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

Lorcan P. McGarvey (Corresponding Author), 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

Research output: Contribution to journalArticlepeer-review

85 Citations (Scopus)

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)704-12.e4
Number of pages13
JournalJournal of Allergy and Clinical Immunology
Volume133
Issue number3
Early online date8 Nov 2013
DOIs
Publication statusPublished - Mar 2014

Keywords

  • Ion channel
  • sensory
  • asthma
  • irritant
  • chemical
  • exacerbation
  • cough

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