Abstract Rationale Airway epithelial remodeling is a key feature of asthma, characterized by impaired mucociliary clearance due to ciliary dysfunction and mucus hypersecretion. While inhaled bronchodilators and corticosteroids are cornerstones of therapy, their direct effects on epithelial remodeling beyond bronchodilation remain underexplored. We investigated the distinct effects of these drug classes, with a particular focus on long-acting muscarinic antagonists (LAMA), on ciliary function and mucus production in an in vitro human airway model. Methods Primary human airway basal cells from non-smokers were cultured at an air-liquid interface (ALI) to form a fully differentiated epithelium. An asthma-like phenotype was established by treating the cells with IL-13 for 7 days. The model was then treated with LAMA (Glycopyrrolate), a long-acting beta2-adrenergic agonist (LABA, Formoterol), or an inhaled corticosteroid (ICS, Budesonide), as well as a triple combination therapy. We evaluated epithelial changes using histological analysis (PAS and MUC5AC staining), gene expression analysis (MUC5AC and FOXJ1), and scanning electron microscopy with ciliary motion analysis. Results The IL-13 treatment successfully induced an asthma-like phenotype, characterized by a significant reduction in cilia density and motion, along with a marked increase in mucus-producing cells (p 0.05). LAMA treatment effectively restored ciliary function, with a significant recovery in cilia length (10.0±3.7µm, p 0.0001), density (90.5±10.7%, p 0.0005), and motion magnitude (p 0.0001). This recovery correlated with a robust increase in FOXJ1 gene expression (1.8±0.2-fold compared to IL-13 treated group, p = 0.006), a key transcription factor for ciliated cell differentiation. Furthermore, LAMA showed a tendency to suppress mucus cell hyperplasia. In contrast, LABA and ICS had less consistent effects on ciliary recovery and, in some cases, promoted mucus production. Conclusion Our study highlights a novel, non-bronchodilator mechanism of action for LAMA. LAMA potently and directly promotes ciliary recovery and restores function, effectively reversing the ciliary damage and dysfunction induced by IL-13. While also mitigating mucus overproduction, the primary finding is LAMA’s direct role in repairing the ciliated epithelium. These results provide critical new insights into the therapeutic potential of LAMA for targeting airway remodeling in asthma. This abstract is funded by: None
Ogawa et al. (Fri,) studied this question.