Oxidative stress–induced mitochondrial dysfunction drives inflammation and airway smooth muscle remodeling in patients with chronic obstructive pulmonary disease - 04/09/15
, Charalambos Michaeloudes, PhD a, ∗, Gulammehdi Haji, MD a, ∗, Priyanka Narang, PhD a, Colin J. Clarke, MSc a, Kirsty E. Russell, PhD a, Wuping Bao, MD a, Stelios Pavlidis, PhD b, Peter J. Barnes, MD a, Justin Kanerva, MSc c, Anton Bittner, PhD c, Navin Rao, PhD c, Michael P. Murphy, PhD d, Paul A. Kirkham, PhD a, Kian Fan Chung, MD a, Ian M. Adcock, PhD aon behalf of
COPDMAP‡
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.
Le texte complet de cet article est disponible en PDF.Key words : Ozone, inflammation, airway smooth muscle, mitochondria, chronic obstructive pulmonary disease, airway hyperresponsiveness, oxidative stress, antioxidant, proliferation, MitoQ
Abbreviations used : AHR, ASM, ATP, BAL, COPD, dTPP, GOLD, JC-1, KC, −logPC100, ΔΨm, NAC, NO, OCR, RL, ROS
Plan
| The MRC-ABPI COPD-MAP consortium (G1001367/1) funded the clinical aspects of this project; in this regard we are also grateful to Professor M. Polkey (RBHFT) for his support for these aspects. Gene arrays were performed by Janssen Research & Development. I.M.A. and P.J.B. are supported by Wellcome Trust grant 093080/Z/10/Z. C.H.W. is a RCUK Research Fellow. This project was supported by the NIHR Respiratory Disease Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College London. The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, The National Institute for Health Research or the Department of Health. |
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| Disclosure of potential conflict of interest: M. P. Murphy has a board membership, consultant arrangements, and stock/stock options with Antipodean Pharmaceuticals and has patents on MitoQ. K. F. Chung is on advisory boards for GlaxoSmithKline, AstraZeneca, Novartis, and Johnson & Johnson; has received research support from the Medical Research Council, European Union, Innovative Medicines Initiative, and National Institutes of Health; and has received payment for lectures from AstraZeneca and Merck. I. M. Adcock has received research support from Medical Research Council–Association of the British Pharmaceutical Industry COPD MAP (grant no. G1001367/1), the Wellcome Trust (grant no. 093080/Z/10/Z), DMT, and the European Research Council; has received payment for lectures from MSD; has a board membership with Almirall; has received payment for development of educational presentations from Webinar; and has received travel support from Boehringer Ingelheim, GlaxoSmithKline, and MSD. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 136 - N° 3
P. 769-780 - septembre 2015 Retour au numéro
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