Glucocorticoids Impair the Airway Epithelial Barrier via Autophagy-Associated Apoptosis in Asthma: A Preliminary Study Both In Vitro and In Vivo.

Glucocorticoid insensitivity affects a subset of asthma patients, yet its mechanism is unclear. Given the key role of airway epithelium in asthma, this study hypothesized that glucocorticoids may impair this barrier. We examined whether glucocorticoid-induced autophagy-associated apoptosis contributes to reduced treatment efficacy. Using an ovalbumin-induced asthma model in BALB/c mice and 16HBE human bronchial epithelial cells treated with dexamethasone and/or autophagy inhibitor EACC (C13H11N3O6S2), we assessed cell viability and apoptosis via CCK-8 and TUNEL assays, respectively. Apoptosis and autophagy markers were analyzed by quantitative polymerase chain reaction (PCR) and western blot. Dexamethasone alleviated airway inflammation but worsened epithelial integrity in asthmatic mice. It failed to downregulate pro-apoptotic factors while reducing anti-apoptotic factors both in vivo and in vitro. Dexamethasone decreased 16HBE cell viability and increased apoptosis. Mechanistically, dexamethasone upregulated autophagy markers and suppressed anti-autophagy factors in mouse lungs and cells, concurrently reducing the phosphorylation of negative regulators of autophagy. Importantly, the autophagy inhibitor EACC enhanced cell viability and attenuated dexamethasone-induced apoptotic signaling in 16HBE cells. These findings suggest glucocorticoids may compromise the airway epithelial barrier via autophagy-associated apoptosis in vitro and in vivo, indicating autophagy inhibition as a potential hypothesis for future therapeutic exploration for glucocorticoid-insensitive asthma.