Crucial Role of TRPA1 and Mast Cells in Induction of Non-Allergic Airway Hyperreactivity in Mice

RATIONALE: 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. OBJECTIVE: To investigate the mechanisms of ClO(-)-OVA-induced non-allergic AHR. METHODS: 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. MEASUREMENTS AND MAIN 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. Kit(W-sh)/Kit(W-sh) mice did not develop AHR in response to ClO(-)-OVA, unless they were reconstituted with BMMCs. CONCLUSION: 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.status: publishe