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

• Published in: Journal of allergy and clinical immunology Vol. 133; no. 3; pp. 704 - 712.e4
• Main Authors: McGarvey, Lorcan P., MD, Butler, Claire A., PhD, Stokesberry, Susan, PhD, Polley, Liam, MD, McQuaid, Stephen, PhD, Abdullah, Hani’ah, PhD, Ashraf, Sadaf, PhD, McGahon, Mary K., PhD, Curtis, Tim M., PhD, Arron, Joe, MD, PhD, Choy, David, BSc, Warke, Tim J., MD, Bradding, Peter, DM, Ennis, Madeleine, PhD, Zholos, Alexander, PhD, Costello, Richard W., MD, Heaney, Liam G., MD
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.03.2014; Elsevier; Elsevier Limited
• Subjects: Adult; Aged; Allergy and Immunology; asthma; Asthma - metabolism; Biological and medical sciences; Biopsy; Bronchi - chemistry; Cells, Cultured; chemical; cough; exacerbation; Experiments; Female; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Gene expression; Humans; Hydrogen-Ion Concentration; Immunohistochemistry; Immunopathology; Ion channel; irritant; Male; Medical sciences; Middle Aged; Pneumology; Proteins; Respiratory system : syndromes and miscellaneous diseases; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; sensory; Studies; TRPV Cation Channels - analysis; TRPV Cation Channels - genetics; TRPV Cation Channels - physiology; Immunohistochemistry; Transient receptor potential vanilloid 1; IHC; Primary bronchial epithelial cell; cough; I-V; TRP; Quantitative real-time PCR; qRT-PCR; asthma; IQR; TRPV1; Ion channel; ER; Transient receptor potential; exacerbation; GINA; sensory; chemical; Global Initiative for Asthma; PBEC; C T; Interquartile range; Cycle threshold; Glyceraldehyde-3-phosphate dehydrogenase; Current-voltage; irritant; Endoplasmic reticulum; GAPDH; CT; Human; Immunopathology; Bronchus; Ionic channel; Respiratory system; Cough; Transitory; Respiratory tract; Exacerbation; Immunology; Severe asthma; Biological receptor
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2013.09.016

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.