Increased expression of bronchial epithelial transient receptor potential vanilloid 1 channels in severe asthma

Lorcan P. McGarvey, Claire A. Butler, Susan Stokesberry, Liam Polley, Stephen McQuaid, Hani'ah Abdullah, Sadaf Ashraf, Mary K. McGahon, Tim M. Curtis, Joe Arron, David Choy, Tim J. Warke, Peter Bradding, Madeleine Ennis, Alexander Zholos, Richard W. Costello, Liam G. Heaney

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Abstract

BACKGROUND: The airway epithelium is exposed to a range of physical and chemical irritants in the environment that are known to trigger asthma. Transient receptor potential (TRP) cation channels play a central role in sensory responses to noxious physical and chemical stimuli. Recent genetic evidence suggests an involvement of transient receptor potential vanilloid 1 (TRPV1), one member of the vanilloid subfamily of TRP channels, in the pathophysiology of asthma. The functional expression of TRPV1 on airway epithelium has yet to be elucidated.

OBJECTIVE: In this study we examined the molecular, functional, and immunohistochemical expression of TRPV1 in asthmatic and healthy airways.

METHODS: Bronchial biopsy specimens and bronchial brushings were obtained from healthy volunteers (n = 18), patients with mild-to-moderate asthma (n = 24), and patients with refractory asthma (n = 22). Cultured primary bronchial epithelial cells from patients with mild asthma (n = 4), nonasthmatic coughers (n = 4), and healthy subjects (n = 4) were studied to investigate the functional role of TRPV1.

RESULTS: Quantitative immunohistochemistry revealed significantly more TRPV1 expression in asthmatic patients compared with healthy subjects, with the greatest expression in patients with refractory asthma (P = .001). PCR and Western blotting analysis confirmed gene and protein expression of TRPV1 in cultured primary bronchial epithelial cells. Patch-clamp electrophysiology directly confirmed functional TRPV1 expression in all 3 groups. In functional assays the TRPV1 agonist capsaicin induced dose-dependent IL-8 release, which could be blocked by the antagonist capsazepine. Reduction of external pH from 7.4 to 6.4 activated a capsazepine-sensitive outwardly rectifying membrane current.

CONCLUSIONS: Functional TRPV1 channels are present in the human airway epithelium and overexpressed in the airways of patients with refractory asthma. These channels might represent a novel therapeutic target for the treatment of uncontrolled asthma.

Original languageEnglish
Pages (from-to)704-712
Number of pages9
JournalJournal of Allergy and Clinical Immunology
Volume133
Issue number3
Early online date08 Nov 2013
DOIs
Publication statusPublished - Mar 2014

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    McGarvey, L. P., Butler, C. A., Stokesberry, S., Polley, L., McQuaid, S., Abdullah, H., Ashraf, S., McGahon, M. K., Curtis, T. M., Arron, J., Choy, D., Warke, T. J., Bradding, P., Ennis, M., Zholos, A., Costello, R. W., & Heaney, L. G. (2014). Increased expression of bronchial epithelial transient receptor potential vanilloid 1 channels in severe asthma. Journal of Allergy and Clinical Immunology, 133(3), 704-712. https://doi.org/10.1016/j.jaci.2013.09.016