Study on TRPV1-mediated mechanism for the hypersecretion of mucus in respiratory inflammation

Transient receptor potential vanilloid 1 (TRPV1) is sensitized by the high affinity TrkA receptor, which promotes pro-inflammatory cytokine production and mediates mucus hypersecretion in bronchial epithelial cells. The purpose of this study was to investigate the mechanism of TRPV1-mediated mucus hypersecretion and respiratory inflammation. Firstly, using Western blot analysis we found that epidermal growth factor receptor (EGFR) and TRPV1 were highly co-expressed in human bronchial epithelial cells (HBE16) with HNE and capsaicin co-treated, the levels of pro-inflammatory cytokines and MUC5AC were also highly co-expressed; however, TRPV1 receptor expression was low in these cells with only HNE stimulation, which demonstrated that sensitization of TRPV1 was not increased in HBE16 cells treated with HNE alone. Secondly, the EGF receptor antagonist (AG1478) and the TrkA receptor inhibitor (K252a) significantly inhibited TRPV1 sensitivity and the expression of MUC5AC and pro-inflammatory cytokines. Furthermore, the PI3K inhibitor LY294002, the PKC inhibitor bisindoylmaleimide (BIM) and the TRPV1 antagonist capsazepine completely abrogated the EGF sensitizing effect. Furthermore, the hypoxia-inducible factor (HIF-1α) inhibitor 2-methoxyestradiol (2-ME2) decreased the activity of PKC by a specific pathway. These findings strongly suggest that TRPV1 sensitization influences the hypersecretion of mucus and inflammatory cytokines, is associated with the PI3K and PKC signaling pathways and is involved HIF-1α activity.

► Comparative airway epithelial cells trials could speed up the development of novel therapies.
► Modeling revealed that transient receptor potential vanilloid 1 (TRPV1) and EGFR molecules are highly conserved.
► PI3K and PKC signaling pathways and HIF-1α activity influence the TRPV1 sensitization, and then increase the hypersecretion of mucus and inflammatory cytokines.
► This knowledge opens up perspectives for the activity of TRPV1 associating with mucus hypersecretion in human airway epithelial cells.