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. 1998 Dec 15;102(12):2165–2172. doi: 10.1172/JCI1995

5-oxo-ETE induces pulmonary eosinophilia in an integrin-dependent manner in Brown Norway rats.

P Stamatiou 1, Q Hamid 1, R Taha 1, W Yu 1, T B Issekutz 1, J Rokach 1, S P Khanapure 1, W S Powell 1
PMCID: PMC509171  PMID: 9854052

Abstract

We have shown previously that the 5-lipoxygenase product 5-oxo-6,8, 11,14-eicosatetraenoic acid (5-oxo-ETE) is a highly potent eosinophil chemoattractant in vitro. To determine whether this substance can induce pulmonary eosinophil infiltration in vivo, it was administered to Brown Norway rats by tracheal insufflation. Eosinophils were then counted in lung sections that had been immunostained with an antibody to eosinophil major basic protein. 5-Oxo-ETE induced a dramatic increase in the numbers of eosinophils (ED50, 2.5 microg) around the walls of the airways, which reached maximal levels (five times control levels) between 15 and 24 h after administration, and then declined. LTB4 also induced pulmonary eosinophil infiltration with a similar ED50 but appeared to be somewhat less effective. In contrast, LTD4 and LTE4 were inactive. 5-Oxo-ETE-induced eosinophilia was unaffected by the LTB4 and PAF antagonists LY255283 and WEB 2170, respectively. However, it was inhibited by approximately 75% by monoclonal antibodies to CD49d (VLA-4) or CD11a (LFA-1) but was not significantly affected by an antibody to CD11b (Mac-1). In conclusion, 5-oxo-ETE induces pulmonary eosinophilia in Brown Norway rats, raising the possibility that it may be a physiological mediator of inflammation in asthma.

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Selected References

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  1. Abraham W. M., Ahmed A., Cortes A., Sielczak M. W., Hinz W., Bouska J., Lanni C., Bell R. L. The 5-lipoxygenase inhibitor zileuton blocks antigen-induced late airway responses, inflammation and airway hyperresponsiveness in allergic sheep. Eur J Pharmacol. 1992 Jul 7;217(2-3):119–126. doi: 10.1016/0014-2999(92)90829-s. [DOI] [PubMed] [Google Scholar]
  2. Barnes P. J. New concepts in the pathogenesis of bronchial hyperresponsiveness and asthma. J Allergy Clin Immunol. 1989 Jun;83(6):1013–1026. doi: 10.1016/0091-6749(89)90441-7. [DOI] [PubMed] [Google Scholar]
  3. 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]
  4. Czech W., Barbisch M., Tenscher K., Schöpf E., Schröder J. M., Norgauer J. Chemotactic 5-oxo-eicosatetraenoic acids induce oxygen radical production, Ca2+-mobilization, and actin reorganization in human eosinophils via a pertussis toxin-sensitive G-protein. J Invest Dermatol. 1997 Jan;108(1):108–112. doi: 10.1111/1523-1747.ep12285653. [DOI] [PubMed] [Google Scholar]
  5. Dahinden C. A., Geiser T., Brunner T., von Tscharner V., Caput D., Ferrara P., Minty A., Baggiolini M. Monocyte chemotactic protein 3 is a most effective basophil- and eosinophil-activating chemokine. J Exp Med. 1994 Feb 1;179(2):751–756. doi: 10.1084/jem.179.2.751. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Daugherty B. L., Siciliano S. J., DeMartino J. A., Malkowitz L., Sirotina A., Springer M. S. Cloning, expression, and characterization of the human eosinophil eotaxin receptor. J Exp Med. 1996 May 1;183(5):2349–2354. doi: 10.1084/jem.183.5.2349. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Eidelman D. H., Bellofiore S., Martin J. G. Late airway responses to antigen challenge in sensitized inbred rats. Am Rev Respir Dis. 1988 May;137(5):1033–1037. doi: 10.1164/ajrccm/137.5.1033. [DOI] [PubMed] [Google Scholar]
  8. Eidelman D. H., Minshall E., Dandurand R. J., Schotman E., Song Y. L., Yasruel Z., Moqbel R., Hamid Q. Evidence for major basic protein immunoreactivity and interleukin 5 gene activation during the late phase response in explanted airways. Am J Respir Cell Mol Biol. 1996 Nov;15(5):582–589. doi: 10.1165/ajrcmb.15.5.8918365. [DOI] [PubMed] [Google Scholar]
  9. Forssmann U., Uguccioni M., Loetscher P., Dahinden C. A., Langen H., Thelen M., Baggiolini M. Eotaxin-2, a novel CC chemokine that is selective for the chemokine receptor CCR3, and acts like eotaxin on human eosinophil and basophil leukocytes. J Exp Med. 1997 Jun 16;185(12):2171–2176. doi: 10.1084/jem.185.12.2171. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Garcia-Zepeda E. A., Combadiere C., Rothenberg M. E., Sarafi M. N., Lavigne F., Hamid Q., Murphy P. M., Luster A. D. Human monocyte chemoattractant protein (MCP)-4 is a novel CC chemokine with activities on monocytes, eosinophils, and basophils induced in allergic and nonallergic inflammation that signals through the CC chemokine receptors (CCR)-2 and -3. J Immunol. 1996 Dec 15;157(12):5613–5626. [PubMed] [Google Scholar]
  11. Garcia-Zepeda E. A., Rothenberg M. E., Ownbey R. T., Celestin J., Leder P., Luster A. D. Human eotaxin is a specific chemoattractant for eosinophil cells and provides a new mechanism to explain tissue eosinophilia. Nat Med. 1996 Apr;2(4):449–456. doi: 10.1038/nm0496-449. [DOI] [PubMed] [Google Scholar]
  12. Gonzalo J. A., Lloyd C. M., Kremer L., Finger E., Martinez-A C., Siegelman M. H., Cybulsky M., Gutierrez-Ramos J. C. Eosinophil recruitment to the lung in a murine model of allergic inflammation. The role of T cells, chemokines, and adhesion receptors. J Clin Invest. 1996 Nov 15;98(10):2332–2345. doi: 10.1172/JCI119045. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Halperin S. A., Issekutz T. B., Kasina A. Modulation of Bordetella pertussis infection with monoclonal antibodies to pertussis toxin. J Infect Dis. 1991 Feb;163(2):355–361. doi: 10.1093/infdis/163.2.355. [DOI] [PubMed] [Google Scholar]
  14. Henderson W. R., Jr, Lewis D. B., Albert R. K., Zhang Y., Lamm W. J., Chiang G. K., Jones F., Eriksen P., Tien Y. T., Jonas M. The importance of leukotrienes in airway inflammation in a mouse model of asthma. J Exp Med. 1996 Oct 1;184(4):1483–1494. doi: 10.1084/jem.184.4.1483. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Herron D. K., Goodson T., Bollinger N. G., Swanson-Bean D., Wright I. G., Staten G. S., Thompson A. R., Froelich L. L., Jackson W. T. Leukotriene B4 receptor antagonists: the LY255283 series of hydroxyacetophenones. J Med Chem. 1992 May 15;35(10):1818–1828. doi: 10.1021/jm00088a018. [DOI] [PubMed] [Google Scholar]
  16. Heuer H. O., Casals-Stenzel J., Muacevic G., Weber K. H. Pharmacologic activity of bepafant (WEB 2170), a new and selective hetrazepinoic antagonist of platelet activating factor. J Pharmacol Exp Ther. 1990 Dec;255(3):962–968. [PubMed] [Google Scholar]
  17. Heuer H. O., Keller B., Urich K. Action of the racemate and the isomers of the platelet-activating factor antagonist bepafant (WEB 2170) after oral administration to guinea-pigs and rats. Naunyn Schmiedebergs Arch Pharmacol. 1991 May;343(5):546–550. doi: 10.1007/BF00169560. [DOI] [PubMed] [Google Scholar]
  18. Irvin C. G., Tu Y. P., Sheller J. R., Funk C. D. 5-Lipoxygenase products are necessary for ovalbumin-induced airway responsiveness in mice. Am J Physiol. 1997 Jun;272(6 Pt 1):L1053–L1058. doi: 10.1152/ajplung.1997.272.6.L1053. [DOI] [PubMed] [Google Scholar]
  19. Israel E., Cohn J., Dubé L., Drazen J. M. Effect of treatment with zileuton, a 5-lipoxygenase inhibitor, in patients with asthma. A randomized controlled trial. Zileuton Clinical Trial Group. JAMA. 1996 Mar 27;275(12):931–936. [PubMed] [Google Scholar]
  20. Issekutz A. C., Issekutz T. B. The contribution of LFA-1 (CD11a/CD18) and MAC-1 (CD11b/CD18) to the in vivo migration of polymorphonuclear leucocytes to inflammatory reactions in the rat. Immunology. 1992 Aug;76(4):655–661. [PMC free article] [PubMed] [Google Scholar]
  21. Issekutz T. B., Wykretowicz A. Effect of a new monoclonal antibody, TA-2, that inhibits lymphocyte adherence to cytokine stimulated endothelium in the rat. J Immunol. 1991 Jul 1;147(1):109–116. [PubMed] [Google Scholar]
  22. Kameyoshi Y., Dörschner A., Mallet A. I., Christophers E., Schröder J. M. Cytokine RANTES released by thrombin-stimulated platelets is a potent attractant for human eosinophils. J Exp Med. 1992 Aug 1;176(2):587–592. doi: 10.1084/jem.176.2.587. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Kane G. C., Pollice M., Kim C. J., Cohn J., Dworski R. T., Murray J. J., Sheller J. R., Fish J. E., Peters S. P. A controlled trial of the effect of the 5-lipoxygenase inhibitor, zileuton, on lung inflammation produced by segmental antigen challenge in human beings. J Allergy Clin Immunol. 1996 Feb;97(2):646–654. doi: 10.1016/s0091-6749(96)70310-x. [DOI] [PubMed] [Google Scholar]
  24. Laberge S., Rabb H., Issekutz T. B., Martin J. G. Role of VLA-4 and LFA-1 in allergen-induced airway hyperresponsiveness and lung inflammation in the rat. Am J Respir Crit Care Med. 1995 Mar;151(3 Pt 1):822–829. doi: 10.1164/ajrccm.151.3.7881677. [DOI] [PubMed] [Google Scholar]
  25. 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]
  26. Lu H., Smith C. W., Perrard J., Bullard D., Tang L., Shappell S. B., Entman M. L., Beaudet A. L., Ballantyne C. M. LFA-1 is sufficient in mediating neutrophil emigration in Mac-1-deficient mice. J Clin Invest. 1997 Mar 15;99(6):1340–1350. doi: 10.1172/JCI119293. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Lukacs N. W., Strieter R. M., Warmington K., Lincoln P., Chensue S. W., Kunkel S. L. Differential recruitment of leukocyte populations and alteration of airway hyperreactivity by C-C family chemokines in allergic airway inflammation. J Immunol. 1997 May 1;158(9):4398–4404. [PubMed] [Google Scholar]
  28. Maghni K., de Brum-Fernandes A. J., Földes-Filep E., Gaudry M., Borgeat P., Sirois P. Leukotriene B4 receptors on guinea pig alveolar eosinophils. J Pharmacol Exp Ther. 1991 Sep;258(3):784–789. [PubMed] [Google Scholar]
  29. McIntyre T. M., Zimmerman G. A., Prescott S. M. Leukotrienes C4 and D4 stimulate human endothelial cells to synthesize platelet-activating factor and bind neutrophils. Proc Natl Acad Sci U S A. 1986 Apr;83(7):2204–2208. doi: 10.1073/pnas.83.7.2204. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Namovic M. T., Walsh R. E., Goodfellow C., Harris R. R., Carter G. W., Bell R. L. Pharmacological modulation of eosinophil influx into the lungs of Brown Norway rats. Eur J Pharmacol. 1996 Nov 7;315(1):81–88. doi: 10.1016/s0014-2999(96)00590-0. [DOI] [PubMed] [Google Scholar]
  31. Norgauer J., Barbisch M., Czech W., Pareigis J., Schwenk U., Schröder J. M. Chemotactic 5-oxo-icosatetraenoic acids activate a unique pattern of neutrophil responses. Analysis of phospholipid metabolism, intracellular Ca2+ transients, actin reorganization, superoxide-anion production and receptor up-regulation. Eur J Biochem. 1996 Mar 15;236(3):1003–1009. doi: 10.1111/j.1432-1033.1996.01003.x. [DOI] [PubMed] [Google Scholar]
  32. O'Flaherty J. T., Cordes J. F., Lee S. L., Samuel M., Thomas M. J. Chemical and biological characterization of oxo-eicosatetraenoic acids. Biochim Biophys Acta. 1994 Dec 15;1201(3):505–515. doi: 10.1016/0304-4165(94)90083-3. [DOI] [PubMed] [Google Scholar]
  33. O'Flaherty J. T., Kuroki M., Nixon A. B., Wijkander J., Yee E., Lee S. L., Smitherman P. K., Wykle R. L., Daniel L. W. 5-Oxo-eicosanoids and hematopoietic cytokines cooperate in stimulating neutrophil function and the mitogen-activated protein kinase pathway. J Biol Chem. 1996 Jul 26;271(30):17821–17828. doi: 10.1074/jbc.271.30.17821. [DOI] [PubMed] [Google Scholar]
  34. O'Flaherty J. T., Kuroki M., Nixon A. B., Wijkander J., Yee E., Lee S. L., Smitherman P. K., Wykle R. L., Daniel L. W. 5-Oxo-eicosatetraenoate is a broadly active, eosinophil-selective stimulus for human granulocytes. J Immunol. 1996 Jul 1;157(1):336–342. [PubMed] [Google Scholar]
  35. Powell W. S., Chung D., Gravel S. 5-Oxo-6,8,11,14-eicosatetraenoic acid is a potent stimulator of human eosinophil migration. J Immunol. 1995 Apr 15;154(8):4123–4132. [PubMed] [Google Scholar]
  36. Powell W. S., Gravel S., Halwani F., Hii C. S., Huang Z. H., Tan A. M., Ferrante A. Effects of 5-oxo-6,8,11,14-eicosatetraenoic acid on expression of CD11b, actin polymerization, and adherence in human neutrophils. J Immunol. 1997 Sep 15;159(6):2952–2959. [PubMed] [Google Scholar]
  37. Powell W. S., Gravel S., MacLeod R. J., Mills E., Hashefi M. Stimulation of human neutrophils by 5-oxo-6,8,11,14-eicosatetraenoic acid by a mechanism independent of the leukotriene B4 receptor. J Biol Chem. 1993 May 5;268(13):9280–9286. [PubMed] [Google Scholar]
  38. Powell W. S., Gravelle F., Gravel S. Metabolism of 5(S)-hydroxy-6,8,11,14-eicosatetraenoic acid and other 5(S)-hydroxyeicosanoids by a specific dehydrogenase in human polymorphonuclear leukocytes. J Biol Chem. 1992 Sep 25;267(27):19233–19241. [PubMed] [Google Scholar]
  39. Richards I. M., Kolbasa K. P., Hatfield C. A., Winterrowd G. E., Vonderfecht S. L., Fidler S. F., Griffin R. L., Brashler J. R., Krzesicki R. F., Sly L. M. Role of very late activation antigen-4 in the antigen-induced accumulation of eosinophils and lymphocytes in the lungs and airway lumen of sensitized brown Norway rats. Am J Respir Cell Mol Biol. 1996 Aug;15(2):172–183. doi: 10.1165/ajrcmb.15.2.8703473. [DOI] [PubMed] [Google Scholar]
  40. Richards I. M., Sun F. F., Taylor B. M., Shields S. K., Griffin R. L., Morris J., Wishka D. G., Smith H. W., Johnson R. A., Dunn C. J. Contribution of leukotriene B4 to airway inflammation and the effect of antagonists. Ann N Y Acad Sci. 1991;629:274–287. doi: 10.1111/j.1749-6632.1991.tb37983.x. [DOI] [PubMed] [Google Scholar]
  41. Rot A., Krieger M., Brunner T., Bischoff S. C., Schall T. J., Dahinden C. A. RANTES and macrophage inflammatory protein 1 alpha induce the migration and activation of normal human eosinophil granulocytes. J Exp Med. 1992 Dec 1;176(6):1489–1495. doi: 10.1084/jem.176.6.1489. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Rothenberg M. E., MacLean J. A., Pearlman E., Luster A. D., Leder P. Targeted disruption of the chemokine eotaxin partially reduces antigen-induced tissue eosinophilia. J Exp Med. 1997 Feb 17;185(4):785–790. doi: 10.1084/jem.185.4.785. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Schwenk U., Morita E., Engel R., Schröder J. M. Identification of 5-oxo-15-hydroxy-6,8,11,13-eicosatetraenoic acid as a novel and potent human eosinophil chemotactic eicosanoid. J Biol Chem. 1992 Jun 25;267(18):12482–12488. [PubMed] [Google Scholar]
  44. Schwenk U., Schröder J. M. 5-Oxo-eicosanoids are potent eosinophil chemotactic factors. Functional characterization and structural requirements. J Biol Chem. 1995 Jun 23;270(25):15029–15036. doi: 10.1074/jbc.270.25.15029. [DOI] [PubMed] [Google Scholar]
  45. Seeds E. A., Kilfeather S., Okiji S., Schoupe T. S., Donigi-Gale D., Page C. P. Role of lipoxygenase metabolites in platelet-activating factor- and antigen-induced bronchial hyperresponsiveness and eosinophil infiltration. Eur J Pharmacol. 1995 Dec 7;293(4):369–376. doi: 10.1016/0926-6917(95)90057-8. [DOI] [PubMed] [Google Scholar]
  46. Sehmi R., Cromwell O., Taylor G. W., Kay A. B. Identification of guinea pig eosinophil chemotactic factor of anaphylaxis as leukotriene B4 and 8(S),15(S)-dihydroxy-5,9,11,13(Z,E,Z,E)-eicosatetraenoic acid. J Immunol. 1991 Oct 1;147(7):2276–2283. [PubMed] [Google Scholar]
  47. Seminario M. C., Gleich G. J. The role of eosinophils in the pathogenesis of asthma. Curr Opin Immunol. 1994 Dec;6(6):860–864. doi: 10.1016/0952-7915(94)90005-1. [DOI] [PubMed] [Google Scholar]
  48. Sirois P., Chagnon M., Borgeat P., Vallerand P. Role of cyclooxygenase products in the lung action of leukotrienes A4, B4, C4, D4 and E4. Pharmacology. 1985;31(4):225–236. doi: 10.1159/000138119. [DOI] [PubMed] [Google Scholar]
  49. 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]
  50. Stellato C., Collins P., Ponath P. D., Soler D., Newman W., La Rosa G., Li H., White J., Schwiebert L. M., Bickel C. Production of the novel C-C chemokine MCP-4 by airway cells and comparison of its biological activity to other C-C chemokines. J Clin Invest. 1997 Mar 1;99(5):926–936. doi: 10.1172/JCI119257. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Wardlaw A. J., Walsh G. M., Symon F. A. Adhesion interactions involved in eosinophil migration through vascular endothelium. Ann N Y Acad Sci. 1996 Oct 31;796:124–137. doi: 10.1111/j.1749-6632.1996.tb32574.x. [DOI] [PubMed] [Google Scholar]
  52. 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]
  53. Ying S., Durham S. R., Barkans J., Masuyama K., Jacobson M., Rak S., Löwhagen O., Moqbel R., Kay A. B., Hamid Q. A. T cells are the principal source of interleukin-5 mRNA in allergen-induced rhinitis. Am J Respir Cell Mol Biol. 1993 Oct;9(4):356–360. doi: 10.1165/ajrcmb/9.4.356. [DOI] [PubMed] [Google Scholar]
  54. Zhang Y., Styhler A., Powell W. S. Synthesis of 5-oxo-6,8,11,14-eicosatetraenoic acid by human monocytes and lymphocytes. J Leukoc Biol. 1996 Jun;59(6):847–854. doi: 10.1002/jlb.59.6.847. [DOI] [PubMed] [Google Scholar]

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