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Inhibition of allergen-induced lung eosinophilia by type-III and combined type III- and IV-selective phosphodiesterase inhibitors in Brown-Norway rats

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Abstract

We examined the effect of a type IV (rolipram) and a combined type III and IV (Org 20421) isoenzymeselective phosphodiesterase inhibitor upon allergeninduced pulmonary eosinophil recruitment in sensitised Brown Norway rats. Rats were sensitised with ovalbumin intraperitoneally and later challenged with ovalbumin aerosol which induced a significant increase in the total eosinophil and neutrophil count in bronchovalveolar lavage fluid at 24 hours (from 0.38 ± 0.12 to 1.36 ± 0.18 × 106,p < 0.01 and from 0.06 ± 0.01 to 0.33 ± 0.07 × 106,p < 0.01) respectively. Pretreatment with rolipram (30 µmol/kg) and Org 20421 (30 µmol/kg) abolished the eosinophilia and neutrophilia evoked by ovalbumin. We conclude that type IV and possibly type III isozyme phosphodiesterase inhibitors may regulate, directly or indirectly, eosinophil and neutrophil activity and/or those cells responsible for attracting them into the lung.

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References

  1. Laitinen LA, Heino M, Laitinen A. Airway hyperresponsiveness, epithelial disruption and epithelial inflammation. In: Farmer SF, Hay DWP, eds. The Airway Epithelium: physiology, pathophysiology and pharmacology. New York: Dekker, 1990:187–211.

    Google Scholar 

  2. Corrigan CJ, Kay AB. Cells and eosinophils in the pathogenesis of asthma. Immunol Today 1992;13:501–7.

    Google Scholar 

  3. Torphy TJ, Undem BD. Phosphodiesterase inhibitors: new opportunities for the treatment of asthma. Thorax 1992;416:512–23.

    Google Scholar 

  4. Beavo JA, Reifsnyder DH. Primary sequence of cyclic nucleotide phosphodiesterase isozymes and the design of selective inhibitors. Trends Pharmacol Sci 1990;11:150–5.

    Google Scholar 

  5. Michaeli T, Bloom TJ, Martins T, et al. Isolation and characterization of a previously undetected human cAMP phosphodiesterase by complementation of cAMMP phosphodiesterase-deficientsaccharomyces cerevisiae. J Biol Chem 1993;268:12925–32.

    Google Scholar 

  6. Nicholson CD, Shahid M. Inhibitors of cyclic nucleotide phosphodiesterase isoenzymes — their potential utility in the therapy of asthma. Pulmonary Pharmacol 1994;7:1–17.

    Google Scholar 

  7. Dent G, Giembycz MA, Rabe KF, Barnes PJ. Inhibition of eosinophil cyclic nucleotide PDE activity and opsonized zymosan-stimulated respiratory burst by “Type IV”-selective PDE inhibitors. Br J Pharmacol 1991;103:1339–46.

    Google Scholar 

  8. Robicsek SA, Krzanowski JJ, Szentiranyi A, Polson JB. High pressure liquid chromatography of cyclic nucleotide phosphodiesterase from purified human T-lymphocytes. Biochem Biophys Res Commun 1989;163:554–60.

    Google Scholar 

  9. Giembycz MA. Could isoenzyme-selective phosphodiesterase inhibitors render bronchodilator therapy redundant in the treatment of bronchial asthma. Biochem Pharmacol 1993;43:2041–51.

    Google Scholar 

  10. Reeves ML, Leigh BK, Rink TJ. The identification of a new cyclic nucleotide phosphodiesterase in human and guinea-pig cardiac ventricle. Biochem J 1987;241:535–41.

    Google Scholar 

  11. Nicholson CD, Shahid M, Bruin J, et al. Org 20241, a cyclic nucleotide phosphodiesterase inhibitor for asthma. Br J Pharmacol 1992;107:252.

    Google Scholar 

  12. Elwood W, Lotvall JO, Barnes PJ, Chung KF. Characterisation of allergen-induced inflammation and bronchial hyperresponsiveness in sensitised Brown-Norway rats. J Allergy Clin Immunol 1991;88:951–60.

    Google Scholar 

  13. Howell RE, Sickels BD, Woeppel SL. Pulmonary antiallergic and bronchodilator effects of isozyme-selective phosphodiesterase inhibitors. J Pharmacol Exp Ther 1993;246:609–15.

    Google Scholar 

  14. Underwood DC, Osborn RR, Novak LB, et al. Inhibition of antigen-induced bronchoconstriction and eosinophil infiltration in the guinea-pig by the cyclic AMP-specific phosphodiesterase inhibitor, rolipram. J Pharmacol Exp Ther 1993;266:306–10.

    Google Scholar 

  15. Schudt C, Winder S, Litze M, Kilian U, Beume R. Zardaverine: a cyclic AMP specific PDE III/IV inhibitor. Agents Actions 1991;34:161–77.

    Google Scholar 

  16. Sanjar S, Aoki S, Kristersson A, Smith D, Morley J. Antigen challenge induces pulmonary airway eosinophil accumulation and airway hyperreactivity in sensitised guinea-pigs: the effect of anti-asthma drugs. Br J Pharmacol 1990;99: 679–86.

    Google Scholar 

  17. Kings MA, Chapman I, Kristersson A, Sanjar S, Morley J. Human recombinant lymphokines and cytokines induce pulmonary eosinophilia in the guinea-pig which is inhibited by ketotifen and AH 21-132. Int Arch Allergy Appl Immunol 1990;91:354–61.

    Google Scholar 

  18. Elwood W, Lotvall J, Barnes PJ, Chung KF. Effects of cyclosporin A and dexamethasone on allergen-induced bronchial hyperresponsiveness and inflammatory cell. Am Rev Respir Dis 1992;145:1289–94.

    Google Scholar 

  19. Waserman S, Olivenstein R, Renzi P, Xu L-J, Martin JG. The relationship between late asthmatic responses and antigenspecific immunoglobulin. J Allergy Clin Immunol 1992;90:661–9.

    Google Scholar 

  20. Haczku A, Chung KF, Sun J, Barnes PJ, Kay AB, Moqbel R. Lymphocyte populations in peripheral blood and bronchoalveolar lavage of Brown-Norway rats sensitized and exposed to ovalbumin. Am Rev Resp Dis 1993;147:A853.

    Google Scholar 

  21. Schudt CHR, Tenor H, Wendel A, et al. Effect of selective phosphodiesterase (PDE) inhibitors on activation of macrophages and lymphocytes. Naunyn Schmiedebergs Arch Pharmacol 1992;345:92.

    Google Scholar 

  22. Tanimoto Y, Maruo H, Bewtra AK, Townley RG. Effects of phosphodiesterase IV inhibitor (WAY-PDE-641) on human eosinophil and neutrophil migrationin vitro. J Allergy Clin Immunol 1994;93:257 (abstr).

    Google Scholar 

  23. Raeburn D, Karlsson JA. Effects of isoenzyme-selective inhibitors of cyclic nucleotide phosphodiesterase on microvascular leak in guinea-pig airways. J Pharmacol Exp Ther 1993;267:1147–52.

    Google Scholar 

  24. Ortiz JL, Cortijo J, Valles JM, Bou J, Morcillo EJ. Rolipram inhibits PAF-induced airway microvascular leakage in guineapig: a comparison with milrinone and theophylline. Fund Clin Pharmacol 1992;6:247–9.

    Google Scholar 

  25. Robicsek SA, Blanchard DK, Djeu JY, Krzanowski JJ, Stertivanyi A, Polson JB. Multiple high-affinity cAMP-phosphodiesterases in human T-lymphocytes. Biochem Pharmacol 1991;42:869–77.

    Google Scholar 

  26. Godfrey RW, Manzi RM, Genarro DE, Hofstein ST. Phospholipid and arachidonic acid metabolism in zymosanstimulated human monocytes: modulation by cAMP. J Cell Physiol 1987;131:384–92.

    Google Scholar 

  27. Nielson CP, Vestal RE, Sturm RJ, Heaslip R. Effects of selective phosphodiesterase inhibitors on the polymorphonuclear leukocyte respiratory burst. J Allergy Clin Immunol 1990;86:801–8.

    Google Scholar 

  28. Souness JE, Carter CM, Diocee BK, Hassall GA, Wood LJ, Turner NC. Characterization of guinea-pig eosinophil phosphodiesterase activity. Assessment of its involvement in regulating superoxide generation. Biochem Pharmacol 1991;42:937–45.

    Google Scholar 

  29. Giembycz MA, Corrigan CJ, Kay AB, Barnes PJ. Inhibition of CD4 and CD8 T-lymphocytes (T-LC) proliferation and cytokine secretion by isoenzyme-selective phosphodiesterase (PDE) inhibitors: correlation with intracellular cyclic AMP (cAMP) concentrations. J Allergy Clin Immunol 1994;93:167 (abstr).

    Google Scholar 

  30. Crocker IC, Townley RG, Khan MM. Phosphodiesterase inhibitors modulate cytokine secretion and proliferation. J Allergy Clin Immunol 1994;93:286 (abstr).

    Google Scholar 

  31. Essayan DM, Kagey-Sobotka A, Lichtenstein LM, Huang S-K. Studies of phosphodiesterase (PDE) isozyme function and expression in human allergic disease. J Allergy Clin Immunol 1994;93:286 (abstr).

    Google Scholar 

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Authors and Affiliations

  1. Department of Thoracic Medicine, National Heart and Lung Institute, Dovehouse Street, SW3 6LY, London, UK

    W. Elwood, J. Sun, P. J. Barnes, M. A. Giembycz & K. F. Chung

Authors
  1. W. Elwood
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  2. J. Sun
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  3. P. J. Barnes
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  4. M. A. Giembycz
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  5. K. F. Chung
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Elwood, W., Sun, J., Barnes, P.J. et al. Inhibition of allergen-induced lung eosinophilia by type-III and combined type III- and IV-selective phosphodiesterase inhibitors in Brown-Norway rats. Inflamm Res 44, 83–86 (1995). https://doi.org/10.1007/BF01793218

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  • DOI: https://doi.org/10.1007/BF01793218

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