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. 2015 Sep;136(3):769-80.
doi: 10.1016/j.jaci.2015.01.046. Epub 2015 Mar 29.

Oxidative stress-induced mitochondrial dysfunction drives inflammation and airway smooth muscle remodeling in patients with chronic obstructive pulmonary disease

Coen H Wiegman  1 , Charalambos Michaeloudes  2 , Gulammehdi Haji  2 , Priyanka Narang  2 , Colin J Clarke  2 , Kirsty E Russell  2 , Wuping Bao  2 , Stelios Pavlidis  3 , Peter J Barnes  2 , Justin Kanerva  4 , Anton Bittner  4 , Navin Rao  4 , Michael P Murphy  5 , Paul A Kirkham  2 , Kian Fan Chung  2 , Ian M Adcock  2 ; COPDMAP
Collaborators, Affiliations

Oxidative stress-induced mitochondrial dysfunction drives inflammation and airway smooth muscle remodeling in patients with chronic obstructive pulmonary disease

Coen H Wiegman et al. J Allergy Clin Immunol. 2015 Sep.

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.

Keywords: MitoQ; Ozone; airway hyperresponsiveness; airway smooth muscle; antioxidant; chronic obstructive pulmonary disease; inflammation; mitochondria; oxidative stress; proliferation.

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Figures

Fig 1
Fig 1
A and B, Airways hyperresponsiveness measured as RL (Fig 1, A) and −logPC100 (Fig 1, B). C-J, BAL fluid total cell (Fig 1, C), neutrophil (Fig 1, D), lymphocyte (Fig 1, E), macrophage (Fig 1, F), and eosinophil (Fig 1, G) counts and GM-CSF (Fig 1, H), KC (Fig 1, I), and IL-6 (Fig 1, J) levels were measured. Data are expressed as means ± SDs of 6-8 mice per group. *P < .05, **P < .01, and ***P < .001 compared with air-exposed control group. #P < .05 compared with 1-week ozone-exposed group.
Fig 2
Fig 2
A, B, G, and H, Membrane potential (ΔΨm; Fig 2, A and G) and mitochondrial ROS (Fig 2, B and H) after ozone exposure. C, D, E, and F, RL (Fig 2, C), −logPC100 (Fig 2, D), BAL total cell counts (Fig 2, E), and KC levels (Fig 2, F) were determined. ΔΨm (Fig 2, G) and ROS content (Fig 2, H) were determined in isolated mitochondria. Data are expressed as means ± SDs of 5-8 mice per group. *P < .05, **P < .01, and ***P < .001 compared with air-exposed control group. #P < .05 and ##P < .01 compared with ozone-exposed group.
Fig 3
Fig 3
ASM cells from healthy subjects, smokers, and patients with COPD were treated with H2O2 with and without NAC before treatment. A-C, GM-CSF (Fig 3, A), CXCL8 (Fig 3, B), and IL-6 (Fig 3, C) levels were determined by means of ELISA. D-H, ΔΨm (Fig 3, D, E and G) and mitochondrial ROS values (Fig 3, F and H) were also measured. Bars represent means ± SEMs of 5 to 6 donors per group. *P < .05 and **P < .01. I-J, Intact mitochondria were isolated from bronchial biopsies from healthy subjects and COPD patients. ΔΨm (Fig 3, I) and mitochondrial ROS values (Fig 3, J) were measured. Dot plots represent means ± SD of 4 subjects or patients per group.
Fig 4
Fig 4
A-F, Baseline mitochondrial respiration determined by measuring OCR and the effect of MitoQ on TGF-β ± FBS–induced DNA synthesis were determined in ASM cells from healthy subjects (Fig 4, A and B), smokers (Fig 4, C and D), and patients with COPD (Fig 4, E and F). G and H, Effects of Tiron on TGF-β ± FBS–induced DNA synthesis (Fig 4, G) and MitoQ on TNF-α–induced CXCL8 release (Fig 4, H) were determined. Bars represent means ± SEMs of 3 (Fig 4, A, C, E, G, and H), 8 (Fig 4, B), 6 (Fig 4, D), and 4 (Fig 4, F) donors. *P < .05, **P < .01, and ***P < .001.
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