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

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:

Species differences in adenosine receptor‐mediated bronchoconstrictor responses

“…In contrast, in an allergic rabbit model having many similarities with allergic asthma (rabbits immunized at birth with antigen [ragweed, house dust mite or Alternaria tenuis ]) airway hyperresponsiveness develops to adenosine [ 45]. Bronchoconstriction is a consequence of activation of A 1 receptors present on the airway smooth muscle cells [ 45–48], which are up regulated as a consequence of the immunization procedure [ 47]. Responses can be blocked by theophylline [ 45] as would be expected from their being A 1 receptor mediated.…”

Onion Bulb Extract Downregulates EGFR/ERK1/2/AKT Signaling Pathway and Synergizes With Steroids to Inhibit Allergic Inflammation

“…Our findings show that treatment with OBE had no effect on this parameter. Although many studies have reported a causal link between airway inflammation and AHR, others have not been able to confirm this relationship, at least not for all types of AHR (Gozzard et al, 1996;Spina et al, 1998;El-Hashim et al, 1999;Spina and Page, 2009). Indeed, there may be a separation between the two phenomena, as not all agents that inhibit airway inflammation reduce AHR and vice versa (Riccio et al, 1997;El-Hashim et al, 2004).…”

Altered secretory activity in rat adrenal chromaffin cells after experimentally induced bronchial asthma and dexamethasone treatment

“…However, asthmatics still exhibit airway hyper-responsiveness (AHR) following even a prolonged treatment with GCS, suggesting an irreversible component to asthma that is not affected by treatment with these drugs [16]. Furthermore, regular treatment of allergic rabbits with GCS failed to reverse baseline airway AHR, even though these drugs clearly inhibited allergeninduced exacerbations of AHR in the same species [17].…”