Journal article
Increased Muc5AC and Decreased Ciliated Cells in Severe Asthma Partially Restored by Inhibition of IL-4Rα Receptor
American journal of respiratory and critical care medicine, Vol.210(12), pp.1409-1420
12/15/2024
DOI: 10.1164/rccm.202307-1266OC
PMCID: PMC11716027
PMID: 38935626
Abstract
Background: The role of IL-13 on the airway epithelium in severe asthma leading to airway remodeling remains poorly understood.
Objective: 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 CT (qCT) lungs and endobronchial biopsies and brushings were obtained in 51 participants (22 severe, 11 non-severe asthma and 18 healthy participants) in the Severe Asthma Research Program (SARPIII) and measured for mucin and cilia related proteins. Epithelial cells were differentiated in air-liquid interphase (ALI) with IL-13 +/-dupilumab and assessed for mucin, cilia, cilia beat frequency (CBF) and epithelial integrity (transepithelial electrical resistance, TEER).
Results: Increased Muc5AC (Δ+263.2±92.7 lums/EpiArea) and decreased ciliated cells (Δ-0.07±0.03 Foxj1+cells/EpiArea) were observed in biopsies from severe asthma when compared to healthy (p<0.01 and p=0.047 respectively). RNAseq of epithelial cell brushes confirmed a Muc5AC increase with a decrease in a 5-gene cilia-related mean in severe asthma compared to healthy (all p<0.05). IL-13 (5 ng/mL) differentiated ALI cultures of healthy and asthmatic (severe and non-severe participants) increased Muc5AC, decreased cilia (α-acytl-tubulin) in healthy (Δ+6.5±1.5%, Δ-14.1±2.7%; all p<0.001 respectively) and asthma (Δ+4.4±2.5%, Δ-13.1±2.7%; p=0.084, p<0.001 respectively); decreased epithelial integrity (TEER) in healthy (-140.9±21.3 [ohms], p<0.001) while decreasing CBF in 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 and asthma participants (absolute increase of 67.5% and 32.5% cilia, all p<0.05 respectively) while 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 IL-4Rα receptor in vitro.
Details
- Title: Subtitle
- Increased Muc5AC and Decreased Ciliated Cells in Severe Asthma Partially Restored by Inhibition of IL-4Rα Receptor
- Creators
- Jonathan Boomer - University of KansasJiwoong Choi - University of KansasAlexander Alsup - University of KansasMary Clare McGregor - Washington University in St. LouisJulia Lieu - Washington University in St. Louis School of MedicineCooper Johnson - Washington University in St. LouisChase Hall - University of KansasXiaosong Shi - University of KansasTaewon Kim - University of KansasCharles Goss - Washington University in St. LouisDaphne Lew - Washington University in St. LouisStephanie Christenson - University of California, San FranciscoPrescott G. Woodruff - University of California, San FranciscoAnnette Hastie - Wake Forest UniversityDavid Mauger - Pennsylvania State UniversitySally E. Wenzel - University of PittsburghEric A. Hoffman - University of Iowa Hospitals and ClinicsKen B. Schechtman - Washington University in St. LouisMario Castro - University of Kansas
- Resource Type
- Journal article
- Publication Details
- American journal of respiratory and critical care medicine, Vol.210(12), pp.1409-1420
- DOI
- 10.1164/rccm.202307-1266OC
- PMID
- 38935626
- PMCID
- PMC11716027
- NLM abbreviation
- Am J Respir Crit Care Med
- ISSN
- 1073-449X
- eISSN
- 1535-4970
- Language
- English
- Electronic publication date
- 06/27/2024
- Date published
- 12/15/2024
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Radiology; Internal Medicine
- Record Identifier
- 9984651155902771
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