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

Abstract

BackgroundInflammation 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.ObjectiveWe 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.MethodsMice 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.ResultsMice 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.ConclusionsMitochondrial 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.

Incapacity, Handicap, and Oxidative Stress Markers of Male Smokers With and Without COPD

“…The present result was similar to what has been previously published and discussed. 3,44,45 However, one interesting result of the present study was that smoking significantly accelerated lung aging of the 2 smoker groups, with a marked acceleration in the COPD group versus the non-COPD group. These results can be used to encourage smoking cessation.…”

What is the Diagnostic Value of Plasma Antioxidative/Oxidative Status in Parapneumonic Effusions in Children?

“…[19][20][21][22] In this way, oxidative stress can affect remodeling of the extracellular matrix, mitochondrial apoptosis, cell proliferation, alveolar repair, and immune modulation. [20][21][22][23] Therefore the test of TAS, TOS, and OSI level may useful for distinguishing exudates and transudates in PPEs.…”

Mitochondrial-Related Gene Expression and Macrophage Signatures in Non-Small Cell Lung Cancer, Including Patients with Emphysema as Co-Morbidity

“…Oxidative stress is a well-recognised driver of carcinogenesis and is present in smokers and COPD patients [11]. The airways of patients with COPD demonstrate an additional increase in oxidative stress, compared to healthy smokers and non-smokers [11].…”

“…The airways of patients with COPD demonstrate an additional increase in oxidative stress, compared to healthy smokers and non-smokers [11]. The production of reactive oxygen species from the mitochondrion is the main source of oxidative stress.…”

“…The production of reactive oxygen species from the mitochondrion is the main source of oxidative stress. The above observation of increased oxidative stress in airway epithelial cells in COPD has been at least partly explained by mitochondrial damage [11]. Under increased oxidative stress, metabolically-active cells may undergo an increase in biogenesis and in degradation of damaged mitochondria within autolysosomes (mitophagy) to replace the old mitochondria which have been damaged by oxidative stress.…”