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Crucial role of transient receptor potential ankyrin 1 and mast cells in induction of nonallergic airway hyperreactivity in mice

: Hox, Valérie; Vanoirbeek, Jeron A.; Alpizar, Yeranddy Aguiar; Voedisch, Sabrina; Callebaut, Ina; Bobic, Sonja; Sharify, Ali; Vooght, Vanessa de; Gerven, Laura van; Devos, Fien; Liston, Adrian; Voets, Thomas; Vennekens, Rudi; Bullens, Dominique M.A.; Vries, Annick de; Hoet, Peter; Braun, Armin; Ceuppens, Jan L.; Talavera, Karel; Nemery, Benoit; Hellings, Peter W.


American Journal of Respiratory and Critical Care Medicine 187 (2013), Nr.5, S.486-493
ISSN: 1073-449X
ISSN: 0003-0805
ISSN: 1535-4970
Fraunhofer ITEM ()
Airway hyperreactivity; Transient receptor potential ankyrin 1; Hypochlorite; Mast cells

Airway hyperreactivity (AHR) is a key feature of bronchial asthma and inhalation of irritants may facilitate development of non-allergic 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(-) prior to ovalbumin (OVA) induces AHR without bronchial inflammatory cells.
To investigate the mechanisms of ClO(-)-OVA-induced non-allergic AHR.
The involvement of the transient receptor potential (TRP) A1 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(-) by 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(W-sh)/Kit(W-sh) mice to ClO(-)-OVA with or without mast cell reconstitution.
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. Kit(W-sh)/Kit(W-sh) mice did not develop AHR in response to ClO(-)-OVA, unless they were reconstituted with BMMCs.
Induction of AHR by exposure to ClO(-)-OVA depends on a neuro-immune interaction that involves TRPA1-dependent stimulation of sensory neurons and mast cell activation.