American journal of respiratory and critical care medicine
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Am. J. Respir. Crit. Care Med. · Dec 2024
Increased Muc5AC and Decreased Ciliated Cells in Severe Asthma Partially Restored by Inhibition of IL-4Rα Receptor.
Rationale: The role of IL-13 on the airway epithelium in severe asthma leading to airway remodeling remains poorly understood. Objectives: To study IL-13-induced airway remodeling on goblet cells and cilia in the airway epithelium in severe asthma and the impact of an anti-IL4Rα antibody, dupilumab, in vitro. Methods: Quantitative computed tomography of the lungs and endobronchial biopsies and brushings were obtained in 51 participants (22 with severe asthma, 11 with nonsevere asthma, and 18 healthy participants) in SARPIII (Severe Asthma Research Program III) and measured for mucin and cilia-related proteins. ⋯ IL-13 (5 ng/ml)-differentiated ALI cultures of healthy and asthmatic samples (from participants with severe and nonsevere asthma) increased Muc5AC, decreased cilia (α-aceytl-tubulin) in samples from healthy participants (Δ + 6.5% ± 1.5%, Δ - 14.1% ± 2.7%; all P < 0.001 respectively) and participants with asthma (Δ + 4.4% ± 2.5%, Δ - 13.1% ± 2.7%; P = 0.084, P < 0.001 respectively), and decreased epithelial integrity (TEER) in samples from healthy participants (-140.9 ± 21.3 [ohms], P < 0.001), while decreasing CBF in samples from participants with asthma (Δ - 4.4 ± 1.7 [Hz], P < 0.01). When dupilumab was added to ALI with IL-13, there was no significant decrease in Mu5AC, but there was restoration of cilia in healthy participants and participants with asthma (absolute increase of 67.5% and 32.5% cilia, all P < 0.05, respectively), whereas CBF increased (Δ + 3.6 ± 1.1 [Hz], P < 0.001) and TEER decreased (only in asthma, Δ - 37.8 ± 16.2 [ohms], P < 0.05). Conclusions: IL-13 drives features of airway remodeling in severe asthma, which are partially reversed by inhibiting the IL-4Rα receptor in vitro.