Increased expression of bronchial epithelial transient receptor potential vanilloid 1 channels in patients with severe asthma - 01/03/14
, Claire A. Butler, PhD a, Susan Stokesberry, PhD a, Liam Polley, MD a, Stephen McQuaid, PhD b, Hani’ah Abdullah, PhD a, Sadaf Ashraf, PhD c, Mary K. McGahon, PhD c, Tim M. Curtis, PhD c, Joe Arron, MD, PhD d, David Choy, BSc d, Tim J. Warke, MD a, Peter Bradding, DM e, Madeleine Ennis, PhD a, Alexander Zholos, PhD c, f, Richard W. Costello, MD g, Liam G. Heaney, MD aAbstract |
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.
Le texte complet de cet article est disponible en PDF.Key words : Ion channel, sensory, asthma, irritant, chemical, exacerbation, cough
Abbreviations used : CT, ER, GAPDH, GINA, IHC, IQR, I-V, PBEC, qRT-PCR, TRP, TRPV1
Plan
| S.S. was supported by a grant from the Northern Ireland Chest Heart & Stroke Association, and L.P. was supported by a grant from the Higher Education Authority (North South Research Programme). Work in Leicester and Belfast was supported in part by grants from Genentech, South San Francisco, California. |
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| Disclosure of potential conflict of interest: L. P. McGarvey has been supported by one or more grants from the Northern Ireland Chest Heart & Stroke Association and from the Health Education Authority (North South Funding); is a member of advisory boards for Almirall, the NAPP, GlaxoSmithKline (GSK), and Boehringer Ingelheim; has consultancy arrangements with the Endpoint Adjudication Committee (served as Chairman and Committee Member), Boehringer Ingelheim, and GSK; has received one or more grants from or has one or more grants pending with Chiesi, the Laboratory Animal Science Association/NC3Rs, the British Heart Foundation, the Northern Ireland Chest Heart & Stroke Association, Royal Belfast Hospital (Sick Children Clinical Fellowship), Asthma UK, and the Research Forum for the Child International PhD studentships; and has received one or more payments for travel/accommodations/meeting expenses from Chiesi, Boehringer Ingelheim, and GSK. C. A. Butler has received one or more payments for travel/accommodations/meeting expenses from GSK. S. Stokesberry has been supported by one or more grants from the Northern Ireland Chest Heart & Stroke Association. L. Polley has been supported by an educational grant from the Higher Education Authority (North South Research Programme) and has received money from GSK (General Practice Education–Asthma Update [SIGN Guidelines]). J. Arron is employed by and has one or more patents (planned, pending, or issued) with Genentech and owns stock/stock options in Roche Holdings. D. Choy is employed by and owns stock/stock options in Genentech. P. Bradding has been supported by one or more grants from Genentech. M. Ennis has been supported by one or more grants from the Northern Ireland Chest Heart and Stroke Association and from the Higher Education Authority (North South Research Programme). L. G. Heaney has received one or more grants from or has one or more grants pending with GSK, MedImmune, Novartis UK, AstraZeneca, Genenetch, the Medical Research Council UK, the Northern Ireland Chest Heart & Stroke Association, Hoffmann la Roche UK, and Asthma UK/the Northern Ireland Chest Heart & Stroke Association; has received one or more payments for lecturing from or is on the speakers' bureau for GSK, Merck Sharpe & Dohme, Nycomed, Novartis, Genentech Inc and AstraZeneca; and has received one or more payments for travel/accommodations/meeting expenses from AstraZeneca, Chiesi, Novartis, and GSK. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 133 - N° 3
P. 704 - mars 2014 Retour au numéro
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