Corticosteroid-induced apoptosis in mouse airway epithelium: Effect in normal airways and after allergen-induced airway inflammation

Background: Damage to the airway epithelium is one prominent feature of the damage seen in chronic asthma. Corticosteroids induce apoptosis in inflammatory cells, which in part explains their ability to suppress airway inflammation. However, corticosteroid therapy does not necessarily reverse the epithelial damage seen in asthmatic airways. Objective: We hypothesized that corticosteroids might induce airway epithelial cell apoptosis as one potential explanation for this persistent damage. Methods: BALB/c mice were treated with 1 mg/kg dexamethasone by means of intraperitoneal injection for 3 days to 4 weeks. Additional mice were sensitized and challenged with ovalbumin and then followed for 14 days with or without dexamethasone treatment starting on day 4 after challenge. Apoptosis was measured by using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling and immunohistochemistry for the p85 cleavage product of poly (adenosine diphosphate-ribose) polymerase. Shed epithelial cells were counted in bronchoalveolar lavage fluid. Results: In a time-dependent manner dexamethasone treatment increased epithelial cell apoptosis and shedding into the airway lumen. This was not associated with any change in the abundance of the apoptotic regulator Bcl-x(L). In animals sensitized and challenged with ovalbumin, treatment with 1 mg/kg dexamethasone starting 4 days after challenge reversed the inflammatory changes but did not reverse either epithelial cell shedding or apoptosis seen after allergen challenge. Conclusion: Corticosteroids might induce apoptotic cell death of airway epithelium in vivo and fail to mitigate epithelial cell shedding and apoptosis elicited by means of allergen challenge. This raises the possibility that at least one of the major components of chronic airway damage in asthma, epithelial shedding, might in part result from a major therapy used for disease control.