the therapeutic and toxic effects of aspirin-like drugs4. The other major group of anti-inflammatory drugs, the coricosteroids, do not have a direct effect on arachidonate metabolizing enzymes but they are thought to interfere with the release of fatty acids from phospholipids7-10. The role of prostaglandins in inflammation and the effects of prostaglandin synthetase inhibitors have been comprehensively reviewed by Ferreira and Vane11.


Arachidonic Acid Leukocyte Migration Arachidonic Acid Metabolism Prostaglandin Endoperoxide Lipoxygenase Product 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Willis, A. L. (1969). Release of histamine, kinin and prostaglandins during carrageenin-induced inflammation of the rat. In Mantegazza, P. and Horton, E. (eds.) Prostaglandins, Peptides and Amines, p. 65. (London Academic Press)Google Scholar
  2. 2.
    Piper, P. J. and Vane, J. R. (1969). Release of additional factors in anaphylaxis and its antagonism by anti-inflammatory drugs. Nature (London), 223, 29CrossRefGoogle Scholar
  3. 3.
    Ryan, G. B. and Majno, G. (1977). Acute inflammation. Am. J. Pathol., 86, 184Google Scholar
  4. 4.
    Vane, J. R. (1971). Inhibition of prostaglandin synthesis as a mechanism of action for the aspirin-like drugs. Nature (London), 231, 232Google Scholar
  5. 5.
    Smith, J. B. and Willis, A. L. (1971). Aspirin selectively inhibits prostaglandin production in human platelets. Nature (London), 231, 235Google Scholar
  6. 6.
    Ferreira, S. H., Moncada, S. and Vane, J. R. (1971). Indomethacin and aspirin abolish prostaglandin release from the spleen. Nature (London), 231, 237CrossRefGoogle Scholar
  7. 7.
    Gryglewski, R. J., Panczenko, B., Korbut, R., Grodzinska, L. and Ocetkiewicz, A. (1975). Corticosteroids inhibit prostaglandin release from perfused lungs of sensitized guinea-pigs. Prostaglandins, 10, 343PubMedGoogle Scholar
  8. 8.
    Hong, S. L. and Levine, L. (1976). Inhibition of arachidonic acid release from cells as the bio-chemical action of anti-inflammatory corticosteroids. Proc. Nat. Acad. Sci (USA)., 73, 1730CrossRefGoogle Scholar
  9. 9.
    Nijkamp, F. P., Flower, R. J., Moncada, S. and Vane, J. R. (1976). Partial purification of RCS-RF (rabbit aorta contracting substance releasing factor) and inhibition of its activity by anti-inflammatory steroids. Nature, (London), 263, 479CrossRefGoogle Scholar
  10. 10.
    Flower, R. J. and Blackwell, G. J. (1979). Anti-inflammatory steroids induce biosynthesis of a phospholipase A-, inhibitor which prevents prostaglandin generation. Nature (London), 278, 456CrossRefGoogle Scholar
  11. 11.
    Ferreira, S. H. and Vane, J. R. (1979). Mode of action of anti-inflammatory agents which are prostaglandin synthetase inhibitors. In Vane, J. R. and Ferreira, S. H. (eds.) Anti-inflammatory drugs. (50/II, 348) (Springer-Verlag)Google Scholar
  12. 12.
    Hamberg, M., Svensson, J., Wakabayashi, T. and Samuelsson, B. (1974). Isolation and structure of two prostaglandin endoperoxides that cause platelet aggregation. Proc. Natl. Acad. Sci (USA), 71, 345CrossRefGoogle Scholar
  13. 13.
    Hamberg, M., Svensson, J. and Samuelsson, B. (1975). Thromboxanes: A new group of biologically active compounds derived from prostaglandin endoperoxides. Proc. Natl. Acad. Sci. (USA), 72, 2994CrossRefGoogle Scholar
  14. 14.
    Moncada, S., Gryglewski, R. J., Bunting, S. and Vane, J. R. (1976). An enzyme isolated from arteries transforms prostaglandin endoperoxides to an unstable substance that inhibits platelet aggregation. Nature (London), 263, 663CrossRefGoogle Scholar
  15. 15.
    Moncada, S. and Vane, J. R. (1979). Pharmacology and endogenous roles of prostaglandin endoperoxides, thromboxane A2 and prostacyclin. Pharm. Rev., 30, 293Google Scholar
  16. 16.
    Hamberg, M. and Samuelsson, B. (1974). Prostaglandin endoperoxides. Novel transformations of arachidonic acid in human platelets. Proc. Natl. Acad. Sci. (USA)., 71, 3400CrossRefGoogle Scholar
  17. 17.
    Nugteren, D. A. Arachidonate lipoxygenase in blood platelets. (1975). Biochim. Biophys. Acta 380, 299PubMedGoogle Scholar
  18. 18.
    Hamberg, M. (1976). On the formation of thromboxane B2 and 12L-hydroxy-5, 8, 10, 14-eicosatetraenoic acid (12 ho — 20:4) in tissues from the guinea pig. Biochim. Biphys. Acta, 431, 651Google Scholar
  19. 19.
    Borgeat, P., Hamberg, M. and Samuelsson, B. (1976). Transformation of arachidonic acid and dihomo-γ-linolenic acid by polymorphonuclear leukocytes. J. Biol. Chem., 251, 7816PubMedGoogle Scholar
  20. 20.
    Murphy, R. C., Hammarstrom, S. and Samuelsson, B. Leukotriene C: A slow-reacting substance from murine mastocytoma cells. Proc. Natl. Acad. Sci. (USA), 76, 4275Google Scholar
  21. 21.
    Hamberg, M. and Samuelsson, B. (1967). On the mechanism of the biosynthesis of prostaglandins E, and F1α, J. Biol. Chem., 242, 5336PubMedGoogle Scholar
  22. 22.
    Nugteren, D. H., Beerthuis, R. K. and Dorp, D. A. van. (1966). The enzymatic conversion of all-cis 8, 11, 14-eicosatrienoic acid into prostaglandin E1. Rec. Trav. Chim. Pays-Bas., 85, 405CrossRefGoogle Scholar
  23. 23.
    Higgs, G. A., Bunting, S., Moncada, S. and Vane, J. R. (1976). Polymorphonuclear leukocytes produce thromboxane A2-like activity during phagocytosis. Prostaglandins, 12, 749PubMedCrossRefGoogle Scholar
  24. 24.
    Goldstein, I. M., Malmsten, C. L., Kaplan, H. B., Jindahl, H., Samuelsson, B. and Weissman, G. (1977). Thromboxane generation by stimulated human granulocytes. Inhibition by glucocorticoids and superoxide dismutase. Clin. Res., 25, 518AGoogle Scholar
  25. 25.
    Davison, E.M., Ford-Hutchinson, A. W., Smith, M. J. H. and Walker, J.R. (1978). The release of thromboxane B2 by rabbit peritoneal polymorphonuclear leukocytes. Br. J. Pharmacol., 63, 407PGoogle Scholar
  26. 26.
    Brune, K., Glatt, M. and Kalin, H. (1978). Pharmacological control of prostaglandin and thromboxane release from macrophages. Nature (London), 274, 261CrossRefGoogle Scholar
  27. 27.
    Murota, S-I., Kawamura, M. and Morita, I. (1978). Transformation of arachidonic acid into thromboxane B2 by the homogenates of activated macrophages. Biochim. Biophys. Acta, 528, 507PubMedGoogle Scholar
  28. 28.
    Chang, W.C., Murota, S-I. and Tsurufuji, S. (1977). Thromboxane B2 transformed from arachidonic acid in carrageenin-induced granuloma. Prostaglandins, 13, 17PubMedCrossRefGoogle Scholar
  29. 29.
    Salmon, J. A., Smith, D.R., Flower, R.J., Moncada, S. and Vane, J.R. (1978). Further studies on the enzymatic conversion of prostaglandin endoperoxide into prostacyclin by porcine aorta microsomes. Biochim. Biophys. Acta, 523, 250PubMedGoogle Scholar
  30. 30.
    Humes, J. L., Bonney, R. J., Peius, L., Dahlgren, M. E., Sadowski, S. J., Kuehl, F. A. and Davies, P. (1977). Macrophages synthesise and release prostaglandins in response to inflammatory stimuli. Nature (London), 269, 149CrossRefGoogle Scholar
  31. 31.
    Chang, W. C., Murota, S-I., Matuso, M. and Tsurufuji, S. (1976). A new prostaglandin transformed from arachidonic acid in carrageenin-induced granuloma. Biochem. Biophys. Res. Commun., 72, 1259PubMedCrossRefGoogle Scholar
  32. 32.
    Johnson, R. A., Morton, D. R., Kinner, J. H., Gorman, R. R., McGuire, J. C., Sun, F. F., Whittaker, N., Bunting, S., Salmon, J. A., Moncada, S. and Vane, J. R. (1976). The chemical structure of prostaglandin X (prostacyclin). Prostaglandins, 12, 915PubMedCrossRefGoogle Scholar
  33. 33.
    Higgs, G. A. and Salmon, J. A. (1979). Cyclo-oxygenase products in carrageenin-induced inflammation. Prostaglandins, 17, 737CrossRefGoogle Scholar
  34. 34.
    Trang, L. E., Granstrom, E. and Lovgren, O. (1977). Levels of prostaglandin F2α and E2 and thromboxane B2 in joint fluid in rheumatoid arthritis. Scand. J. Rheum., 6, 151PubMedCrossRefGoogle Scholar
  35. 35.
    Dusting, G. J., Moncada, S. and Vane, J. R. (1978). Vascular actions of arachidonic acid and its metabolites in perfused mesenteric and femoral beds of the dog. Eur. J. Pharmacol., 49, 65PubMedCrossRefGoogle Scholar
  36. 36.
    Armstrong, J. M., Lattimer, N., Moncada, S. and Vane, J. R. (1978). Comparison of the vasodepressor effects of prostacyclin and 6-oxo-prostaglandin F1α with those of prostaglandin E2 in rats and rabbits. Br. J. Pharmacol., 62, 125PubMedGoogle Scholar
  37. 37.
    Whittle, B. J. R., Boughton-Smith, N. K., Moncada, S. and Vane, J. R. (1978). Actions of protacyclin (PGI2) and its product, 6-oxo-PGF1α on the rat gastric mucosa in vivo and in vitro Prostaglandins, 15, 955PubMedCrossRefGoogle Scholar
  38. 38.
    Williams, T. J. (1979). Prostaglandin E2, prostaglandin I2 and the vascular changes of inflammation. Br. J. Pharmacol., 65, 517PubMedGoogle Scholar
  39. 39.
    Higgs, G.A., Cardinal, D.C., Moncada, S. and Vane, J. R. (1979). Mircrocirculatory effects of prostacyclin (PGI2) in the hamster cheek pouch. Microvasc. Res., 18, 245PubMedCrossRefGoogle Scholar
  40. 40.
    Williams, T.J. and Peck, M.J. (1977). Role of prostaglandin-mediated vasodilation in inflammation. Nature (London), 270, 530CrossRefGoogle Scholar
  41. 41.
    Williams, T. J. and Morley, J. (1973). Prostaglandins as potentiators of increased vascular permeability in inflammation. Nature (London), 246, 215CrossRefGoogle Scholar
  42. 42.
    Moncada, S., Ferreira, S. H. and Vane, J. R. (1973). Prostaglandins, aspirin-like drugs and the oedema of inflammation. Nature (London), 246, 217CrossRefGoogle Scholar
  43. 43.
    Higgs, E.A., Moncada, S. and Vane, J. R. (1978). Inflammatory effects of prostacyclin (PGI2) and 6-oxo-PGF1α in the rat paw. Prostaglandins, 16, 153PubMedCrossRefGoogle Scholar
  44. 44.
    Komoriya, K., Ohmori, H., Azuma, A., Kurozumi, S., Hashimoto, Y., Nicolaou, K. C., Barnette, W. E. and Magolda, R. L. (1978). Prostaglandin I2 as a potentiator of acute inflammation in rats. Prostaglandins, 15, 557PubMedCrossRefGoogle Scholar
  45. 45.
    Ferreira, S. H. (1972). Prostaglandins, aspirin-like drugs and analgesia. Nature (London), 240, 200CrossRefGoogle Scholar
  46. 46.
    Moncada, S., Ferreira, S. H. and Vane, J. R. (1974). Sensitization of pain receptors of dog knee joint by prostaglandins. In Robinson, H. J. and Vane, J. R. (eds.) Prostagandin Synthetase Inhibitors, p. 189. (New York: Raven Press)Google Scholar
  47. 47.
    Ferreira, S. H., Nakamura, M. and Abreu Castro, M. S. (1978). The hyperalgesic effects of protacyclin and PGE2. Prostaglandins, 16, 31PubMedCrossRefGoogle Scholar
  48. 48.
    Rivkin, I., Rosenblatt, J. and Becker, E. L. (1974). The role of cyclic AMP in the chemotactic responsiveness and spontaneous motility of rabbit peritoneal neutrophils. J. Immunol., 115, 1126Google Scholar
  49. 49.
    Tateson, J. E., Moncada, S. and Vane, J. R. (1977). Effects of prostacyclin (PGX) on cyclic AMP concentrations in human platelets. Prostaglandins, 13, 389PubMedCrossRefGoogle Scholar
  50. 50.
    Gorman, R. R., Bunting, S. and Miller, O. V. (1977). Modulation of human platelet adenylate cyclase by prostacyclin (PGX). Prostaglandins, 13, 377PubMedCrossRefGoogle Scholar
  51. 51.
    Weksler, B.B., Knapp, J. M., and Jaffe, E. A. (1977). Prostacyclin (PGI2) synthesised by cultured endothelial cells modulates polymorphonuclear leukocyte function. Blood, 50, (Suppl. 1), 287Google Scholar
  52. 52.
    Higgs, G. A., Moncada, S. and Vane, J. R. (1978). Prostacyclin reduces the number of ‘slow moving’ leukocytes in hamster cheek pouch venules. J. Physiol., 280, 55PGoogle Scholar
  53. 53.
    Moncada, S. and Vane, J. R. (1978). Unstable metabolites of arachidonic acid and their role in haemostasis and thrombosis. Br. Med. Bull, 34, 129PubMedGoogle Scholar
  54. 54.
    Moncada, S., Needleman, P., Bunting, S. and Vane, J. R. (1976). Prostaglandin endoperox-ide and thromboxane generating systems and their selective inhibition. Prostaglandins, 12, 323PubMedCrossRefGoogle Scholar
  55. 55.
    Kitchen, E. A., Boot, J. R. and Dawson, W. (1978). Chemotactic activity of thromboxane B2, prostaglandins and their metabolitcs for polymorphonuclear leukocytes. Prostaglandins, 16, 239PubMedCrossRefGoogle Scholar
  56. 56.
    Goetzl, E.J. and Gorman, R. R. (1978). Chemotactic and chemokinetic stimulation of human eosinophil and neutrophil polymorphonuclear leukocytes by 12-L-hydroxy-5, 8, 10-heptadecatrienoic acid (HHT). J. Immunol., 120, 526PubMedGoogle Scholar
  57. 57.
    Kuehl, F.A., Humes, J.L., Egan, R.W., Ham, E.A., Beveridge, G.C. and Van Arman, C. G. (1977). Role of prostaglandin endoperoxide PGG2 in inflammatory processes. Nature (London), 265, 170CrossRefGoogle Scholar
  58. 58.
    Moncada, S. (1979). New developments in the knowledge of arachidonic acid metabolic products in inflammation. Eur. J. Rheum. Inflam., 2, 90Google Scholar
  59. 59.
    McCarty, J. and Goetzl, E. J. (1979). Stimulation of human T-lymphocyte chemokinesis by arachidonic acid. Cell Immunol., 43, 103PubMedCrossRefGoogle Scholar
  60. 60.
    Ubatuba, F. B., Harvey, E. A. and Ferreira, S. H. (1975). Are platelets important in inflammation? Agents Actions, 5, 31PubMedCrossRefGoogle Scholar
  61. 61.
    Samuelsson, B., Borgeat, P., Hammarstrom, S. and Murphy, R. C. (1979). Introduction of a nomenclature: Leukotrienes. Prostaglandins, 17, 785PubMedCrossRefGoogle Scholar
  62. 62.
    Hammarstrom, S., Murphy, R. C., Samuelsson, B., Clark, D. A., Mioskowski, C. and Corey, E.J. (1979). Structure of Leukotriene C: Identification of the amino acid part. Biochem. Biophys. Res. Commun, 91, 1266PubMedCrossRefGoogle Scholar
  63. 63.
    Bragt, P. C. and Bonta, I. L. (1979). In vivo metabolism of [1–14C] arachidonic acid during different phases of granuloma development in the rat. Biochem. Pharmacol., 28, 1581PubMedCrossRefGoogle Scholar
  64. 64.
    Hammarstrom, S., Hamberg, M., Samuelsson, B., Duell, E. A., Stawiski, M. and Voorhees, J. J. (1975), Increased concentrations of non-esterified arachidonic acid, 12L-hydroxy 5, 8, 10, 14-eicosatetraenoic acid, prostaglandin E2 and prostaglandin F2α in epidermis of psoriasis. Proc. Natl. Acad. Sci. (USA), 72, 5130CrossRefGoogle Scholar
  65. 65.
    Voorhees, J. J., Duell, E. A., Anderson, T. and Stawiski, M. Glucocorticoid reduces the elevated arachidonic acid and 12L-hydroxy-5, 8, 10, 14-eicosatetraenoic acid levels in involved psoriasis epidermis. Fed. Proc., (In press)Google Scholar
  66. 66.
    Borgeat, P. and Samuelsson, B. (1979). Arachidonic acid metabolism in polymorphonuclear leukocytes: Effects of ionophore A23187. Proc. Natl. Acad. Sci (USA), 76, 2148CrossRefGoogle Scholar
  67. 67.
    Turner, S. R., Tainer, J. A. and Lynn, W. S. (1975). Biogenesis of chemotactic molecules by the arachidonate lipoxygenase system of platelets. Nature (London), 257, 680CrossRefGoogle Scholar
  68. 68.
    Goetzl, E. J., Woods, J. M. and Gorman, R. R. (1977). Stimulation of human eosinophil and neutrophil polymorphonoclear leukocyte Chemotaxis and random migration by 12-L-Hydroxy-5, 8, 10, 14-eicosatetraenoic acid. J. Clin. Invest., 59, 179PubMedCrossRefGoogle Scholar
  69. 69.
    Goetzl, E. J., Brash, A. R., Oates, J. A. and Hubbard, W. C. (1979). Functional determinants of the monohydroxy eicosatetraenoic acids (HETEs) which stimulate human neutrophil and eosinophil Chemotaxis. Fed. Proc, 38, 1085Google Scholar
  70. 70.
    Palmer, R. M. J., Salmon, J. A., Narumiya, S., Higgs, G. A. and Eakins, K. E. (1980). Arachidonic acid metabolism by lipoxygenase in leukocytes of different species and the chemokinetic activity of some products. This volume, Chap. 35Google Scholar
  71. 71.
    Ford-Hutchinson, A. W., Bray, M. A. and Smith, M. J. H. (1980). Are there biologically active products of lipoxygenase pathways produced by polymorphonuclear leucocytes? This volume, Chap. 34Google Scholar
  72. 72.
    Austen, K. (1978). Homeostasis of effector systems which can also be recruited for imuno-logic reactions. J. Immunol. 121, 793PubMedGoogle Scholar
  73. 73.
    Eakins, K.E., Higgs, G. A., Moncada, S., Mugridge, K. G. and Vane, J. R. (1980). The effects of indomethacin and B W755C on leukocyte migration and prostaglandin production in carrageenin-induced inflammation. Br. J. Pharmacol. 69, 270Google Scholar
  74. 74.
    Eakins, K.E., Higgs, G. A., Moncada, S. and Mugridge, K. G. (1980). Non-steroid antiinflammatory drugs which potentiate leukocyte migration in carrageenin-induced inflammation. Br. J. Pharmacol. 70, 182Google Scholar
  75. 75.
    Adams, S.S., Burrows, C. A., Skeldon, N. and Yates, D.B. (1977). Inhibition of prostaglandin synthesis and leukocyte migration by flurbiprofen. Cur. Med. Res., 5, 11CrossRefGoogle Scholar
  76. 76.
    Siegel, M. I., McConnel, R. T. and Cuatrecasas, P. (1979). Aspirin-like drugs interfere with arachidonate metabolism by inhibition of the HPETE peroxidase activity of the lipoxygenase pathway. Proc. Natl. Acad. Sci. (USA)., 76, 3774CrossRefGoogle Scholar
  77. 77.
    Siegel, M. I., McConnell, R.T., Porter, N. A., Selph, J.L., Truax, J.D., Vinegar, R. and Cuatrecasas, P. (1980). Aspirin-like drugs inhibit arachidonic acid metabolism via lipoxygenase and cyclo-oxygenase in rat neutrophils from carrageenin pleural exudates. This volume, Chap. 36Google Scholar
  78. 78.
    Higgs, G. A., Flower, R. J. and Vane, J. R. (1979). A new approach to anti-inflammatory drugs. Biochem. Pharmacol., 28, 1959PubMedCrossRefGoogle Scholar
  79. 79.
    Radmark, O., Malmsten, C. and Samuelsson, B. (1980). The inhibitory effects of BW755C on arachidonic acid metabolism in human polymorphonuclear leukocytes. FEBS Lett 110, 213PubMedCrossRefGoogle Scholar
  80. 80.
    Walker, J. R. and Dawson, W. (1980). Inhibitory effect of benoxaprofen and BW755C on rabbit PMN leucocyte lipoxygenase. This volume, Chap. 38Google Scholar
  81. 81.
    Meacock, S. C. R. and Kitchen, E. A. (1979). Effects of the non-steroid anti-inflammatory drug benoxaprofen on leukocyte migration. J. Pharm. Pharmacol, 31, 366PubMedCrossRefGoogle Scholar

Copyright information

© MTP Press Limited 1980

Authors and Affiliations

  • G. Higgs
    • 1
  • K. Eakins
    • 1
  1. 1.UK

Personalised recommendations