Characterisation of a Murine Ovalbumin Model of Asthma and its Responses to Dexamethasone

Zakky Cholisoh, Emma Kidd, William Ford, Kenneth Broadley. Cardiff University, Cardiff, UK

Asthma is a chronic inflammatory disease characterised by several hallmarks including inflammatory cell infiltration in the lungs and airway hypersensitivity. Mice have been used extensively as a model of allergic asthma because they show some similar features to human asthma such as Th2 immune response, cellular infiltration in the airway, and airway hyper-responsiveness after allergen sensitisation and challenge1. Early and late asthmatic responses are also observed after antigen provocation.

Corticosteroids are primary treatment for asthma and this study investigated the effect of systemic dexamethasone in a murine acute asthma ovalbumin model. Twelve male BALB/c mice were sensitised with a solution containing ovalbumin (100 µg/mouse) and aluminium hydroxide (50 mg/mouse) on days 0 and 5. Starting on day 11, mice were injected intraperitoneally with 6 mg/kg of dexamethasone in PBS once a day for 5 days, while control group of mice were injected with the respective volume of PBS. Twelve days after the last sensitisation mice were challenged with nebulised ovalbumin (0.5%) for 1 hour twice, 4 hours apart. Airway functions (PenH/enhanced pause) were recorded from 0 to 10 hours after the last ovalbumin challenge to identify early and late phase asthmatic responses. Airway hyper-responsiveness to increasing dose of methacholine chloride (1-100 mg/ml) were measured 24 hours after the first ovalbumin challenge. Animals were then killed and bronchoalveolar fluid was collected to identify the inflammatory cell influx into the airways. Data was analysed using unpaired t-test (p<0.05).

Dexamethasone significantly attenuated late phase (22.7±6.5% increase in baseline PenH in the dexamethasone treated group compared to 56.8±11.9% increase in baseline PenH in the PBS treated group, p<0.05) but not early phase asthmatic response (33.9±4.6% increase in baseline PenH in the dexamethasone treated group compared to 30.8±3.9% increase in baseline PenH in the PBS treated group, p<0.05). Total cell numbers in the dexamethasone treated group (4.2±0.9.105 cells/ml) was significantly (p<0.05) reduced compared to PBS treated animals (13.7±2.8.105 cells/ml). Eosinophil influx as a hallmark of asthma was also significantly (p<0.05) reduced. Dexamethasone also significantly (p<0.05) reduced maximum airway response to methacholine chloride from 2,104±433.9% increase in baseline PenH in PBS treated group to 857.3±307.7% increase in baseline PenH in dexamethasone treated group.

In summary, we demonstrated that dexamethasone can reduce the late asthmatic response, airway hyper-responsiveness, and inflammatory cell influx in the airways of murine model of asthma. These effects replicate those seen in man and therefore provide a model to investigate further the mechanism of corticosteroid responsiveness in mice.

1. Wills-Karp M. 2000. Murine models of asthma in understanding immune dysregulation in human asthma. Immunopharmacology. 48. 263-268