Chest

Chest

Volume 144, Issue 1, July 2013, Pages 266-273
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Translating Basic Research into Clinical Practice
Oxidative Stress in COPD

https://doi.org/10.1378/chest.12-2664Get rights and content

Oxidative stress is now recognized as a major predisposing factor in the pathogenesis of COPD. Existing therapies for COPD are ineffective at halting disease progression, with bronchodilators being the mainstay of pharmacotherapy, providing symptomatic relief only. It is, therefore, important for a better understanding of the underlying mechanisms by which oxidative stress drives disease pathogenesis to develop novel and more effective therapies. Antioxidant capacity in COPD is substantially reduced as a result of cigarette smoking and exacerbations, with oxidative stress persisting long after the cessation of cigarette smoking or exacerbation, due to the continued production of reactive oxygen species from endogenous sources. We discuss (1) how oxidative stress arises in the lung, (2) how it is neutralized, (3) what genetic factors may predispose to the development of COPD, and (4) how this impacts inflammation and autoimmunity in the development of emphysema and small airways disease. Finally, various strategies have been considered to neutralize the increased oxidative burden present in COPD. This review highlights why current antioxidant strategies have so far failed and what promising alternatives are on the horizon. Moreover, a number of studies have shown that there is no single “magic bullet” to combat oxidative stress, but instead a combination therapy, targeting oxidative stress in the various subcellular compartments, may prove to be more effective in COPD.

Section snippets

Persistent Lung and Systemic Oxidative Stress in COPD

There is evidence for oxidative and carbonyl stress in COPD, particularly during acute exacerbations. Alveolar macrophages from patients with COPD are more activated and release increased amounts of ROS in the form of the superoxide radical and hydrogen peroxide.6 Similarly, activated peripheral blood neutrophils from patients with COPD release increased amounts of ROS, particularly during exacerbations. Markers of oxidative stress and carbonyl stress in COPD include elevated concentrations of

Source of ROS in the Lung

The lung is particularly vulnerable to injury from environmental oxidative stress due in part to its anatomic structure. It is constantly exposed to sources of endogenous oxidative stress generated by mitochondrial respiration and inflammatory responses to bacterial and viral infections within the lung. The environmental sources of airborne oxidative stress include oxidant gases and ultrafine particulate material and nanoparticles from industrial pollution and car exhaust fumes. However, the

Carbonyl Stress in COPD

ROS generation has been directly linked to oxidation of proteins, lipids, carbohydrates, and DNA. The major outcome is the formation of reactive carbonyls and their reaction with proteins, otherwise known as protein carbonylation. This accumulation of reactive carbonyls and subsequent protein carbonylation has been commonly referred to as “carbonyl stress,” predominantly associated with chronic disease24 and aging. Unlike other posttranslational modifications, protein carbonylation is

Antioxidant Defenses in the Lung

Because the lung is constantly exposed to both external and endogenous sources of oxidative stress, it has evolved a number of efficient antioxidant defensive strategies, of which reduced glutathione (GSH) plays an important part. Moreover, up to 20% of all glutathione produced is found within the mitochondria to neutralize endogenous ROS production as a by-product of metabolism.28 Protecting the exposed surface of the lung from the environment is the epithelial lining fluid, which contains

Oxidative Stress and Inflammation in the Airways

At least 50 different cytokines and chemokines have been found to be associated with COPD. Many of the intracellular signaling pathways triggered and/or driving the release of these inflammatory mediators are sensitive to oxidative stress as they incorporate redox-sensitive molecular targets, such as the transcription factor nuclear factor-κB (NF-κB) and signaling molecules such as Ras/Rac, Jun-N-terminal kinase, p38 mitogen-activated protein kinase, and protein tyrosine phosphatases. Oxidative

Oxidative Stress and Autoimmunity in COPD

Accumulating evidence has shown that there is an autoimmune component in COPD.60 Until recently, a mechanistic link between exposure to oxidative stress and developing autoimmunity in COPD was not established. However, autoantibodies against carbonyl-modified self-proteins, as a result of oxidative stress, are elevated in COPD serum and increase with disease severity. Since these autoantibodies are complement fixing, they could contribute to parenchymal lung destruction.26 Carbonyl-modified

Therapeutic Implications

There are currently no treatments that reverse or even slow the progression of COPD. Inhaled corticosteroids are highly effective in reducing the inflammatory component in asthma, but provide little therapeutic benefit in COPD. While they may have a small effect in reducing exacerbation frequency, they fail to reduce the inflammatory component and halt the inexorable decline in lung function. This resistance can be attributed to cigarette smoke or oxidative stress.69 Targeting

Conclusions

Elevated levels of ROS and carbonyls are found in COPD and these may be associated with increased inflammation, airway remodeling, autoimmunity, and corticosteroid resistance. In addition, systemic oxidative stress may also be a causal link in many COPD comorbidities such as cardiovascular diseases and metabolic syndrome. Local oxidative stress may also promote the development of lung cancer. Following the initial environmental exposure to ROS, the subsequent intracellular sources and

Acknowledgments

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Kirkham has received research funding from both industry and research councils over the last 3 years, has been a consultant for the pharmaceutical industry, and has a patent application pending. Research funding sources include Novartis AG; Pfizer, Inc; The Royal Society; Medical Research Council; British Lung Foundation; and the EPSRC. Prof Barnes has received research funding from

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