Please use this identifier to cite or link to this item: http://hdl.handle.net/2381/36752
Title: Oxidative stress-induced mitochondrial dysfunction drives inflammation and airway smooth muscle remodeling in patients with chronic obstructive pulmonary disease
Authors: Wiegman, C. H.
Michaeloudes, C.
Haji, G.
Narang, P.
Clarke, C. J.
Russell, K. E.
Bao, W.
Pavlidis, S.
Barnes, P. J.
Kanerva, J.
Bittner, A.
Rao, N.
Murphy, M. P.
Kirkham, P. A.
Chung, K. F.
Adcock, I. M.
Brightling, Christopher Edward
Davies, D. E.
Finch, D. K.
Fisher, A. J.
Gaw, A.
Knox, A. J.
Mayer, R. J.
Polkey, M.
Salmon, M.
Singh, D.
First Published: 29-Mar-2015
Publisher: Elsevier (Mosby) for American Academy of Allergy, Asthma and Immunology
Citation: Journal of Allergy and Clinical Immunology, 2015, 136 (3), pp. 769-780
Abstract: Background Inflammation and oxidative stress play critical roles in patients with chronic obstructive pulmonary disease (COPD). Mitochondrial oxidative stress might be involved in driving the oxidative stress-induced pathology. Objective We sought to determine the effects of oxidative stress on mitochondrial function in the pathophysiology of airway inflammation in ozone-exposed mice and human airway smooth muscle (ASM) cells. Methods Mice were exposed to ozone, and lung inflammation, airway hyperresponsiveness (AHR), and mitochondrial function were determined. Human ASM cells were isolated from bronchial biopsy specimens from healthy subjects, smokers, and patients with COPD. Inflammation and mitochondrial function in mice and human ASM cells were measured with and without the presence of the mitochondria-targeted antioxidant MitoQ. Results Mice exposed to ozone, a source of oxidative stress, had lung inflammation and AHR associated with mitochondrial dysfunction and reflected by decreased mitochondrial membrane potential (ΔΨm), increased mitochondrial oxidative stress, and reduced mitochondrial complex I, III, and V expression. Reversal of mitochondrial dysfunction by the mitochondria-targeted antioxidant MitoQ reduced inflammation and AHR. ASM cells from patients with COPD have reduced ΔΨm, adenosine triphosphate content, complex expression, basal and maximum respiration levels, and respiratory reserve capacity compared with those from healthy control subjects, whereas mitochondrial reactive oxygen species (ROS) levels were increased. Healthy smokers were intermediate between healthy nonsmokers and patients with COPD. Hydrogen peroxide induced mitochondrial dysfunction in ASM cells from healthy subjects. MitoQ and Tiron inhibited TGF-β-induced ASM cell proliferation and CXCL8 release. Conclusions Mitochondrial dysfunction in patients with COPD is associated with excessive mitochondrial ROS levels, which contribute to enhanced inflammation and cell hyperproliferation. Targeting mitochondrial ROS represents a promising therapeutic approach in patients with COPD.
DOI Link: 10.1016/j.jaci.2015.01.046
ISSN: 0091-6749
eISSN: 1097-6825
Links: http://www.sciencedirect.com/science/article/pii/S0091674915002651
http://hdl.handle.net/2381/36752
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © 2015 The Authors. Published by Mosby, Inc. Open Access funded by Medical Research Council Under a Creative Commons license ( http://creativecommons.org/licenses/by/4.0/ ) which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Appears in Collections:Published Articles, Dept. of Infection, Immunity and Inflammation

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