Kinetics of airway hyperresponsiveness and airway eosinophilia in BALB/c mice and their modulation by different dexamethasone treatment regimens.
The mechanisms of airway hyperresponsiveness (AHR) are still poorly understood. In this study we have established a model of persistent AHR and eosinophilia and evaluated the prophylactic vs. therapeutic effects of dexamethasone on these parameters. Mice were immunised with ovalbumin (OVA) on day 0 and challenged intranasally on days 10, 11, 12 and 13 with OVA or phosphate buffer saline (PBS). Airway responsiveness to methacholine, measured 24-h post multiple intranasal OVA challenges, was significantly increased compared to time matched PBS-controls (P<0.05). AHR could be detected for up to 14 days after the last OVA challenge although the magnitude of the AHR had diminished by day 14 compared to day 1. OVA challenge of mice induced a significant airway eosinophilia at 24h (P<0.05); this persisted for 2 weeks after the challenge. Prophylactic treatment with dexamethasone (1mg x kg (-1)) reduced the OVA induced AHR, eosinophilia and mucus cell hyperplasia/metaplasia measured 24h post challenge. Therapeutic treatment, with dexamethasone (2 mg x kg(-1)), significantly inhibited established airway eosinophilia, measured at 72 h post OVA challenge, only when treatment was initiated at 24h but not 48 h after challenge. In contrast, AHR measured at 72 h post OVA challenge was significantly reduced when treatment was started at either 24 or 48 h post challenge. Our data shows that the immunization and challenge procedures employed resulted in a persistent type of AHR. Prophylactic intervention with steroids almost completely inhibited its development; however therapeutic intervention only partially resolved AHR.
El-Hashim
A Z
AZ
Department of Pharmacology, Respiratory Disease Therapeutic Area, Novartis Horsham Research Centre, Horsham, West Sussex, United Kingdom. ahmed.elhashim@hsc.kuniv.edu.kw
Wyss
D
D
Zuany-Amorim
C
C
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D016535:Bronchial Hyperreactivity / Q000276:immunology* / Q000517:prevention & control; D003907:Dexamethasone / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D011657:Pulmonary Eosinophilia / Q000276:immunology*; D013997:Time Factors
D000893:Anti-Inflammatory Agents; D003907:Dexamethasone; D010047:Ovalbumin