TRPV1 mediates oxidative stress and autophagy pathways to regulate airway MUC5AC secretion

Airway mucus hypersecretion is a prevalent chronic inflammatory disorder characterized by elevated mucin5AC (MUC5AC) expression, which exacerbates airflow limitation and increases susceptibility to lung infections. Transient receptor potential vanilloid 1 (TRPV1) channels, widely distributed across the airways, play a pivotal role in lung inflammation and tissue damage; however, the specific mechanism by which TRPV1 modulates airway MUC5AC expression remains unclear. To address this gap, we established an in vivo model of airway mucus hypersecretion in C57BL/6 mice via intratracheal administration of Pseudomonas aeruginosa (PA), followed by measurement of MUC5AC and TRPV1 expression levels. TRPV1 knockout mice were generated to assess lung inflammation, airway mucus secretion, and changes in MUC5AC and autophagy-related proteins following PA exposure. In vitro, an airway mucus hypersecretion model was created using Pyocyanin-treated NCI-H292 cells to measure intracellular TRPV1 and MUC5AC levels and investigate interactions between TRPV1, MUC5AC, oxidative stress, and autophagy. Both in vivo and in vitro models demonstrated that TRPV1 inhibition significantly reduced MUC5AC secretion, concurrent with decreased reactive oxygen species (ROS) production, mitigated oxidative stress, and attenuated autophagy. Further analysis revealed that the ROS scavenger N-acetylcysteine effectively decreased intracellular autophagy, while the autophagy inhibitor 3-Methyladenine significantly reduced MUC5AC secretion. Collectively, these findings indicate that TRPV1 inhibition reduces airway MUC5AC secretion through modulation of oxidative stress and autophagy pathways, suggesting TRPV1 as a promising therapeutic target for airway mucus hypersecretion diseases.