Vitamin D attenuates airway mucus hypersecretion in mild chronic obstructive pulmonary disease by regulating autophagy via the mTOR signaling pathway

Background Chronic obstructive pulmonary disease (COPD) is marked by persistent airway inflammation and mucus hypersecretion, which accelerate disease progression and exacerbate symptoms. MUC5AC, a predominant mucin in airway secretions, critically mediates mucus production. The role of vitamin D in modulating immune responses is well-documented; however, its influence on airway mucus hypersecretion in COPD remains inadequately explored. Methods We assessed the impact of serum 25-hydroxyvitamin D (25[OH]D) levels on airway mucus secretion in patients with mild COPD (n = 24) compared to healthy controls (n = 22). Measurements included serum 25(OH)D and MUC5AC levels in induced sputum, along with inflammatory cytokines. An in vitro model was established using BEAS-2B human airway epithelial cells exposed to hydrogen peroxide (H₂O₂) to simulate oxidative stress. Autophagy flux was evaluated through transmission electron microscopy and RFP-GFP-LC3 lentivirus transfection; protein levels were analyzed via Western blotting. Results Patients with mild COPD showed lower serum 25(OH)D levels and higher MUC5AC levels in sputum compared to controls. Vitamin D deficiency correlated with increased pro-inflammatory cytokines (IL-6, IL-17A) and decreased IL-10 levels. In vitro, H₂O₂-induced oxidative stress escalated MUC5AC secretion and pro-inflammatory cytokine production, which were mitigated by 1,25[OH]₂D₃ treatment. Furthermore, vitamin D inhibited autophagosome formation and altered the expression of autophagy-related proteins (LC3B, Beclin-1, and Atg5) through the mTOR signaling pathway. These modifications were verified by autophagy flux analysis and TEM, demonstrating a decrease in autophagic vacuoles following 1,25(OH)₂D₃ administration. Conclusion Our findings indicate that low serum 25(OH)D levels are linked to increased MUC5AC expression and compromised lung function in mild COPD, suggesting that vitamin D supplementation could mitigate these pathological changes. In vitro, 1,25(OH)₂D₃ diminishes oxidative stress-induced inflammation and mucus hypersecretion by modulating autophagy through the mTOR pathway, providing insight into the mechanistic basis for vitamin D's potential therapeutic role in the pathogenesis of mild COPD.