Role of leukotrienes and platelet activating factor in gastric mucosal damage and repair

• Autorzy: Konturek S.J. , Brzozowski T.
• Języki publikacji: EN

Abstrakty

EN

Gastric mucosal integrity depends upon the balance between „aggressive” factors and „defensive” mechanisms. The formation of mucosal lesions results from the disruption of defense lines, including the breaking of unstirred mucus layer, the reduction of surface hydrophobicity, extensive exfoliation of surface epithelium, penetration of offending agents deeply into the mucosa and damage to the microvessels. The release of proinflam- matory and vasoactive mediators such as leukotrienes (LT), thromboxanes, platelet activating factor (PAP), endothelins and others has been thought to be involved in the pathomechanism of mucosal injury, especially damage to the micro vascular endothelium, increased vascular permeability, reduction in mucosal blood flow, vascular stasis, tissue ischemia and glandular cell necrosis. This paper reviews the mechanisms and possible pathogenetic implication of two related compounds, LT and PAP in acute mucosal injury by topical irritants such as ethanol, aspirin, bile salts and by stress. LT and PAP arise from similar membrane phospholipids and may regulate the biosynthesis of one another in the damaged mucosa. Although pharmacological studies have clearly demonstrated the noxious effects of cysteinyl LT and PAP on the mucosa, especially when exposed to topical irritants, recent publications have challenged the primary role of these mediators in the pathogenesis of mucosal lesions and ulcerations because the treatment with agents that selectively antagonize their biosynthesis or the receptor sites at the target cells did not always interrupt the chain of events leading to mucosal injury. The role of these mediators in the mucosal repair processes has been little studied but both cysteinyl LT and PAP seem to delay the restitution and healing of the mucosa. Further studies are necessary to clarify to what extent the biosynthesis of LT and PAP and the pharmacological inhibition of their action on the target tissues is related to noxious, protective and reparative events in the mucosa exposed to mild irritants and ulcerogens.

Słowa kluczowe

EN

cytoprotection; microvasculature; phospholipid; leukotriene; platelet-activating factor; gastric mucosal damage; repair

• Wydawca: -
• Czasopismo: Journal of Physiology and Pharmacology
• Rocznik: 1991
• Tom: 42
• Numer: 2
• Opis fizyczny: p.107-133,fig.,ref.

Twórcy

autor

Konturek S.J.

• Institute of Physiology, Academy of Medicine, Grzegorzecka 16, 31-531 Krakow, Poland

autor

Brzozowski T.

• Institute of Physiology, Academy of Medicine, Grzegorzecka 16, 31-531 Krakow, Poland

Bibliografia

• 1. Robert A. Cytoprotection by prostaglandins. Gastroenterology 1979; 77: 761-767.
• 2. Robert A, Nezamis BE, Lancaster C, Hanchar A. Cytoprotection by prostaglandins in rats: prevention of gastric necrosis produced by alcohol, HC1, NaOH, hypertonic NaCl and thermal injury. Gastroenterology 1979; 77: 433-443.
• 3. Davenport H. The gastric mucosal barrier. Past, present and future. Mayo Cain Proc 1975; 50: 507-514.
• 4. Hollander D, Tarnawski AS (eds). Gastric Cytoprotection. New York; Plenum 1989.
• 5. Lacy DR, Ito S. Microscopic analysis of ethanol damage to rat gastric mucosa after treatment with a prostaglandins. Gastroenterology 1982; 83: 619-625.
• 6. Lacy DR, Ito S. Rapid epithelium restitution on the rat gastric mucosa after ethanol injury. Lab Invest 1984; 51: 573-583.
• 7. Wallace J. Increased resistance of the rat gastric mucosa to hemorrhagic damage after exposure to an irritant. Role of the „mucoid cap” and prostaglandins synthesis. Gastroenterology 1988; 94: 22-32.
• 8. Wallace J. McKnight G. The mucoid cap over superficial gastric damage in the rat. A high-pH microenviroment dissipated by nonmaterial anti-inflammatory drugs and endothelin. Gastroenterology 1990; 99: 295-304.
• 9. Guth PH, Paulsen G, Nagata H. Histology and microcirculatory changes in alcohol-induced gastric lesions in the rat: Effect of prostaglandins cytoprotection. Gastroenterology 1984; 87: 1083-1090.
• 10. Szabo S, Trier AS, Brown A, Schnoor J. Early vascular injury and increased vascular permeability in gastric mucosal injury caused by ethanol in rat. Gastroenterology 1985; 88: 1948-1953.
• 11. Szabo S, Phial G, Trier AS. Alterations in blood vessels during gastric injury and protection. Scand J Gastroenterology 1986; 21: S92-96.
• 12. Pihan G, Majzoubi D, Handenschild C, Trier AS, Szabo S. Early microcirculatory stasis in acute gastric mucosal injury in the rat and prevention by 16, 16-dimethyl prostaglandin E2 or sodium thiosulfate. Gastroenterology 1986; 91: 1415-1426.
• 13. Wallace JR. Endogenous Mediators of Gastrointestinal Diseases. Boca Raton; CRC 1989.
• 14. Hamberg M, Samuelsson B. Prostaglandin endoperoxides; Novel transformation of arachidonic acid in human platelets. Proc Natl Acad Sci USA 1974; 71: 3400- 3408.
• 15. Samuelsson B. The Leukotrienes: Mediators of immediate hypersensitivity reactions and inflammations. Science 1983; 220: 568-575.
• 16. Lewis RA, Austen KF. The biologically active leukotrienes. Biosynthesis metabolism, receptors, functions and pharmacology. J Clin Invest 1984; 73: 889-910.
• 17. Goldenberg MM, Subers EM. The reactivity of rat isolated gastrointestinal tissues to leukotrienes. Eur J Pharmacol 1982; 78: 463-470.
• 18. Whittle ВJR, Oren-Woman, Guth PH. Gastric vasoconstrictor actions of leukotriene C₄ , PG₂ and thromboxane mimetic V-46619 on rat submucosal microcirculation un vivo. Am J Physiol 1985; 248: G580-586.
• 19. Pawlik W, Konturek S, Gustaw P, Sendur R, Czarnobilski K, Beck G, Jendralla M. Gastric vasoconstrictive and secretory effects of leukotrienes C₄ and D₄ in canine stomach. In Samuelsson B, Paoletti R, Ramwell (eds) Advances in Prostaglandin, Thromboxane and Leukotriene Research, Vol. 17, New York, Raven 1987, pp. 357-360,
• 20. Konturek S, Bilski J, Dembiński A, Warzecha Z, Beck G, Jendralla H. Effects of leukotrienes on gastric acid and alkaline secretions. Gastroenterology 1987; 92: 1209-1214.
• 21. Schepp W, Kath D, Tatge C et al. Leukotrienes C and D potentiate acid production by isolated rat parietal cells. Gastroenterology 1989; 97: 1420-1429.
• 22. Pihan G, Rogers C, Szabo S. Vascular injury in acute gastric mucosal damage. Mediatory role of leukotrienes. Dig Dis Sci 1988; 33: 625-632.
• 23. Konturek S, Brzozowski T, Drozdowicz D, Beck G. Role of leukotrienes in acute gastric lesions induced by ethanol, taurocholate, aspirin, platelet activating factor and stress in rats. Dig Dis Sci 1988; 33: 806-813.
• 24. Oates P, Hakkinen UP. Studies on the mechanism of ethanol-induced gastric damage in rats. Gastroenterology 1988; 94: 10-21.
• 25. Peskar AM, Lange K, Hope V, Peskar BA. Ethanol stimulates formation of leukotrienes C₄ in rat gastric mucosa. Prostaglandins 1986; 31: 283-292.
• 26. Wallace J, Beck PL, Morris GP. Is there a role for leukotrienes as mediators of ethanol-induced gastric mucosal damage? Am J Physiol 1988; 254: G117-123.
• 27. Boughton-Smith NK, Whittle В JR. Failure of the inhibition of rat gastric mucosal 5-lipoxygenase by novel acetohydroxamic acids to prevent ethanol-induced damage. Eur J Pharmacol 1988; 95: 155-162.
• 28. Wallace J, Whittle BJR. Role of prostanoids in the protective actions of BW755c on the gastric mucosa. Eur J Pharmacol 1985; 115: 45-52.
• 29. Konturek S, Brzozowski T, Drozdowicz, Garlicki J, Beck G. Role of leukotrienes and platelet activating factor in acute gastric mucosal lesions in rats. Eur J Pharmacol 1989; 164: 285-292.
• 30. Peskar BM. Leukotrienes in mucosal damage and protection. J Physiol Pharmacol 1991; 42: 135-145
• 31. Peskar BM, Hoppe V, Lange K, Peskar BA. Effects of non-steroidal antiinflammatory drugs on rat gastric mucosal leukotriene C₄ and prostaglandin release relation to ethanol - induced injury. Br J Pharmacol 1988; 93: 937-943.
• 32. Peskar BM. Lipooxygnase products in gastric damage and protection. Adv Prostaglandin Thromboxane Leukotriene Res 1990; 21: 753-760.
• 33. Holzer P, Pabst MA, Lippe IT, et al. Afferent nerve-mediated protection against deep mucosal damage in the rat stomach. Gastroenterology 1990; 98: 838-848.
• 34. Osada T, Goto H, Tsukamoto Y, et al. Role of leukotrienes in hydrochloric acid-induced gastric lesions in rats. Dig Dis Sci 1990; 35: 186-192.
• 35. Wallace JL, McKnight GW, Keenan CM, et al. Effects of leukotrienes on susceptibility of the rat stomach to damage and investigation of the mechanism of action. Gastroenterology 1990; 98: 1178-1186.
• 36. Wallace JL. Lipid mediators of inflammation in gastric ulcer. Am J Physiol 1990; 258: Gl-Gll.
• 37. Wallace JL, Whittle BJR. Acceleration of recovery of gastric epithelial integrity by 16,16 dimethyl prostaglandin E₂. Br J Pharmacol 1985; 86: 837-842.
• 38. Schmidt KL, Bellard RL, Smith GS, Hanagan JM, Miller TA. Influence of prostaglandin on repair of rat stomach damaged by absolute ethanol. J Surg Res 1986; 41: 367-377.
• 39. Kuroiwa M, Sugiyama S, Goto H, et al. The role of mucosal prostaglandin levels in healing of water immersion induced gastric ulcers in rats. Scand J Gastroenterol 1990; 25: 59-65.
• 40. Brzozowski T, Drozdowicz D, Konturek SJ et al. Leukotrienes in healing of acute gastric lesions induced by water immersion and restraint stress. Digestion (in publication)
• 41. Benveniste J. PAF-a new mediator of anaphylaxis and immune complex deposition from rabbit and human basophlis. Nature 1974; 249: 581-582.
• 42. Chignard M, LeCouedic IP, Tence M, Vargaftig BB, Benveniste J. The role of PAF in platelet aggregation. Nature 1979; 279: 799.
• 43. Lynch IM, Lotner G, Betz S, Henson PM. The release of a platelet activating factor by stimulated rabbit neutrophiles. J Immun 1979; 123: 1219.
• 44. Chilton FH, O’Flattery IT, Wash CE, Thomas MJ, Wykle RL, Dechatelet IR, Waite BM. Platelet activating factor. Stimulation of the lipoxygenase pathway in polymorphonuclear leukocytes by l-0-ally-2-0-acetic-ns-glycerin-3-phosphocholine. J Biol Chem 1982; 257: 5402-5407.
• 45. Blackwell G, Carnuccio R, Dirks M, Flower R, Parent L, Perish P. Macrocortin: a polypeptide causing the anti-phospholipase effect of glucocortycoids. Nature 1980; 287: 147-149.
• 46. Wallace IL. Glucocortycoids-induced gastric mucosal damage: Inhibition of leukotriene, but not prostaglandin biosynthesis. Prostaglandins 1987; 34: 311-323.
• 47. Heymans F, Michel E, Borrel W et al. New total synthesis and high resolution HNMR spectrum of platelet activating factor; its enantiomer and racemic mixture. Biochim Biophys Acta 1981; 666: 230-240.
• 48. Flower RJ, Blackwell GJ Anti-inflammatory steroids induce biosynthesis of a phospholipase A₂ inhibitor which prevents prostaglandin generation. Nature 1979; 278: 456-459.
• 49. Whittle BJR, Morisiten T, Ohya Y, Lung F, Guth PH. Microvascular actions of platelet activating factor on rat gastric mucosa and submucosa. Am J Physiol 1986; 251: 6722-6778
• 50. Terashita Z, Imura Y, Nishikawa K, Sumida S. Is platelet activating factor (PAF) a mediator of endotoxin shock? Eur J Pharmacol 1985; 109: 257-262.
• 51. Wallace JL, Steel G, Whittle BJR, Lagemente V, Vargaftic B. Evidence for platelet activating factor as a mediator of endotoxin-induced gastrointestinal damage in the rat: effects of three platelet-activating factor antagonists. Gastroenterology 1987; 93: 765-773.
• 52. Doebber TW, Wu MS, Robbins IC, Choy BM, Chang MN, Shen TY. Platelet activating factor (PAF) involvement in endotoxin-induced hypotension in rats. Studies with PAF-receptor antagonist kadsurenone. Biochem Biophys Res Comm 1985; 127: 799-802.
• 53. Wallace JL, Whittle BJR. Prevention of endotoxin-induced gastrointestinal damage by TV-3988 an antagonist of platelet activating factor. Eur J Pharmacol 1986; 124: 209-210.
• 54. Wallace JL, Whittle BJR. Gastrointestinal damage induced by platelet activating factor. Inhibition by the corticoid, dexamethasone. Dig Dis Sci 1988; 33: 225-232.
• 55. Braquet P, Paubert-Braquet M, Bessin P, Vargaftig B. Platelet activating factor a potential mediator of shock. In; Samuelsson В (ed) Advances in Prostaglandin, Thromboxane and Leukotrienes Research. New York, Raven 1986; 17 pp. 823-829.
• 56. Braquet P, Paubert-Braquet M, Koltai M, Bourgain R, Bussolino F, Hosford D. Is there a case for PAF antagonists in the treatment of ischemic states? TiPS 1989; 10: 23-30.
• 57. Rosam AC, Wallace JL, Whittle В JR. Potent ulcerogenic actions of platelet activating factor on the stomach. Nature 1986; 319: 54-56.
• 58. Etienne A, Hecquet F, Soulard C, Spinnewyn B, Closutre F, Braquet P. In vivo inhibition of plasma protein leakage and salmonella antagonist: BN 52021. Agents and Actions 1985; 17: 368-370.
• 59. Wallace JL, Whittle BJR. Effects of inhibitors of arachidonic acid metabolism on PAF-induced gastric mucosal necrosis and haemoconcentration. Br J Pharmacol 1986; 89: 415-422.
• 60. Wallace JL, Whittle BJR. Picomole doses of platelet activating factor predispose the gastric mucosa to damage by topical irritants. Prostaglandins 1986; 31: 1989- 1998.
• 61. Braquet P, Etienne A, Mencia-Huerta JM, Clostre F.. Effects of the specific platelet activating factor antagonists, BN 52021 and BN 52063 on various experimental gastrointestinal ulcerations. Eur J Pharmacol 1988; 150: 269-276.
• 62. Dembinska-Kiec A, Peskar BA, Muller OK, Peskar AM. The effects of platelet activating factor on flow rate and eicosanoid release in the isolated perfused rat gastric vascular bed. Prostaglandins 1989; 37: 69-91.
• 63. Hsueh W, Gonzales-Crussi F, Arroyave J. Platelet activating factor induced ischemic bowel necrosis. An investigation of secondary mediators in its pathogenesis. Am J Path 1986; 122: 231-239.
• 64. Hsueh W, Gonzales-Crussi F, Arroyave J. Release of leukotriene C₄ by isolated prefused rat small intestine in response to platelet activating factor. J Clin Invest 1986; 78: 108-114.
• 65. Cucala M, Wallace J, Salas A, Guarner F, Rodriguez R, Malagelada J-R. Central regulation of gastric acid secretion by platelet activating factor in anesthesized rats. Prostaglandins 1989; 37: 275-285.