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Mechanistic link between diesel exhaust particles and respiratory reflexes

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Title: Mechanistic link between diesel exhaust particles and respiratory reflexes
Authors: Robinson, RK
Birrell, MA
Adcock, JJ
Wortley, MA
Dubuis, ED
Chen, S
McGilvery, CM
Hu, S
Shaffer, MSP
Bonvini, SJ
Maher, SA
Mudway, IS
Porter, AE
Carlsten, C
Tetley, TD
Belvisi, MG
Item Type: Journal Article
Abstract: Background Diesel exhaust particles (DEPs) are a major component of particulate matter in Europe's largest cities, and epidemiologic evidence links exposure with respiratory symptoms and asthma exacerbations. Respiratory reflexes are responsible for symptoms and are regulated by vagal afferent nerves, which innervate the airway. It is not known how DEP exposure activates airway afferents to elicit symptoms, such as cough and bronchospasm. Objective We sought to identify the mechanisms involved in activation of airway sensory afferents by DEPs. Methods In this study we use in vitro and in vivo electrophysiologic techniques, including a unique model that assesses depolarization (a marker of sensory nerve activation) of human vagus. Results We demonstrate a direct interaction between DEP and airway C-fiber afferents. In anesthetized guinea pigs intratracheal administration of DEPs activated airway C-fibers. The organic extract (DEP-OE) and not the cleaned particles evoked depolarization of guinea pig and human vagus, and this was inhibited by a transient receptor potential ankyrin-1 antagonist and the antioxidant N-acetyl cysteine. Polycyclic aromatic hydrocarbons, major constituents of DEPs, were implicated in this process through activation of the aryl hydrocarbon receptor and subsequent mitochondrial reactive oxygen species production, which is known to activate transient receptor potential ankyrin-1 on nociceptive C-fibers. Conclusions This study provides the first mechanistic insights into how exposure to urban air pollution leads to activation of guinea pig and human sensory nerves, which are responsible for respiratory symptoms. Mechanistic information will enable the development of appropriate therapeutic interventions and mitigation strategies for those susceptible subjects who are most at risk.
Issue Date: 19-May-2017
Date of Acceptance: 1-May-2017
URI: http://hdl.handle.net/10044/1/48400
DOI: https://dx.doi.org/10.1016/j.jaci.2017.04.038
ISSN: 1097-6825
Publisher: Elsevier
Start Page: 1074
End Page: 1084.e9
Journal / Book Title: Journal of Allergy and Clinical Immunology
Volume: 141
Issue: 3
Copyright Statement: © 2017 The Authors. Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
Sponsor/Funder: National Institutes of Health
Medical Research Council (MRC)
Funder's Grant Number: H50669
MR/K020293/1
Keywords: Pollution
oxidative stress
sensory nerves
transient receptor potential ion channels
vagus
1107 Immunology
Allergy
Publication Status: Published
Appears in Collections:Faculty of Engineering
Materials
Chemistry
National Heart and Lung Institute
Airway Disease
Faculty of Medicine
Faculty of Natural Sciences



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