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

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.