Skip to main content
PMC home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1996 Jul;118(5):1201–1208. doi: 10.1111/j.1476-5381.1996.tb15524.x

Effect of the glucocorticosteroid budesonide and a novel phosphodiesterase type 4 inhibitor CDP840 on antigen-induced airway responses in neonatally immunised rabbits.

N Gozzard 1, A el-Hashim 1, C M Herd 1, S M Blake 1, M Holbrook 1, B Hughes 1, G A Higgs 1, C P Page 1
PMCID: PMC1909605  PMID: 8818344

Abstract

1. The effects of the inhaled corticosteroid budesonide and a novel PDE 4 inhibitor CDP840 given systematically, were evaluated in a model of antigen-induced airway inflammation in the rabbit. 2. Adult litter-matched NZW rabbits (2.4-3.5 kg) immunised within 24 h of birth with Alternaria tenuis antigen were pretreated with budesonide (total dose 100 micrograms, inhaled over 2 days) or CDP840 (total dose 7 mg kg-1, i.p. over 3 days), before antigen challenge. For each drug-treated group a parallel group of rabbits was pretreated with the appropriate vehicle. In all groups airway responsiveness to inhaled histamine was assessed and bronchoalveolar lavage (BAL) performed 24 h before and after antigen challenge. 3. Basal lung function in terms of total lung resistance (RL; cmH2O l 1s-1) and dynamic compliance (Cdyn; ml cmH2O-1) were unaltered by pretreatment with budesonide or CDP840 compared to their respective vehicles 24 h before or after antigen challenge. 4. The RL component of the acute bronchoconstriction induced by inhaled Alternaria tenuis aerosol was unaffected by pretreatment with budesonide. However, budesonide prevented the fall in Cdyn due to antigen. Treatment with CDP840 significantly reduced antigen-induced acute bronchoconstriction in terms of both RL and Cdyn. 5. Airway hyperresponsiveness (AHR) to inhaled histamine was indicated by reduced RL PC50 (2.4-4.5 fold) and Cdyn PC35 (2.1-3.9 fold) values 24 h after antigen challenge. Treatment with either budesonide or CDP840 abolished the antigen-induced increase in responsiveness to inhaled histamine. 6. Total cells recovered per ml of BAL fluid increased 24 h after antigen challenge. Antigen-induced pulmonary eosinophilia was reduced (93%) in budesonide and (85%) in CDP840 treated rabbits. Antigen-induced increases in neutrophil numbers were reduced (76%) with budesonide but not CDP840 pretreatment. 7. Inhalation of Alternaria tenuis aerosol elicited an acute bronchoconstriction, followed 24 hours later by an increased responsiveness to inhaled histamine and pulmonary neutrophil and eosinophil recruitment. CDP840 was more effective than budesonide in preventing the antigen-induced increase in total lung resistance (RL); however, both drugs prevented the antigen-induced reduction in dynamic compliance (Cdyn). CDP840 and budesonide also prevented antigen-induced AHR and eosinophilia in the immunised rabbit.

Full text

PDF
1201

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Banner K. H., Page C. P. Acute versus chronic administration of phosphodiesterase inhibitors on allergen-induced pulmonary cell influx in sensitized guinea-pigs. Br J Pharmacol. 1995 Jan;114(1):93–98. doi: 10.1111/j.1476-5381.1995.tb14910.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Banner K. H., Roberts N. M., Page C. P. Differential effect of phosphodiesterase 4 inhibitors on the proliferation of human peripheral blood mononuclear cells from normals and subjects with atopic dermatitis. Br J Pharmacol. 1995 Dec;116(8):3169–3174. doi: 10.1111/j.1476-5381.1995.tb15120.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Barnes P. J. Our changing understanding of asthma. Respir Med. 1989 May;83 (Suppl A):17–23. doi: 10.1016/s0954-6111(89)80246-x. [DOI] [PubMed] [Google Scholar]
  4. Bloom J. W., Baumgartener-Folkerts C., Palmer J. D., Halonen M. Airway cholinergic responsiveness in rabbits in relation to antigen sensitization and challenge. Immunopharmacology. 1988 May-Jun;15(3):157–167. doi: 10.1016/0162-3109(88)90027-6. [DOI] [PubMed] [Google Scholar]
  5. Chan S. C., Hanifin J. M. Differential inhibitor effects on cyclic adenosine monophosphate-phosphodiesterase isoforms in atopic and normal leukocytes. J Lab Clin Med. 1993 Jan;121(1):44–51. [PubMed] [Google Scholar]
  6. Cockcroft D. W., Murdock K. Y. Comparative effects of inhaled salbutamol, sodium cromoglycate, and beclomethasone dipropionate on allergen-induced early asthmatic responses, late asthmatic responses, and increased bronchial responsiveness to histamine. J Allergy Clin Immunol. 1987 May;79(5):734–740. doi: 10.1016/0091-6749(87)90204-1. [DOI] [PubMed] [Google Scholar]
  7. Endres S., Fülle H. J., Sinha B., Stoll D., Dinarello C. A., Gerzer R., Weber P. C. Cyclic nucleotides differentially regulate the synthesis of tumour necrosis factor-alpha and interleukin-1 beta by human mononuclear cells. Immunology. 1991 Jan;72(1):56–60. [PMC free article] [PubMed] [Google Scholar]
  8. Giembycz M. A., Dent G. Prospects for selective cyclic nucleotide phosphodiesterase inhibitors in the treatment of bronchial asthma. Clin Exp Allergy. 1992 Mar;22(3):337–344. doi: 10.1111/j.1365-2222.1992.tb03095.x. [DOI] [PubMed] [Google Scholar]
  9. Gozzard N., Herd C. M., Blake S. M., Holbrook M., Hughes B., Higgs G. A., Page C. P. Effects of theophylline and rolipram on antigen-induced airway responses in neonatally immunized rabbits. Br J Pharmacol. 1996 Apr;117(7):1405–1412. doi: 10.1111/j.1476-5381.1996.tb15299.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Herd C. M., Donigi-Gale D., Shoupe T. S., Burroughs D. A., Yeadon M., Page C. P. Effect of a 5-lipoxygenase inhibitor and leukotriene antagonist (PF 5901) on antigen-induced airway responses in neonatally immunized rabbits. Br J Pharmacol. 1994 May;112(1):292–298. doi: 10.1111/j.1476-5381.1994.tb13067.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Herd C. M., Gozzard N., Page C. P. Capsaicin pre-treatment prevents the development of antigen-induced airway hyperresponsiveness in neonatally immunised rabbits. Eur J Pharmacol. 1995 Aug 25;282(1-3):111–119. doi: 10.1016/0014-2999(95)00291-r. [DOI] [PubMed] [Google Scholar]
  12. Holbrook M., Gozzard N., James T., Higgs G., Hughes B. Inhibition of bronchospasm and ozone-induced airway hyperresponsiveness in the guinea-pig by CDP840, a novel phosphodiesterase type 4 inhibitor. Br J Pharmacol. 1996 Jul;118(5):1192–1200. doi: 10.1111/j.1476-5381.1996.tb15523.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Howell R. E., Sickels B. D., Woeppel S. L. Pulmonary antiallergic and bronchodilator effects of isozyme-selective phosphodiesterase inhibitors in guinea pigs. J Pharmacol Exp Ther. 1993 Feb;264(2):609–615. [PubMed] [Google Scholar]
  14. Hughes B., Howat D., Lisle H., Holbrook M., James T., Gozzard N., Blease K., Hughes P., Kingaby R., Warrellow G. The inhibition of antigen-induced eosinophilia and bronchoconstriction by CDP840, a novel stereo-selective inhibitor of phosphodiesterase type 4. Br J Pharmacol. 1996 Jul;118(5):1183–1191. doi: 10.1111/j.1476-5381.1996.tb15522.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Larsen G. L., Wilson M. C., Clark R. A., Behrens B. L. The inflammatory reaction in the airways in an animal model of the late asthmatic response. Fed Proc. 1987 Jan;46(1):105–112. [PubMed] [Google Scholar]
  16. Marsh W. R., Irvin C. G., Murphy K. R., Behrens B. L., Larsen G. L. Increases in airway reactivity to histamine and inflammatory cells in bronchoalveolar lavage after the late asthmatic response in an animal model. Am Rev Respir Dis. 1985 Jun;131(6):875–879. doi: 10.1164/arrd.1985.131.6.875. [DOI] [PubMed] [Google Scholar]
  17. Minshall E. M., Riccio M. M., Herd C. M., Douglas G. J., Seeds E. A., McKenniff M. G., Sasaki M., Spina D., Page C. P. A novel animal model for investigating persistent airway hyperresponsiveness. J Pharmacol Toxicol Methods. 1993 Dec;30(4):177–188. doi: 10.1016/1056-8719(93)90015-7. [DOI] [PubMed] [Google Scholar]
  18. Nicholson C. D., Shahid M. Inhibitors of cyclic nucleotide phosphodiesterase isoenzymes--their potential utility in the therapy of asthma. Pulm Pharmacol. 1994 Feb;7(1):1–17. doi: 10.1006/pulp.1994.1001. [DOI] [PubMed] [Google Scholar]
  19. Pober J. S., Cotran R. S. Cytokines and endothelial cell biology. Physiol Rev. 1990 Apr;70(2):427–451. doi: 10.1152/physrev.1990.70.2.427. [DOI] [PubMed] [Google Scholar]
  20. Pober J. S., Slowik M. R., De Luca L. G., Ritchie A. J. Elevated cyclic AMP inhibits endothelial cell synthesis and expression of TNF-induced endothelial leukocyte adhesion molecule-1, and vascular cell adhesion molecule-1, but not intercellular adhesion molecule-1. J Immunol. 1993 Jun 1;150(11):5114–5123. [PubMed] [Google Scholar]
  21. Qian Y., Girard V., Martin C. A., Molimard M., Advenier C. Rolipram, but not siguazodan or zaprinast, inhibits the excitatory noncholinergic neurotransmission in guinea-pig bronchi. Eur Respir J. 1994 Feb;7(2):306–310. doi: 10.1183/09031936.94.07020306. [DOI] [PubMed] [Google Scholar]
  22. Spina D., Harrison S., Page C. P. Regulation by phosphodiesterase isoenzymes of non-adrenergic non-cholinergic contraction in guinea-pig isolated main bronchus. Br J Pharmacol. 1995 Oct;116(4):2334–2340. doi: 10.1111/j.1476-5381.1995.tb15074.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Tinkelman D. G., Reed C. E., Nelson H. S., Offord K. P. Aerosol beclomethasone dipropionate compared with theophylline as primary treatment of chronic, mild to moderately severe asthma in children. Pediatrics. 1993 Jul;92(1):64–77. [PubMed] [Google Scholar]
  24. Torphy T. J., Undem B. J. Phosphodiesterase inhibitors: new opportunities for the treatment of asthma. Thorax. 1991 Jul;46(7):512–523. doi: 10.1136/thx.46.7.512. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Turner C. R., Andresen C. J., Smith W. B., Watson J. W. Effects of rolipram on responses to acute and chronic antigen exposure in monkeys. Am J Respir Crit Care Med. 1994 May;149(5):1153–1159. doi: 10.1164/ajrccm.149.5.8173755. [DOI] [PubMed] [Google Scholar]
  26. Underwood D. C., Kotzer C. J., Bochnowicz S., Osborn R. R., Luttmann M. A., Hay D. W., Torphy T. J. Comparison of phosphodiesterase III, IV and dual III/IV inhibitors on bronchospasm and pulmonary eosinophil influx in guinea pigs. J Pharmacol Exp Ther. 1994 Jul;270(1):250–259. [PubMed] [Google Scholar]
  27. Underwood D. C., Osborn R. R., Novak L. B., Matthews J. K., Newsholme S. J., Undem B. J., Hand J. M., Torphy T. J. 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 Jul;266(1):306–313. [PubMed] [Google Scholar]
  28. Wellicome S. M., Thornhill M. H., Pitzalis C., Thomas D. S., Lanchbury J. S., Panayi G. S., Haskard D. O. A monoclonal antibody that detects a novel antigen on endothelial cells that is induced by tumor necrosis factor, IL-1, or lipopolysaccharide. J Immunol. 1990 Apr 1;144(7):2558–2565. [PubMed] [Google Scholar]
  29. Wiebicke W., Jörres R., Magnussen H. Comparison of the effects of inhaled corticosteroids on the airway response to histamine, methacholine, hyperventilation, and sulfur dioxide in subjects with asthma. J Allergy Clin Immunol. 1990 Dec;86(6 Pt 1):915–923. doi: 10.1016/s0091-6749(05)80155-1. [DOI] [PubMed] [Google Scholar]
  30. Yeadon M., Wilkinson D., Darley-Usmar V., O'Leary V. J., Payne A. N. Mechanisms contributing to ozone-induced bronchial hyperreactivity in guinea-pigs. Pulm Pharmacol. 1992;5(1):39–50. doi: 10.1016/0952-0600(92)90016-a. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Pharmacology are provided here courtesy of The British Pharmacological Society

RESOURCES