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. 1991 Jun;46(6):441–445. doi: 10.1136/thx.46.6.441

Participation of the cysteinyl leukotrienes in the acute bronchoconstrictor response to inhaled platelet activating factor in man.

D A Spencer 1, J M Evans 1, S E Green 1, P J Piper 1, J F Costello 1
PMCID: PMC463193  PMID: 1858084

Abstract

To determine whether the effects of platelet activating factor on the airways may be due to the production of leukotrienes we studied the effects of pretreatment with the selective cysteinyl leukotriene antagonist SK&F 104353-Z2 on the airway and cellular responses to inhaled platelet activating factor. Eight healthy men were studied in a randomised, double blind placebo controlled cross-over study. A single dose of platelet activating factor that caused a fall of at least 35% in specific airways conductance (sGaw) was determined initially for each subject. Challenge with this dose of platelet activating factor was then carried out on two further occasions after pretreatment with a single nebulised dose of SK&F 104353-Z2 or placebo. The % reductions in specific airways conductance and of partial flow at 30% of vital capacity (PVmax30) were less after SK&F 104353-Z2 than after placebo (22 versus 34 for sGaw, 19 versus 31 for PVmax30). The mean (95% confidence limits (CL] differences in the maximum % fall from control values for SK&F 104353-Z2 and placebo were -12.6 (-23.8, -1.4) for sGaw and -12.5, (-20.8 -4.2) for PVmax30. The mean % fall in neutrophil count was similar after SK&F 104353-Z2 (46%) and after placebo (50%) (95% CL of difference 13.6, 6.6). Bronchial responsiveness to methacholine did not increase above baseline values in any subject when measured two weeks after challenge by platelet activating factor. This study suggests that leukotrienes play a part in the response to platelet activating factor in man.

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Selected References

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  1. Arm J. P., Spur B. W., Lee T. H. The effects of inhaled leukotriene E4 on the airway responsiveness to histamine in subjects with asthma and normal subjects. J Allergy Clin Immunol. 1988 Oct;82(4):654–660. doi: 10.1016/0091-6749(88)90979-7. [DOI] [PubMed] [Google Scholar]
  2. Barnes P. J., Chung K. F., Page C. P. Inflammatory mediators and asthma. Pharmacol Rev. 1988 Mar;40(1):49–84. [PubMed] [Google Scholar]
  3. Barnes P. J., Chung K. F., Page C. P. Platelet-activating factor as a mediator of allergic disease. J Allergy Clin Immunol. 1988 May;81(5 Pt 1):919–934. doi: 10.1016/0091-6749(88)90952-9. [DOI] [PubMed] [Google Scholar]
  4. Bland J. M., Altman D. G. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet. 1986 Feb 8;1(8476):307–310. [PubMed] [Google Scholar]
  5. Bonnet J., Thibaudeau D., Bessin P. Dependency of the Paf-acether induced bronchospasm on the lipoxygenase pathway in the guinea-pig. Prostaglandins. 1983 Sep;26(3):457–466. doi: 10.1016/0090-6980(83)90180-6. [DOI] [PubMed] [Google Scholar]
  6. Bruynzeel P. L., Koenderman L., Kok P. T., Hameling M. L., Verhagen J. Platelet-activating factor (PAF-acether) induced leukotriene C4 formation and luminol dependent chemiluminescence by human eosinophils. Pharmacol Res Commun. 1986 Aug;18 (Suppl):61–69. doi: 10.1016/0031-6989(86)90039-1. [DOI] [PubMed] [Google Scholar]
  7. Camussi G., Montrucchio G., Antro C., Bussolino F., Tetta C., Emanuelli G. Platelet-activating factor-mediated contraction of rabbit lung strips: pharmacologic modulation. Immunopharmacology. 1983 Aug;6(2):87–96. doi: 10.1016/0162-3109(83)90002-4. [DOI] [PubMed] [Google Scholar]
  8. Chung K. F., Aizawa H., Leikauf G. D., Ueki I. F., Evans T. W., Nadel J. A. Airway hyperresponsiveness induced by platelet-activating factor: role of thromboxane generation. J Pharmacol Exp Ther. 1986 Mar;236(3):580–584. [PubMed] [Google Scholar]
  9. Cockcroft D. W., Berscheid B. A. Measurement of responsiveness to inhaled histamine: comparison of FEV1 and SGaw. Ann Allergy. 1983 Sep;51(3):374–377. [PubMed] [Google Scholar]
  10. Cuss F. M., Dixon C. M., Barnes P. J. Effects of inhaled platelet activating factor on pulmonary function and bronchial responsiveness in man. Lancet. 1986 Jul 26;2(8500):189–192. doi: 10.1016/s0140-6736(86)92489-x. [DOI] [PubMed] [Google Scholar]
  11. DUBOIS A. B., BOTELHO S. Y., COMROE J. H., Jr A new method for measuring airway resistance in man using a body plethysmograph: values in normal subjects and in patients with respiratory disease. J Clin Invest. 1956 Mar;35(3):327–335. doi: 10.1172/JCI103282. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Dent G., Ukena D., Chanez P., Sybrecht G., Barnes P. Characterization of PAF receptors on human neutrophils using the specific antagonist, WEB 2086. Correlation between receptor binding and function. FEBS Lett. 1989 Feb 27;244(2):365–368. doi: 10.1016/0014-5793(89)80564-2. [DOI] [PubMed] [Google Scholar]
  13. Drazen J. M., Austen K. F. Leukotrienes and airway responses. Am Rev Respir Dis. 1987 Oct;136(4):985–998. doi: 10.1164/ajrccm/136.4.985. [DOI] [PubMed] [Google Scholar]
  14. Fuller R. W., Dixon C. M., Dollery C. T., Barnes P. J. Prostaglandin D2 potentiates airway responsiveness to histamine and methacholine. Am Rev Respir Dis. 1986 Feb;133(2):252–254. doi: 10.1164/arrd.1986.133.2.252. [DOI] [PubMed] [Google Scholar]
  15. Hay D. W., Muccitelli R. M., Tucker S. S., Vickery-Clark L. M., Wilson K. A., Gleason J. G., Hall R. F., Wasserman M. A., Torphy T. J. Pharmacologic profile of SK&F 104353: a novel, potent and selective peptidoleukotriene receptor antagonist in guinea pig and human airways. J Pharmacol Exp Ther. 1987 Nov;243(2):474–481. [PubMed] [Google Scholar]
  16. Hwang S. B., Lam M. H., Shen T. Y. Specific binding sites for platelet activating factor in human lung tissues. Biochem Biophys Res Commun. 1985 Apr 30;128(2):972–979. doi: 10.1016/0006-291x(85)90142-1. [DOI] [PubMed] [Google Scholar]
  17. Jancar S., Thériault P., Lauzière M., Braquet P., Sirois P. Paf-induced release of spasmogens from guinea-pig lungs. Br J Pharmacol. 1989 Jan;96(1):153–162. doi: 10.1111/j.1476-5381.1989.tb11795.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Lai C. K., Jenkins J. R., Polosa R., Holgate S. T. Inhaled PAF fails to induce airway hyperresponsiveness to methacholine in normal human subjects. J Appl Physiol (1985) 1990 Mar;68(3):919–926. doi: 10.1152/jappl.1990.68.3.919. [DOI] [PubMed] [Google Scholar]
  19. Larsson K., Hedenström H., Malmberg P. Learning effects, variation during office hours and reproducibility of static and dynamic spirometry. Respiration. 1987;51(3):214–222. doi: 10.1159/000195204. [DOI] [PubMed] [Google Scholar]
  20. Phillips G. D., Holgate S. T. Interaction of inhaled LTC4 with histamine and PGD2 on airway caliber in asthma. J Appl Physiol (1985) 1989 Jan;66(1):304–312. doi: 10.1152/jappl.1989.66.1.304. [DOI] [PubMed] [Google Scholar]
  21. Piper P. J. Formation and actions of leukotrienes. Physiol Rev. 1984 Apr;64(2):744–761. doi: 10.1152/physrev.1984.64.2.744. [DOI] [PubMed] [Google Scholar]
  22. Rubin A. H., Smith L. J., Patterson R. The bronchoconstrictor properties of platelet-activating factor in humans. Am Rev Respir Dis. 1987 Nov;136(5):1145–1151. doi: 10.1164/ajrccm/136.5.1145. [DOI] [PubMed] [Google Scholar]
  23. Sisson J. H., Prescott S. M., McIntyre T. M., Zimmerman G. A. Production of platelet-activating factor by stimulated human polymorphonuclear leukocytes. Correlation of synthesis with release, functional events, and leukotriene B4 metabolism. J Immunol. 1987 Jun 1;138(11):3918–3926. [PubMed] [Google Scholar]
  24. Smith L. J., Rubin A. H., Patterson R. Mechanism of platelet activating factor-induced bronchoconstriction in humans. Am Rev Respir Dis. 1988 May;137(5):1015–1019. doi: 10.1164/ajrccm/137.5.1015. [DOI] [PubMed] [Google Scholar]
  25. Stimler N. P., O'Flaherty J. T. Spasmogenic properties of platelet-activating factor: evidence for a direct mechanism in the contractile response of pulmonary tissues. Am J Pathol. 1983 Oct;113(1):75–84. [PMC free article] [PubMed] [Google Scholar]
  26. Tattersfield A. E., Keeping I. M. Assessing change in airway calibre--measurement of airway resistance. Br J Clin Pharmacol. 1979 Oct;8(4):307–319. doi: 10.1111/j.1365-2125.1979.tb04711.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Voelkel N. F., Worthen S., Reeves J. T., Henson P. M., Murphy R. C. Nonimmunological production of leukotrienes induced by platelet-activating factor. Science. 1982 Oct 15;218(4569):286–289. doi: 10.1126/science.7123233. [DOI] [PubMed] [Google Scholar]
  28. Weiss J. W., Drazen J. M., McFadden E. R., Jr, Weller P., Corey E. J., Lewis R. A., Austen K. F. Airway constriction in normal humans produced by inhalation of leukotriene D. Potency, time course, and effect of aspirin therapy. JAMA. 1983 May 27;249(20):2814–2817. [PubMed] [Google Scholar]
  29. Weiss P. H., Klein L. The quantitative relationship of urinary peptide hydroxyproline excretion to collagen degradation. J Clin Invest. 1969 Jan;48(1):1–10. doi: 10.1172/JCI105957. [DOI] [PMC free article] [PubMed] [Google Scholar]

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