Abstract
Asthma is a chronic inflammatory airway disease characterized by acute exacerbations triggered by inhaled allergens, respiratory infections, or air pollution. Ozone (O(3)), a major component of air pollution, can damage the lung epithelium in healthy individuals. Despite this association, little is known about the effects of O(3) and its impact on chronic lung disease. Epidemiological data have demonstrated that elevations in ambient O(3) are associated with increased asthma exacerbations. To identify mechanisms by which O(3) exposure leads to asthma exacerbations, we developed a two-hit mouse model where mice were sensitized and challenged with three common allergens (dust mite, ragweed and Aspergillus fumigates, DRA) to induce allergic inflammation prior to exposure to O(3) (DRAO(3)). Changes in lung physiology, inflammatory cells, and inflammation were measured. Exposure to O(3) following DRA significantly increased airway hyperreactivity (AHR), which was independent of TLR4. DRA exposure resulted in increased BAL eosinophilia while O(3) exposure resulted in neutrophilia. Additionally, O(3) exposure following DRA blunted anti-inflammatory and antioxidant responses. Finally, there were significantly less monocytes and innate lymphoid type 2 cells (ILC2s) in the dual challenged DRA-O(3) group suggesting that the lack of these immune cells may influence O(3)-induced AHR in the setting of allergic inflammation. In summary, we developed a mouse model that mirrors some aspects of the clinical course of asthma exacerbations due to air pollution and identified that O(3) exposure in the asthmatic lung leads to impaired endogenous anti-inflammatory and antioxidant responses and alterations inflammatory cell populations.