Journal
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
Volume 132, Issue 3, Pages 676-+Publisher
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2013.04.012
Keywords
Asthma; pediatric; airway remodeling; steroid resistance; IL-33; therapy
Categories
Funding
- Intermediate Clinical Fellowship from the Wellcome Trust, United Kingdom
- NIHR Respiratory Disease Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust
- Imperial College London
- Wellcome Trust
- MRC [MR/J010529/1] Funding Source: UKRI
- Asthma UK [MRC-AsthmaUKCentre, 10/058] Funding Source: researchfish
- Medical Research Council [G1000758B, MR/J010529/1, G1000758] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0510-10192] Funding Source: researchfish
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Background: T(H)2 cytokines are not responsible for the ongoing symptoms and pathology in children with severe therapy-resistant asthma (STRA). IL-33 induces airway hyperresponsiveness, but its role in airway remodeling and steroid resistance is unknown. Objective: We sought to investigate the relationship between IL-33 and airway remodeling in pediatric patients with STRA. Methods: IL-33 levels were quantified in neonatal mice given inhaled house dust mite (HDM), and the effect of blocking IL-13 on remodeling and IL-33 levels was assessed. HDM-induced allergic airways disease (AAD) in neonatal ST2(-/-) mice lacking the IL-33 receptor was assessed, together with collagen production after IL-33 administration. The effect of steroid therapy on IL-33 levels in patients with neonatal AAD was explored. IL-33 expression was quantified in endobronchial biopsy (EB) specimens from children with STRA and related to remodeling, and collagen production by airway fibroblasts from pediatric patients stimulated with IL-33 and budesonide was quantified. Results: Blocking IL-13 after AAD was established in neonatal mice and did not reduce remodeling or IL-33 levels; airway hyperresponsiveness was only partially reduced. IL-33 promoted collagen synthesis both from asthmatic fibroblasts from pediatric patients and after intranasal administration in mice. Increased cellular expression of IL-33, but not IL-13, was associated with increased reticular basement membrane thickness in EB specimens from children with STRA, whereas remodeling was absent in HDM-exposed ST2(-/-) mice. IL-33 levels were maintained, whereas IL-13 levels were abrogated by steroid treatment in neonatal HDM-exposed mice and in EB specimens from children with STRA. Conclusion: IL-33 is a relatively steroid-resistant mediator that promotes airway remodeling in patients with STRA and is an important therapeutic target.
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