Effects of dexamethasone on airway hyper-responsiveness to the adenosine A1 receptor agonist cyclo-pentyl adenosine in an allergic rabbit model

Authors

  • Ahmed Z El-Hashim,

    1. The Sackler Institute of Pulmonary Pharmacology, Division of Pharmacology & Therapeutics, Guy's, King's and St. Thomas' School of Biomedical Sciences, King's College London, Manresa Road, London SW3 6LX, UK
    Search for more papers by this author
    • 2

      Current address: Biology Department, Novartis Horsham Research Centre, Wimblehurst Rd., Horsham, W. Sussex RH12 4AB

  • Katharine H Banner,

    1. The Sackler Institute of Pulmonary Pharmacology, Division of Pharmacology & Therapeutics, Guy's, King's and St. Thomas' School of Biomedical Sciences, King's College London, Manresa Road, London SW3 6LX, UK
    Search for more papers by this author
    • 3

      Current address: Discovery Biology Dept., Pfizer Central Research Limited, Sandwich, Kent CT13 9NJ

  • William Paul,

    1. The Sackler Institute of Pulmonary Pharmacology, Division of Pharmacology & Therapeutics, Guy's, King's and St. Thomas' School of Biomedical Sciences, King's College London, Manresa Road, London SW3 6LX, UK
    Search for more papers by this author
  • Clive P Page

    Corresponding author
    1. The Sackler Institute of Pulmonary Pharmacology, Division of Pharmacology & Therapeutics, Guy's, King's and St. Thomas' School of Biomedical Sciences, King's College London, Manresa Road, London SW3 6LX, UK
    Search for more papers by this author

The Sackler Institute of Pulmonary Pharmacology, Division of Pharmacology & Therapeutics, Guy's, King's and St. Thomas' School of Biomedical Sciences, King's College London, Manresa Road, London SW3 6LX, UK. E-mail: clive.page@kcl.ac.uk

Abstract

  • New Zealand White (NZW) rabbits were immunized within 24 h of birth with Alternaria tenuis in aluminium hydroxide (Al (OH)3) (i.p.) or sham immunized (saline plus Al (OH)3 i.p.) and subsequently injected with the allergen (i.p.) or sham-immunized for the next 3 months. At 3 months of age, baseline airway responsiveness was assessed using cyclo-pentyl adenosine (CPA). Bronchoalveolar lavage (BAL) was performed in all animals and samples of peripheral blood were collected from some animals for estimation of dexamethasone levels. In some animals, blood was collected at the end of the experiment and cellular function was assessed by measurement of ex vivo proliferation of mononuclear cells in response to phytohaemagglutinin (PHA).

  • Allergen immunization significantly increased baseline airway responsiveness to inhaled CPA (P<0.05) in comparison with sham-immunized animals, at 3 months after immunization. Dexamethasone (0.5 mg kg−1 day−1) treatment for 1 month did not modify this established airway hyper-responsiveness to CPA. Dexamethasone treatment did not affect either total or differential cell numbers in BAL fluid during the 4 week period, although significant plasma levels of dexamethasone were achieved in dexamethasone treated animals.

  • Treatment of rabbits with dexamethasone (0.1 mg kg−1 i.p.), 6 h prior to each allergen injection from the neonatal stage, significantly reduced baseline airway hyper-responsiveness to CPA measured at 3 months (P<0.05). There was no significant difference in either total or differential cell numbers in BAL fluid, or any difference in mitogen-induced proliferation of mononuclear cells between dexamethasone and vehicle treated rabbits.

  • These results suggest that introduction of glucocorticosteroids in early life can prevent baseline airway hyper-responsiveness to inhaled CPA in allergic rabbits. However, once established, such underlying airway hyper-responsiveness is difficult to resolve, even with prolonged treatment with glucocorticosteroids.

British Journal of Pharmacology (1999) 126, 1513–1521; doi:10.1038/sj.bjp.0702455

Ancillary