title: Distal airways are protected from goblet cell metaplasia by diminished expression of IL-13 signalling components.
abstract: BACKGROUND
  Increased mucus production is a critical factor impairing lung function in patients suffering from bronchial asthma, the most common chronic inflammatory lung disease worldwide.
  
  
  OBJECTIVE
  This study aimed at investigating whether goblet cell (GC) metaplasia and mucus production are differentially regulated in proximal and distal airways.
  
  
  METHODS
  Female Balb/c mice were sensitized to ovalbumin (OVA) and challenged with an OVA-aerosol on two consecutive days for 1 week (acute) or 12 weeks (chronic). Real-time RT-PCR analysis was applied on microdissected airways.
  
  
  RESULTS
  In acutely and chronically OVA-challenged mice, GC metaplasia and mucus production were observed in proximal but not in distal airways. In contrast, inflammation reflected by the infiltration of eosinophils and expression of the TH2-type cytokines IL-4 and IL-13 was increased in both proximal and distal airways. Abundance of IL-13Rα1 was lower in distal airways of healthy control mice. Under acute and chronic OVA-exposure, activation of IL-13Rα1-dependent signalling cascade, reflected by Spdef and Foxo3A transcription factors, was attenuated in distal compared to proximal airways.
  
  
  CONCLUSIONS
  These data indicate that distal airways might be less sensitive to IL-13-induced GC metaplasia and mucus production through lower expression of IL-13Rα1 and attenuated activation of downstream signalling. This might represent a protective strategy to prevent mucus plugging of distal airways and thus impaired ventilation of attached alveoli.
authors.affiliation: Division of Experimental Pneumology, Priority Area Asthma & Allergy, Research Center Borstel, Airway Research Center North (ARCN), German Center for Lung Research, Borstel, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Vock
authors.affiliation: Comprehensive Pneumology Center, Institute of Lung Biology and Disease, Helmholtz Zentrum München, German Center for Lung Research, Neuherberg, Germany.
authors.forename: A Ö
authors.initials: AÖ
authors.lastname: Yildirim
authors.affiliation: Division of Invertebrate Models, Priority Area Asthma & Allergy, Research Center Borstel, Borstel, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Wagner
authors.affiliation: Division of Experimental Pneumology, Priority Area Asthma & Allergy, Research Center Borstel, Airway Research Center North (ARCN), German Center for Lung Research, Borstel, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Schlick
authors.affiliation: Division of Asthma Mouse Models, Priority Area Asthma & Allergy, Research Center Borstel, Airway Research Center North (ARCN), German Center for Lung Research, Borstel, Germany.
authors.forename: L P
authors.initials: LP
authors.lastname: Lunding
authors.affiliation: Frank L. Day Professor of Biology, Warren Alpert School of Medicine, Brown University, Providence, RI, USA.
authors.forename: C G
authors.initials: CG
authors.lastname: Lee
authors.affiliation: Frank L. Day Professor of Biology, Warren Alpert School of Medicine, Brown University, Providence, RI, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Elias
authors.affiliation: Division of Experimental Pneumology, Priority Area Asthma & Allergy, Research Center Borstel, Airway Research Center North (ARCN), German Center for Lung Research, Borstel, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Fehrenbach
authors.affiliation: Division of Asthma Mouse Models, Priority Area Asthma & Allergy, Research Center Borstel, Airway Research Center North (ARCN), German Center for Lung Research, Borstel, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Wegmann
mesh_terms: D000818:Animals; D001249:Asthma / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology*; D020397:Goblet Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018793:Interleukin-13 / Q000096:biosynthesis / Q000276:immunology*; D053661:Interleukin-13 Receptor alpha1 Subunit / Q000096:biosynthesis / Q000276:immunology; D015847:Interleukin-4 / Q000096:biosynthesis / Q000276:immunology; D008168:Lung / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008679:Metaplasia; D051379:Mice; D008807:Mice, Inbred BALB C; D009093:Mucus / Q000276:immunology / Q000378:metabolism; D050783:Proto-Oncogene Proteins c-ets / Q000096:biosynthesis / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; C508183:Il13ra1 protein, mouse; D018793:Interleukin-13; D053661:Interleukin-13 Receptor alpha1 Subunit; D050783:Proto-Oncogene Proteins c-ets; C519908:Spdef protein, mouse; D015847:Interleukin-4
keywords: asthma; interleukin 13 receptor; mucus hyperproduction