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Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1994 Aug 16;91(17):8156–8159. doi: 10.1073/pnas.91.17.8156

Intrinsic 5-lipoxygenase activity is required for neutrophil responsivity.

D M Guidot 1, M J Repine 1, J Y Westcott 1, J E Repine 1
PMCID: PMC44564  PMID: 8058773

Abstract

We found that intrinsic neutrophil 5-lipoxygenase activity was necessary for human neutrophil adherence and chemotaxis in vitro and human neutrophil-mediated acute edematous injury in isolated perfused rat lungs given interleukin 8 intratracheally. Treatment with either Zileuton (a specific reversible competitive inhibitor of 5-lipoxygenase) or MK886 (a specific irreversible inhibitor of the 5-lipoxygenase activator protein) prevented stimulated neutrophil adherence and chemotaxis (but not superoxide anion production) in vitro. Zileuton- or MK886-inhibited neutrophil chemotaxis was not restored by adding leukotriene B4 in vitro. Perfusion with neutrophils and either Zileuton or MK886, or with MK886-pretreated neutrophils (without adding MK886 to the perfusate), also prevented lung injury (reflected by lung weight gain and lung Ficoll retention) and perfusate leukotriene B4 increases in isolated rat lungs given interleukin 8 intratracheally. Again, adding leukotriene B4 to the perfusate did not damage interleukin 8-treated isolated lungs perfused with Zileuton-inhibited neutrophils. We conclude that intrinsic 5-lipoxygenase activity is required for neutrophil adherence and chemotaxis and neutrophil-mediated lung injury.

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Selected References

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  1. Antoine C., Lellouche J. P., Maclouf J., Pradelles P. Development of enzyme immunoassays for leukotrienes using acetylcholinesterase. Biochim Biophys Acta. 1991 Oct 10;1075(2):162–168. doi: 10.1016/0304-4165(91)90247-e. [DOI] [PubMed] [Google Scholar]
  2. Bell R. L., Young P. R., Albert D., Lanni C., Summers J. B., Brooks D. W., Rubin P., Carter G. W. The discovery and development of zileuton: an orally active 5-lipoxygenase inhibitor. Int J Immunopharmacol. 1992 Apr;14(3):505–510. doi: 10.1016/0192-0561(92)90182-k. [DOI] [PubMed] [Google Scholar]
  3. Brom J., König W. Cytokine-induced (interleukins-3, -6 and -8 and tumour necrosis factor-beta) activation and deactivation of human neutrophils. Immunology. 1992 Feb;75(2):281–285. [PMC free article] [PubMed] [Google Scholar]
  4. Crapo J. D., McCord J. M., Fridovich I. Preparation and assay of superoxide dismutases. Methods Enzymol. 1978;53:382–393. doi: 10.1016/s0076-6879(78)53044-9. [DOI] [PubMed] [Google Scholar]
  5. Cunningham S. K., Keaveny T. V. Effect of a xanthine oxidase inhibitor on adenine nucleotide degradation in hemorrhagic shock. Eur Surg Res. 1978;10(5):305–313. doi: 10.1159/000128020. [DOI] [PubMed] [Google Scholar]
  6. Donnelly S. C., Strieter R. M., Kunkel S. L., Walz A., Robertson C. R., Carter D. C., Grant I. S., Pollok A. J., Haslett C. Interleukin-8 and development of adult respiratory distress syndrome in at-risk patient groups. Lancet. 1993 Mar 13;341(8846):643–647. doi: 10.1016/0140-6736(93)90416-e. [DOI] [PubMed] [Google Scholar]
  7. Fitzpatrick F., Liggett W., McGee J., Bunting S., Morton D., Samuelsson B. Metabolism of leukotriene A4 by human erythrocytes. A novel cellular source of leukotriene B4. J Biol Chem. 1984 Sep 25;259(18):11403–11407. [PubMed] [Google Scholar]
  8. Grimminger F., Sibelius U., Aktories K., Suttorp N., Seeger W. Inhibition of cytoskeletal rearrangement by botulinum C2 toxin amplifies ligand-evoked lipid mediator generation in human neutrophils. Mol Pharmacol. 1991 Oct;40(4):563–571. [PubMed] [Google Scholar]
  9. Grimminger F., Sibelius U., Seeger W. Amplification of LTB4 generation in AM-PMN cocultures: transcellular 5-lipoxygenase metabolism. Am J Physiol. 1991 Aug;261(2 Pt 1):L195–L203. doi: 10.1152/ajplung.1991.261.2.L195. [DOI] [PubMed] [Google Scholar]
  10. Haines K. A., Giedd K. N., Rich A. M., Korchak H. M., Weissmann G. The leukotriene B4 paradox: neutrophils can, but will not, respond to ligand-receptor interactions by forming leukotriene B4 or its omega-metabolites. Biochem J. 1987 Jan 1;241(1):55–62. doi: 10.1042/bj2410055. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hoch R. C., Rodriguez R., Manning T., Bishop M., Mead P., Shoemaker W. C., Abraham E. Effects of accidental trauma on cytokine and endotoxin production. Crit Care Med. 1993 Jun;21(6):839–845. doi: 10.1097/00003246-199306000-00010. [DOI] [PubMed] [Google Scholar]
  12. Kunkel S. L., Standiford T., Kasahara K., Strieter R. M. Interleukin-8 (IL-8): the major neutrophil chemotactic factor in the lung. Exp Lung Res. 1991 Jan-Feb;17(1):17–23. doi: 10.3109/01902149109063278. [DOI] [PubMed] [Google Scholar]
  13. MacGregor R. R., Spagnuolo P. J., Lentnek A. L. Inhibition of granulocyte adherence by ethanol, prednisone, and aspirin, measured with an assay system. N Engl J Med. 1974 Sep 26;291(13):642–646. doi: 10.1056/NEJM197409262911302. [DOI] [PubMed] [Google Scholar]
  14. Marcus A. J., Broekman M. J., Safier L. B., Ullman H. L., Islam N., Serhan C. N., Weissmann G. Production of arachidonic acid lipoxygenase products during platelet-neutrophil interactions. Clin Physiol Biochem. 1984;2(2-3):78–83. [PubMed] [Google Scholar]
  15. Miller E. J., Cohen A. B., Nagao S., Griffith D., Maunder R. J., Martin T. R., Weiner-Kronish J. P., Sticherling M., Christophers E., Matthay M. A. Elevated levels of NAP-1/interleukin-8 are present in the airspaces of patients with the adult respiratory distress syndrome and are associated with increased mortality. Am Rev Respir Dis. 1992 Aug;146(2):427–432. doi: 10.1164/ajrccm/146.2.427. [DOI] [PubMed] [Google Scholar]
  16. Pradelles P., Grassi J., Maclouf J. Enzyme immunoassays of eicosanoids using acetylcholine esterase as label: an alternative to radioimmunoassay. Anal Chem. 1985 Jun;57(7):1170–1173. doi: 10.1021/ac00284a003. [DOI] [PubMed] [Google Scholar]
  17. Repine J. E. Scientific perspectives on adult respiratory distress syndrome. Lancet. 1992 Feb 22;339(8791):466–469. doi: 10.1016/0140-6736(92)91067-i. [DOI] [PubMed] [Google Scholar]
  18. Rouzer C. A., Ford-Hutchinson A. W., Morton H. E., Gillard J. W. MK886, a potent and specific leukotriene biosynthesis inhibitor blocks and reverses the membrane association of 5-lipoxygenase in ionophore-challenged leukocytes. J Biol Chem. 1990 Jan 25;265(3):1436–1442. [PubMed] [Google Scholar]
  19. 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]
  20. Schröder J. M. The monocyte-derived neutrophil activating peptide (NAP/interleukin 8) stimulates human neutrophil arachidonate-5-lipoxygenase, but not the release of cellular arachidonate. J Exp Med. 1989 Sep 1;170(3):847–863. doi: 10.1084/jem.170.3.847. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Seeger W., Grimminger F., Barden M., Becker G., Lohmeyer J., Heinrich D., Lasch H. G. Omega-oxidized leukotriene B4 detected in the broncho-alveolar lavage fluid of patients with non-cardiogenic pulmonary edema, but not in those with cardiogenic edema. Intensive Care Med. 1991;17(1):1–6. doi: 10.1007/BF01708400. [DOI] [PubMed] [Google Scholar]

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