Prostanoids and related mediators in gastric damage and disease

  • B. J. R. Whittle
  • J. L. Wallace


Endogenous metabolites of arachidonic acid, formed via the cyclo-oxygenase and lipoxygenase enzymic pathways (Figure 9.1) have been implicated as local mediators or modulators of gastric mucosal function and disease. Prostaglandins of the E and I series, PGE2 and prostacyclin respectively, are formed by gastric mucosal tissue1. These prostanoids can inhibit gastric acid secretion, stimulate gastric bicarbonate and mucus secretion, can induce vasodilation in the mucosal microcirculation and prevent the vascular stasis induced by damaging agents and can affect sodium and chloride ionic flux2-6. These prostanoids and their synthetic analogues protect the gastric mucosa from damage, an action which may be brought about by their effects on several of the above parameters1-6.


Gastric Mucosa Platelet Activate Factor Sodium Salicylate Gastric Damage Gastric Mucosal Damage 
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  1. 1.
    Whittle, B.J.R. and Vane, J.R. (1987). Prostanoids as regulators of gastrointestinal function. In Johnson, L.R. (ed.) Physiology of the Gastro-intestinal Tract, 2nd Edn pp. 143–80 (New York, Raven Press)Google Scholar
  2. 2.
    Robert, A. (1976). Antisecretory, antiulcer, cytoprotective and diarrheogenic properties of prostaglandins. In B. Samuelsson and J.R. Vane (eds) Advances in Prostaglandin and Thromboxane Research, 2, pp. 507–20 (Raven Press: New York)Google Scholar
  3. 3.
    Allen, A. and Garner, A. (1980). Mucus and bicarbonate secretion in the stomach and their possible role in mucosal protection. Gut, 21, 249–62PubMedCrossRefGoogle Scholar
  4. 4.
    Miller, T.A. (1983). Protective effects of prostaglandins against gastric mucosal damage: Current knowledge and proposed mechanisms. Am. J. Physiol., 245, G601-G623PubMedGoogle Scholar
  5. 5.
    Hawkey, C.J. and Rampton, D.S. (1985). Prostaglandins and the gastrointestinal mucosa: are they important in its function, disease, or treatment? Gastroenterology, 89, 1162–88PubMedGoogle Scholar
  6. 6.
    Robert, A., Nezamis, J.E., Lancaster, C. and Hanchar, A.J. (1979). Cytoprotection by prostaglandins in rats — prevention of gastric necrosis produced by alcohol, HC1, NaOH, hypertonic NaCl and thermal injury. Gastroenterology, 77, 433–43PubMedGoogle Scholar
  7. 7.
    Whittle, B.J.R., Kauffman, G.L. and Moncada, S. (1981). Vasoconstriction and thromboxane A2 induces ulceration of the gastric mucosa. Nature (London), 292, 472–74CrossRefGoogle Scholar
  8. 8.
    Rosam, A-C., Wallace, J.L. and Whittle, B.J.R. (1986). Potent ulcerogenic actions of platelet activating factor on the stomach. Nature (London), 319, 54–6CrossRefGoogle Scholar
  9. 9.
    Fitzpatrick, F.A. and Wynalda, M.A. (1976). In vivo suppression of prostaglandin biosynthesis by non-steroidal anti-inflammatory agents. Prostaglandins, 12, 1037–51PubMedCrossRefGoogle Scholar
  10. 10.
    Main, I.H.M. and Whittle, B.J.R. (1975). Investigation of the vasodilator and antisecretory role of prostaglandins in the rat gastric mucosa by use of non-steroidal anti-inflammatory drugs. Br. J. Pharmacol, 53, 217–24PubMedGoogle Scholar
  11. 11.
    Whittle, B.J.R., Higgs, G.A., Eakins, K.E., Moncada, S. and Vane. J.R. (1980). Selective inhibition of prostaglandin production in inflammatory exudates and gastric mucosa. Nature (London), 284, 271–3CrossRefGoogle Scholar
  12. 12.
    Konturek, S.J., Piastucki, I., Brzozowski, T., Radecki, T., Dembinskia-Kiec, A., Zmuda, A. and Gryglewski, R. (1981). Role of prostaglandins in the formation of aspirin-induced gastric ulcers. Gastroenterology, 80, 4–9PubMedGoogle Scholar
  13. 13.
    Ligumsky, M., Grossman, M.I. and Kauffman, G.L. Jr, (1982). Endogenous gastric mucosal prostaglandins: their role in mucosal integrity. Am. J. Physiol., 242, G337-G341PubMedGoogle Scholar
  14. 14.
    Whittle, B.J.R., Hansen, D. and Salmon, J.A. (1985). Gastric ulcer formation and cyclo-oxygenase inhibition in cat antrum follows parenteral administration of aspirin but not salicylate. Eur. J. Pharmacol., 115, 153–7CrossRefGoogle Scholar
  15. 15.
    Bunnett, N.W., Walsh, J.H., Debas, H.T., Kauffman, G.L. and Golanska, E.M. (1983). Measurement of prostaglandin E2 in the interstitial fluid from dog stomach after feeding and indomethacin. Gastroenterology, 85, 1391–8PubMedGoogle Scholar
  16. 16.
    Rainsford, K.D. and Willis, C. (1982). Relationship of gastric mucosal damage induced in pigs by anti-inflammatory drugs to their effects on prostaglandin production. Dig. Dis. Sci., 27, 624–35PubMedCrossRefGoogle Scholar
  17. 17.
    Konturek, S.J., Obtulowicz, W., Sito, E., Oleksy, J., Wilkon, S. and Kiec-Dembinska, A. (1981). Distribution of prostaglandins in gastric and duodenal mucosa of healthy subjects and duodenal ulcer patients: Effects of aspirin and paracetamol. Gut, 22, 283–9PubMedCrossRefGoogle Scholar
  18. 18.
    Cohen, M.M. and MacDonald, W.C. (1982). Mechanism of aspirin injury to the human gastroduodenal mucosa. Prost. Leuk. Med., 9, 241–55CrossRefGoogle Scholar
  19. 19.
    Boughton-Smith, N.K. and Whittle, B.J.R. (1983). Stimulation and inhibition of prostacyclin formation in the gastric mucosa and ileum in vitro by anti-inflammatory agents. Br. J. Pharmac., 78, 172–80Google Scholar
  20. 20.
    Bennett A., Stamford, I.F. and Unger, W.G. (1973). Prostaglandin E2 and gastric acid secretion in man. J. Physiol., 229, 349–60PubMedGoogle Scholar
  21. 21.
    Peskar, B.M. (1977). On the synthesis of prostaglandins by human gastric mucosa and its modification by drugs. Biochem. Biophys. Acta, 487, 307–14PubMedGoogle Scholar
  22. 22.
    Peskar, B.M., Weiler, H. and Peskar, B.A. (1982). Effects of BW 755C on prostaglandin synthesis in the rat stomach. Biochem. Pharmacol, 31, 1652–3PubMedCrossRefGoogle Scholar
  23. 23.
    Leonards, J.R. and Levy, G. (1973). Gastrointestinal blood loss from aspirin and sodium salicylate tablets in man. Clin. Pharmacol. Ther., 14, 62–6PubMedGoogle Scholar
  24. 24.
    Van Kolfscholten, A.A., Dembinska-Kiec, A. and Basista, M. (1981). Interaction between aspirin and paracetamol on the production of prostaglandins in the rat gastric mucosa. J. Pharm. Pharmacol., 33, 462–3CrossRefGoogle Scholar
  25. 25.
    Whittle, B.J.R. (1983). The potentiation of taurocholate-induced rat gastric erosions following parenteral administration of cyclo-oxygenase inhibitors. Br. J. Pharmac., 80, 545— 51Google Scholar
  26. 26.
    Whittle, B.J.R. (1977). Mechanisms underlying gastric mucosal damage induced by indo-methacin and bile salts, and the actions of prostaglandins. Br. J. Pharmacol., 60, 455–60PubMedGoogle Scholar
  27. 27.
    Lewi, H.J. and Carter, D.C. (1980). Intravenous prostaglandin synthetase inhibitors potentiate the effect of topical taurocholate on transmucosal ion flux. In Fielding, L.R. (ed.) Gastrointestinal Mucosal Blood Flow, pp. 192–201 (Churchill Livingstone: London)Google Scholar
  28. 28.
    Whittle, B.J.R. and Moncada, S. (1983). Ulceration induced by an endoperoxide analogue and by indomethacin in the canine stomach. In Samuelsson, B., Paoletti, R. and Ramwell, P. (eds.) Advances in Prostaglandin, Thromboxane and Leukotriene Research, 12, pp. 373–8 (Raven Press: New York)Google Scholar
  29. 29.
    Wallace, J.L. and Cohen, M.M. (1984). Gastric mucosal protection with chronic mild restraint: role of endogenous prostaglandins. Am. J. Physiol., 247, G127–132Google Scholar
  30. 30.
    Konturek, S.J., Brzozowski, T., Piastucki, I., Radecki, T., Dembinski, A. and Dembinska, A. (1982). Role of locally generated prostaglandins in adaptive gastric cytoprotection. Dig. Dis. Sci., 27, 967–71PubMedCrossRefGoogle Scholar
  31. 31.
    Robert, A., Nezamis, J.E., Lancaster, C., Davis, J.P., Field, S.O. and Hanchar, A.J. (1983). Mild irritants prevent gastric necrosis through ‘adaptive cytoprotection mediated by prostaglandins. Am. J. Physiol., 245, G113-G121PubMedGoogle Scholar
  32. 32.
    Wright, J.P., Young, G.O., Klaft, L.J., Weers, L.A., Price, S.K. and Marks, I.N. (1982). Gastric mucosal prostaglandin E levels in patients with gastric ulcer disease and carcinoma. Gastroenterology, 82, 263–267PubMedGoogle Scholar
  33. 33.
    Rachmilewitz, D., Branski, D., Sharon, P. and Karmeli, F. (1984). Possible role of endogenous prostanoids in the pathogenesis of peptic ulcer. In Allen, A., Flemstrom, G., Garner, A., Silen, W. and Turnberg, L.A. (eds.) Mechanisms of mucosal protection in the upper gastrointestinal tract, pp. 329–33 (Raven Press: New York)Google Scholar
  34. 34.
    Hillier, K., Smith, C.L., Jewell, R., Arthur, M.J.P. and Ross, G. (1985). Duodenal mucosa synthesis of prostaglandins in duodenal ulcer disease. Gut, 26, 237–240PubMedCrossRefGoogle Scholar
  35. 35.
    Whittle, B.J.R. and Moncada, S. (1983). The pharmacological interactions between prostacyclin and thromboxanes. Br. Med. Bull., 39, 232–8PubMedGoogle Scholar
  36. 36.
    Kauffman, G.L. and Whittle, B.J.R. (1982). Gastric vascular actions of prostanoids and the dual effect of arachidonic acid. Am. J. Physiol., 242, G582–587PubMedGoogle Scholar
  37. 37.
    Walus, K.M., Gustaw, P. and Konturek, S.J. (1980). Differential effects of prostaglandins and arachidonic acid on gastric circulation and oxygen consumption. Prostaglandins, 20, 1089–102PubMedCrossRefGoogle Scholar
  38. 38.
    Kauffman, G.L., Whittle, B.J.R. and Salmon, J.A. (1982). Gastric venous prostaglandin concentrations during basal and stimulated acid secretion in the dog. Proc. Soc. Exptl. Med., 169, 233–238Google Scholar
  39. 39.
    Guth, P.H., Paulson, G. and Nagata, H. (1984). Histologic and microcirculatory changes in alcohol-induced gastric lesions in the rat: Effect of prostaglandin cytoprotection. Gastroenterology, 87, 1083–90PubMedGoogle Scholar
  40. 40.
    Whittle, B.J.R., Oren-Wolman, N. and Guth, P.H. (1985). Gastric vasoconstrictor actions of leukotriene C4, PGF2a and thromboxane mimetic U-46619 on rat submucosal microcirculation in vivo. Am. J. Physiol., 248, G580-G586PubMedGoogle Scholar
  41. 41.
    Konturek, S.J., Brzozowski, T., Prastuki, I., Radecki, T. and Dembinska-Kiec, A. (1963). Role of prostaglandins and thromboxane biosynthesis in gastric necrosis produced by taurocholate and ethanol. Dig. Dis. Sci., 28, 154–60CrossRefGoogle Scholar
  42. 42.
    Whittle, B.J.R. (1984). Cellular mediators in gastric damage: actions of thromboxane A2 and its inhibitors. In Allen, A., Garner, A., Flemstrom, G., Silen, W. and Turnberg, L.A. (eds) Mechanisms of Mucosal Protection in the Upper Gastrointestinal Tract pp. 295–301 (Raven Press: New York)Google Scholar
  43. 43.
    Whittle, B.J.R., Kauffman, G.L. and Moncada, S. (1986). Hemostatic mechanisms, independent of platelet aggregation arrest gastric mucosal bleeding. Proc. Natl. Acad. Sci. USA, 83, 5683–7PubMedCrossRefGoogle Scholar
  44. 44.
    Palmer, R.M.J., Stepney, R., Higgs, G.A. and Eakins, K.E. (1980). Chemokinetic activity of arachidonic acid lipoxygenase products on leukocytes from different species. Prostaglandins, 20, 411–18PubMedCrossRefGoogle Scholar
  45. 45.
    Samuelsson, B., Hammarstrom, S., Murphy, R.C. and Borgeat, P. (1980). Leukotrienes and slow reacting substances of anaphylaxis (SRS-A). Allergy, 35, 373–81CrossRefGoogle Scholar
  46. 46.
    Piper, P.J. (ed.) (1986). The Leukotrienes. Their Biological Significance. (New York: Raven Press)Google Scholar
  47. 47.
    Morris, G.P. and Wallace, J.L. (1981). The roles of ethanol and of acid in the production of gastric mucosal erosions in rats. Virchow’s Arch. (Cell Pathol.), 38, 23–38CrossRefGoogle Scholar
  48. 48.
    Lacy, E.R. and Ito, S. (1982). Microscopic analysis of ethanol damage to rat gastric mucosa after treatment with a prostaglandin. Gastroenterology, 83, 619–625PubMedGoogle Scholar
  49. 49.
    Peskar, B.M., Lange, K., Hoppe, U. and Peskar, B.A. (1986). Ethanol stimulates formation of leukotriene C4 in rat gastric mucosa. Prostaglandins, 31, 283–293PubMedCrossRefGoogle Scholar
  50. 50.
    Boughton-Smith, N.K. and Whittle, B.J.R. (1987). Prostaglandin inhibition of ethanol-induced release of gastric mucosal leukotrienes. Gastroenterology, 92, 1325Google Scholar
  51. 51.
    Wallace, J.L. and Whittle, B.J.R. (1985). Role of prostanoids in the protective actions of BW 755C on the gastric mucosa. Eur. J. Pharmacol., 115, 45–52PubMedCrossRefGoogle Scholar
  52. 52.
    Benveniste, J. (1974). PAF — a new mediator of anaphylaxis and immune complex deposition from rabbit and human basophils. Nature (London), 249, 581–2CrossRefGoogle Scholar
  53. 53.
    Demopoulos, C.A., Pinckard, R.N. and Hanahan, D.J. (1979). Platelet-activating factor: evidence for l-0-alkyl-2-acetyl-sn-glyceryl-3-phosphorylcholine as the active component (a new class of lipid chemical mediators). J. Biol. Chem., 254, 9355–8PubMedGoogle Scholar
  54. 54.
    Braquet, P., Shen, T.Y., Touqui, L. and Vargaftig, B.B. (1987). Perspectives in platelet activating factor research. Pharmacol. Rev., 39, 97–145PubMedGoogle Scholar
  55. 55.
    Gonzalez-Crussi, F. and Hsueh, W. (1983). Experimental model of ischemic bowel necrosis. The role of platelet-activating factor and endotoxin. Am. J. Pathol., 112, 127–135PubMedGoogle Scholar
  56. 56.
    Wallace, J.L. and Whittle, B.J.R. (1986). Profile of gastrointestinal damage induced by platelet-activating factor. Prostaglandins, 32, 137–141PubMedCrossRefGoogle Scholar
  57. 57.
    Wallace, J.L. and Whittle, B.J.R. (1986). Picomole doses of platelet-activating factor predispose the gastric mucosa to damage by topical irritants. Prostaglandins, 31, 989–998PubMedCrossRefGoogle Scholar
  58. 58.
    Humphrey, D.M., McMannus, L.M., Satouchi, K., Hanahan, D.J. and Pinckard, R.N. (1982). Vasoactive properties of acetyl glyceryl ether phosphorylcholine and analogues. Lab. Invest., 46, 422–7PubMedGoogle Scholar
  59. 59.
    Whittle, B.J.R., Morishita, T., Ohya, T., Leung, F.W. and Guth, P.H. (1986). Microvascular actions of platelet-activating factor (PAF) on the rat gastric mucosa and submucosa. Am. J. Physiol., 251, 772–778Google Scholar
  60. 60.
    Doebber, J.W., Wu, M.S. and Shen, T.Y. (1984). Platelet activating factor intravenous infusion in rats stimulates vascular lysosomal hydrolase secretion independent of blood neutrophils. Biochem. Biophys. Res. Comm., 125, 980–987PubMedCrossRefGoogle Scholar
  61. 61.
    Steel, G., Wallace, J.L. and Whittle, B.J.R. (1987). Failure of prostaglandin E2 and its 16, 16-dimethyl analogue to prevent the gastric mucosal damage induced by PAF. Br. J. Pharmac., 90, 365–371Google Scholar
  62. 62.
    Wallace, J.L. and Whittle, B.J.R. (1986). Effects of inhibitors of arachidonic acid metabolism on PAF-induced gastric mucosal necrosis and haemoconcentration. Br. J. Pharmac., 89, 415–422Google Scholar
  63. 63.
    Shumer, W. (1979). Septic shock. J. Am. Med. Assoc., 242, 1906–7CrossRefGoogle Scholar
  64. 64.
    Bessin, P., Bonnet, J., Apffel, D., Soulard. C., Desgroux, L., Pelas, I. and Benveniste, J. (1983).Acute circulatory collapse caused by platelet-activating factor (PAF-acether) in dogs. Eur. J. Pharmacol., 86, 403–13PubMedCrossRefGoogle Scholar
  65. 65.
    Payne, J.G. and Bowen, J.C. (1981). Hypoxia of the canine gastric mucosa caused by Escherichia coli sepsis and prevented by methyl prednisolone therapy. Gastroenterology, 80, 84–9PubMedGoogle Scholar
  66. 66.
    Nicholson, D.P. (1982). Glucocorticoids in the treatment of shock and the adult respiratory distress syndrome. Clin. Chest Med., 3, 121–32PubMedGoogle Scholar
  67. 67.
    Flower, R.J. and Blackwell, G.J. (1979). Anti-inflammatory steroids induce biosynthesis of a phospholipase A2 inhibitor which prevents prostaglandin generation. Nature (London), 278, 456–9CrossRefGoogle Scholar
  68. 68.
    Mencia-Huerta, J.M. and Benveniste, J. (1979). Platelet-activating factor and macrophages, I. Evidence for the release from rat and mouse peritoneal macrophages and not from mastocytes. Eur. J. Immunol., 9, 409–15PubMedCrossRefGoogle Scholar
  69. 69.
    Doebber, T.W., Wu, M.S., Robbins, J.C., Choy, M., Chang, M.N. and Shen, T.Y. (1985). Platelet activating factor (PAF) involvement in endotoxin-induced hypotension in rats. Studies with PAF-receptor antagonist kadsurenone. Biochem. Biophys. Res. Comm., 127, 799–808PubMedCrossRefGoogle Scholar
  70. 70.
    Terashita, Z., Imura, Y., Nishikawa, K. and Sumida, S. (1985). Is platelet activating factor (PAF) a mediator of endotoxin shock? Eur. J. Pharmacol., 109, 257–261PubMedCrossRefGoogle Scholar
  71. 71.
    Wallace, J.L. and Whittle, B.J.R. (1986). Prevention of endotoxin-induced gastrointestinal damage by CV-3988, an antagonist of platelet-activating factor. Eur. J. Pharmac., 124, 209–10CrossRefGoogle Scholar
  72. 72.
    Wallace, J.L., Steel, G., Whittle, B.J.R., Lagente, V. and Vargeftig, B. (1987). Evidence for platelet-activating factor (PAF) as a mediator of endotoxin-induced gastro-intestinal damage in the rat: Effects of three PAF antagonists. Gastroenterology, 93, 765–773PubMedGoogle Scholar
  73. 73.
    Whittler, B.J.R., Boughton-Smith, N.K., Hutcheson, I.R., Espluges, J.V. and Wallace, J.L. (1987). Increased intestinal formation of Paf in endotoxin-induced damage in the rat. Br. J. Pharmacol., 92, 3–4Google Scholar
  74. 74.
    McCready, D.R., Clark, L. and Cohen, M.M. (1985). Cigarette smoking reduces human gastric luminal prostaglandin E2. Gut, 26, 1192–6PubMedCrossRefGoogle Scholar

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© MTP Press Limited 1988

Authors and Affiliations

  • B. J. R. Whittle
  • J. L. Wallace

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