title: Crucial role of transient receptor potential ankyrin 1 and mast cells in induction of nonallergic airway hyperreactivity in mice.
abstract: BACKGROUND
  Airway hyperreactivity (AHR) is a key feature of bronchial asthma, and inhalation of irritants may facilitate development of nonallergic AHR. Swimmers exposed to hypochlorite (ClO(-))-containing water show a higher risk of developing AHR. We developed a mouse model in which instillation of ClO(-) before ovalbumin (OVA) induces AHR without bronchial inflammatory cells.
  
  
  OBJECTIVE
  To investigate the mechanisms of ClO(-)-OVA-induced nonallergic AHR.
  
  
  METHODS
  The involvement of the transient receptor potential ankyrin (TRPA)1 channel was checked in vivo by the use of TRPA1(-/-) mice and in vitro by Ca(2+) imaging experiments. The role of substance P (SP) was investigated by pretreating animals with the receptor antagonist RP67580, by replacing ClO(-) with SP in vivo, and by immunofluorescent staining of large airways of exposed mice. The role of mast cells was evaluated by exposing mast cell-deficient Kit(Wh)/Kit(Wsh) mice to ClO(-)-OVA with or without mast cell reconstitution.
  
  
  RESULTS
  ClO(-)-OVA did not induce AHR in TRPA1(-/-) mice, and ClO(-) generates a Ca(2+) influx in TRPA1-transfected cells. Pretreatment with RP67580 reduces ClO(-)-OVA-induced AHR, although no increased SP expression was shown in the airways. SP-OVA exposure resulted in the same AHR as induced by ClO(-)-OVA. Kit(Wsh)/Kit(Wsh) mice did not develop AHR in response to ClO(-)-OVA unless they were reconstituted with bone marrow-derived mast cells.
  
  
  CONCLUSIONS
  Induction of AHR by exposure to ClO(-)-OVA depends on a neuroimmune interaction that involves TRPA1-dependent stimulation of sensory neurons and mast cell activation.
authors.affiliation: Laboratory of Clinical Immunology, Department of Microbiology and Immunology, KULeuven, Leuven, Belgium.
authors.forename: Valérie
authors.initials: V
authors.lastname: Hox
authors.forename: Jeroen A
authors.initials: JA
authors.lastname: Vanoirbeek
authors.forename: Yeranddy A
authors.initials: YA
authors.lastname: Alpizar
authors.forename: Sabrina
authors.initials: S
authors.lastname: Voedisch
authors.forename: Ina
authors.initials: I
authors.lastname: Callebaut
authors.forename: Sonja
authors.initials: S
authors.lastname: Bobic
authors.forename: Ali
authors.initials: A
authors.lastname: Sharify
authors.forename: Vanessa
authors.initials: V
authors.lastname: De Vooght
authors.forename: Laura
authors.initials: L
authors.lastname: Van Gerven
authors.forename: Fien
authors.initials: F
authors.lastname: Devos
authors.forename: Adrian
authors.initials: A
authors.lastname: Liston
authors.forename: Thomas
authors.initials: T
authors.lastname: Voets
authors.forename: Rudi
authors.initials: R
authors.lastname: Vennekens
authors.forename: Dominique M A
authors.initials: DM
authors.lastname: Bullens
authors.forename: Annick
authors.initials: A
authors.lastname: De Vries
authors.forename: Peter
authors.initials: P
authors.lastname: Hoet
authors.forename: Armin
authors.initials: A
authors.lastname: Braun
authors.forename: Jan L
authors.initials: JL
authors.lastname: Ceuppens
authors.forename: Karel
authors.initials: K
authors.lastname: Talavera
authors.forename: Benoit
authors.initials: B
authors.lastname: Nemery
authors.forename: Peter W
authors.initials: PW
authors.lastname: Hellings
mesh_terms: D000818:Animals; D016535:Bronchial Hyperreactivity / Q000209:etiology / Q000503:physiopathology*; D002478:Cells, Cultured; D006997:Hypochlorous Acid / Q000009:adverse effects*; D007509:Irritants / Q000009:adverse effects*; D008407:Mast Cells / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D015213:Neuroimmunomodulation; D009619:Nociceptors / Q000276:immunology; D010047:Ovalbumin / Q000009:adverse effects; D013373:Substance P / Q000378:metabolism; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels / Q000276:immunology*
chemical_list: D007509:Irritants; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; D013373:Substance P; D006997:Hypochlorous Acid; D010047:Ovalbumin