Dissociation by steroids of eosinophilic inflammation from airway hyperresponsiveness in murine airways

Abstract

Background: The link between eosinophils and the development of airway hyperresponsiveness (AHR) in asthma is still controversial. This question was assessed in a murine model of asthma in which we performed a dose ranging study to establish whether the dose of steroid needed to inhibit the eosinophil infiltration correlated with that needed to block AHR.

Methods: The sensitised BALB/c mice were dosed with vehicle or dexamethasone (0.01-3 mg/kg) 2 hours before and 6 hours after each challenge (once daily for 6 days) and 2 hours before AHR determination by whole-body plethysmography. At 30 minutes after the AHR to aerosolised methacholine the mice were lavaged and differential white cell counts were determined. Challenging with antigen caused a significant increase in eosinophils in the bronchoalveolar lavage (BAL) fluid and lung tissue, and increased AHR.

Results: Dexamethasone reduced BAL and lung tissue eosinophilia (ED50 values of 0.06 and 0.08 mg/kg, respectively), whereas a higher dose was needed to block AHR (ED50 of 0.32 mg/kg at 3 mg/ml methacholine. Dissociation was observed between the dose of steroid needed to affect AHR in comparison with eosinophilia and suggests that AHR is not a direct consequence of eosinophilia.

Conclusion: This novel pharmacological approach has revealed a clear dissociation between eosinophilia and AHR by using steroids that are the mainstay of asthma therapy. These data suggest that eosinophilia is not associated with AHR and questions the rationale that many pharmaceutical companies are adopting in developing low-molecular-mass compounds that target eosinophil activation/recruitment for the treatment of asthma.

Figure 1

Effect of dexamethasone treatment on BAL (A) and lung tissue (B) eosinophil number 24 hours after the last antigen challenge in sensitised mice. Results represent mean ± s.e.m. (n = 10). * P < 0.05 compared with relevant vehicle dosed control group.

Figure 2

Effect of dexamethasone (0.01 - 3 mg/kg) on peak changes in PenH measured after aerosolised methacholine (3 mg/ml for 60sec) 24 hours after the last antigen challenge in sensitised mice (Figure 2A). Effect of dexamethasone (1 mg/kg) on peak changes in PenH measured after aerosolised methacholine (3 - 100 mg/ml for 60sec) 24 hours after the last antigen challenge in sensitised mice (Figure 2B). Results represent mean ± s.e.m. (n = 10). * P < 0.05 compared with relevant vehicle dosed control group.