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. 1996 Oct 1;184(4):1483–1494. doi: 10.1084/jem.184.4.1483

The importance of leukotrienes in airway inflammation in a mouse model of asthma

PMCID: PMC2192843  PMID: 8879219

Abstract

Inhalation of antigen in immunized mice induces an infiltration of eosinophils into the airways and increased bronchial hyperreactivity as are observed in human asthma. We employed a model of late-phase allergic pulmonary inflammation in mice to address the role of leukotrienes (LT) in mediating airway eosinophilia and hyperreactivity to methacholine. Allergen intranasal challenge in OVA-sensitized mice induced LTB4 and LTC4 release into the airspace, widespread mucus occlusion of the airways, leukocytic infiltration of the airway tissue and broncho-alveolar lavage fluid that was predominantly eosinophils, and bronchial hyperreactivity to methacholine. Specific inhibitors of 5- lipoxygenase and 5-lipoxygenase-activating protein (FLAP) blocked airway mucus release and infiltration by eosinophils indicating a key role for leukotrienes in these features of allergic pulmonary inflammation. The role of leukotrienes or eosinophils in mediating airway hyperresponsiveness to aeroallergen could not be established, however, in this murine model.

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Selected References

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  1. AMDUR M. O., MEAD J. Mechanics of respiration in unanesthetized guinea pigs. Am J Physiol. 1958 Feb;192(2):364–368. doi: 10.1152/ajplegacy.1958.192.2.364. [DOI] [PubMed] [Google Scholar]
  2. Albert R. K., Lamm W. J., Henderson W. R., Bolin R. W. Effect of leukotrienes B4, C4, and D4 on segmental pulmonary vascular pressures. J Appl Physiol (1985) 1989 Jan;66(1):458–464. doi: 10.1152/jappl.1989.66.1.458. [DOI] [PubMed] [Google Scholar]
  3. Basten A., Boyer M. H., Beeson P. B. Mechanism of eosinophilia. I. Factors affecting the eosinophil response of rats to Trichinella spiralis. J Exp Med. 1970 Jun 1;131(6):1271–1287. doi: 10.1084/jem.131.6.1271. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Beasley R., Roche W. R., Roberts J. A., Holgate S. T. Cellular events in the bronchi in mild asthma and after bronchial provocation. Am Rev Respir Dis. 1989 Mar;139(3):806–817. doi: 10.1164/ajrccm/139.3.806. [DOI] [PubMed] [Google Scholar]
  5. Bousquet J., Chanez P., Lacoste J. Y., Barnéon G., Ghavanian N., Enander I., Venge P., Ahlstedt S., Simony-Lafontaine J., Godard P. Eosinophilic inflammation in asthma. N Engl J Med. 1990 Oct 11;323(15):1033–1039. doi: 10.1056/NEJM199010113231505. [DOI] [PubMed] [Google Scholar]
  6. Carter G. W., Young P. R., Albert D. H., Bouska J., Dyer R., Bell R. L., Summers J. B., Brooks D. W. 5-lipoxygenase inhibitory activity of zileuton. J Pharmacol Exp Ther. 1991 Mar;256(3):929–937. [PubMed] [Google Scholar]
  7. Casale T. B., Wood D., Richerson H. B., Trapp S., Metzger W. J., Zavala D., Hunninghake G. W. Elevated bronchoalveolar lavage fluid histamine levels in allergic asthmatics are associated with methacholine bronchial hyperresponsiveness. J Clin Invest. 1987 Apr;79(4):1197–1203. doi: 10.1172/JCI112937. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Chan C. C., McKee K., Tagari P., Chee P., Ford-Hutchinson A. Eosinophil-eicosanoid interactions: inhibition of eosinophil chemotaxis in vivo by a LTD4-receptor antagonist. Eur J Pharmacol. 1990 Dec 4;191(3):273–280. doi: 10.1016/0014-2999(90)94159-u. [DOI] [PubMed] [Google Scholar]
  9. Chapman I. D., Foster A., Morley J. The relationship between inflammation and hyperreactivity of the airways in asthma. Clin Exp Allergy. 1993 Mar;23(3):168–171. doi: 10.1111/j.1365-2222.1993.tb00877.x. [DOI] [PubMed] [Google Scholar]
  10. Coles S. J., Neill K. H., Reid L. M., Austen K. F., Nii Y., Corey E. J., Lewis R. A. Effects of leukotrienes C4 and D4 on glycoprotein and lysozyme secretion by human bronchial mucosa. Prostaglandins. 1983 Feb;25(2):155–170. doi: 10.1016/0090-6980(83)90101-6. [DOI] [PubMed] [Google Scholar]
  11. Corry D. B., Folkesson H. G., Warnock M. L., Erle D. J., Matthay M. A., Wiener-Kronish J. P., Locksley R. M. Interleukin 4, but not interleukin 5 or eosinophils, is required in a murine model of acute airway hyperreactivity. J Exp Med. 1996 Jan 1;183(1):109–117. doi: 10.1084/jem.183.1.109. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Czarnetzki B. M., Rosenbach T. Chemotaxis of human neutrophils and eosinophils towards leukotriene B4 and its 20-w-oxidation products in vitro. Prostaglandins. 1986 May;31(5):851–858. doi: 10.1016/0090-6980(86)90018-3. [DOI] [PubMed] [Google Scholar]
  13. Dahlén S. E., Hansson G., Hedqvist P., Björck T., Granström E., Dahlén B. Allergen challenge of lung tissue from asthmatics elicits bronchial contraction that correlates with the release of leukotrienes C4, D4, and E4. Proc Natl Acad Sci U S A. 1983 Mar;80(6):1712–1716. doi: 10.1073/pnas.80.6.1712. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Dixon R. A., Diehl R. E., Opas E., Rands E., Vickers P. J., Evans J. F., Gillard J. W., Miller D. K. Requirement of a 5-lipoxygenase-activating protein for leukotriene synthesis. Nature. 1990 Jan 18;343(6255):282–284. doi: 10.1038/343282a0. [DOI] [PubMed] [Google Scholar]
  15. Drazen J. M., Austen K. F., Lewis R. A., Clark D. A., Goto G., Marfat A., Corey E. J. Comparative airway and vascular activities of leukotrienes C-1 and D in vivo and in vitro. Proc Natl Acad Sci U S A. 1980 Jul;77(7):4354–4358. doi: 10.1073/pnas.77.7.4354. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Ford-Hutchinson A. W. Leukotriene B4 in inflammation. Crit Rev Immunol. 1990;10(1):1–12. [PubMed] [Google Scholar]
  17. Foster P. S., Hogan S. P., Ramsay A. J., Matthaei K. I., Young I. G. Interleukin 5 deficiency abolishes eosinophilia, airways hyperreactivity, and lung damage in a mouse asthma model. J Exp Med. 1996 Jan 1;183(1):195–201. doi: 10.1084/jem.183.1.195. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Fung D. C., Somerville M., Richardson P. S., Sheehan J. K. Mucus glycoconjugate complexes released from feline trachea by a bacterial toxin. Am J Respir Cell Mol Biol. 1995 Mar;12(3):296–306. doi: 10.1165/ajrcmb.12.3.7873196. [DOI] [PubMed] [Google Scholar]
  19. Gavett S. H., O'Hearn D. J., Li X., Huang S. K., Finkelman F. D., Wills-Karp M. Interleukin 12 inhibits antigen-induced airway hyperresponsiveness, inflammation, and Th2 cytokine expression in mice. J Exp Med. 1995 Nov 1;182(5):1527–1536. doi: 10.1084/jem.182.5.1527. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Gillard J., Ford-Hutchinson A. W., Chan C., Charleson S., Denis D., Foster A., Fortin R., Leger S., McFarlane C. S., Morton H. L-663,536 (MK-886) (3-[1-(4-chlorobenzyl)-3-t-butyl-thio-5-isopropylindol-2-yl]-2,2 - dimethylpropanoic acid), a novel, orally active leukotriene biosynthesis inhibitor. Can J Physiol Pharmacol. 1989 May;67(5):456–464. doi: 10.1139/y89-073. [DOI] [PubMed] [Google Scholar]
  21. Henderson W. R., Jr, Chi E. Y. Degranulation of cystic fibrosis nasal polyp mast cells. J Pathol. 1992 Apr;166(4):395–404. doi: 10.1002/path.1711660412. [DOI] [PubMed] [Google Scholar]
  22. Henderson W. R., Jr The role of leukotrienes in inflammation. Ann Intern Med. 1994 Nov 1;121(9):684–697. doi: 10.7326/0003-4819-121-9-199411010-00010. [DOI] [PubMed] [Google Scholar]
  23. Hoffstein S. T., Malo P. E., Bugelski P., Wheeldon E. B. Leukotriene D4 (LTD4) induces mucus secretion from goblet cells in the guinea pig respiratory epithelium. Exp Lung Res. 1990 Nov-Dec;16(6):711–725. doi: 10.3109/01902149009087890. [DOI] [PubMed] [Google Scholar]
  24. Ingram R. H., Jr Asthma and airway hyperresponsiveness. Annu Rev Med. 1991;42:139–150. doi: 10.1146/annurev.me.42.020191.001035. [DOI] [PubMed] [Google Scholar]
  25. Johnson H. G., McNee M. L. Secretogogue responses of leukotriene C4, D4: comparison of potency in canine trachea in vivo. Prostaglandins. 1983 Feb;25(2):237–243. doi: 10.1016/0090-6980(83)90107-7. [DOI] [PubMed] [Google Scholar]
  26. Laitinen L. A., Laitinen A., Haahtela T., Vilkka V., Spur B. W., Lee T. H. Leukotriene E4 and granulocytic infiltration into asthmatic airways. Lancet. 1993 Apr 17;341(8851):989–990. doi: 10.1016/0140-6736(93)91073-u. [DOI] [PubMed] [Google Scholar]
  27. Levitt R. C., Mitzner W. Expression of airway hyperreactivity to acetylcholine as a simple autosomal recessive trait in mice. FASEB J. 1988 Jul;2(10):2605–2608. doi: 10.1096/fasebj.2.10.3384240. [DOI] [PubMed] [Google Scholar]
  28. Logun C., Mullol J., Rieves D., Hoffman A., Johnson C., Miller R., Goff J., Kaliner M., Shelhamer J. Use of a monoclonal antibody enzyme-linked immunosorbent assay to measure human respiratory glycoprotein production in vitro. Am J Respir Cell Mol Biol. 1991 Jul;5(1):71–79. doi: 10.1165/ajrcmb/5.1.71. [DOI] [PubMed] [Google Scholar]
  29. Lundgren J. D., Shelhamer J. H. Pathogenesis of airway mucus hypersecretion. J Allergy Clin Immunol. 1990 Feb;85(2):399–417. doi: 10.1016/0091-6749(90)90147-v. [DOI] [PubMed] [Google Scholar]
  30. Mancino D., Ovary Z. Adjuvant effects of amorphous silica and of aluminium hydroxide on IgE and IgG1 antibody production in different inbred mouse strains. Int Arch Allergy Appl Immunol. 1980;61(3):253–258. doi: 10.1159/000232443. [DOI] [PubMed] [Google Scholar]
  31. Marom Z., Shelhamer J. H., Bach M. K., Morton D. R., Kaliner M. Slow-reacting substances, leukotrienes C4 and D4, increase the release of mucus from human airways in vitro. Am Rev Respir Dis. 1982 Sep;126(3):449–451. doi: 10.1164/arrd.1982.126.3.449. [DOI] [PubMed] [Google Scholar]
  32. Martin T. R., Gerard N. P., Galli S. J., Drazen J. M. Pulmonary responses to bronchoconstrictor agonists in the mouse. J Appl Physiol (1985) 1988 Jun;64(6):2318–2323. doi: 10.1152/jappl.1988.64.6.2318. [DOI] [PubMed] [Google Scholar]
  33. McEwen B. J., Wilcock B. P., Eyre P. The effect of leukotriene B4, leukotriene C4, zymosan activated serum, histamine, tabanid extract and N-formyl-methionyl-leucyl-phenylalanine on the in vitro migration of equine eosinophils. Can J Vet Res. 1990 Oct;54(4):400–404. [PMC free article] [PubMed] [Google Scholar]
  34. Morita E., Schröder J. M., Christophers E. Differential sensitivities of purified human eosinophils and neutrophils to defined chemotaxins. Scand J Immunol. 1989 Jun;29(6):709–716. doi: 10.1111/j.1365-3083.1989.tb01175.x. [DOI] [PubMed] [Google Scholar]
  35. Nakajima H., Iwamoto I., Tomoe S., Matsumura R., Tomioka H., Takatsu K., Yoshida S. CD4+ T-lymphocytes and interleukin-5 mediate antigen-induced eosinophil infiltration into the mouse trachea. Am Rev Respir Dis. 1992 Aug;146(2):374–377. doi: 10.1164/ajrccm/146.2.374. [DOI] [PubMed] [Google Scholar]
  36. Peatfield A. C., Piper P. J., Richardson P. S. The effect of leukotriene C4 on mucin release into the cat trachea in vivo and in vitro. Br J Pharmacol. 1982 Nov;77(3):391–393. doi: 10.1111/j.1476-5381.1982.tb09310.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Renz H., Smith H. R., Henson J. E., Ray B. S., Irvin C. G., Gelfand E. W. Aerosolized antigen exposure without adjuvant causes increased IgE production and increased airway responsiveness in the mouse. J Allergy Clin Immunol. 1992 Jun;89(6):1127–1138. doi: 10.1016/0091-6749(92)90296-e. [DOI] [PubMed] [Google Scholar]
  38. Rokach J., Hayes E. C., Girard Y., Lombardo D. L., Maycock A. L., Rosenthal A. S., Young R. N., Zamboni R., Zweerink H. J. The development of sensitive and specific radioimmunoassays for leukotrienes. Prostaglandins Leukot Med. 1984 Jan;13(1):21–25. doi: 10.1016/0262-1746(84)90098-2. [DOI] [PubMed] [Google Scholar]
  39. Samuelsson B., Dahlén S. E., Lindgren J. A., Rouzer C. A., Serhan C. N. Leukotrienes and lipoxins: structures, biosynthesis, and biological effects. Science. 1987 Sep 4;237(4819):1171–1176. doi: 10.1126/science.2820055. [DOI] [PubMed] [Google Scholar]
  40. Shelhamer J. H., Marom Z., Kaliner M. Immunologic and neuropharmacologic stimulation of mucous glycoprotein release from human airways in vitro. J Clin Invest. 1980 Dec;66(6):1400–1408. doi: 10.1172/JCI109993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Skloot G., Permutt S., Togias A. Airway hyperresponsiveness in asthma: a problem of limited smooth muscle relaxation with inspiration. J Clin Invest. 1995 Nov;96(5):2393–2403. doi: 10.1172/JCI118296. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Sladek K., Dworski R., Fitzgerald G. A., Buitkus K. L., Block F. J., Marney S. R., Jr, Sheller J. R. Allergen-stimulated release of thromboxane A2 and leukotriene E4 in humans. Effect of indomethacin. Am Rev Respir Dis. 1990 Jun;141(6):1441–1445. doi: 10.1164/ajrccm/141.6.1441. [DOI] [PubMed] [Google Scholar]
  43. Spada C. S., Nieves A. L., Krauss A. H., Woodward D. F. Comparison of leukotriene B4 and D4 effects on human eosinophil and neutrophil motility in vitro. J Leukoc Biol. 1994 Feb;55(2):183–191. doi: 10.1002/jlb.55.2.183. [DOI] [PubMed] [Google Scholar]
  44. Su M., Chi E. Y., Bishop M. J., Henderson W. R., Jr Lung mast cells increase in number and degranulate during pulmonary artery occlusion/reperfusion injury in dogs. Am Rev Respir Dis. 1993 Feb;147(2):448–456. doi: 10.1164/ajrccm/147.2.448. [DOI] [PubMed] [Google Scholar]
  45. Sun F. F., Crittenden N. J., Czuk C. I., Taylor B. M., Stout B. K., Johnson H. G. Biochemical and functional differences between eosinophils from animal species and man. J Leukoc Biol. 1991 Aug;50(2):140–150. doi: 10.1002/jlb.50.2.140. [DOI] [PubMed] [Google Scholar]
  46. Thornton D. J., Holmes D. F., Sheehan J. K., Carlstedt I. Quantitation of mucus glycoproteins blotted onto nitrocellulose membranes. Anal Biochem. 1989 Oct;182(1):160–164. doi: 10.1016/0003-2697(89)90735-5. [DOI] [PubMed] [Google Scholar]
  47. Watanabe A., Rossi P., Renzi P. M., Xu L. J., Guttmann R. D., Martin J. G. Adoptive transfer of allergic airway responses with sensitized lymphocytes in BN rats. Am J Respir Crit Care Med. 1995 Jul;152(1):64–70. doi: 10.1164/ajrccm.152.1.7599864. [DOI] [PubMed] [Google Scholar]
  48. Wenzel S. E., Larsen G. L., Johnston K., Voelkel N. F., Westcott J. Y. Elevated levels of leukotriene C4 in bronchoalveolar lavage fluid from atopic asthmatics after endobronchial allergen challenge. Am Rev Respir Dis. 1990 Jul;142(1):112–119. doi: 10.1164/ajrccm/142.1.112. [DOI] [PubMed] [Google Scholar]
  49. Wenzel S. E., Trudeau J. B., Kaminsky D. A., Cohn J., Martin R. J., Westcott J. Y. Effect of 5-lipoxygenase inhibition on bronchoconstriction and airway inflammation in nocturnal asthma. Am J Respir Crit Care Med. 1995 Sep;152(3):897–905. doi: 10.1164/ajrccm.152.3.7663802. [DOI] [PubMed] [Google Scholar]
  50. Wenzel S. E., Westcott J. Y., Larsen G. L. Bronchoalveolar lavage fluid mediator levels 5 minutes after allergen challenge in atopic subjects with asthma: relationship to the development of late asthmatic responses. J Allergy Clin Immunol. 1991 Feb;87(2):540–548. doi: 10.1016/0091-6749(91)90013-e. [DOI] [PubMed] [Google Scholar]
  51. Yong E. C., Chi E. Y., Henderson W. R., Jr Toxoplasma gondii alters eicosanoid release by human mononuclear phagocytes: role of leukotrienes in interferon gamma-induced antitoxoplasma activity. J Exp Med. 1994 Nov 1;180(5):1637–1648. doi: 10.1084/jem.180.5.1637. [DOI] [PMC free article] [PubMed] [Google Scholar]

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