The Role of ROS in COPD Progression and Therapeutic Strategies
Rashmi Bathri1, Protiti Bose2, Vikram S. Gujar3, and Lalit Kumar4
1Department of Transfusion Medicine, Bhopal Memorial Hospital and Research Centre, Bhopal MP 462038, India; 2Department of Microbiology, Bhopal Memorial Hospital and Research Centre, Bhopal MP 462038, India; 3Department of Research, Bhopal Memorial Hospital and Research Centre, Bhopal MP 462038, India; 4Department of Pulmonary Medicine, Bhopal Memorial Hospital and Research Centre, Bhopal MP 462038, India
Correspondence: firstname.lastname@example.org (P.B.)
Bathri R et al. Reactive Oxygen Species 4(10):237–250, 2017; ©2017 Cell Med Press
(Received: March 4, 2017; Revised: April 7, 2017; Accepted: April 8, 2017)
ABSTRACT | The atmosphere is replete with a mixture of toxic substances. Inhalation of toxic substances produces a variety of insults on the pulmonary system. Lung poisons include industrial materials and a large number of environmental contaminants. This review will give an in-depth knowledge of how the development and progression of chronic obstructive pulmonary disease (COPD) are associated with increased oxidative stress or reduced antioxidant resources. It has been documented that several indicators of oxidative stress, such as hydrogen peroxide exhalation, lipid peroxidation products, and degraded proteins, are indeed elevated in COPD patients, and as a result, the antioxidant capacity decreases. The fall in antioxidant capacity of blood from COPD patients should not only be regarded as a reflection of the occurrence of oxidative stress but also as evidence that oxidative stress spreads out to the circulation and can therefore generate a systemic effect. An effective wide-spectrum antioxidant therapy that has good bioavailability and potency is a good approach to redressing the lungs antioxidant capacity to control the localized oxidative and inflammatory processes that occur in the pathogenesis of COPD.
KEYWORDS | Chronic obstructive pulmonary disease; Oxidative stress; Reactive oxygen species
ABBREVIATIONS | AAT1, alpha-1 antitrypsin; BAL, broncho-alveolar lavage; COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in the first second of a forced exhalation; GSH, reduced form of glutathione; 4-HNE, 4-hydroxynonenal; MDA, malondialdehyde; MPO, myeloperoxidase; MSI, microsatellite DNA instability; NO, nitric oxide; RNS, reactive nitrogen species; ROS, reactive oxygen species; SOD, superoxide dismutase; VEGF, vascular endothelial growth factor; XO, xanthine oxidase
2. COPD—A Disease Hand in Hand with Oxidative Damage
3. ROS and Their Sources
3.1. Cell-Derived ROS
3.2. Environmental Sources of ROS
4. Consequences of Oxidative Stress—Lipid Peroxidation
4.1. Oxidative Stress and Protein Modification
4.2. Oxidative Stress and Inflammation
4.3. Oxidative Stress and Apoptosis
4.4. Oxidative Stress and Protease-Antiprotease Imbalance
5. Systemic Oxidative Stress Especially Involving the Lungs—COPD Exacerbations
5.1. Biomarkers for COPD
5.2. Oxidative Stress Biomarkers in Exhaled Breath Condensate
5.3. Antioxidant Defense in COPD
6. Genetic Response to Oxidative Stress
7. Therapeutic Intervention
All life forms maintain a reducing environment within their cells, which is preserved by enzymes that maintain the reduced state through a constant input of metabolic energy. Any disturbances in this normal redox state can cause toxic effects through the production of peroxides and free radicals, better known as reactive oxygen species (ROS) that damage all components of the cell, including proteins, lipids, and DNA . ROS and reactive nitrogen species (RNS) are reactive products required by the body for both beneficial and deleterious purposes. In the cells, their production in balanced amounts is essential for maintaining normal physiological functions ; however, sometimes when produced in excess, they result in damage to tissues unless regulated by an antioxidant system.
ROS-mediated oxidative stress is known to play an important role in pathogenesis of chronic obstructive pulmonary disorder (COPD), since it results in inactivation of antiproteinases, induces airspace epithelial injury, mucus hypersecretion, increased influx of neutrophils into the lungs, transcription factor activation, and gene expression of pro-inflammatory mediators . COPD affects about 6% of the general world population and is the leading cause of morbidity and mortality worldwide .China and India are bearing a disproportionate burden of COPD morbidity and mortality. Since both countries together constitute one third of worldwide humanity, burden of COPD would have considerable impact on their economy. Worldwide only 10–15% of all cases are identified medically, out of which about 1% is attributed to alpha-antitrypsin (A1AT) . The central Indian population has seen a large influx of patients with respiratory complaints having obstructive and restrictive respiratory functions in the past decade [6, 7] resulting in additional economic burden on the society.
2. COPD—A DISEASE HAND IN HAND WITH OXIDATIVE DAMAGE
COPD is a heterogeneous disorder resulting in dysfunction of the small and large airways, and destruction of lung parenchyma and vasculature. In a healthy individual, the lower airways are sterile, and in order for microorganisms (bacteria/viruses) to reach the lungs, they must pass through the upper airway first. Surprisingly, research on microbial colonization in patients with COPD exacerbations has found no potentially pathogenic microorganism but normal respiratory flora responsible for progression in the disease state .The lungs, compared to other organs, are highly vulnerable as they are directly exposed to high levels of oxygen from the atmosphere. Consequently, respiratory epithelium is a major target for oxidative injury from oxidants generated either exogenously (cigarette smoke/toxic pollutants) or endogenously (from phagocytes and other cell types). Thus, the lungs are rich in efficient enzymatic and non-enzymatic antioxidant defense systems to protect themselves from oxidant-induced damage  (Figure 1). If the balance between oxidants and antioxidants shifts in favor of the former, it would result in airway tissue inflammation, airway limitation, and mucus hypersecretion. In COPD, oxidant stress occurs in small airways, lung parenchyma, and alveolar regions, and is associated with the activation of cytokines and growth factors and activated inflammatory cells that produce large amounts of ROS and RNS. Most of the ROS and RNS produced in the lung tissue come from neutrophils, alveolar macrophages, and eosinophils, but bronchial and alveolar epithelial cells and endothelial cells are also capable of producing ROS .
FIGURE 1. Schematic representation depicting oxidative injury to the lung tissue leading to COPD exacerbations. See text for detailed description. COPD denotes chronic obstructive pulmonary disease.
Based on genotype-environment interactions, Wood and Stockley  have defined COPD pathogenesis according to clinical phenotypes thus influencing the risk of acquiring the disease at different levels. According to them, there are three main theories suggesting COPD pathogenesis: (1) the protease-anti-protease theory, stating that there is an imbalance between proteases that digest elastin, together with other components of the extracellular matrix, and anti-proteases that protect against this; (2) the oxidant-antioxidant theory, stating that disparity between levels of harmful oxidants and protective antioxidants leads to oxidative stress, which in turn influences the actions of anti-proteases, and the expression of proinflammatory mediators; and (3) the importance of inflammation in the pathogenesis of COPD. The first two theories are in fact linkrd to the third one. Polymorphisms in genes relating to proteases, antioxidants, and inflammation have been found that relate to the presence of features of COPD, suggesting reasons for the heterogeneity of the observed clinical phenotypes.
3. ROS AND THEIR SOURCES
ROS are produced by living organisms as a result of normal cellular metabolism. At low to moderate concentrations, ROS function in physiological cell processes, but at high concentrations, they create undesirable effects. COPD is a progressive disease which manifests itself slowly and gradually.The pathogenesis of COPD apart from oxidative stress, inflammation, and protease/antiprotease imbalance also involves alteration in immunity (autoantibody production), apoptosis, alteration of cell proliferation, and cellular senescence/aging, induced by air pollutants, modified by genetic factors, and exacerbated by viruses and bacteria . Prevalence of acquiring this disease is doubled in elderly people than at younger age, and thus COPD is known as an aging associated disease. The evidence for the role of accelerated aging in COPD progression is senescence . As suggested in the “free radical theory of aging” , ROS account for progressive deleterious changes called aging or senescence. This results in accumulating modifications in cell components, such as lipids, proteins, and DNA , and imbalance between oxidants and antioxidants resulting in oxidative stress .
3.1. Cell-Derived ROS
Various sources can generate ROS intracellularly in a metabolically active cell. The chief ROS-generating enzyme is NADPH oxidase, which is present in phagocytes and epithelial cells. Phagocytes employ NADPH oxidase and other enzymes to produce ROS, which further involve the activity of heme peroxidases, such as myeloperoxidase (MPO) and eosinophil peroxidase (EPO). The oxidative stress derived from MPO plays an important role in the pathogenesis of COPD. Superoxide anion and H2O2 can also be generated by mitochondria and the xanthine/xanthine oxidase (XO) reaction. XO activity has been shown to be increased in cell-free broncho-alveolar lavage (BAL) fluid and plasma from COPD patients, compared with normal individuals . RNS in the form of nitric oxide (NO) production is generated by nitric oxide synthase in the same manner. Similarly, NO forms the more effectual and damaging peroxynitrite molecules in the presence of superoxide anion .
3.2. Environmental Sources of ROS
Cigarette smoke contains many oxidants and free radicals and organic compounds, such as superoxide and nitric oxide . Inhalation of cigarette smoke activates certain endogenous mechanisms in the lung, such as accumulation of neutrophils and macrophages, which further increase oxidant injury. Ozone exposure can cause lipid peroxidation and induce influx of neutrophils into the airway epithelium. Short-term exposure to ozone also causes the release of inflammatory mediators, such as MPO and eosinophil cationic proteins along with lactate dehydrogenase and albumin . Ozone exposure also results in reduction in pulmonary functions even in healthy subjects  developing conditions like hyperoxia––higher oxygen levels than normal partial pressure of oxygen in the lungs or other body tissues––that lead to greater production of ROS and RNS [22, 23].
Ionizing radiation, in the presence of O2, converts hydroxyl radicals, superoxide, and organic radicals to hydrogen peroxide and organic hydroperoxides. These hydroperoxide species react with redox active metal ions, such as iron and copper via Fenton reactions and thus induce oxidative stress [24, 25]. Heavy metal ions, such as iron, copper, cadmium, mercury, nickel, lead, and arsenic can bring on generation of reactive radicals and cause cellular damage via depletion of enzyme activities through lipid peroxidation and reaction with nuclear proteins and DNA .
There is evidence that accidental exposures to noxious chemicals like isocyanates can induce DNA damage, apoptosis, inflammation, and oxidative stress , and such victims with evidence of residual lung damage might run a clinical course similar to COPD with recurrent respiratory illnesses .
4. CONSEQUENCES OF OXIDATIVE STRESS—LIPID PEROXIDATION
In biological systems, phospholipids in cell membrane can be hydrolyzed by the phospholipase enzyme, producing nonesterified arachidonic acid that undergoes peroxidation through two pathways: (1) the enzymatic pathway, involving cyclooxygenases and lipoxygenases; and (2) a non-enzymatic pathway through the participation of ROS, RNS, transition metals, and other free radicals . ROS can activate the peroxidation of polyunsaturated fatty acids in biological tissues resulting in the transformation of the fatty acids into lipid hydroperoxides. Lipid peroxides and lipid hydroperoxides can then interact with enzymatic or nonenzymatic antioxidants or decompose after reacting with metal ions or iron-containing proteins, forming hydrocarbon gases and unsaturated aldehydes as byproducts .
The hydrocarbon ethane is another byproduct of fatty acid peroxidation. Patients with COPD display an increased level of exhaled ethane compared to control subjects. This increased level is negatively correlated with lung function, suggesting that lipid peroxidation is an important factor in the progression of COPD [30, 31]. Furthermore, the lungs are also involved in the elimination of ethane transported from other organs such as intestine, brain, kidney, liver, heart, and testes. Therefore, it is suggested that the systemic oxidative stress in smokers and COPD patients may contribute to the total exhaled ethane concentration .
4.1. Oxidative Stress and Protein Modification
ROS can cause crumbling of the peptide chain, modification of electrical charge of proteins, cross-linking of proteins, and oxidation of specific amino acids and therefore lead to increased susceptibility to proteolysis by precise proteases . These oxidative modifications can inactivate the enzymatic functions and cause structural degeneration of the proteins or activate transcription factors and proteolytic systems. Paster and coworkers  in their study have identified differential proteomic profiles related to oxidative stress response in COPD patients. Indeed, human plasma proteins are indeed modified to carbonyl-containing proteins with lost sulfhydryl groups after exposure to gas phase cigarette smoking . Both saturated and unsaturated aldehydes present in cigarette smoke contribute to this modification of proteins. Additionally, exposure of human plasma to cigarette smoke in vitro also results in depletion of plasma protein sulfhydryls and elevation of the carbonyl protein levels [36, 37]. Plasma proteins can also be degraded through nitration and oxidation by RNS, the formation of which is stimulated by cigarette smoking . Levels of oxidised proteins are significantly higher in smokers than in non-smokers .
4.2. Oxidative Stress and Inflammation
The role of ROS in generating inflammatory response occurs in both central and peripheral airways of COPD patients [38, 40]. A common attribute of lung inflammation is the activation of epithelial cells and resident macrophages as well as activation of neutrophils. Oxidants in cigarette smoke are capable of stimulating alveolar macrophages thus releasing a number of mediators, attracting neutrophils and other inflammatory cells into the lungs inflammatory response [38, 41]. Increased numbers of both macrophages and neutrophils migrate into the lungs of smokers generating ROS via NADPH oxidase system [41, 42]. The MPO content of the neutrophils is certainly linked with cigarette smoking, suggesting an increased production of oxidants like hypochlorous acid in smokers . A relationship has been shown between the circulating neutrophil numbers and the FEV1 (forced expiratory volume in the first second of a forced exhalation) [44, 45], suggesting decreased airflow as a result of the ROS production. Smokers who develop COPD have increased ROS release from the circulating neutrophils compared to smokers who do not develop the disease .
Under physiological conditions, the control of redox-sensitive signaling involves temporary deviation from the redox state toward an increase in the concentration of oxidants. These small oxidative episodes generate low cellular concentrations of ROS when stimulated by cytokines (IL-1, IL-6, IL-3, and TNF-α), angiotensin II, and growth factors. The signals for the elements responsible for the expression of certain genes are normally transmitted to the nucleus by a class of proteins known as transcription factors. This process of signaling transduction results in biological functions such as muscle contraction, gene expression, cell growth, and nervous transmission. Therefore, the initiation and correct functioning of various transduction pathways depend on ROS as signaling molecules, which act as second messengers . Under pathological conditions, however, abnormally high concentrations of ROS in the cells might lead to permanent changes in signaling transduction and gene expression, as observed in chronic inflammatory diseases, including COPD .
4.3. Oxidative Stress and Apoptosis
Data mining of recent studies has highlighted the importance of apoptosis in the pathogenesis of COPD [49, 50]. There is evidence that vascular endothelial growth factor (VEGF) is necessary for the maintenance of the cellular structure of the lungs . The interruption of the VEGF signalling to VEGF receptor 2 results in arrested lung development, which manifests clinically as bronchopulmonary dysplasia in children and as emphysema in adults .
It has recently been reported that oxidative stress is associated with a reduction in the levels of VEGF in the sputum of patients with COPD. It has been suggested that oxidative stress can lead to epithelial cell damage, thus reducing VEGF levels and consequently favoring the development of emphysema . Another mechanism that has been reported in inducing apoptosis through oxidative stress is the activation of certain mitochondrial enzymes, including caspase-3 .
4.4. Oxidative Stress and Protease-Antiprotease Imbalance
Three classes of proteases are considered relevant to the etiopathogenesis of COPD. They are: (1) serine proteases, which can degrade elastin and certain forms of collagen; (2) cysteine proteases, which degrade matrix components; and (3) matrix metalloproteinases, which act on collagen, gelatin, and laminin. Each of these classes of enzymes can be inhibited by one or more antiproteases. Oxidants can potentiate the effects of proteases on COPD through activation of these enzymes. Reactive species increase the activity of matrix metalloproteinases by activating metalloproteinase precursors. The oxidation of methionine residues at active sites of alpha-1 antitrypsin (AAT1) results in a dramatic reduction in its in vitro inhibitory ability. Therefore, this pathway has been reported as one of the possible causes of the imbalance in favor of proteases [49, 50]. In COPD, the protease burden in the lungs is increased because of the influx and activation of inflammatory leukocytes that release proteases. It has been proposed that a relative deficiency of antiproteases such as AAT1, because of their inactivation by oxidants, creates a protease-antiprotease imbalance in the lungs. This hypothesis forms the basis of the protease-antiprotease theory of the pathogenesis of emphysema [54, 55].
Inactivation of AAT1 by oxidants occurs at a critical methionine residue in its active site and can be produced by oxidants from cigarette smoke or oxidants released from inflammatory leukocytes, resulting in a marked reduction in the inhibitory capacity of AAT1 in vitro [55, 56]. An In vivo study of the acute effects of cigarette smoke on the functional activity of AAT1 shows transient but non-significant fall in the antiprotease activity of BAL fluid shortly after cigarette smoking . In addition, in vitro exposure of lung epithelial cells to proteases leads to increased release of ROS, suggesting that proteases increase oxidative stress .
5. SYSTEMIC OXIDATIVE STRESS ESPECIALLY INVOLVING THE LUNGS—COPD EXACERBATIONS
COPD is considered to have local lung and systemic effects . Decreased peripheral muscle function and weight loss leading to reduced survival are the main evidence of systemic effects . Increased sequestration of neutrophils in the pulmonary circulation during smoking and during exacerbations of COPD is also an oxidant-mediated event . Many studies have shown an inverse relationship between circulating neutrophil numbers and FEV1 [44, 45]. Moreover, a similar relationship has also been shown between the change in peripheral blood neutrophil count and the change in airflow limitation over time . Similarly, an association between superoxide anion release by peripheral blood neutrophils and bronchial hyperresponsiveness in patients with COPD has been seen, suggesting a role for systemic ROS in the pathogenesis of airway abnormalities in COPD .
Cigarette smoking increases the formation of RNS and results in nitration and oxidation of plasma proteins. The levels of nitrated proteins (fibrinogen, transferrin, plasminogen, and ceruloplasmin) were higher in smokers when compared with non-smokers. The levels of nitrotyrosine along with inducible NO synthase (iNOS) were higher in airway inflammatory cells obtained by induced sputum from patients with COPD compared with those with asthma .
Systemic markers of oxidative stress and elevated plasma levels of inflammatory mediators have been reported in smokers and in patients with COPD [65, 66]. Lipid peroxidation products are also increased in the plasma of smokers with COPD, particularly in state of exacerbation. Oxidative stress and chronic inflammation are some of the factors involved in the mechanism that generates the systemic manifestations (e.g., weight loss and skeletal muscle dysfunction) observed in some patients with COPD. Patients with COPD are also at increased risk of cardiovascular disease and one of the probable mechanisms for this increase is the endothelial damage caused by systemic inflammation and systemic oxidative stress in these patients .
5.1. Biomarkers for COPD
COPD is irreversible and known to get exaggerated due to smoking. However, not all smokers develop clinically relevant COPD. Thus, variable response to cigarette smoke clearly suggests genetic susceptibility. Among the COPD candidate genes are those that: (a) affect the production of proteases and antiproteases; (b) modulate the metabolism of toxic substances in cigarette smoke; (c) are involved in mucocilliary clearance; and (d) influence inflammatory mediators. Recently, microsatellite DNA instability (MSI)-positive sputum cells from smokers with and without COPD have been found to be a useful marker of genetic susceptibility. Nevertheless, COPD lacks established viable biomarkers to predict and monitor disease progression and outcome variations. Such monitoring tools may be induced sputum, exhaled air condensate, peripheral blood, urine, bronchial biopsies, and BAL fluid .
5.2. Oxidative Stress Biomarkers in Exhaled Breath Condensate
Oxidative stress can be measured through direct quantification of the production of oxidants or, indirectly, through quantification of the products resulting from lipid peroxidation, such as 8-isoprostane, 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA) in the alveolar space, exhaled air, sputum, and blood .
Recent studies have focused on non-invasive techniques, such as biomarkers in exhaled breath condensate to evaluate oxidative stress in COPD [70, 71]. The collection of exhaled breath condensate (EBC) is a non-invasive method for obtaining samples of material from the lower respiratory tract. Non-specific lipid peroxidation products, such as thiobarbituric acid reactive substances (TBARS), have also been shown to be elevated in breath condensate and in the lungs of patients with stable COPD . Other specific products of lipid peroxidation such as MDA and 4-HNE have also been shown to be greater than before in exhaled breath condensate of COPD patients [72, 73].
Among the indirect measures for assessing oxidative stress is an examination of the increased activity of the heme oxygenase system, which is reflected by the carbon monoxide levels in exhaled breath. Assessment of the effects of oxidative stress on target molecules may include measuring the reaction of ROS with lipids, proteins, or nucleic acids to form markers of oxidative stress. These markers can be measured in the blood, breath condensate, BAL fluid, and lung tissue as an indicator of the effects of free radicals on target molecules .
5.3. Antioxidant Defense in COPD
Under normal condition, the lungs have well coordinated and efficient endogenous antioxidant defense systems, which protect against the injurious effects of oxidants by electron transfer, enzymatic removal, and scavenging, and by keeping transition metal ions tightly sequestered . Dietary antioxidant supplementation is one of the simplest approaches to boosting antioxidant defence systems. Supplementation of vitamin C, vitamin E, and β-carotene has been attempted in cigarette smokers and patients with COPD . Dietary polyunsaturated fatty acids may also protect cigarette smokers against the development of COPD . These studies support the concept that dietary antioxidant supplementation including polyphenols may be a possible therapy to prevent or inhibit oxidative stress and inflammatory responses, which are key features in the development of COPD. The most direct way to redress the oxidant imbalance in COPD would be to increase the lung’s capacity to produce antioxidants.
Increased activity of antioxidant enzymes superoxide dismutase (SOD) and catalase in alveolar macrophages from young smokers has been reported . Another spectacular discovery is spin traps, such as α-phenyl-N-tert-butyl nitrone, which directly react with ROS and RNS at the site of inflammation . It has also been reported in animal models that intratracheal instillation of a catalytic antioxidant, manganese(III) mesotetrakis, was able to inhibit cigarette smoke-induced inflammatory response (decreased number of neutrophils and macrophages) . These compounds mimic extracellular SOD and catalase and are capable of scavenging both lipid peroxides and peroxynitrite.
Ebselen, a seleno-organic compound with enzymatic activity similar to glutathione peroxidise increases the efficiency of the reduced form of glutathione (GSH) as an antioxidant and can thus be used as a therapeutic agent against oxidative stress and inflammation [80, 81]. Molecular engineering of antioxidant genes such as glutathione peroxidase or alteration of genes involved in the synthesis of GSH itself could be a future therapeutic option in genomic medicine.
Dietary polyphenols have antioxidant and anti-inflammatory properties that may explain their beneficial effects . Curcumin, the active principal gradient in turmeric, is used in many ailments, particularly as an anti-inflammatory agent. It has multiple properties to protect against cigarette smoke-mediated oxidative stress  and acts as an ROS scavenger, increases antioxidant GSH levels by induction of GCL (gamma-glutamylcysteine ligase), and acts as an anti-inflammatory agent.
6. GENETIC RESPONSE TO OXIDATIVE STRESS
The most common biological target for these highly reactive ROS entities is DNA. Evidence shows that continuous oxidative damage of DNA is involved in the pathophysiology of various diseases including COPD. Oxidative stress due to abnormal accumulation of inflammatory cells, including neutrophils and macrophages, and ROS from cigarette smoke can impair vasodilation and endothelial cell growth, followed by modification of proteins, lipids, carbohydrates, and DNA, consequently degrading lung tissue. Although oxidants cannot degrade the extracellular matrix (ECM), they can modify elastins which are highly susceptible to proteolytic cleavage . Thus, there are a cascade of sequences causing lung tissue damage in COPD patients due to excess oxidants, and the interplay of both genetic and environmental factors leading to COPD pathogenesis cannot be ignored. It has been reported that 8-hydroxy-2′-deoxygunosine (8-OH-dG) expression is significantly increased in the peripheral lung tissues of smokers (with and without COPD) compared with non-smokers, while the number of DNA damage and repair sites were increased in smokers compared with non-smokers and patients with COPD, implying the existence of a DNA damage/repair imbalance in COPD [85–87].
ROS damage nucleic acids forming oxidative products, requiring multiple repair mechanisms. Moreover given the important role of mitochondria in the DNA damage and the antioxidant capacity in humans, researchers have evaluated the inner mitochondrial membrane proteins (prohibitins, PHB1 and PHB2) in COPD patients and reported that these proteins interact with NADH dehydrogenase protein complex, which is essential for oxidoreductase activity within cells . Smoking, due to increased ROS production, damages the mitochondrial respiratory machinery [89–91]. The oxidative DNA damage in the lung generally affects the base composition of the repeated sequences (microsatellite DNA) especially when coupled with DNA mismatch repair system (MMR) deficiency [86, 92]. The study of MSI in blood samples of COPD patient of Bhopal gas victims offers an index of the estimated DNA disturbance which is achieved with the use of microsatellite markers (CA)8RG and (CA)8R[Y-Q], targeting specific chromosomal loci near or in genes that could be implicated in the pathogenesis of the disease . The induction of MSI by oxidants in COPD has significant biological relevance, given the association of MSI with chronic inflammation, where oxidant production would be enhanced .
7. THERAPEUTIC INTERVENTION
COPD is a multi-factorial, irreversible disease with airflow limitation involving chronic bronchitis and emphysema apart from a myriad of systemic manifestations which tend to worsen the disease state. No single mechanism can account for the complex pathology in COPD. It is likely that there exists a synchronization of airway inflammation, protease/anti-protease imbalance, oxidative stress, and apoptosis that worsens conditions in emphysema. However, it is treatable if therapy and patient self management measures of the disease are followed regularly.
Current pharmacotherapy aims at improving symptoms, exercise tolerance, and health status. Patients symptomatic of COPD in the population should be screened and subjected to pharmacological interventions via the use of short-acting bronchodilators to rescue symptoms as a first line of action. However, when symptoms do not improve, a combination of bronchodilators of different classes is effective. Furthermore, long-acting β-agonists plus inhaled corticosteroids are beneficial . Thiol antioxidants, carbocysteine, erdosteine, and fudosteine are frequently used for increasing lung thiol content. Improvement in cigarette smoke-induced oxidative stress and changes in cellular levels has also been reported to be altered by synthetic molecules, such as spin traps, catalytic antioxidants, porphyrins, and lipid peroxidation and protein carbonylation blockers/inhibitors. Pre-clinical and clinical trials have also shown that these antioxidants can reduce oxidative stress, affect redox and GSH biosynthesis genes, and pro-inflammatory gene expression .
The current therapy uses antioxidants for COPD is symptomatic. For example, the thiol-based therapy is mainly mucolytic, thereby minimizing the bacterial/viral load. Additionally, antioxidant compounds may also enhance the efficiency of glucocorticoids by quenching oxidants and aldehydes in COPD patients. Antioxidant therapy may affect important outcomes in COPD, such as overcoming steroid resistance, mucus hypersecretion, inflammation, and extracellular matrix remodeling. Furthermore, the effects of a combination of various antioxidants along with thiols, spin traps, lipid peroxidation/protein carbonylation inhibitors/blockers, or enzyme mimetics is an attractive strategy worth inspecting in patients with COPD. Antioxidants (e.g., thiols and other molecules) may be combined with anti-inflammatories/PDE4 inhibitors/Sirtuin1 activators, bronchodilators, steroids, antibiotics, and statins. Furthermore, new antioxidant strategies can be used as supplementing/pre-emptying agents in the management of COPD, as well as in susceptible smokers . The lung functioning in COPD can deteriorate over time despite receiving the best available care. Antioxidant properties associated with vitamin C (also known as ascorbate or L-ascorbic acid) play significant roles in the immune response including allergic reaction, maintenance of connective tissue, and even tumor suppression. Reduced levels of vitamin C have been associated significantly with elevated wheezing, dyspnea, and exacerbation of COPD. Dietary vitamin C has also been shown to decrease oxidative stress, increase collagen synthesis, and restore vascular endothelial growth factor levels leading to proliferation of alveolar cells in the lungs. Extensive studies have shown that vitamin C intake provides protection against the development of COPD . In addition to the medical therapies, regular exercise/training and individualized rehabilitation are also of major importance.
COPD continues to progress long after a person quits smoking, as free radicals are partly to be blamed. COPD involves chronic inflammation, and inflammatory cells release abundant free radicals. As a result, the lungs of COPD patients exist in a constant state of oxidative stress––an imbalance of free radicals and antioxidants. Oxidative stress has important implications in several events of lung physiology and in the pathogenesis of COPD. These include oxidative inactivation of antiproteases and surfactants, mucus hypersecretion, membrane lipid peroxidation, dysfunction of mitochondrial respiration, alveolar epithelial injury, remodeling of extracellular matrix, and apoptosis. An increased level of ROS produced in the airways is reflected by increased markers of oxidative stress in the airspaces, sputum, breath, lungs, and blood in patients with COPD. There are several small molecule compounds in clinical trials that target oxidant signalling or quench oxidants derived from cigarette smoke. Antioxidant and/or anti-inflammatory agents such as thiol molecules, spin traps, dietary polyphenols, antioxidant mimetics, and inhibitors of oxidative stress-induced signalling pathways present potential means to treat this element of COPD.
The authors wish to thank Bhopal Memorial Hospital and Research Centre for rendering the necessary support. The authors declare no conflicts of interest.
- Birben E, Sahiner UM, Sackesen C, Erzurum S, Kalayci O. Oxidative stress and antioxidant defense. World Allergy Organ J 2012; 5(1):9–19. doi: 10.1097/WOX.0b013e3182439613.
- Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol 2007; 39(1):44–84. doi: 10.1016/j.biocel.2006.07.001.
- Bialas AJ, Sitarek P, Milkowska-Dymanowska J, Piotrowski WJ, Gorski P. The role of mitochondria and oxidative/antioxidative imbalance in pathobiology of chronic obstructive pulmonary disease. Oxid Med Cell Longev 2016; 2016:7808576. doi: 10.1155/2016/7808576.
- Ambrosino N, Palmiero G, Strambi SK. New approaches in pulmonary rehabilitation. Clin Chest Med 2007; 28(3):629–38, vii. doi: 10.1016/j.ccm.2007.06.001.
- Soriano JB. An epidemiological overview of chronic obstructive pulmonary disease: what can real-life data tell us about disease management? COPD 2017; 14(sup1):S3–S7. doi: 10.1080/15412555.2017.1286165.
- De S. Annual change in spirometric parameters among patients affected in Bhopal gas disaster: a retrospective observational study. Lung India 2013; 30(2):103–7. doi: 10.4103/0970-2113.110414.
- De S. Retrospective analysis of lung function abnormalities of Bhopal gas tragedy affected population. Indian J Med Res 2012; 135:193–200.
- Hurst JR, Perera WR, Wilkinson TM, Donaldson GC, Wedzicha JA. Systemic and upper and lower airway inflammation at exacerbation of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2006; 173(1):71–8. doi: 10.1164/rccm.200505-704OC.
- Macnee W. Pathogenesis of chronic obstructive pulmonary disease. Clin Chest Med 2007; 28(3):479–513, v. doi: 10.1016/j.ccm.2007.06.008.
- Kinnula VL, Crapo JD, Raivio KO. Generation and disposal of reactive oxygen metabolites in the lung. Lab Invest 1995; 73(1):3–19.
- Wood AM, Stockley RA. The genetics of chronic obstructive pulmonary disease. Respir Res 2006; 7:130. doi: 10.1186/1465-9921-7-130.
- Mishra PK, Panwar H, Bhargava A, Gorantla VR, Jain SK, Banerjee S, et al. Isocyanates induces DNA damage, apoptosis, oxidative stress, and inflammation in cultured human lymphocytes. J Biochem Mol Toxicol 2008; 22(6):429–40. doi: 10.1002/jbt.20260.
- Harman D. Free radical theory of aging: an update: increasing the functional life span. Ann N Y Acad Sci 2006; 1067:10–21. doi: 10.1196/annals.1354.003.
- Valko M, Rhodes CJ, Moncol J, Izakovic M, Mazur M. Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem Biol Interact 2006; 160(1):1–40. doi: 10.1016/j.cbi.2005.12.009.
- Halliwell B, Gutteridge JMC. Free Radicals in Biology and Medicine. 3rd Edition. Oxford University Press, London, UK.1999.
- Yui K, Tanuma N, Yamada H, Kawasaki Y. Decreased total antioxidant capacity has a larger effect size than increased oxidant levels in urine in individuals with autism spectrum disorder. Environ Sci Pollut Res Int 2017; 24(10):9635–44. doi: 10.1007/s11356-017-8595-3.
- Church DF, Pryor WA. Free-radical chemistry of cigarette smoke and its toxicological implications. Environ Health Perspect 1985; 64:111–26.
- Hiltermann JT, Lapperre TS, van Bree L, Steerenberg PA, Brahim JJ, Sont JK, et al. Ozone-induced inflammation assessed in sputum and bronchial lavage fluid from asthmatics: a new noninvasive tool in epidemiologic studies on air pollution and asthma. Free Radic Biol Med 1999; 27(11–12):1448–54.
- Nightingale JA, Rogers DF, Barnes PJ. Effect of inhaled ozone on exhaled nitric oxide, pulmonary function, and induced sputum in normal and asthmatic subjects. Thorax 1999; 54(12):1061–9.
- Comhair SA, Thomassen MJ, Erzurum SC. Differential induction of extracellular glutathione peroxidase and nitric oxide synthase 2 in airways of healthy individuals exposed to 100% O(2) or cigarette smoke. Am J Respir Cell Mol Biol 2000; 23(3):350–4. doi: 10.1165/ajrcmb.23.3.4076.
- Matthay MA, Geiser T, Matalon S, Ischiropoulos H. Oxidant-mediated lung injury in the acute respiratory distress syndrome. Crit Care Med 1999; 27(9):2028–30.
- Biaglow JE, Mitchell JB, Held K. The importance of peroxide and superoxide in the X-ray response. Int J Radiat Oncol Biol Phys 1992; 22(4):665–9.
- Chiu SM, Xue LY, Friedman LR, Oleinick NL. Copper ion-mediated sensitization of nuclear matrix attachment sites to ionizing radiation. Biochemistry 1993; 32(24):6214–9.
- Stohs SJ, Bagchi D. Oxidative mechanisms in the toxicity of metal ions. Free Radic Biol Med 1995; 18(2):321–36.
- Technical Report on Population Based Long Term Clinical Studies. Bhopal Gas Disaster Research Centre, New Delhi, India. 1985–1994.
- Lima ES, Abdalla DSP. Peroxidação lipídica: mecanismos e avaliação em amostras biológicas. Rev Bras Cienc Farm 2001; 37(3):293–303.
- Repine JE, Bast A, Lankhorst I. Oxidative stress in chronic obstructive pulmonary disease. Oxidative Stress Study Group. Am J Respir Crit Care Med 1997; 156(2 Pt 1):341–57. doi: 10.1164/ajrccm.156.2.9611013.
- Montuschi P, Barnes PJ, Roberts LJ, 2nd. Isoprostanes: markers and mediators of oxidative stress. FASEB J 2004; 18(15):1791–800. doi: 10.1096/fj.04-2330rev.
- Nowak D, Kasielski M, Antczak A, Pietras T, Bialasiewicz P. Increased content of thiobarbituric acid-reactive substances and hydrogen peroxide in the expired breath condensate of patients with stable chronic obstructive pulmonary disease: no significant effect of cigarette smoking. Respir Med 1999; 93(6):389–96. doi: 10.1053/rmed.1999.0574.
- Habib MP, Katz MA. Source of ethane in expirate of rats ventilated with 100% oxygen. J Appl Physiol (1985) 1989; 66(3):1268–72.
- Habib MP, Clements NC, Garewal HS. Cigarette smoking and ethane exhalation in humans. Am J Respir Crit Care Med 1995; 151(5):1368–72. doi: 10.1164/ajrccm.151.5.7735586.
- Rahman I, van Schadewijk AA, Crowther AJ, Hiemstra PS, Stolk J, MacNee W, et al. 4-Hydroxy-2-nonenal, a specific lipid peroxidation product, is elevated in lungs of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2002; 166(4):490–5. doi: 10.1164/rccm.2110101.
- Reznick AZ, Cross CE, Hu ML, Suzuki YJ, Khwaja S, Safadi A, et al. Modification of plasma proteins by cigarette smoke as measured by protein carbonyl formation. Biochem J 1992; 286 ( Pt 2):607–11.
- Nagler R, Lischinsky S, Diamond E, Drigues N, Klein I, Reznick AZ. Effect of cigarette smoke on salivary proteins and enzyme activities. Arch Biochem Biophys 2000; 379(2):229–36. doi: 10.1006/abbi.2000.1877.
- O’Neill CA, Halliwell B, van der Vliet A, Davis PA, Packer L, Tritschler H, et al. Aldehyde-induced protein modifications in human plasma: protection by glutathione and dihydrolipoic acid. J Lab Clin Med 1994; 124(3):359–70.
- MacNee W. Oxidative stress and lung inflammation in airways disease. Eur J Pharmacol 2001; 429(1–3):195–207.
- Pignatelli B, Li CQ, Boffetta P, Chen Q, Ahrens W, Nyberg F, et al. Nitrated and oxidized plasma proteins in smokers and lung cancer patients. Cancer Res 2001; 61(2):778–84.
- Petruzzelli S, Puntoni R, Mimotti P, Pulera N, Baliva F, Fornai E, et al. Plasma 3-nitrotyrosine in cigarette smokers. Am J Respir Crit Care Med 1997; 156(6):1902–7. doi: 10.1164/ajrccm.156.6.9702075.
- Ichinose M, Sugiura H, Yamagata S, Koarai A, Shirato K. Increase in reactive nitrogen species production in chronic obstructive pulmonary disease airways. Am J Respir Crit Care Med 2000; 162(2 Pt 1):701–6. doi: 10.1164/ajrccm.162.2.9908132.
- Rahman I, MacNee W. Oxidant/antioxidant imbalance in smokers and chronic obstructive pulmonary disease. Thorax 1996; 51(4):348–50.
- Aaron SD, Angel JB, Lunau M, Wright K, Fex C, Le Saux N, et al. Granulocyte inflammatory markers and airway infection during acute exacerbation of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001; 163(2):349–55. doi: 10.1164/ajrccm.163.2.2003122.
- Yeung MC, Buncio AD. Leukocyte count, smoking, and lung function. Am J Med 1984; 76(1):31–7.
- van Antwerpen VL, Theron AJ, Richards GA, Steenkamp KJ, van der Merwe CA, van der Walt R, et al. Vitamin E, pulmonary functions, and phagocyte-mediated oxidative stress in smokers and nonsmokers. Free Radic Biol Med 1995; 18(5):935–41.
- Noguera A, Busquets X, Sauleda J, Villaverde JM, MacNee W, Agusti AG. Expression of adhesion molecules and G proteins in circulating neutrophils in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998; 158(5 Pt 1):1664–8. doi: 10.1164/ajrccm.158.5.9712092.
- Park HS, Kim SR, Lee YC. Impact of oxidative stress on lung diseases. Respirology 2009; 14(1):27–38. doi: 10.1111/j.1440-1843.2008.01447.x.
- Cavalcante AG, de Bruin PF. The role of oxidative stress in COPD: current concepts and perspectives. J Bras Pneumol 2009; 35(12):1227–37.
- Tuder RM, Yoshida T, Arap W, Pasqualini R, Petrache I. State of the art. Cellular and molecular mechanisms of alveolar destruction in emphysema: an evolutionary perspective. Proc Am Thorac Soc 2006; 3(6):503–10. doi: 10.1513/pats.200603-054MS.
- Demedts IK, Demoor T, Bracke KR, Joos GF, Brusselle GG. Role of apoptosis in the pathogenesis of COPD and pulmonary emphysema. Respir Res 2006; 7:53. doi: 10.1186/1465-9921-7-53.
- McGrath-Morrow SA, Cho C, Cho C, Zhen L, Hicklin DJ, Tuder RM. Vascular endothelial growth factor receptor 2 blockade disrupts postnatal lung development. Am J Respir Cell Mol Biol 2005; 32(5):420–7. doi: 10.1165/rcmb.2004-0287OC.
- Tuder RM, Zhen L, Cho CY, Taraseviciene-Stewart L, Kasahara Y, Salvemini D, et al. Oxidative stress and apoptosis interact and cause emphysema due to vascular endothelial growth factor receptor blockade. Am J Respir Cell Mol Biol 2003; 29(1):88–97. doi: 10.1165/rcmb.2002-0228OC.
- Kanazawa H, Yoshikawa J. Elevated oxidative stress and reciprocal reduction of vascular endothelial growth factor levels with severity of COPD. Chest 2005; 128(5):3191–7. doi: 10.1378/chest.128.5.3191.
- MacNee W. Pulmonary and systemic oxidant/antioxidant imbalance in chronic obstructive pulmonary disease. Proc Am Thorac Soc 2005; 2(1):50–60. doi: 10.1513/pats.200411-056SF.
- Barnes PJ, Shapiro SD, Pauwels RA. Chronic obstructive pulmonary disease: molecular and cellular mechanisms. Eur Respir J 2003; 22(4):672–88.
- Evans MD, Pryor WA. Damage to human alpha-1-proteinase inhibitor by aqueous cigarette tar extracts and the formation of methionine sulfoxide. Chem Res Toxicol 1992; 5(5):654–60.
- Abboud RT, Fera T, Richter A, Tabona MZ, Johal S. Acute effect of smoking on the functional activity of alpha1-protease inhibitor in bronchoalveolar lavage fluid. Am Rev Respir Dis 1985; 131(1):79–85. doi: 10.1164/arrd.19188.8.131.52.
- Aoshiba K, Yasuda K, Yasui S, Tamaoki J, Nagai A. Serine proteases increase oxidative stress in lung cells. Am J Physiol Lung Cell Mol Physiol 2001; 281(3):L556–64.
- Rahman I, Morrison D, Donaldson K, MacNee W. Systemic oxidative stress in asthma, COPD, and smokers. Am J Respir Crit Care Med 1996; 154(4 Pt 1):1055–60. doi: 10.1164/ajrccm.154.4.8887607.
- Berry JK, Baum C. Reversal of chronic obstructive pulmonary disease-associated weight loss : are there pharmacological treatment options? Drugs 2004; 64(10):1041–52.
- MacNee W, Wiggs B, Belzberg AS, Hogg JC. The effect of cigarette smoking on neutrophil kinetics in human lungs. N Engl J Med 1989; 321(14):924–8. doi: 10.1056/NEJM198910053211402.
- Chan-Yeung M, Abboud R, Buncio AD, Vedal S. Peripheral leucocyte count and longitudinal decline in lung function. Thorax 1988; 43(6):462–6.
- Postma DS, Renkema TE, Noordhoek JA, Faber H, Sluiter HJ, Kauffman H. Association between nonspecific bronchial hyperreactivity and superoxide anion production by polymorphonuclear leukocytes in chronic air-flow obstruction. Am Rev Respir Dis 1988; 137(1):57–61. doi: 10.1164/ajrccm/137.1.57.
- Kanazawa H, Shiraishi S, Hirata K, Yoshikawa J. Imbalance between levels of nitrogen oxides and peroxynitrite inhibitory activity in chronic obstructive pulmonary disease. Thorax 2003; 58(2):106–9.
- Gan WQ, Man SF, Senthilselvan A, Sin DD. Association between chronic obstructive pulmonary disease and systemic inflammation: a systematic review and a meta-analysis. Thorax 2004; 59(7):574–80.
- Takabatake N, Nakamura H, Abe S, Inoue S, Hino T, Saito H, et al. The relationship between chronic hypoxemia and activation of the tumor necrosis factor-alpha system in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000; 161(4 Pt 1):1179–84. doi: 10.1164/ajrccm.161.4.9903022.
- Barnes PJ, Celli BR. Systemic manifestations and comorbidities of COPD. Eur Respir J 2009; 33(5):1165–85. doi: 10.1183/09031936.00128008.
- Tzortzaki EG, Tsoumakidou M, Makris D, Siafakas NM. Laboratory markers for COPD in “susceptible” smokers. Clin Chim Acta 2006; 364(1–2):124–38. doi: 10.1016/j.cca.2005.06.008.
- Rahman I, Kelly F. Biomarkers in breath condensate: a promising new non-invasive technique in free radical research. Free Radic Res 2003; 37(12):1253–66.
- Rahman I, Biswas SK. Non-invasive biomarkers of oxidative stress: reproducibility and methodological issues. Redox Rep 2004; 9(3):125–43. doi: 10.1179/135100004225005219.
- Horvath I, Hunt J, Barnes PJ, Alving K, Antczak A, Baraldi E, et al. Exhaled breath condensate: methodological recommendations and unresolved questions. Eur Respir J 2005; 26(3):523–48. doi: 10.1183/09031936.05.00029705.
- Bieth JG. The antielastase screen of the lower respiratory tract. Eur J Respir Dis Suppl 1985; 139:57–61.
- Kostikas K, Papatheodorou G, Psathakis K, Panagou P, Loukides S. Oxidative stress in expired breath condensate of patients with COPD. Chest 2003; 124(4):1373–80.
- Rahman I, MacNee W. Role of transcription factors in inflammatory lung diseases. Thorax 1998; 53(7):601–12.
- Rahman I, Swarska E, Henry M, Stolk J, MacNee W. Is there any relationship between plasma antioxidant capacity and lung function in smokers and in patients with chronic obstructive pulmonary disease? Thorax 2000; 55(3):189–93.
- Aoshiba K, Koinuma M, Yokohori N, Nagai A. Immunohistochemical evaluation of oxidative stress in murine lungs after cigarette smoke exposure. Inhal Toxicol 2003; 15(10):1029–38. doi: 10.1080/08958370390226431.
- Siafaka NM. Management of Chronic Obstructive Pulmonary Disease. European Respiratory Society. 2006.
- Rangasamy T, Cho CY, Thimmulappa RK, Zhen L, Srisuma SS, Kensler TW, et al. Genetic ablation of Nrf2 enhances susceptibility to cigarette smoke-induced emphysema in mice. J Clin Invest 2004; 114(9):1248–59. doi: 10.1172/JCI21146.
- Shahar E, Boland LL, Folsom AR, Tockman MS, McGovern PG, Eckfeldt JH. Docosahexaenoic acid and smoking-related chronic obstructive pulmonary disease. The Atherosclerosis Risk in Communities Study Investigators. Am J Respir Crit Care Med 1999; 159(6):1780–5. doi: 10.1164/ajrccm.159.6.9810068.
- McCusker K, Hoidal J. Selective increase of antioxidant enzyme activity in the alveolar macrophages from cigarette smokers and smoke-exposed hamsters. Am Rev Respir Dis 1990; 141(3):678–82. doi:
- Chabrier PE, Auguet M, Spinnewyn B, Auvin S, Cornet S, Demerle-Pallardy C, et al. BN 80933, a dual inhibitor of neuronal nitric oxide synthase and lipid peroxidation: a promising neuroprotective strategy. Proc Natl Acad Sci USA 1999; 96(19):10824–9.
- Smith KR, Uyeminami DL, Kodavanti UP, Crapo JD, Chang LY, Pinkerton KE. Inhibition of tobacco smoke-induced lung inflammation by a catalytic antioxidant. Free Radic Biol Med 2002; 33(8):1106–14.
- Haddad el B, McCluskie K, Birrell MA, Dabrowski D, Pecoraro M, Underwood S, et al. Differential effects of ebselen on neutrophil recruitment, chemokine, and inflammatory mediator expression in a rat model of lipopolysaccharide-induced pulmonary inflammation. J Immunol 2002; 169(2):974–82.
- Zhang M, Nomura A, Uchida Y, Iijima H, Sakamoto T, Iishii Y, et al. Ebselen suppresses late airway responses and airway inflammation in guinea pigs. Free Radic Biol Med 2002; 32(5):454–64.
- Arts IC, Hollman PC. Polyphenols and disease risk in epidemiologic studies. Am J Clin Nutr 2005; 81(1 Suppl):317S–25S.
- Shishodia S, Potdar P, Gairola CG, Aggarwal BB. Curcumin (diferuloylmethane) down-regulates cigarette smoke-induced NF-kappaB activation through inhibition of IkappaBalpha kinase in human lung epithelial cells: correlation with suppression of COX-2, MMP-9 and cyclin D1. Carcinogenesis 2003; 24(7):1269-79. doi: 10.1093/carcin/bgg078.
- Vijayan VK. Chronic obstructive pulmonary disease. Indian J Med Res 2013; 137(2):251–69.
- Caramori G, Adcock IM, Casolari P, Ito K, Jazrawi E, Tsaprouni L, et al. Unbalanced oxidant-induced DNA damage and repair in COPD: a link towards lung cancer. Thorax 2011; 66(6):521–7. doi: 10.1136/thx.2010.156448.
- Anderson GP, Bozinovski S. Acquired somatic mutations in the molecular pathogenesis of COPD. Trends Pharmacol Sci 2003; 24(2):71–6. doi: 10.1016/S0165-6147(02)00052-4.
- Pastor MD, Nogal A, Molina-Pinelo S, Melendez R, Romero-Romero B, Mediano MD, et al. Identification of oxidative stress related proteins as biomarkers for lung cancer and chronic obstructive pulmonary disease in bronchoalveolar lavage. Int J Mol Sci 2013; 14(2):3440–55. doi: 10.3390/ijms14023440.
- Soulitzis N, Neofytou E, Psarrou M, Anagnostis A, Tavernarakis N, Siafakas N, et al. Downregulation of lung mitochondrial prohibitin in COPD. Respir Med 2012; 106(7):954–61. doi: 10.1016/j.rmed.2012.03.019.
- Ciencewicki J, Trivedi S, Kleeberger SR. Oxidants and the pathogenesis of lung diseases. J Allergy Clin Immunol 2008; 122(3):456–68; quiz 469–470. doi: 10.1016/j.jaci.2008.08.004.
- Merkwirth C, Langer T. Prohibitin function within mitochondria: essential roles for cell proliferation and cristae morphogenesis. Biochim Biophys Acta 2009; 1793(1):27–32. doi: 10.1016/j.bbamcr.2008.05.013.
- Theiss AL, Sitaraman SV. The role and therapeutic potential of prohibitin in disease. Biochim Biophys Acta 2011; 1813(6):1137–43. doi: 10.1016/j.bbamcr.2011.01.033.
- Boyer JC, Yamada NA, Roques CN, Hatch SB, Riess K, Farber RA. Sequence dependent instability of mononucleotide microsatellites in cultured mismatch repair proficient and deficient mammalian cells. Hum Mol Genet 2002; 11(6):707–13.
- Bose P, Bathri R. Association of microsatellite instability and chronic obstructive pulmonary disorder in isocyanate-Exposed population of Bhopal. Indian J Hum Genet 2012; 18(2):172–6. doi: 10.4103/0971-6866.100754.
- Tzortzaki EG, Dimakou K, Neofytou E, Tsikritsaki K, Samara K, Avgousti M, et al. Oxidative DNA damage and somatic mutations: a link to the molecular pathogenesis of chronic inflammatory airway diseases. Chest 2012; 141(5):1243–50. doi: 10.1378/chest.11-1653.
- Spruit MA, Wouters EF. New modalities of pulmonary rehabilitation in patients with chronic obstructive pulmonary disease. Sports Med 2007; 37(6):501–18.
- Rahman I, MacNee W. Antioxidant pharmacological therapies for COPD. Curr Opin Pharmacol 2012; 12(3):256–65. doi: 10.1016/j.coph.2012.01.015.
- Rahman I. Pharmacological antioxidant strategies as therapeutic interventions for COPD. Biochim Biophys Acta 2012; 1822(5):714–28. doi: 10.1016/j.bbadis.2011.11.004.