title: Airway responsiveness to mannitol in asthma is associated with chymase-positive mast cells and eosinophilic airway inflammation.
abstract: BACKGROUND
  Airway hyperresponsiveness (AHR) to inhaled mannitol is associated with indirect markers of mast cell activation and eosinophilic airway inflammation. It is unknown how AHR to mannitol relates to mast cell phenotype, mast cell function and measures of eosinophilic inflammation in airway tissue. We compared the number and phenotype of mast cells, mRNA expression of mast cell-associated genes and number of eosinophils in airway tissue of subjects with asthma and healthy controls in relation to AHR to mannitol.
  
  
  METHODS
  Airway hyperresponsiveness to inhaled mannitol was measured in 23 non-smoking, corticosteroid-free asthmatic individuals and 10 healthy controls. Mast cells and eosinophils were identified in mucosal biopsies from all participants. Mast cells were divided into phenotypes based on the presence of chymase. mRNA expression of mast cell-associated genes was measured by real-time PCR.
  
  
  RESULTS
  The proportion of submucosal MCTC was higher in asthmatic individuals with AHR to mannitol compared with asthmatic individuals without AHR (median: 40.3% vs. 18.7%, P = 0.03). Increased submucosal MCTC numbers were associated with increased levels of mRNA for thymic stromal lymphopoietin (TSLP) and CPA3 in asthmatics. Reactivity to mannitol correlated significantly with eosinophils in submucosa (r(s): 0.56, P = 0.01).
  
  
  CONCLUSIONS
  Airway hyperresponsiveness to inhaled mannitol is associated with an altered submucosal mast cell profile in asthmatic individuals. This mast cell profile is associated with increased levels of TSLP and CPA3. The degree of AHR to mannitol is correlated with the degree of eosinophilic inflammation in the airway submucosa.
authors.affiliation: University Hospital Bispebjerg, Copenhagen, Denmark.
authors.forename: A
authors.initials: A
authors.lastname: Sverrild
authors.affiliation: Respiratory Medicine and Allergology and Experimental Medical Science, Lund University, Lund, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Bergqvist
authors.affiliation: Centre for Asthma and Respiratory Disease, The University of Newcastle, Newcastle, NSW, Australia.
authors.forename: K J
authors.initials: KJ
authors.lastname: Baines
authors.affiliation: University Hospital Bispebjerg, Copenhagen, Denmark.
authors.forename: C
authors.initials: C
authors.lastname: Porsbjerg
authors.affiliation: Respiratory Medicine and Allergology and Experimental Medical Science, Lund University, Lund, Sweden.
authors.forename: C K
authors.initials: CK
authors.lastname: Andersson
authors.affiliation: Department of Dermatology, Bispebjerg Hospital, Copenhagen, Denmark.
authors.forename: S F
authors.initials: SF
authors.lastname: Thomsen
authors.affiliation: Department of Pulmonary Medicine B, Institute for Clinical Medicine, Aarhus University, Aarhus, Denmark.
authors.forename: H J
authors.initials: HJ
authors.lastname: Hoffmann
authors.affiliation: Centre for Asthma and Respiratory Disease, The University of Newcastle, Newcastle, NSW, Australia.
authors.forename: P
authors.initials: P
authors.lastname: Gibson
authors.affiliation: Respiratory Medicine and Allergology and Experimental Medical Science, Lund University, Lund, Sweden.
authors.forename: J S
authors.initials: JS
authors.lastname: Erjefält
authors.affiliation: University Hospital Bispebjerg, Copenhagen, Denmark.
authors.forename: V
authors.initials: V
authors.lastname: Backer
mesh_terms: D000328:Adult; D001249:Asthma / Q000276:immunology*; D016535:Bronchial Hyperreactivity / Q000276:immunology*; D043422:Carboxypeptidases A / Q000096:biosynthesis / Q000276:immunology; D053818:Chymases / Q000276:immunology; D003430:Cross-Sectional Studies; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D004804:Eosinophils / Q000276:immunology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000276:immunology*; D008297:Male; D008353:Mannitol / Q000276:immunology / Q000494:pharmacology; D008407:Mast Cells / Q000276:immunology*; D060888:Real-Time Polymerase Chain Reaction; D012129:Respiratory Function Tests / Q000379:methods; D020545:Respiratory Mucosa / Q000276:immunology; D059467:Transcriptome; D055815:Young Adult; D000094632:Thymic Stromal Lymphopoietin
chemical_list: D016207:Cytokines; D008353:Mannitol; C468648:CPA3 protein, human; D043422:Carboxypeptidases A; D053818:Chymases; D000094632:Thymic Stromal Lymphopoietin
keywords: CPA3; TSLP; airway hyperresponsiveness; asthma; mannitol; mast cells