Advertisement

Die Rolle von Arachidonsäuremetaboliten in der Pathogenese des Asthma bronchiale

  • W. Seeger
  • F. Grimminger
Conference paper
Part of the Verhandlungen der Deutschen Gesellschaft für Innere Medizin book series (VDGINNERE, volume 96)

Zusammenfassung

Asthma bronchiale ist eine heterogene Erkrankung, deren Auslöser klassischerweise in „allergische“ und „endogene“ (intrinsische, kryptogene) unterteilt werden. Neuere Klassifikationen ordnen die Triggerung des Geschehens an der Schnittstelle von Allergie, Schleimhautirritation, Infektion und endogenen Komponenten ein. Für das Verständnis der reversiblen Atemwegsobstruktion sind 2 Konzepte bedeutsam: Hyperreagibilität der Atemwege besagt, daß eine generell erhöhte Empfindlichkeit gegenüber verschiedenen bronchokonstriktorischen Stimuli besteht; diese läßt sich durch inhalative Provokation mit entsprechenden Agenzien (auch im Intervall) dokumentieren (z.B. Histamin-, Methacholininhalation). Atemwegsentzündung hebt hervor, daß den Phänomenen der Bronchokonstriktion, des Bronchialschleimhautödems und der Dyskrinie heterogen getriggerte inflammatorische Prozesse zugrunde liegen. Eine Vielzahl von humoralen und nervalen Effektoren ist möglicherweise an der Pathogenese dieser Veränderungen beteiligt. Eine vereinfachte Skizzierung der gegenwärtigen Vorstellungen ist in Abb. 1 wiedergegeben.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Literatur

  1. 1.
    Abraham WM (1987) The importance of lipoxygenase products of arachidonic acid in allergeninduced late responses. Am Rev Respir Dis 135:S49–S53.PubMedGoogle Scholar
  2. 2.
    Abraham WM, Stevenson JS, Garrido R (1988) A leukotriene and thromboxane inhibitor (Sch 37 224) blocks antigen-induced immediate and late responses and airway hyperresponsiveness in allergic sheep. J Pharmacol Exp Ther 247:1004.PubMedGoogle Scholar
  3. 3.
    Aharony D, Catanese CA, Falcone RC (1988) Kinetic and pharmacologic analysis of (3H) leukotriene E4 binding to receptors on guinea pig lung membranes: evidence for selective binding to a subset of leukotriene D4 receptors. J Pharmacol Exp Ther 248:581.Google Scholar
  4. 4.
    Arm JP, Horton CE, Spur BW, Mencia-Huerta J-M, Lee TH (1989) The effects of dietary supplementation with fish oil lipids on the airways response to inhaled allergen in bronchial asthma. Am Rev Respir Dis 139:1395–1400.PubMedGoogle Scholar
  5. 5.
    Barnes NC, Piper PJ, Costello JF (1984) Comparative effects of inhaled leukotriene C4, leukotriene D4, and histamine in normal human subjects. Thorax 39:500–504.PubMedCrossRefGoogle Scholar
  6. 6.
    Beasley RCE, Featherstone RL, Church MK et al. (1989) Effect of a thromboxane receptor antagonist on PGD2-and allergen-induced bronchoconstriction. J Appl Physiol 66:1685–1693.PubMedGoogle Scholar
  7. 7.
    Bel EH, Kramps JA, Dijman JH, Sterk PJ (1987) Leukotriene D4 heightens the level of maximal airway narrowing in normal humans in vivo. Am Rev Respir Dis 135: A89.Google Scholar
  8. 8.
    Bel EH, Timmers MC, Dijkman JH, Sterk PJ (1989) The effect of an inhaled leukotriene antagonist L-648-051 on allergen-induced early and late asthmatic reactions in man. Am Rev Respir Dis 139:A460.CrossRefGoogle Scholar
  9. 9.
    Black PN, Salmon BT, Ewan P, Fuller RW (1989) The effect of CGS 12 970, a thromboxane synthetase inhibitor, on the response to inhaled allergen. Am Rev Respir Dis 139: A93.Google Scholar
  10. 10.
    Britton JR, Hanley SP, Tattersfield AE (1987) The effect of an oral leukotriene D antagonist L-649, 923 on the response to inhaled antigen in asthma. J Allergy Clin Immunol 78:811–816.CrossRefGoogle Scholar
  11. 11.
    Chung KF, Aizawa H, Becker AB, Frick O, Gold WN, Nadel JA (1986) Inhibition of antigeninduced airway hyperresponsiveness by a thromboxane synthetase inhibitor (OKY-046) in allergic dogs. Am Rev Respir Dis 134:258–261.PubMedGoogle Scholar
  12. 12.
    Chung KF, Aizawa H, Leikauf GD, Ueki IF, Evans TW, Nadel JA (1986) Airway hyperresponsiveness induced by platelet-activating factor: role of thromboxane generation. J Pharmacol Exp Ther 236:580.PubMedGoogle Scholar
  13. 13.
    Cloud ML, Enas GC, Kemp J et al. (1989) A specific LTD4/LTE4-receptor antagonist improves pulmonary function in patients with mild, chronic asthma. Am Rev Respir Dis 140:1336–1339.PubMedCrossRefGoogle Scholar
  14. 14.
    Coles SJ, Neill KH, Reid LM, Austen KF, Nii Y, Corey EJ, Lewis RA (1983) Effects of leukotrienes C4 and D4 on glycoprotein and lysozyme secretion by human bronchial mucosa. Prostaglandins 25:155–170.PubMedCrossRefGoogle Scholar
  15. 15.
    Creticos PS, Peters SP, Adkinson Jr NF, Naclerio RN, Hayes EC, Norman PS, Lichtenstein LM (1984) Peptide leukotriene release after antigen challenge in patients sensitive to ragweed. N Engl J Med 310:1626–1630.PubMedCrossRefGoogle Scholar
  16. 16.
    Dahlen S-E, Bjork J, Hedqvist P (1981) Leukotrienes promote vascular leakage and leukocyte adherence in postcapillary venules: in vivo effects with relevance to the acute inflammatory response. Proc Natl Acad Sci USA 78:3887–3891.PubMedCrossRefGoogle Scholar
  17. 17.
    Dahlen SE, Hansson G, Hedquist P, Björck T, Granström E, Dahlen B (1983) Allergen challenge of lung tissue from asthmatics elicits bronchial contraction that correlates with the release of leukotriene C4, D4 and E4. Proc Natl Acad Sci USA 80:1712–1716.PubMedCrossRefGoogle Scholar
  18. 18.
    Davidson AB, Lee TH, Scanion PD, et al. (1987) Bronchoconstrictor effects of leukotriene E4 in normal and asthmatic subjects. Am Rev Respir Dis 135:333–337.PubMedGoogle Scholar
  19. 19.
    Diaz P, Gonzalez MC, Galleguillos FR, et al. (1989) Leukocytes and mediators in bronchoalveolar lavage during allergen-induced late-phase asthmatic reactions. Am Rev Respir Dis 139:1383–1389.PubMedGoogle Scholar
  20. 20.
    Drazen JM, Austin KF, Lewis RA, Clark DA, Goto G, Marfat A, Corey EJ (1980) Comparative airway and vascular activities of leukotrienes C-1 and D in vivo and in vitro. Proc Natl Acad Sci USA 77:4354–4358.PubMedCrossRefGoogle Scholar
  21. 21.
    Eiser N, Hayhurst M, Denman W (1989) The contribution of histamine and leukotriene release to the production of early and late asthmatic responses to antigen. Am Rev Respir Dis 139:A462.Google Scholar
  22. 22.
    Evans TW, Rogers DF, Aursudkij B, Chung KF, Barnes PJ (1988) Inflammatory mediators involved in antigen-induced airway microvascular leakage in guinea pigs. Am Rev Respir Dis 138:395–399.PubMedCrossRefGoogle Scholar
  23. 23.
    Ferreri NR, Howland WC, Stevenson DD, Spiegelberg HL (1988) Release of leukotrienes, prostaglandins, and histamine into nasal secretions of aspirin-sensitive asthmatics during reaction to aspirin. Am Rev Respir Dis 137:847–864.PubMedGoogle Scholar
  24. 24.
    Gray PR, Derksen FJ, Robinson NE, Carpenter-Deyo LJ, Johnson HG, Roth RA (1989) The role of cyclooxygenase products in the acute airway obstruction and airway hyperreactivity of ponies with heaves. Am Rev Respir Dis 140:154–160.PubMedCrossRefGoogle Scholar
  25. 25.
    Grimminger F, Becker G, Seeger W (1988) High yield enzymatic conversion of intravascular leukotriene A4 in blood-free perfused lungs. J Immunol 141:2431–2436.PubMedGoogle Scholar
  26. 26.
    Grimminger F, Menger M, Becker G, Seeger W (1988) Potentiation of leukotriene production following sequestration of neutrophils in isolated lungs: indirect evidence for intercellular leukotriene A4 transfer. Blood 72:1687–1692.PubMedGoogle Scholar
  27. 27.
    Hahn H-L (1988) Beitrag von Entzündungsmediatoren zur Pathogenese obstruktiver Bronchialerkrankungen: Konsequenzen für die Therapie. Verh Dtsch Ges Inn Med 94:364–375.PubMedGoogle Scholar
  28. 28.
    Henke D, Danilowicz RM, Curtis JF, Boucher RC, Eling TE (1988) Metabolism of arachidonic acid by human nasal and bronchial epithelial cells. Arch Biochem Biophys 267:426–436.PubMedCrossRefGoogle Scholar
  29. 28a.
    Holgate ST, Kay AB (1985) Mast cells, mediators and asthma. Clin Allergy 15:221.PubMedCrossRefGoogle Scholar
  30. 29.
    Holroyde MC, Cole M, Altounyan REC, Dixon M, Elliot EV (1981) Bronchoconstriction produced in man by leukotrienes C and D. Lancet, July 4:17–20.CrossRefGoogle Scholar
  31. 30.
    Hunter JA, Finkbeiner WE, Nadel JA, Goetzl EJ, Holtzman MJ (1985) Predominant generation of 15-lipoxygenase metabolites of arachidonic acid by epithelial cells from human trachea. Proc Natl Acad Sci USA 82:4633–4637.PubMedCrossRefGoogle Scholar
  32. 31.
    Israel E, Juniper EF, Callaghan JT et al. (1989) Effect of a leukotriene antagonist, LY171.883, on cold air-induced bronchoconstriction in asthmatics. Am Rev Respir Dis 140:1348–1353.PubMedCrossRefGoogle Scholar
  33. 32.
    Kaliner M, Shelhamer JH, Borson B, Nadel J, Patow C, Marom Z (1986) Human respiratory mucus. Am Rev Respir Dis 134:612–621.PubMedGoogle Scholar
  34. 33.
    Kirby JG, Hargreave FE, O’Byrne PM (1987) Indomethacin inhibits allergen-induced airway hyperresponsiveness but not allergen-induced asthmatic responses. Am Rev Respir Dis 135:A312.Google Scholar
  35. 34.
    Kirsch CM, Payan DG, Wong MY et al. (1988) Effect of eicosapentaenoic acid in asthma. Clin Allergy 18:177–187.PubMedCrossRefGoogle Scholar
  36. 35.
    Lam S, Chan H, LeRiche JC, Chan-Yeung M, Salari H (1988) Relase of leukotrienes in patients with bronchial asthma. J Allergy Clin Immunol 81:711–717.PubMedCrossRefGoogle Scholar
  37. 36.
    Lanes S, Stevenson JS, Doias E, Hernandez A, Sielczak MW, Wanner A, Abraham WM (1986) Indomethacin and FPL-57 231 inhibit antigen-induced airway hyperresponsiveness in sheep. J Appl Physiol 61:864–872.PubMedGoogle Scholar
  38. 37.
    Lee TH, Walport MJ, Wilkinson AH, Turner-Warwick M, Kay AB (1981) Slow-reacting substance of anaphylaxis antagonist FPL 55 172 in chronic asthma. Lancet, Aug 8:304–305.CrossRefGoogle Scholar
  39. 38.
    Leikauf GD, Doupnik CA, Leming LM, Wey HE (1989) Sulfidopeptide leukotrienes mediate acrolein-induced bronchial hyperresponsiveness. J Appl Physiol 66:1838–1845.PubMedGoogle Scholar
  40. 39.
    Mann JS, Robinson C, Sheridan AQ, Clement P, Bach MK, Holgate ST (1986) Effect of inhaled Piriprost (U-60,257), a novel leukotriene inhibitor, on allergen and exercise induced bronchoconstriction in asthma. Thorax 41:746–752.PubMedCrossRefGoogle Scholar
  41. 40.
    Manning PJ, Rokach J, Malo JL et al. (1989) Urinary leukotriene D4 levels during early and late asthmatic responses. Am Rev Respir Dis 139: A92.Google Scholar
  42. 41.
    Martin TR, Pistorese BP, Chi EY, Goodman RB, Matthay MA (1989) Effects of leukotriene C4 in the human lung. Recruitment of neutrophils into the alveolar spaces without a change in protein permeability. J Clin Invest 84:1609–1619.PubMedCrossRefGoogle Scholar
  43. 42.
    Mong S, Wu H-L, Scott MO et al. (1985) Molecular heterogeneity of leukotriene receptors: correlation of smooth muscle contraction and radioligand binding in guinea-pig lung. J Pharmacol Exp Ther 234:316.PubMedGoogle Scholar
  44. 43.
    Murray JJ, Tonnel AB, Brash AR et al. (1986) Release of prostaglandin D2 into human airways during acute antigen challenge. N Engl J Med 315:800–804.PubMedCrossRefGoogle Scholar
  45. 44.
    Naclerio RM, Proud D, Togias AG et al. (1985) Inflammatory mediators in late antigen-induced rhinitis. N Engl J Med 313:65–70.PubMedCrossRefGoogle Scholar
  46. 45.
    O’Byrne PM, Leikauf GD, Aizawa H, Bethel RA, Ueki IF, Holtzman MH, Nadel JA (1985) Leukotriene B4 induce airway hyperresponsiveness in dogs. J Appl Physiol 59:1941–1946.PubMedGoogle Scholar
  47. 46.
    Okayama H, Aikawa T, Ohtsu H, Sasaki H, Takishima T (1989) Leukotriene C4 and B4 in bronchoalveolar lavage fluid during biphasic allergic bronchoconstriction in sheep. Am Rev Respir Dis 139:725–731.PubMedGoogle Scholar
  48. 47.
    Philipps GD, Rafferty P, Robinson C, Holgate ST (1988) Dose related antagonism of leukotriene D4-induced bronchoconstriction by p. o. administration of LY171.883 in nonasthmatic subjects. J Pharmacol Exp Ther 245:732–738.Google Scholar
  49. 48.
    Pichurko BM, Ingram Jr RH, Sperling RI, Lafleur JE, Corey EJ, Austin KF, Drazen JM (1989) Localization of the site of the bronchoconstrictor effects of leukotriene C4 compared with that of histamine in asthmatic subjects. Am Rev Respir Dis 140:334–339.PubMedCrossRefGoogle Scholar
  50. 49.
    Silbaugh SA, Stengel PW, Pechous PA, Marshall WS (1989) Reversal of leukotriene D4-and leukotriene E4-induced airway constriction in the guinea pig. Am Rev Respir Dis 140:610–614.PubMedGoogle Scholar
  51. 50.
    Smith LJ, Greenberger PA, Patterson R, Krell RD, Bernstein PR (1985) The effect of inhaled leukotriene D4 in humans. Am Rev Respir Dis 131:366–372.Google Scholar
  52. 51.
    Taylor G, Ritter J, Fuller R, Moore K, Taylor L, Dollery C (1989) Urinary leukotriene E4 excretion: a measure of cysteinyl leukotriene production in man? Am Rev Respir Dis 139: A96.Google Scholar
  53. 52.
    Wardlaw AJ, Hay H, Cromwell O, Collins JV, Kay AB (1989) Leukotrienes, LTC4 and LTB4 in bronchoalveolar lavage in bronchial asthma and other respiratory diseases. J Allergy Clin Immunol 84:6.CrossRefGoogle Scholar
  54. 53.
    Wenzel SE, Westcott JY, Voelkel NF, Larsen GL (1989) Adhérences in mediator levels post endobronchial allergen challenge in asthmatic subjects with and without a late asthmatic response. Am Rev Respir Dis 139:A465.CrossRefGoogle Scholar
  55. 54.
    Yamai R, Watanabe S, Motojima S, Fukuda R, Makino S (1989) The significance of leukotriene in antigen-induced late asthmatic response. Am Rev Respir Dis 139:A462.Google Scholar

Copyright information

© Springer-Verlag, Berlin Heidelberg 1990

Authors and Affiliations

  • W. Seeger
    • 1
  • F. Grimminger
    • 1
  1. 1.Zentrum für Innere MedizinUniversität GießenDeutschland

Personalised recommendations