title: IL-33 promotes airway remodeling in pediatric patients with severe steroid-resistant asthma.
abstract: BACKGROUND
  TH2 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.
  
  
  CONCLUSIONS
  IL-33 is a relatively steroid-resistant mediator that promotes airway remodeling in patients with STRA and is an important therapeutic target.
authors.affiliation: Leukocyte Biology Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom; Respiratory Paediatrics, Royal Brompton Hospital, and National Heart & Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Sejal
authors.initials: S
authors.lastname: Saglani
authors.affiliation: Leukocyte Biology Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Stephen
authors.initials: S
authors.lastname: Lui
authors.affiliation: Leukocyte Biology Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom; Respiratory Paediatrics, Royal Brompton Hospital, and National Heart & Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Nicola
authors.initials: N
authors.lastname: Ullmann
authors.affiliation: Leukocyte Biology Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Gaynor A
authors.initials: GA
authors.lastname: Campbell
authors.affiliation: Leukocyte Biology Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Rebekah T
authors.initials: RT
authors.lastname: Sherburn
authors.affiliation: Leukocyte Biology Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Sara A
authors.initials: SA
authors.lastname: Mathie
authors.affiliation: Leukocyte Biology Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Laura
authors.initials: L
authors.lastname: Denney
authors.affiliation: Respiratory Paediatrics, Royal Brompton Hospital, and National Heart & Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Cara J
authors.initials: CJ
authors.lastname: Bossley
authors.affiliation: Leukocyte Biology Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Timothy
authors.initials: T
authors.lastname: Oates
authors.affiliation: Leukocyte Biology Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Simone A
authors.initials: SA
authors.lastname: Walker
authors.affiliation: Respiratory Paediatrics, Royal Brompton Hospital, and National Heart & Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: Bush
authors.affiliation: Leukocyte Biology Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom. Electronic address: c.lloyd@imperial.ac.uk.
authors.forename: Clare M
authors.initials: CM
authors.lastname: Lloyd
mesh_terms: D000293:Adolescent; D056151:Airway Remodeling / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D001249:Asthma / Q000188:drug therapy / Q000276:immunology / Q000473:pathology*; D016535:Bronchial Hyperreactivity / Q000276:immunology* / Q000473:pathology; D019819:Budesonide / Q000627:therapeutic use; D002648:Child; D003094:Collagen / Q000276:immunology; D004351:Drug Resistance; D005260:Female; D005938:Glucocorticoids / Q000627:therapeutic use; D006801:Humans; D018793:Interleukin-13 / Q000276:immunology; D000067596:Interleukin-33; D007378:Interleukins / Q000008:administration & dosage / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D039981:Pyroglyphidae / Q000276:immunology
chemical_list: D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids; C506536:IL33 protein, human; C506535:Il33 protein, mouse; D018793:Interleukin-13; D000067596:Interleukin-33; D007378:Interleukins; D019819:Budesonide; D003094:Collagen
keywords: AAD; AHR; Airway hyperresponsiveness; Allergic airways disease; Asthma; BAL; Bronchoalveolar lavage; EB; Endobronchial biopsy; HDM; House dust mite; IL-33; RBM; Reticular basement membrane; STRA; Severe therapy-resistant asthma; airway remodeling; pediatric; steroid resistance; therapy