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


CONCLUSIONS
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.
Birrell
Mark A
MA
Imperial College School of Medicine, London, UK.
Battram
Cliff H
CH
Woodman
Paul
P
McCluskie
Kerryn
K
Belvisi
Maria G
MG
D000280:Administration, Inhalation; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D016535:Bronchial Hyperreactivity / Q000175:diagnosis / Q000517:prevention & control*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D016085:Bronchoconstrictor Agents / Q000008:administration & dosage; D003907:Dexamethasone / Q000008:administration & dosage* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004802:Eosinophilia / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D007114:Immunization; D008168:Lung / Q000473:pathology; D008297:Male; D016210:Methacholine Chloride / Q000008:administration & dosage; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000276:immunology
D000893:Anti-Inflammatory Agents; D016085:Bronchoconstrictor Agents; D016210:Methacholine Chloride; D003907:Dexamethasone; D010047:Ovalbumin