title: Impaired mucus clearance exacerbates allergen-induced type 2 airway inflammation in juvenile mice.
abstract: BACKGROUND
  Type 2 airway inflammation plays a central role in the pathogenesis of allergen-induced asthma, but the underlying mechanisms remain poorly understood. Recently, we demonstrated that reduced mucociliary clearance, a characteristic feature of asthma, produces spontaneous type 2 airway inflammation in juvenile β-epithelial Na+channel (Scnn1b)-transgenic (Tg) mice.
  
  
  OBJECTIVE
  We sought to determine the role of impaired mucus clearance in the pathogenesis of allergen-induced type 2 airway inflammation and identify cellular sources of the signature cytokine IL-13.
  
  
  METHODS
  We challenged juvenile Scnn1b-Tg and wild-type mice with Aspergillus fumigatus and house dust mite allergen and compared the effects on airway eosinophilia, type 2 cytokine levels, goblet cell metaplasia, and airway hyperresponsiveness. Furthermore, we determined cellular sources of IL-13 and effects of genetic deletion of the key type 2 signal-transducing molecule signal transducer and activator of transcription 6 (STAT6) and evaluated the effects of therapeutic improvement of mucus clearance.
  
  
  RESULTS
  Reduced mucociliary allergen clearance exacerbated Stat6-dependent secretion of type 2 cytokines, airway eosinophilia, and airway hyperresponsiveness in juvenile Scnn1b-Tg mice. IL-13 levels were increased in airway epithelial cells, macrophages, type 2 innate lymphoid cells, and TH2 cells along with increased Il33 expression in the airway epithelium of Scnn1b-Tg mice. Treatment with the epithelial Na+channel blocker amiloride, improving airway surface hydration and mucus clearance, reduced allergen-induced inflammation in Scnn1b-Tg mice.
  
  
  CONCLUSIONS
  Our data support that impaired clearance of inhaled allergens triggering IL-13 production by multiple cell types in the airways plays an important role in the pathogenesis of type 2 airway inflammation and suggests therapeutic improvement of mucociliary clearance as a novel treatment strategy for children with allergen-induced asthma.
authors.affiliation: Department of Translational Pulmonology, Translational Lung Research Center Heidelberg (TLRC), Member of the German Center for Lung Research (DZL), University of Heidelberg, Heidelberg, Germany.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Fritzsching
authors.affiliation: Department of Translational Pulmonology, Translational Lung Research Center Heidelberg (TLRC), Member of the German Center for Lung Research (DZL), University of Heidelberg, Heidelberg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Hagner
authors.affiliation: Department of Translational Pulmonology, Translational Lung Research Center Heidelberg (TLRC), Member of the German Center for Lung Research (DZL), University of Heidelberg, Heidelberg, Germany.
authors.forename: Lu
authors.initials: L
authors.lastname: Dai
authors.affiliation: Department of Translational Pulmonology, Translational Lung Research Center Heidelberg (TLRC), Member of the German Center for Lung Research (DZL), University of Heidelberg, Heidelberg, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Christochowitz
authors.affiliation: Department of Translational Pulmonology, Translational Lung Research Center Heidelberg (TLRC), Member of the German Center for Lung Research (DZL), University of Heidelberg, Heidelberg, Germany.
authors.forename: Raman
authors.initials: R
authors.lastname: Agrawal
authors.affiliation: Department of Translational Pulmonology, Translational Lung Research Center Heidelberg (TLRC), Member of the German Center for Lung Research (DZL), University of Heidelberg, Heidelberg, Germany.
authors.forename: Charlotte
authors.initials: C
authors.lastname: van Bodegom
authors.affiliation: Department of Translational Pulmonology, Translational Lung Research Center Heidelberg (TLRC), Member of the German Center for Lung Research (DZL), University of Heidelberg, Heidelberg, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Schmidt
authors.affiliation: Department of Translational Pulmonology, Translational Lung Research Center Heidelberg (TLRC), Member of the German Center for Lung Research (DZL), University of Heidelberg, Heidelberg, Germany.
authors.forename: Jolanthe
authors.initials: J
authors.lastname: Schatterny
authors.affiliation: Department of Translational Pulmonology, Translational Lung Research Center Heidelberg (TLRC), Member of the German Center for Lung Research (DZL), University of Heidelberg, Heidelberg, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Hirtz
authors.affiliation: Department of Translational Pulmonology, Translational Lung Research Center Heidelberg (TLRC), Member of the German Center for Lung Research (DZL), University of Heidelberg, Heidelberg, Germany.
authors.forename: Ryan
authors.initials: R
authors.lastname: Brown
authors.affiliation: Department of Translational Pulmonology, Translational Lung Research Center Heidelberg (TLRC), Member of the German Center for Lung Research (DZL), University of Heidelberg, Heidelberg, Germany.
authors.forename: Michelle
authors.initials: M
authors.lastname: Goritzka
authors.affiliation: Department of Translational Pulmonology, Translational Lung Research Center Heidelberg (TLRC), Member of the German Center for Lung Research (DZL), University of Heidelberg, Heidelberg, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Duerr
authors.affiliation: Department of Translational Pulmonology, Translational Lung Research Center Heidelberg (TLRC), Member of the German Center for Lung Research (DZL), University of Heidelberg, Heidelberg, Germany.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Zhou-Suckow
authors.affiliation: Department of Translational Pulmonology, Translational Lung Research Center Heidelberg (TLRC), Member of the German Center for Lung Research (DZL), University of Heidelberg, Heidelberg, Germany. Electronic address: Marcus.Mall@med.uni-heidelberg.de.
authors.forename: Marcus A
authors.initials: MA
authors.lastname: Mall
mesh_terms: D000485:Allergens / Q000276:immunology; D000584:Amiloride / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001232:Aspergillus fumigatus / Q000276:immunology; D001249:Asthma / Q000188:drug therapy / Q000276:immunology* / Q000503:physiopathology*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002452:Cell Count; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology; D053503:Epithelial Sodium Channels / Q000235:genetics; D018793:Interleukin-13 / Q000276:immunology*; D008168:Lung / Q000166:cytology / Q000276:immunology; D008822:Mice, Transgenic; D009079:Mucociliary Clearance; D039981:Pyroglyphidae / Q000276:immunology; D050800:STAT6 Transcription Factor / Q000235:genetics; D026941:Sodium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000485:Allergens; D053503:Epithelial Sodium Channels; D018793:Interleukin-13; D050800:STAT6 Transcription Factor; C507049:Scnn1b protein, mouse; D026941:Sodium Channel Blockers; C494100:Stat6 protein, mouse; D000584:Amiloride
keywords: IL-13; IL-33; Type 2 inflammation; airway epithelium; mucociliary clearance