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

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

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Asthma
Transient Receptor Potential Channels
Healthy Volunteers
Epithelium
Epithelial Cells
vanilloid receptor subtype 1
Irritants
Electrophysiology
Capsaicin
Interleukin-8
Western Blotting
Immunohistochemistry
Biopsy
Gene Expression
Polymerase Chain Reaction
Membranes
Therapeutics
Proteins

Keywords

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

Cite this

Increased expression of bronchial epithelial transient receptor potential vanilloid 1 channels in patients with severe asthma. / McGarvey, Lorcan P. (Corresponding Author); Butler, Claire A; Stokesberry, Susan; Polley, Liam; McQuaid, Stephen; Abdullah, Hani'ah; Ashraf, Sadaf; McGahon, Mary K; Curtis, Tim M; Arron, Joe; Choy, David; Warke, Tim J; Bradding, Peter; Ennis, Madeleine; Zholos, Alexander; Costello, Richard W; Heaney, Liam G.

In: Journal of Allergy and Clinical Immunology, Vol. 133, No. 3, 03.2014, p. 704-12.e4.

Research output: Contribution to journalArticle

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 patients with severe asthma', Journal of Allergy and Clinical Immunology, vol. 133, no. 3, pp. 704-12.e4. https://doi.org/10.1016/j.jaci.2013.09.016
McGarvey, Lorcan P. ; Butler, Claire A ; Stokesberry, Susan ; Polley, Liam ; McQuaid, Stephen ; Abdullah, Hani'ah ; Ashraf, Sadaf ; McGahon, Mary K ; Curtis, Tim M ; Arron, Joe ; Choy, David ; Warke, Tim J ; Bradding, Peter ; Ennis, Madeleine ; Zholos, Alexander ; Costello, Richard W ; Heaney, Liam G. / Increased expression of bronchial epithelial transient receptor potential vanilloid 1 channels in patients with severe asthma. In: Journal of Allergy and Clinical Immunology. 2014 ; Vol. 133, No. 3. pp. 704-12.e4.
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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.",
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note = "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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T1 - Increased expression of bronchial epithelial transient receptor potential vanilloid 1 channels in patients with 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

N1 - 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.

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.

KW - Ion channel

KW - sensory

KW - asthma

KW - irritant

KW - chemical

KW - exacerbation

KW - cough

U2 - 10.1016/j.jaci.2013.09.016

DO - 10.1016/j.jaci.2013.09.016

M3 - Article

VL - 133

SP - 704-12.e4

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

SN - 0091-6749

IS - 3

ER -