Ozone Inhalation Attenuated the Effects of Budesonide on -Induced Airway Inflammation and Hyperreactivity in Mice.

Inhaled glucocorticoids form the mainstay of asthma treatment because of their anti-inflammatory effects in the lung. Exposure to the air pollutant ozone (O) exacerbates chronic airways disease. We and others showed that presence of the epithelial-derived surfactant protein-D (SP-D) is important in immunoprotection against inflammatory changes including those induced by O inhalation in the airways. SP-D synthesis requires glucocorticoids. We hypothesized here that O exposure impairs glucocorticoid responsiveness (including SP-D production) in allergic airway inflammation. The effects of O inhalation and glucocorticoid treatment were studied in a mouse model of allergic asthma induced by sensitization and challenge with () . The role of O and glucocorticoids in regulation of SP-D expression was investigated in A549 and primary human type II alveolar epithelial cells . Budesonide inhibited airway hyperreactivity, eosinophil counts in the lung and bronchoalveolar lavage (BAL) and CCL11, IL-13, and IL-23p19 release in the BAL of mice sensitized and challenged with ( < 0.05). The inhibitory effects of budesonide were attenuated on inflammatory changes and were completely abolished on airway hyperreactivity after O exposure of mice sensitized and challenged with . O stimulated release of pro-neutrophilic mediators including CCL20 and IL-6 into the airways and impaired the inhibitory effects of budesonide on CCL11, IL-13 and IL-23. O also prevented budesonide-induced release of the immunoprotective lung collectin SP-D into the airways of allergen-challenged mice. O had a bi-phasic direct effect with early (<12 h) inhibition and late (>48 h) activation of SP-D mRNA () . Dexamethasone and budesonide induced transcription and translation in human type II alveolar epithelial cells in a glucocorticoid receptor and STAT3 (an IL-6 responsive transcription factor) dependent manner. Our study indicates that O exposure counteracts the effects of budesonide on airway inflammation, airway hyperreactivity, and SP-D production. We speculate that impairment of SP-D expression may contribute to the acute O-induced airway inflammation. Asthmatics exposed to high ambient O levels may become less responsive to glucocorticoid treatment during acute exacerbations.