Current concepts on oxidative/carbonyl stress, inflammation and epigenetics in pathogenesis of chronic obstructive pulmonary disease

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Abstract

Chronic obstructive pulmonary disease (COPD) is a global health problem. The current therapies for COPD are poorly effective and the mainstays of pharmacotherapy are bronchodilators. A better understanding of the pathobiology of COPD is critical for the development of novel therapies. In the present review, we have discussed the roles of oxidative/aldehyde stress, inflammation/immunity, and chromatin remodeling in the pathogenesis of COPD. An imbalance of oxidants/antioxidants caused by cigarette smoke and other pollutants/biomass fuels plays an important role in the pathogenesis of COPD by regulating redox-sensitive transcription factors (e.g., NF-κB), autophagy and unfolded protein response leading to chronic lung inflammatory response. Cigarette smoke also activates canonical/alternative NF-κB pathways and their upstream kinases leading to sustained inflammatory response in lungs. Recently, epigenetic regulation has been shown to be critical for the development of COPD because the expression/activity of enzymes that regulate these epigenetic modifications have been reported to be abnormal in airways of COPD patients. Hence, the significant advances made in understanding the pathophysiology of COPD as described herein will identify novel therapeutic targets for intervention in COPD.

Introduction

Chronic obstructive pulmonary disease (COPD) is a major and increasing global health problem and is the fourth most common cause of death in the developed countries. It is a disabling condition associated with progressive breathlessness. COPD will account for over six million deaths per year and is predicted to increase from the sixth to the third leading cause of death by 2020 worldwide. In America, COPD affects 9% of residents aged 60 years and above, and is ranked the fourth in the recent morbidity survey of the elderly population. It is estimated that approximately 23.4 million people in the United States have COPD and the health burden is $36.1 billion per year. The burden of COPD for the patient is high as patients experience a poorer quality of life, suffer from comorbidites (3.7 comorbidities per patient), and direct healthcare amounted to 20.9 billion dollars in the United States in 2004.

Cigarette smoke is the major risk factor for the development of COPD. It is likely to account for ~ 80–90% of COPD cases in the United States (Sethi and Rochester, 2000). Cigarette smoke contains an estimated 1015–1017 oxidants/free radicals and ~ 4700 different chemical compounds, including reactive aldehydes and quinones, per puff (Church and Pryor, 1985). COPD (emphysema and chronic bronchitis) is characterized by accelerated decline in lung function, inflammation and premature aging of the lung. However, only 10–20% of the smokers develop COPD pointing to an additional risk factor, such as genetic susceptibility, e.g., the polymorphisms in genes coding for (anti-) proteases like alpha-1 antitrypsin (1AAT), a disintegrin and metalloproteinase 33 (ADAM33), or antioxidant superoxide dismutase (SOD), and proinflammatory mediators tumor necrosis factor-α (TNF-α) (Harrison et al., 1997, Keatings et al., 2000, Sandford et al., 2001, Kucukaycan et al., 2002, Celedon et al., 2004, Young et al., 2006). Other noxious environmental gases/particles such as NO2, SO2, and particulate matters, as well as exposure to second hand tobacco smoke and biomass fuel can also cause oxidative stress and trigger inflammatory responses in the lungs of a susceptible population. Cessation of smoking reduces progression of the disease only if applied early and has little effect after significant symptoms ensues. At present, no effective treatment exists to halt the decline of lung function in smokers who get the disease. This in turn reflects a lack of understanding of the specific cellular and biochemical pathways triggered in the lung by tobacco smoke. Thus, it is essential that COPD research should focus on improving our understanding of the specific cellular and biochemical injury induced by tobacco smoke within the lung. Most treatments for COPD are mainly palliative, and no single therapy exists that can halt the decline in lung function or progressive destruction of the airways. The mainstays of pharmacotherapy are bronchodilators (to relieve the symptoms of bronchoconstriction), corticosteroids (to reduce the airway inflammation), and combination of bronchodilators with corticosteroids. However, current corticosteroid therapy in COPD is poorly effective (Barnes et al., 2004). This has prompted an intense search for new anti-inflammatory therapeutic targets based on a better understanding of the underlying pathophysiology of COPD.

Section snippets

Pathogenesis

COPD is characterized by airflow limitation that is usually irreversible and progressive, and associated with an abnormal inflammatory response of the lung to noxious particles or gases (Rabe et al., 2007). COPD can be classified into four classes of severity based on lung function [GOLD Guidelines]. Emphysema, chronic bronchitis with airway obstruction, and small airways disease are the distinct phenotypes of COPD, but most patients show a combination of different phenotypes. Emphysema is

Oxidative and aldehyde/carbonyl stress in COPD

Formation of reactive and unstable free radicals such as superoxide anion (O2•ˉ), nitric oxide, peroxynitrite (ONOO-) and hydroxyl radicals (OH) lead to a series of chain reactions resulting in uncontrolled (if not ablated) tissue destruction as a result of oxidation. The importance of oxidative stress has been confirmed by several studies that have identified the presence of oxidative stress/free radical biomarkers in patients with COPD. Increased level of 8-hydroxy-deoxyguanosine was

Inflammatory response in COPD

The chronic inflammation of COPD is characterized by an accumulation of neutrophils, macrophages, B-cells, lymphoid aggregates, CD4+, CD8+ T-cells, and eosinophils, particularly in the small airways (Turato et al., 2002, Hogg, 2004a; Saha and Brightling, 2006, Siva et al., 2007) (Fig. 2) and the degree of inflammation increases with the severity of disease as classified by the GOLD guidelines (Hogg et al., 2004b).

Epigenetics in pathogenesis of COPD

Epigenetics refers to heritable changes in gene expression without the alteration of DNA sequence. However, it is controlled by post-translational modifications in histone proteins and DNA. These modifications include chromatin remodeling (histone acetylation, methylation, ubiquination, phosphorylation, and sumoylation) and DNA methylation.

Conclusions and future directions

Oxidative stress is critical for lung inflammatory response to cigarette smoke/environmental pollutants through the upregulation of redox-sensitive transcription factors, and induction of autophagy and unfolded protein response. Hence, development of antioxidants/thiol agents or other pharmacological agents, such as enzyme mimetics-ECSOD, Nrf2 activator or reversing its post-translational modifications by aldehyde dehydrogenases/reducatases to boost the endogenous antioxidant system, could be

Acknowledgments

This study was supported by NIH 1R01HL085613, 1R01HL097751, 1R01HL092842, and NIEHS Environmental Health Sciences Center grant ES01247. We thank Dr. Saravanan Rajendrasozhan for useful discussions.

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