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

doi:10.1016/j.jaci.2013.09.016

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 language	English
Pages (from-to)	704-712
Number of pages	9
Journal	Journal of Allergy and Clinical Immunology
Volume	133
Issue number	3
Early online date	08 Nov 2013
DOIs	https://doi.org/10.1016/j.jaci.2013.09.016
Publication status	Published - Mar 2014

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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Increased expression of bronchial epithelial transient receptor potential vanilloid 1 channels in patients with severe asthma
Copyright 2014 Elsevier. This manuscript is distributed under a Creative Commons Attribution-NonCommercial-NoDerivs License (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits distribution and reproduction for non-commercial purposes, provided the author and source are cited.
Accepted author manuscript, 4.89 MBLicence: CC BY-NC-ND

Lorcan McGarvey
- l.mcgarveyqub.acuk
- School of Medicine, Dentistry and Biomedical Sciences - Clinical Professor
- Wellcome Wolfson Institute for Experimental Medicine
Person: Academic

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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

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title = "Increased expression of bronchial epithelial transient receptor potential vanilloid 1 channels in severe asthma",

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.",

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

year = "2014",

month = mar,

doi = "10.1016/j.jaci.2013.09.016",

language = "English",

volume = "133",

pages = "704--712",

journal = "Journal of Allergy and Clinical Immunology",

issn = "0091-6749",

publisher = "Elsevier Inc.",

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McGarvey, LP, Butler, CA, Stokesberry, S, Polley, L, McQuaid, S, Abdullah, H, Ashraf, S, McGahon, MK , Curtis, TM, Arron, J, Choy, D, Warke, TJ, Bradding, P, Ennis, M, Zholos, A, Costello, RW & Heaney, LG 2014, 'Increased expression of bronchial epithelial transient receptor potential vanilloid 1 channels in severe asthma', Journal of Allergy and Clinical Immunology, vol. 133, no. 3, pp. 704-712. https://doi.org/10.1016/j.jaci.2013.09.016

TY - JOUR

T1 - Increased expression of bronchial epithelial transient receptor potential vanilloid 1 channels in severe asthma

AU - McGarvey, Lorcan P.

AU - Butler, Claire A.

AU - Stokesberry, Susan

AU - Polley, Liam

AU - McQuaid, Stephen

AU - Abdullah, Hani'ah

AU - Ashraf, Sadaf

AU - McGahon, Mary K.

AU - Curtis, Tim M.

AU - Arron, Joe

AU - Choy, David

AU - Warke, Tim J.

AU - Bradding, Peter

AU - Ennis, Madeleine

AU - Zholos, Alexander

AU - Costello, Richard W.

AU - Heaney, Liam G.

PY - 2014/3

Y1 - 2014/3

N2 - 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.

AB - 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.

U2 - 10.1016/j.jaci.2013.09.016

DO - 10.1016/j.jaci.2013.09.016

M3 - Article

C2 - 24210884

SN - 0091-6749

VL - 133

SP - 704

EP - 712

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

IS - 3

ER -

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

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