Agents and Actions

, Volume 30, Issue 3–4, pp 329–337 | Cite as

Platelet activating factor and tracheobronchial respiratory glycoconjugate release in feline and human explants: Involvement of the lipoxygenase pathway

  • J. D. Lundgren
  • M. Kaliner
  • C. Logun
  • J. H. Shelhamer
Inflammation and Immunomodulation


It has been suggested that platelet activating factor (PAF) may participate in many aspects of bronchial asthma, including stimulation of mucus secretion. Feline tracheal and human bronchial explant production of respiratory glycoconjugates (RGC) in response to platelet activating factor (PAF) was investigatet, in order to differentiate the actions of this putative mediator on mucus secretion. PAF caused a dose-dependent increase in RGC release in concentrations ranging from 100–0.5 μM during a 1–2 hours incubation with either feline or human explants, and the effect was inhibited by the PAF receptor antagonists Ro 19-3704. Several lines of evidence suggest that PAF enhances RGC release indirectly through stimulation of the production of lipoxygenase metabolites of arachidonic acid. 1) Incubation of 10 μM PAF together with arachidonic acid (100 μg/ml) enhances PAF's stimulatory effect on RGC release in cats. 2) The cyclooxygenase inhibitor ibuprofen (65 and 420 μM) either failed to effect or slightly enhanced PAF induced RGC release in both species. 3) The combined cyclooxygenase and lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA) as well as the putatively specific 5-lipoxygenase inhibitor L-651, 392 (both at 50 μM) inhibited the response to PAF in both species. 4) The putative LTD4 receptor antagonists (L-660, 711, 100 μM) slightly reduced the PAF secretory response in human bronchi. We conclude that PAF causes specific receptor mediated RGC release. This response is indirectly mediated through the generation of lipoxygenase metabolite formation including 5-lipoxygenase pathway metabolites.


Arachidonic Acid Ibuprofen Platelet Activate Factor Mucus Secretion Nordihydroguaiaretic Acid 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. [1]
    R. N. Pinckard, J. C. Ludwig and L. M. McManus,Platelet-activating factors. InInflammation: Basic principles and clinical correlates. (Ed. J. I. Gallin, I. M. Goldstein, R. Snyderman) pp 139–167, Raven Press, New York 1988.Google Scholar
  2. [2]
    P. J. Barnes, K. F. Chung and C. P. Page,Platelet-activating factor as a mediator of allergic diseases. J. Allergy. Clin. Immunol81, 919–934 (1988)CrossRefPubMedGoogle Scholar
  3. [3]
    P. Guinot, C. Brambilla, J. Duchier, P. Braquet, B. Bonvoisin and A. Cournot,Effect of BN 52063, a specific PAF-acether antagonist, on bronchial provocation test to allergens in asthmatic patients, a preliminary study. Prostaglandins34, 723–731 (1987).CrossRefPubMedGoogle Scholar
  4. [4]
    K. F. Chung, G. Dent and P. J. Barnes,Effects of salbutamol on bronchoconstriction, bronchial hyperresponsiveness, and leukocyte responses induced by platelet activating factor in man. Thorax44, 102–107, (1989).PubMedGoogle Scholar
  5. [5]
    A Lellouch-Tubiana, J. Lefort, M.-T. Simon, A. Pfister and B. B. Vargaftig,Eosinophil recruitment into guinea pig lungs after PAF-acether and allergen administration. Am. Rev. Respir. Dis.137, 948–954 (1988).PubMedGoogle Scholar
  6. [6]
    B. Arnoux, A. Denjean, C. P. Page, D. Nolibe, J. Morley and J Benveniste,Accumulation of platelets and eosinophils in baboon lung after PAF-acether challenge. Am. Rev. Respir. Dis.137, 855–860 (1988).PubMedGoogle Scholar
  7. [7]
    J. D. Lundgren, M. A. Kaliner and J. H. Shelhamer,Mechanisms by which glucocorticosteroids inhibit secretion of mucus in asthmatic airways. Am. Rev. Respir. Dis., 1989 (in press).Google Scholar
  8. [8]
    H.-L. Hahn, I. Purnama, M. Lang and U. Sannwald,Effects of platelet activating factor on tracheal mucus secretion, on airway mechanics and on circulating blood cells in live ferrets. Eur. J. Respir. Dis.69 (suppl. 146), 277–284 (1986).Google Scholar
  9. [9]
    M. Lang, D. Hansen and H.-L. Hahn,Effects of the PAF-antagonist CV-3988 on PAF-induced changes in mucus secretion and in respiratory and circulatory variables in ferrets. Agents and Action21, 245–252 (1987).Google Scholar
  10. [10]
    K. B. Adler, J. E. Schwartz, W. H. Anderson and A. F. Welton,Platelet activating factor stimulates secretion of mucin by explants of rodent airways in organ culture. Exp. Lung. Res.13, 25–43 (1987).PubMedGoogle Scholar
  11. [11]
    N. F. Voelkel, S. Worthen, J. T. Reeves, P. M. Hensen and R. C. Murphy,Nonimmunological production of leukotrienes induced by platelet-activating factor. Science218, 286–288 (1982).PubMedGoogle Scholar
  12. [12]
    V. Di Marzo, J. R. Tippins and H. R. Morris,Platelet activating factor-mediated leukotriene biosynthesis in rat lungs: effect of prostaglandins E1 and F1α. Biochim. Biophys. Res. Comm.147, 1213–1218 (1987).CrossRefGoogle Scholar
  13. [13]
    J. Kuiper, Y. B. de Rijke, F. J. Zijlstra, M. P. van Waas and T. J. C. van Berkel,The induction of glycogenolysis in the perfused liver by platelet activating factor is mediated by prostaglandin D2 from Kupffer cells. Biochem. Biophys. Res. Comm.157, 1288–1295 (1988).CrossRefPubMedGoogle Scholar
  14. [14]
    L. Levine,Platelet-activating factor stimulates arachidonic acid metabolism in rat liver cells (C-9 cell line) by a receptor-mediated mechanism. Mol. Pharmacol34, 793–799 (1988).PubMedGoogle Scholar
  15. [15]
    W. Hsueh, F. Gonzalez-Crussi and J. L. Arroyava,Release of leukotriene C 4 by isolated, perfused rat small intestine in response to platelet-activating factor. J. Clin. Invest78, 108–114 (1986).PubMedGoogle Scholar
  16. [16]
    F. J. Zijlstra, M. Barchelet, M. A. Vermeer and J. E. Vincent,The effects of PAF-acether and FMLP on eicosanoid production in guinea pig alveolar macrophages. Agents and Actions26, 115–116 (1989).PubMedGoogle Scholar
  17. [17]
    L. B. Pieter, P. L. B. Bruijnzeel, P. T. M. Kok, M. L. Hamelink, A. M. Kijne and J. Verhagen,Platelet-activating factor induces leukotriene C 4 synthesis by purified human eosinophils. Prostaglandins34, 205–214 (1987).CrossRefPubMedGoogle Scholar
  18. [18]
    F. H. Chilton, J. T. O'Flaherty, C. E. Walsh et al.,Platelet activating factor. Stimulation of the lipoxygenase pathway in polymorphonuclear leukocytes by 1-O-alkyl-2-O-acethyl-snglycero-3-phosphocholine. J. Biol. Chem.257, 5402–5407 (1982).PubMedGoogle Scholar
  19. [20]
    J. D. Lundgren, F. Hirata, Z. Marom, et al.,Dexamethasone inhibits respiratory glycoconjugate secretion from feline airways in vitro by the induction of lipocortin (lipomodulin) synthesis. Am. Rev. Respir. Dis.137, 353–357 (1988).PubMedGoogle Scholar
  20. [21]
    P. Hadvary and H. R. Baumgartner,Interference of PAF-acether antagonists with platelet aggregation and with the formation of platelet thrombi. Prostaglandins30, 694 (1985).CrossRefGoogle Scholar
  21. [22]
    T. R. Jones, R. Zamboni, M. Belley, et al.,Pharmacology of L-660,711 (MK-571): A novel potent and selective leukotriene D4 receptor antagonist. Can. J. Physiol. Pharmacol.67, 17–28 (1989).PubMedGoogle Scholar
  22. [23]
    Y. Guindon, Y. Girard, A. Maycock, et al.,L-651,392: A novel, potent and selective 5-lipoxygenase inhibitor. InAdv. Prosta. Throm. Leukotr. Res. Vol.17. (Ed B. Samuelsson, R. Paoletti and R. W. Ramwell) pp 554–557, 1987.Google Scholar
  23. [24]
    Z. Marom, J. H. Shelhamer, M. K. Bach, D. R. Morton and M. Kaliner,Slow-reacting substance, leukotriene C4 and D4, increases the release of mucus from human airways in vitro. Am. Rev. Respir. Dis.126, 449–451 (1982).PubMedGoogle Scholar
  24. [25]
    S.-B. Hwang, M.-H. Lam and T. Y. Shen,Specific binding sites for platelet activating factor in human lung tissue. Biochem. Biophys. Res. Comm.128, 972–979 (1985).PubMedGoogle Scholar
  25. [26]
    M. L. Blank, T.-C. Lee, V. Fitzgerald and F. Snyder,A specific acetylhydrolase for 1-alkyl-2-acetyl-sn-glycero-3-phosphocholine (a hypotensive and platelet-activating lipid). J. Biol. Chem.256, 175–178 (1981).PubMedGoogle Scholar
  26. [27]
    Z. Marom, J. H. Shelhamer and M. Kaliner,Effects of arachidonic acid, monohydroxyeicosatetraenoic acid, and prostaglandins on the release of mucous glycoproteins from human airways in vitro. J. Clin. Invest.67, 1695–1702 (1981).PubMedGoogle Scholar
  27. [28]
    M. Brachelet, J. Masliah, B. B. Vargaftig, G. Bereziat and O. Colard,Changes induced by PAF-acether in diacyl and ether phospholipids from guinea-pig alveolar macrophages. Biochem. Biophys. Acta878, 177–183 (1986).PubMedGoogle Scholar
  28. [29]
    H. Kawaguchi and H. Yasuda,Effect of platelet-activating factor on arachidonic acid metabolism in renal epithelial cells. Biochim. Biophys. Acta875, 525–534 (1986).PubMedGoogle Scholar
  29. [30]
    J. Y. Vanderhoek and J. M. Bailey,Activation of a 15-lipoxygenase/leukotriene pathway in human polymorphonuclear leukocytes by the anti-inflammatory agent ibuprofen. J. Biol. Chem.259, 6752–6756 (1984).PubMedGoogle Scholar
  30. [31]
    A. C. Peatfield, P. J. Piper and P. S. Richardson,The effect of leukotriene C4 on mucus release into the cat trachea in vivo and in vitro. Br. J. Pharmacol77, 391–393 (1982).PubMedGoogle Scholar
  31. [32]
    Z. Marom, J. H. Shelhamer and M. Kaliner,Human airway monohydroxyeicosatetraenoic acid generation and mucus release. J. Clin. Invest.72, 122–127 (1983).PubMedGoogle Scholar
  32. [33]
    T. E. Eling, R. M. Danilowics, D. C. Henke, K. Sivarajah, J. R. Yankaskas and R. C. Boucher,Arachidonic acid metabolism by canine tracheal epithelial cells. J. Biol. Chem.261, 12841–12849 (1986).PubMedGoogle Scholar
  33. [34]
    J. A. Hunter, W. E. Finkbeiner, J. A. Nadel, E. J. Goetzl and M. J. Holtzman,Predominant generation of 15-lipoxygenase metabolites of arachidonic acid by epithelial cells from human trachea. Proc. Natl. Acad. Sci. USA82, 4633–4637 (1985).PubMedGoogle Scholar
  34. [35]
    G. D. Leikauf, K. E. Driscoll and H. E. Wey,Ozone-induced augmentation of eicosanoid metabolism in epithelial cells from bovine trachea. Am. Rev. Respir. Dis.137, 435–442, (1988).PubMedGoogle Scholar
  35. [36]
    G. P. Anderson and M. R. Fennery,Lipoxygenase metabolites mediate increased airways responsiveness to histamine after acute platelet activating factor exposure in the guineapig. Agents and Actions24, 8–19 (1988).PubMedGoogle Scholar

Copyright information

© Birkhäuser Verlag 1990

Authors and Affiliations

  • J. D. Lundgren
    • 1
  • M. Kaliner
    • 2
  • C. Logun
    • 1
  • J. H. Shelhamer
    • 1
  1. 1.Gritical Care Medicine Department, Clinical Center, National Institutes of Allergy and Infectious DiseasesNational Institutes of HealthBethesda
  2. 2.Allergic Disease Section, National Institutes of Allergy and Infectious DiseasesNational Institutes of HealthBethesda

Personalised recommendations