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. 1985 Dec 1;162(6):1904–1915. doi: 10.1084/jem.162.6.1904

Studies on the release of leukotrienes and histamine by human lung parenchymal and bronchial fragments upon immunologic and nonimmunologic stimulation. Effects of nordihydroguaiaretic acid, aspirin, and sodium cromoglycate

PMCID: PMC2187985  PMID: 2415659

Abstract

Fragments of human lung parenchyma or bronchi were studied by high performance liquid chromatography, gas chromatography-mass spectrometry, and bioassay for the biosynthesis of 5-lipoxygenase metabolites of arachidonic acid, and by radioenzymatic assay for the release of histamine, upon immunologic and nonimmunologic stimulation. Human lung parenchyma were passively sensitized with serum from timothy- positive allergic patients (radioallergosorbent test, 30-40%) and challenged with 0.5 microgram/ml of timothy allergen. Analysis of the incubation media showed the presence of LTB4, LTC4, LTD4, LTE4, and histamine. Maximum release of LTB4 and LTD4 was observed after 15 min of challenge (92.8 +/- 21, and 67.8 +/- 14 pmol/g tissue wet weight, respectively; mean +/- SEM) whereas maximum release of LTC4 was observed after 5 min of challenge (25 +/- 7.1 pmol). In parallel to leukotriene formation, histamine was released rapidly and reached a maximum after approximately 15 min of challenge (2.85 +/- 0.76 nmol/g tissue). When fragments of human lung parenchyma were stimulated with ionophore A23187 (4 microM), we observed a profile of leukotriene and histamine release similar to that seen in response to the allergen. Ionophore A23187 stimulated the release of two- to fivefold greater amounts of leukotrienes and histamine than did the allergen. Release of LTC4 and histamine was maximal after 5 min of stimulation (83 +/- 22.2 and 5.2 +/- 0.95 nmol/g tissue, respectively), whereas LTB4 and LTD4 release reached a maximum after 15 min (438 +/- 66.6 and 205 +/- 68 nmol/g tissue, respectively). In addition, human lung parenchyma metabolized LTB4 into omega-OH-LTB4 and omega-COOH-LTB4. This tissue also released 5-hydroxy-eicosatetraenoic acid (5-Hete), 12-Hete, and 15- Hete. Fragments of human lung bronchi also released a similar profile of leukotrienes (except LTC4) and histamine when challenged with the allergen or ionophore A23187. Maximum release of LTB4 and LTD4 by allergen or ionophore stimulation was observed after approximately 15 min (40 +/- 7.5 and 21 +/- 8 pmol/g tissue, respectively, upon allergen challenge; 100 +/- 13 and 47 +/- 10.6 pmol/g tissue, respectively, upon ionophore stimulation). The maximum release of histamine by bronchi was observed after approximately 15 min of allergen challenge and 5 min of ionophore stimulation (2.25 +/- 0.65 and 3.15 +/- 0.9 nmol/g tissue, respectively). The release of leukotrienes but not of histamine by human lung parenchyma upon both allergen and ionophore challenge was inhibited by nordihydroguaiaretic acid (NDGA) (ID50, 2 X 10(- 6)M).(ABSTRACT TRUNCATED AT 400 WORDS)

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Selected References

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  1. Borgeat P., Fruteau de Laclos B., Rabinovitch H., Picard S., Braquet P., Hébert J., Laviolette M. Eosinophil-rich human polymorphonuclear leukocyte preparations characteristically release leukotriene C4 on ionophore A23187 challenge. J Allergy Clin Immunol. 1984 Sep;74(3 Pt 2):310–315. doi: 10.1016/0091-6749(84)90122-2. [DOI] [PubMed] [Google Scholar]
  2. Borgeat P., Picard S., Vallerand P., Sirois P. Transformation of arachidonic acid in leukocytes. Isolation and structural analysis of a novel dihydroxy derivative. Prostaglandins Med. 1981 Jun;6(6):557–570. doi: 10.1016/0161-4630(81)90117-8. [DOI] [PubMed] [Google Scholar]
  3. Borgeat P., Samuelsson B. Metabolism of arachidonic acid in polymorphonuclear leukocytes. Structural analysis of novel hydroxylated compounds. J Biol Chem. 1979 Aug 25;254(16):7865–7869. [PubMed] [Google Scholar]
  4. Borgeat P., Samuelsson B. Transformation of arachidonic acid by rabbit polymorphonuclear leukocytes. Formation of a novel dihydroxyeicosatetraenoic acid. J Biol Chem. 1979 Apr 25;254(8):2643–2646. [PubMed] [Google Scholar]
  5. Borgeat P., Samuelsson B. Transformation of arachidonic acid by rabbit polymorphonuclear leukocytes. Formation of a novel dihydroxyeicosatetraenoic acid. J Biol Chem. 1979 Apr 25;254(8):2643–2646. [PubMed] [Google Scholar]
  6. Camp R. D., Woollard P. M., Mallet A. I., Fincham N. J., Ford-Hutchinson A. W., Bray M. A. Neutrophil aggregating and chemokinetic properties of a 5,12,20-trihydroxy-6,8,10,14-eicosatetraenoic acid isolated from human leukocytes. Prostaglandins. 1982 May;23(5):631–641. doi: 10.1016/s0090-6980(82)80003-8. [DOI] [PubMed] [Google Scholar]
  7. 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]
  8. Craps L. Ketotifen in the oral prophylaxis of bronchial asthma: a review. Pharmatherapeutica. 1981;3(1):18–35. [PubMed] [Google Scholar]
  9. Dahlén S. E., Björk J., Hedqvist P., Arfors K. E., Hammarström S., Lindgren J. A., Samuelsson B. Leukotrienes promote plasma leakage and leukocyte adhesion in postcapillary venules: in vivo effects with relevance to the acute inflammatory response. Proc Natl Acad Sci U S A. 1981 Jun;78(6):3887–3891. doi: 10.1073/pnas.78.6.3887. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Dahlén S. E., Hedqvist P., Hammarström S., Samuelsson B. Leukotrienes are potent constrictors of human bronchi. Nature. 1980 Dec 4;288(5790):484–486. doi: 10.1038/288484a0. [DOI] [PubMed] [Google Scholar]
  11. 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]
  12. Fels A. O., Pawlowski N. A., Cramer E. B., King T. K., Cohn Z. A., Scott W. A. Human alveolar macrophages produce leukotriene B4. Proc Natl Acad Sci U S A. 1982 Dec;79(24):7866–7870. doi: 10.1073/pnas.79.24.7866. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Ford-Hutchinson A. W., Bray M. A., Doig M. V., Shipley M. E., Smith M. J. Leukotriene B, a potent chemokinetic and aggregating substance released from polymorphonuclear leukocytes. Nature. 1980 Jul 17;286(5770):264–265. doi: 10.1038/286264a0. [DOI] [PubMed] [Google Scholar]
  14. Ford-Hutchinson A. W., Rackham A., Zamboni R., Rokach J., Roy S. Comparative biological activities of synthetic leukotriene B4 and its omega-oxidation products. Prostaglandins. 1983 Jan;25(1):29–37. doi: 10.1016/0090-6980(83)90132-6. [DOI] [PubMed] [Google Scholar]
  15. Godfrey S., König P. Inhibition of exercise-induced asthma by different pharmacological pathways. Thorax. 1976 Apr;31(2):137–143. doi: 10.1136/thx.31.2.137. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Goetzl E. J. Mediators of immediate hypersensitivity derived from arachidonic acid. N Engl J Med. 1980 Oct 2;303(14):822–825. doi: 10.1056/NEJM198010023031421. [DOI] [PubMed] [Google Scholar]
  17. Griffin M., Weiss J. W., Leitch A. G., McFadden E. R., Jr, Corey E. J., Austen K. F., Drazen J. M. Effects of leukotriene D on the airways in asthma. N Engl J Med. 1983 Feb 24;308(8):436–439. doi: 10.1056/NEJM198302243080807. [DOI] [PubMed] [Google Scholar]
  18. Hanna C. J., Bach M. K., Pare P. D., Schellenberg R. R. Slow-reacting substances (leukotrienes) contract human airway and pulmonary vascular smooth muscle in vitro. Nature. 1981 Mar 26;290(5804):343–344. doi: 10.1038/290343a0. [DOI] [PubMed] [Google Scholar]
  19. Hansson G., Björck T., Dahlén S. E., Hedqvist P., Granström E., Dahlén B. Specific allergen induces contraction of bronchi and formation of leukotrienes C4, D4, and E4 in human asthmatic lung. Adv Prostaglandin Thromboxane Leukot Res. 1983;12:153–159. [PubMed] [Google Scholar]
  20. Hansson G., Lindgren J. A., Dahlén S. E., Hedqvist P., Samuelsson B. Identification and biological activity of novel omega-oxidized metabolites of leukotriene B4 from human leukocytes. FEBS Lett. 1981 Jul 20;130(1):107–112. doi: 10.1016/0014-5793(81)80676-x. [DOI] [PubMed] [Google Scholar]
  21. Holroyde M. C., Altounyan R. E., Cole M., Dixon M., Elliott E. V. Bronchoconstriction produced in man by leukotrienes C and D. Lancet. 1981 Jul 4;2(8236):17–18. doi: 10.1016/s0140-6736(81)90254-3. [DOI] [PubMed] [Google Scholar]
  22. 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]
  23. Jubiz W., Rådmark O., Malmsten C., Hansson G., Lindgren J. A., Palmblad J., Udén A. M., Samuelsson B. A novel leukotriene produced by stimulation of leukocytes with formylmethionylleucylphenylalanine. J Biol Chem. 1982 Jun 10;257(11):6106–6110. [PubMed] [Google Scholar]
  24. 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]
  25. Morris H. R., Taylor G. W., Piper P. J., Samhoun M. N., Tippins J. R. Slow reacting substances (SRSs): the structure identification of SRSs from rat basophil leukaemia (RBL-1) cells. Prostaglandins. 1980 Feb;19(2):185–201. doi: 10.1016/0090-6980(80)90019-2. [DOI] [PubMed] [Google Scholar]
  26. Murphy R. C., Hammarström S., Samuelsson B. Leukotriene C: a slow-reacting substance from murine mastocytoma cells. Proc Natl Acad Sci U S A. 1979 Sep;76(9):4275–4279. doi: 10.1073/pnas.76.9.4275. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. O'Flaherty J. T., Thomas M. J., Cousart S. L., Salzer W. L., McCall C. E. Neutropenia induced by systemic infusion of 5,12-dihydroxy-6,8,10,14-eicosatetraenoic acid: correlation with its in vitro effects upon neutrophils. J Clin Invest. 1982 Apr;69(4):993–998. doi: 10.1172/JCI110539. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Patel K. R. Calcium antagonists in exercise-induced asthma. Br Med J (Clin Res Ed) 1981 Mar 21;282(6268):932–933. doi: 10.1136/bmj.282.6268.932. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Pepys J., Davies R. J., Breslin A. B., Hendrick D. J., Hutchcroft B. J. The effects of inhaled beclomethasone dipropionate (Becotide) and sodium cromoglycate on asthmatic reactions to provocation tests. Clin Allergy. 1974 Mar;4(1):13–24. doi: 10.1111/j.1365-2222.1974.tb01358.x. [DOI] [PubMed] [Google Scholar]
  30. Peters S. P., Kagey-Sobotka A., MacGlashan D. W., Jr, Siegel M. I., Lichtenstein L. M. The modulation of human basophil histamine release by products of the 5-lipoxygenase pathway. J Immunol. 1982 Aug;129(2):797–803. [PubMed] [Google Scholar]
  31. Peters S. P., MacGlashan D. W., Jr, Schulman E. S., Schleimer R. P., Hayes E. C., Rokach J., Adkinson N. F., Jr, Lichtenstein L. M. Arachidonic acid metabolism in purified human lung mast cells. J Immunol. 1984 Apr;132(4):1972–1979. [PubMed] [Google Scholar]
  32. Peters S. P., Siegel M. I., Kagey-Sobotka A., Lichtenstein L. M. Lipoxygenase products modulate histamine release in human basophils. Nature. 1981 Jul 30;292(5822):455–457. doi: 10.1038/292455a0. [DOI] [PubMed] [Google Scholar]
  33. Powell W. S. Rapid extraction of oxygenated metabolites of arachidonic acid from biological samples using octadecylsilyl silica. Prostaglandins. 1980 Nov;20(5):947–957. doi: 10.1016/0090-6980(80)90144-6. [DOI] [PubMed] [Google Scholar]
  34. SCHILD H. O., HAWKINS D. F., MONGAR J. L., HERXHEIMER H. Reactions of isolated human asthmatic lung and bronchial tissue to a specific antigen; histamine release and muscular contraction. Lancet. 1951 Sep 1;2(6679):376–382. doi: 10.1016/s0140-6736(51)91554-1. [DOI] [PubMed] [Google Scholar]
  35. Salari H., Braquet P., Borgeat P. Comparative effects of indomethacin, acetylenic acids, 15-HETE, nordihydroguaiaretic acid and BW755C on the metabolism of arachidonic acid in human leukocytes and platelets. Prostaglandins Leukot Med. 1984 Jan;13(1):53–60. doi: 10.1016/0262-1746(84)90102-1. [DOI] [PubMed] [Google Scholar]
  36. Samuelsson B. The leukotrienes: an introduction. Adv Prostaglandin Thromboxane Leukot Res. 1982;9:1–17. [PubMed] [Google Scholar]
  37. Sirois P., Roy S., Tétrault J. P., Borgeat P., Picard S., Corey E. J. Pharmacological activity of leukotrienes A4, B4, C4 and D4 on selected guinea-pig, rat, rabbit and human smooth muscles. Prostaglandins Med. 1981 Oct;7(4):327–340. doi: 10.1016/0161-4630(81)90137-3. [DOI] [PubMed] [Google Scholar]
  38. Smith M. J., Ford-Hutchinson A. W., Bray M. A. Leukotriene B: a potential mediator of inflammation. J Pharm Pharmacol. 1980 Jul;32(7):517–518. doi: 10.1111/j.2042-7158.1980.tb12985.x. [DOI] [PubMed] [Google Scholar]
  39. Stenson W. F., Parker C. W., Sullivan T. J. Augmentation of IgE-mediated release of histamine by 5-hydroxyeicosatetraenoic acid and 12-hydroxyeicosatetraenoic acid. Biochem Biophys Res Commun. 1980 Oct 16;96(3):1045–1052. doi: 10.1016/0006-291x(80)90058-3. [DOI] [PubMed] [Google Scholar]
  40. Ts'ao C. H., Metzger W. J., Patterson R., Suszko I. M. Histamine-containing cells in bronchial lavage fluid. I. Ultrastructural characterization and comparison with mast cells in three types of tissues of rhesus monkeys. Int Arch Allergy Appl Immunol. 1976;52(1-4):315–324. [PubMed] [Google Scholar]
  41. Verburg K. M., Bowsher R. R., Henry D. P. A new radioenzymatic assay for histamine using purified histamine N-methyltransferase. Life Sci. 1983 Jun 20;32(25):2855–2867. doi: 10.1016/0024-3205(83)90322-3. [DOI] [PubMed] [Google Scholar]
  42. Weiss J. W., Drazen J. M., Coles N., McFadden E. R., Jr, Weller P. F., Corey E. J., Lewis R. A., Austen K. F. Bronchoconstrictor effects of leukotriene C in humans. Science. 1982 Apr 9;216(4542):196–198. doi: 10.1126/science.7063880. [DOI] [PubMed] [Google Scholar]

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