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Eur Respir J 2003; 22:14s-27s
Copyright ©ERS Journals Ltd 2003

Oxidant metabolism in chronic obstructive pulmonary disease

A.W. Boots, G.R.M.M. Haenen and A. Bast

Dept of Pharmacology and Toxicology, Faculty of Medicine, University of Maastricht, Maastricht, The Netherlands

CORRESPONDENCE: A. Bast, Dept of Pharmacology and Toxicology, Faculty of Medicine, University of Maastricht, P.O. Box 616, 6200 MD, Maastricht, The Netherlands. Fax: 31 43 3884149. E-mail: A.Bast@farmaco.unimaas.nl

Keywords: chronic obstructive pulmonary disease, metabolism, oxidative stress, systemic

Received: June 30, 2003
Accepted June 30, 2003


   ABSTRACT
TOP
 ABSTRACT
Indicators of oxidative stress...
 Antioxidant capacity in chronic...
 Body composition and chronic...
 Carcinogenesis and chronic...
 Conclusion
 REFERENCES
 
The development and progression of chronic obstructive pulmonary disease (COPD) have been associated with increased oxidative stress or reduced antioxidant resources. Several indicators of oxidative stress, such as hydrogen peroxide exhalation, lipid peroxidation products and degraded proteins, are indeed elevated in COPD patients. As a result, the antioxidant capacity decreases in COPD patients.

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.

COPD is linked to weight loss and in particular to loss in fat­free mass by skeletal muscle wasting. This systemic effect can be mediated by both oxidative stress and oxidative stress­mediated processes like apoptosis and inflammation. Furthermore, COPD is a predisposition for lung cancer through several mechanisms including oxidative stress and oxidative stress­mediated processes such as inflammation and disruption of genomic integrity.

Current therapeutic interventions against the far­reaching consequences of the systemic oxidative stress in chronic obstructive pulmonary disease are not yet optimised. A diet designed to reduce chronic metabolic stress might form an effective therapeutic strategy in chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a heterogenous syndrome characterised by irreversible progressive airflow limitation 1–3. It is expected that in 2020 COPD will become the third instead of the current fourth leading cause of death worldwide 4. The most prominent risk factor for the clinical manifestations and progression of COPD is tobacco smoking. Although about 90% of all COPD patients are smokers, for unknown reasons only 20% of all smokers develop the disease 5, 6. Other risk factors include {alpha}1-antitrypsin deficiency, air pollution, socioeconomic status and lower birth weight 5. Recently, the development of COPD has also become associated with increased oxidative stress or reduced antioxidant resources 7, 8. The purpose of this review is to evaluate the role of the oxidant­antioxidant imbalance in the development of COPD and of the oxidant metabolism in the systemic effects of COPD. Therapeutic approaches to alter this oxidant­antioxidant imbalance in COPD will also be discussed.


   Indicators of oxidative stress in chronic obstructive pulmonary disease
TOP
 ABSTRACT
 Indicators of oxidative stress...
Antioxidant capacity in chronic...
 Body composition and chronic...
 Carcinogenesis and chronic...
 Conclusion
 REFERENCES
 
Hydrogen peroxide exhalation
Hydrogen peroxide in exhaled breath directly reflects oxidant generation in the lung. Smokers as well as patients with COPD have higher levels of exhaled hydrogen peroxide (H2O2) than exsmokers with COPD or nonsmokers 9, 10. During acute exacerbations of COPD these H2O2-levels are even higher 11. The source of the enhanced exhalation of H2O2 is unknown, but has been suggested to partly originate from the increased release of superoxide anion (O2–) by the alveolar macrophages from smokers compared with that by the alveolar macrophages from nonsmokers 11, 12. Moreover, the intracellular iron content of the alveolar macrophages from smokers is also increased compared with that of nonsmokers 13. The presence of increased amounts of free iron in the airspaces of smokers may increase the generation of even more reactive oxygen species through the Fenton­reaction 3, 14. Additionally, the combination xanthine/xanthine oxidase, capable of generating superoxide anion radical and H2O2, is increased in the bronchoalveolar lavage and plasma of COPD patients and smokers when compared with healthy subjects and nonsmokers respectively 15, 16. Furthermore, it was shown that COPD patients performing strenuous exercise experience systemic oxidative stress, which can be inhibited by blocking xanthine oxidase 15.

NO• exhalation
The gas NO• is produced endogenously in the lung by NO synthase (NOS) that exists in both constitutive isoforms (cNOS) and an inducible isoform (iNOS) 17. The latter can be induced by inflammatory stimuli in the lung and may therefore reflect airway inflammation. Consequently, exhaled NO• levels are considered a marker for airway inflammation and an indirect measure of oxidative stress 17–19. However, the results regarding the use of NO• levels as a marker for COPD are inconclusive. Some studies report a higher level of exhaled NO• 20, 21 while others found either normal or even lower exhaled NO• concentrations in stable COPD patients compared with control subjects 22, 23. These discrepancies may be due to the use of different methods of measurement or different criteria for patient selection. Furthermore, NO• itself is short­lived in vivo and can be easily transformed into NOx by its fast reaction with superoxide. It has been proposed that NO• may form stable S-nitrothiols (RS-NOs) with low molecular weight thiols like glutathione or N-acetylcysteine in order to enhance its bioactivity 24–26. In that way, RS-NOs rather than NO• are seen as the major products of NOS and inflammation. Studies regarding the RS-NOs levels in inflammatory airway diseases show increased levels in the exhaled breath condensate of COPD patients and smokers compared to nonsmokers and healthy control subjects 17.

Lipid peroxidation products
Reactive oxygen species (ROS) can trigger 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 iron­containing proteins, forming hydrocarbon gases and unsaturated aldehydes as by­products 5.

Lipid peroxidation (LPO) products, measured as thiobarbituric acid­reacting substances, display higher levels in breath condensate and in lungs of stable COPD patients 27. In addition, these LPO products negatively correlate with the lung function marker forced expiratory volume in one second (FEV1), suggesting that lipid peroxidation plays an important role in the decline of lung function 28. In the plasma and lung lavages of healthy smokers the levels of LPO products are also increased. Furthermore, increased levels of LPO products are inversely correlated with the time expired from the last exposure to tobacco smoke and with the degree of small airway obstruction 5.

The specific endproduct of lipid peroxidation 4-hydroxy-2,3-nonenal is capable of modifying cellular proteins. Airway epithelial cells and endothelial cells from smokers with airway obstruction display increased 4-hydroxy-2,3-nonenal­modified protein levels compared to nonsmokers or subjects without airway obstruction 29.

The hydrocarbon ethane is a by­product of the peroxidation of fatty acids such as 9,12,15-linolenic acid 18. Patients with COPD display an increased level of exhaled ethane compared with control subjects. This increased level is negatively correlated with lung function, suggesting that lipid peroxidation is an important factor in the progression of COPD 18, 30. Furthermore, ethane produced in several other organs than the lung, such as intestine, brain, kidney, liver, heart and testis, will be transported to the lung for elimination. Therefore, it is suggested that the systemic oxidative stress in smokers and COPD patients may contribute to the total exhaled ethane concentration 18, 31, 32.

Isoprostanes are made by ROS-mediated peroxidation of arachidonic acid which circulate in the plasma and can be excreted in the urine 33. Isoprostanes also reflect systemic effects caused by ROS. Levels of 8-isoprostane are increased in exhaled air condensate in smokers and are negatively correlated with the severity of the airway obstruction 34. In plasma, the levels of free and esterified F2-isoprostanes are enhanced in smokers and decrease after smoking cessation for 2 weeks 35. In urine, the levels of isoprostane F2{alpha}-III are elevated in COPD patients in comparison to healthy controls with the highest levels during exacerbations 36.

These studies show that oxidative stress, determined as products originated from LPO, is negatively associated with lung function.

Inflammatory response
Various studies have investigated the role of ROS in the generation of the inflammatory response occurring in both the central and the peripheral airways of COPD patients 3, 37. A common feature of lung inflammation is the activation of epithelial cells and resident macrophages as well as the recruitment and activation of neutrophils 3. Oxidants in cigarette smoke are capable of stimulating alveolar macrophages to release a number of mediators, some of which attract neutrophils and other inflammatory cells into the lungs 3, 38. Increased numbers of both macrophages and neutrophils migrate into the lungs of smokers where they generate ROS via the reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase system 38, 39. Moreover, lungs of smokers with airway obstruction have more neutrophils than smokers without such an obstruction 40. Peripheral blood neutrophils from both smokers and COPD patients during acute excerbations display an increased production of superoxide anion. In the latter group the production returned to its normal level when the patients were re­studied when clinically stable 41, 42. The myeloperoxidase content of the neutrophils is positively associated with cigarette smoking, suggesting an increased production of oxidants like hypochlorous acid in smokers 43.

A relationship has been shown between circulating neutrophil numbers and the FEV1 44, 45, suggesting an increased airflow limitation as a result of the ROS production of the increased number of neutrophils. Smokers that develop COPD have increased ROS release from these circulating neutrophils compared to smokers who do not develop the disease 46.

Degradation of proteins
Oxidative stress renders proteins more susceptible to proteolytic degradation by modifying amino acid chains, forming protein aggregates and cleaving peptide bonds 47. During this process, some amino acid residues are converted to carbonyl residues that can be found systemically. Human plasma proteins are indeed modified to carbonyl­containing proteins with lost sulfhydryl groups after exposure to gas­phase cigarette smoking 48. Both the saturated and the unsaturated aldehydes present in cigarette smoke contribute to this modification of proteins 49, 50. 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 49. Oxidative damage of proteins, and therefore the formation of carbonyl proteins, caused by cigarette smoke can be almost completely prevented by ascorbic acid and partially by glutathione 50, 51.

Plasma proteins can also be degraded through nitration and oxidation by reactive nitrogen species (RNS), the formation of which is stimulated by cigarette smoking 3. Levels of oxidised proteins are significantly higher in smokers than in nonsmokers 52. Smokers display higher levels of nitrated proteins, such as fibrinogen, transferrin, ceruloplasmin and plasminogen, compared to nonsmokers 52.

Furthermore, aldehydes present in cigarette smoke may react with the sulfhydryl­ and amino­ moieties of plasma proteins by a Michael addition reaction 53. Conversion of the amino acid tyrosine into 3-nitrotyrosine and dityrosine can also be regarded as an indicator for free radical damage and protein damage 54. Nitrotyrosine levels are elevated in plasma and epithelial lining fluid of smokers and negatively correlated with the FEV1 55.

Finally, the activity of the elastase inhibitor alpha 1-proteinase inhibitor (alpha 1PI) that plays an important role in preventing emphysema in COPD patients can be decreased by oxidising agents 56. Oxidation of a critical methionine amino acid residue in alpha 1PI into methionine sulfoxide leads to a dramatic reduction of the inhibitory capacity of alpha 1 PI 57, 58. Lung lavage of smokers display alpha 1 PI that contains only half of its normal activity and 4 moles of methionine sulfoxide per mole while the alpha 1 PI from lung washings of nonsmokers is fully active with only native methionine 56.

The evidence that oxidative stress plays an important role in the development and progression of COPD is summarised in fig. 1Go.


Figure 1
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  		Evidence that links systemic oxidative stress to the development and progression of chronic obstructive pulmonary disease (COPD). LPO: lipid peroxidation; EBC: exhaled breath condensate; H2O2: hydrogen peroxide; NO•: nitric oxide.

 

   Antioxidant capacity in chronic obstructive pulmonary disease
TOP
 ABSTRACT
 Indicators of oxidative stress...
 Antioxidant capacity in chronic...
Body composition and chronic...
 Carcinogenesis and chronic...
 Conclusion
 REFERENCES
 
The fall in antioxidant capacity of blood from smokers and COPD patients can not only be regarded as a reflection of the occurrence of oxidative stress but even more as evidence that oxidative stress spreads out to the circulation and can therefore generate a systemic effect 59.

Numerous studies have investigated the relationship between antioxidants and pulmonary function as well as respiratory diseases 60, 61. Analysis of this relationship is frequently performed using data on the dietary intake of antioxidants. Dietary intake data have for example been obtained from the American Nutrition Examination Survey (NHANES) or the Dutch Monitoring Project on Risk Factors for Chronic Diseases (MORGEN) study, a monitoring project on risk factors and health in the Netherlands.

In a subsample of NHANES I a lower dietary intake of vitamin C is directly related to lower values of FEV1. Moreover, the protective effect of vitamin C is even greater in asthma and bronchitis subjects 61. Cigarette smokers display lower concentrations of serum vitamin C due to a decreased intake and an increased metabolism 62. The latter phenomenon may result from the so­called protective utilisation of vitamin C under conditions of increased oxidative stress like smoking 63. Data obtained in NHANES II display an inverse association between both dietary and serum vitamin C with chronic respiratory symptoms 64. NHANES III shows that the jointly considered serum antioxidants vitamin C, vitamin E, selenium and β-carotene are associated with lung function 60. Serum vitamin C has the same association with FEV1 among smokers, former smokers and nonsmokers. The association between lung function and serum selenium is stronger among current smokers compared to former or nonsmokers while both dietary and serum β-carotene levels display a weaker association among current smokers that even decreased further with increasing smoking dose 60.

So, the effect of the various serum antioxidants changes with the smoking status. This could be explained in two different ways: 1) some antioxidants may be more efficient than others in neutralising general versus cigarette smoke oxidants; and 2) the level of oxidant burden may have an effect on the efficiency of an antioxidant i.e. that some antioxidants display a stronger effect when the oxidant burden is high 60.

Analysis of the data obtained in the MORGEN study also reveals that a high intake of vitamin C and β-carotene is associated with a higher FEV1 than a low intake of these antioxidants. Since no consistent associations are observed with respiratory symptoms, only a protective effect on lung function is suggested for the antioxidants vitamin C and β-carotene 65. The only confounding factor in the relationship between lung function and antioxidants is the educational level. A possible explanation may be that the educational level can be regarded as a healthy life style indicator, since subjects in this higher educational level are more likely to have a healthy lifestyle including a high intake of antioxidants 65.

A lack of association between dietary vitamin E intake and lung function has been reported in several studies 65, 66. These results are not consistent with other studies that show a positive relationship between dietary intake of vitamin E and lung function 67 or between dietary intake of vitamin E and incidence of asthma 68.

Data from the MORGEN study also show an independent beneficial association of fruits (>180 g·day–1), whole grains (>45 g·day–1) and alcohol with COPD (1–30 g·day–1) 69. In subjects with a positive intake of these foods, the FEV1 was significantly higher and the prevalence of COPD symptoms significantly lower. These beneficial effects are also found in nonsmokers, so confounding by smoking cannot explain the observed effect of diet on COPD totally. An association with COPD was not found for fish and vegetable intake.

The findings of the MORGEN study are consistent with others that have also shown an association between COPD-related outcomes and fruit intake 70–74 but not with vegetable intake 72, 75. A possible explanation for the lack of association with vegetables could be that vegetables are usually boiled before consumption, which leads to loss of antioxidants like vitamin C. The positive association between whole grain consumption and COPD can be explained as a result of the antioxidant components of whole grains like vitamin E and phenolic acids 76. The effect of low alcohol consumption on COPD found in the MORGEN study is consistent with other studies 72, 77 and may be caused by the inhibitory effects of alcohol on inflammatory cells 78, 79. Studies that have investigated the effect of fish intake on COPD are however not conclusive 64, 72, 74.

Finally, data from the MORGEN study show a beneficial association between the intake of three flavonoid subclasses, i.e. catechins, flavonols and flavones, and the FEV1 80. All three subclasses display anti­inflammatory and antioxidant activity and may therefore exert a positive effect on COPD. Indeed, catechin intake shows a strong positive association with all COPD symptoms but the intake of flavonols and flavones is only associated with cough. No beneficial effect of tea, the main dietary source of the catechins, on COPD is found indicating that the observed effect of the catechins is not causal. Instead the proposed effect of catechin may be caused by a substance not derived from tea, the intake of which is related to that of the catechins 80. More direct studies have also linked a decreased antioxidant capacity of blood with tobacco smoking and COPD. Smokers display in their erythrocytes a decreased glutathione peroxidase activity 81. Whole blood glutathione levels are decreased in smokers, but will return to normal values in 3 weeks after smoking cessation 82. Cigarette smoke has also been associated with both a decreased serum antioxidant activity 39 and decreased plasma levels of the antioxidants ascorbate, vitamin E, β-carotene, uric acid and selenium 81, 83–87. Vitamin E will be consumed only after complete depletion of ascorbic acid, suggesting that ascorbic acid acts as a general antioxidant reservoir and spares the use of the more specific vitamin E 83. This reduction in plasma antioxidant levels in smokers is positively correlated with increased levels of protein carbonyls and lipid peroxides 48, 88. Moreover, reduced plasma antioxidant levels appear to be associated with a family history of lung disease 89.

A decreased total antioxidant capacity also occurs in the plasma of COPD patients having an acute exacerbation 41 with a rise after the exacerbation when they were considered to be stable again 59. However, their antioxidant levels did not return to the normal levels seen in clinically stable COPD patients who were studied at least 6 weeks after their last exacerbation. This decrease in total antioxidant capacity of blood is more pronounced in patients with a current smoking history than in former smokers 59. This fall in antioxidant capacity correlates with the increased release of ROS from circulating neutrophils in COPD patients with exacerbations 41. The decreased antioxidant capacity in plasma can have several causes, including depletion of protein sulfhydryls that become oxidised 59, 90.

Some smokers however display an increased level of antioxidants such as vitamin E, vitamin C and glutathione 83, 91. Additionally, increased levels of the antioxidant enzymes superoxide dismutase and catalase occur in circulating red blood cells from smokers 92. This increased enzymatic antioxidant activity might be the result of the upregulation of protective antioxidant enzymes as an adaptive response triggered by the increased oxidative stress in COPD 3. This adaptive reaction may serve as protection and, since not all smokers are capable of increasing their antioxidants, may also explain why not all smokers develop COPD 5.


   Body composition and chronic obstructive pulmonary disease
TOP
 ABSTRACT
 Indicators of oxidative stress...
 Antioxidant capacity in chronic...
 Body composition and chronic...
Carcinogenesis and chronic...
 Conclusion
 REFERENCES
 
Chronic conditions like COPD are generally accompanied with wasting of the body cell mass (BCM), which consists of both the actively metabolising (organs) and the contracting (muscles) tissue 93. Since BCM is not directly measurable, weight loss and especially loss in fat­free mass (FFM) are considered as important markers of changes in BCM. Patients with advanced COPD often display weight loss, which is inversely correlated with the occurrence of exacerbations and can be seen as an independent predictor of outcome 94, 95. The most important tissue in which weight loss occurs in COPD patients is the skeletal muscle, because wasting of the respiratory muscles implies an increased energy cost of breathing due to a loss of power and endurance 96, 97. Other factors that display an adverse effect on the loss of FFM are peripheral muscle function, exercise capacity and health status 98–100.

Several factors influencing the loss in weight and in FFM in COPD patients are suggested including malnutrition, an imbalance in overall protein turnover and hormones involved in this process, tissue hypoxia and pulmonary inflammation 93, 97, 99, 101. There is also some evidence that links the wasting that occurs in COPD patients to both oxidative stress and oxidative stress­mediated processes, such as apoptosis, inflammation, disruption of the excitation­contraction coupling and atrophy 97, 102–104. This effect of oxidative stress on skeletal muscle wasting in COPD is shown in figure 2Go.


Figure 2
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  		The effect of oxidative stress on skeletal muscle wasting in chronic obstructive pulmonary disease.

 
Effect and consequences of systemic oxidative stress
Oxidative stress is regarded as a disbalance between formation of and protection against ROS and RNS and can result in damage to biomolecules.

Oxidative stress present in the systemic circulation of COPD patients can influence the skeletal muscle mass loss by stimulation of muscle proteolysis 105, 106. This is especially the case when the regulation of several important intracellular antioxidants like glutathione is disturbed 107.

Oxidative stress caused by overproduction of NO• can be the result of an upregulated expression of iNOS in the muscle initiated by, for example, tissue hypoxia and systemic inflammation, processes that both occur in COPD 102, 108–110. Skeletal muscles of COPD patients that suffer from weight loss indeed show such an upregulation of iNOS 111.

Furthermore, overproduction of NO• may lead to oxidative stress and oxidative stress­mediated pathologies such as muscle wasting by impairment of antioxidant enzymes like superoxide dismutase or catalase 108. Two commonly used models of skeletal muscle wasting, namely the hindlimb suspension and the chronic coronary occlusion, display an upregulation of iNOS, an increase in oxidative stress and a significant decrease in skeletal muscle antioxidant enzyme activity 112–115. Muscle wasting pathologies such as cachexia also increase the production of ROS and RNS production and enhance the iNOS levels 116, 117. Generation of ROS and RNS could lead to impairment of the antioxidant protection in skeletal muscles. A recent study using RNS challenge of skeletal muscle samples as a pathophysiological model showed that RNS are indeed capable of substantial downregulation of antioxidant enzymes in skeletal muscle. The degree of this down­regulation showed specificity for the various antioxidant enzymes and RNS donors, indicating that different antioxidants have different sensitivities to specific RNS donors 108.

Moreover, ROS can cause damage to lipids in biomembranes and to proteins both present in skeletal muscles 118. Peroxidation of these lipids increases the permeability of membranes and in case of the mitochondrial inner membrane this can lead to leakage of ions, resulting in damage to the mitochondrial function and thereby reduction of the energy production. Reactions of ROS with proteins result in the formation of carbonyl groups on amino acid residues. Since this may change the structure and chemical properties of the proteins, their function will decline and they become more susceptible to proteinases or complete protein unfolding 119. Both the lipid and the protein reactions with ROS may contribute to muscle wasting or muscle dysfunctioning.

Finally, oxidative stress is also an important factor in the ageing process that is characterised by changes in the skeletal muscles, including loss of muscle mass and function, atrophy of mainly type II muscle fibres and a decline of metabolic capacity 103, 120, 121. It is therefore often suggested that a premature and/or accelerated ageing process contributes to the muscle wasting in COPD. However, since type I muscle fibres increase proportionally in elderly it can be suggested that the observed fibre­type redistribution in COPD, namely an increase of type II and a decrease in type I fibres, is not dependent of ageing 103. Moreover, most studies in COPD patients make use of healthy age­matched control groups so that age­related changes have to be present in both groups, unless the reaction of patients to ageing is different from that of healthy controls 103. These potential differences need to be further explored in order to elucidate the contribution of ageing to the muscle wasting seen in COPD patients.

Apoptosis
Apoptosis, an active process of cell death, is triggered by oxidative stress in experimental animals 122. In mononucleated cells apoptosis will lead to cell death whereas in multinucleated cells like the myocytes cell atrophy will occur 123, 124. The unexplained weight loss in COPD patients is mainly caused by skeletal muscle atrophy, indicating that excessive apoptosis may occur in these patients 125. Furthermore, several triggers of apoptosis like hypoxia, oxidative stress and systemic inflammation do exist in COPD patients 126, 127. A recent study in COPD patients with a low body weight indicates that increased apoptosis of skeletal muscles indeed occurs in these patients 102.

Exercise
In normal conditions skeletal muscles produce both ROS and RNS and they are associated with excitation­contraction 106, 128–130. Exercise can cause an overproduction of these reactive species, leading to oxidative stress 128, 131. Paradoxically, the disuse of muscles can also generate oxidative stress since a lower antioxidant­stimulating trigger consequently results in a lower antioxidant status 128, 132. An occasional occurrence of exercise may in that case generate more reactive species than can be scavenged by the present antioxidants, resulting in a hypersensitivity for oxidative stress 133.

Furthermore, COPD patients display exercise­induced oxidation of blood glutathione 134 and increased lipid peroxidation products 15, 135. It is striking that both COPD patients and healthy subjects display the same degree of this exercise­induced glutathione oxidation. Since it is generally suggested that during exercise most ROS are generated in the oxidative metabolism in the mitochondria, it would be expected that the ROS production diminishes due to the reduced oxygen consumption that COPD patients display during maximal exercise. However, the observed enhanced oxidative stress in COPD patients during exercise can also be explained by disturbances in the mitochondrial respiratory chain, contribution of other sources besides the mitochondria to exercise­induced ROS generation and decreased antioxidant levels in COPD 130. As explained below, excessive ROS can affect skeletal muscle functions in several ways.

Excitation­contraction coupling
Skeletal muscle­contractility is affected by ROS in a dose­ and time­dependent way. Low levels of the ROS generator xanthine oxidase cause a potentiation of muscle tension whereas higher levels result in a severe depression of contractility 136. A comparable paradoxical role on muscle contractility is demonstrated for NO• in various muscle preparations 137.

Various studies have indeed demonstrated that exposure to excessive oxidative stress causes contractile dysfunction of skeletal muscles 138–140. Chronic exposure of skeletal muscle fibres to H2O2 reduced the force generation 138. Increased lipid peroxidation, a result of ROS, in chronically­loaded diaphragms is related positively with reduction in strength and with fatigability 139. Noteworthy is the fact that in most studies the effect of oxidative stress could successfully be reversed by various types of antioxidants 141, 142, suggesting a possible mechanistic role for oxidative stress in the pathophysiology of muscle dysfunction 104.

ROS can affect skeletal muscle functions in various ways, for example by generating a blunted calcium­release from the sarcoplasmatic reticulum 143, by reducing the calcium sensitivity in skeletal muscles 138 or by causing enzymatic dysfunction within the glycolytic pathway, the citric acid cycle and the electron transport system leading to impairment of the cellular energetics 144, 145. Taken together, it can be suggested that increased oxidative stress may impair the excitation­contraction coupling as well as the redox status, thereby accounting for at least a part of the skeletal muscle dysfunction seen in COPD 104.

Inflammation
Oxidative stress and inflammation are associated. There is evidence for the influence of oxidants on inflammation 3, 146 as well as for the role of inflammation in the induction of oxidative stress 147, 148.

On the one hand, the lung inflammatory response is initiated and mediated by increased levels of ROS that can activate the transcription of pro­inflammatory cytokine and chemokine genes as well as of transcription factors like nuclear factor kappa B (NF-{kappa}B), upregulate adhesion molecules and increase the release of pro­inflammatory mediators 3, 146, 149–151.

On the other hand, several studies indicate that the inflammatory initiator and mediator tumour necrosis factor (TNF)-{alpha} is capable of stimulating oxidative stress in various cells and tissues 147, 148, 152. Transfected animals expressing the inflammatory mediator TNF-{alpha} have higher levels of LPO products together with a stimulated NOS expression in their skeletal muscles. This indicates the induction of an oxidative pathway in these TNF-{alpha} animals 106, 153–155.

In COPD patients, inflammation indeed contributes to the observed weight loss in both a direct way, through for example inflammatory mediators like TNF-{alpha} and cytokines, and a more indirect way, through catabolic intermediary metabolism 156, 157.

Both oxidative stress and NO• overproduction are directly capable of mediating muscle wasting and skeletal muscle abnormalities, like a disturbed muscle contraction due to a decreased affinity of junD for the myosine creatinine phosphokinase (MCK) enhancer 106. By binding to the MCK enhancer, junD stimulates MCK that is critical for differentiated skeletal muscle function since it delivers the energy required for muscle contraction by catalysing the adenosine triphosphate (ATP) formation from phosphocreatine 158.

Furthermore, increased circulating levels of TNF-{alpha} and interleukin-6 as well as of their soluble receptors in subjects with a normal body mass index are associated with skeletal muscle loss, indicating an overall inverse relationship between skeletal muscle mass and these cytokines 97. In differentiated myotubes, total protein content as well as adult myosin heavy chain content reduce in a time­ and concentration­dependent manner after treatment with TNF-{alpha} 159. Furthermore, TNF-{alpha} animals show a myosin depletion and a disrupted organisation in the skeletal muscle fibrils that can be prevented through treatment with various antioxidants like {alpha}-tocopherol. These findings suggest that the TNF-{alpha} induced oxidative pathways and NOS stimulation contribute specifically to the development of muscle wasting 106.

Skeletal muscle loss in differentiated muscle cell lines can also be caused by TNF-{alpha} induced activation of NF-{kappa}B 159. Activated NF-{kappa}B can inhibit the differentiation of skeletal muscles through suppression of the messenger ribonucleic acid (mRNA), and therefore of the protein levels, of transcription factor MyoD at post­transcriptional level 160. Furthermore, TNF-{alpha} induced NF-{kappa}B activation may inhibit the myogenic differentiation since it interferes with the expression of muscle proteins and the muscle creatine kinase activity in differentiating myoblasts 93, 161.

The influence of the more indirect catabolic intermediary metabolism can be seen in the increased nitrogen excretion, the excessive loss of nitrogen for FFM and the relationship between both a reduced FFM and a reduced skeletal muscle mass and the calculated protein catabolic rate 97. Increased levels of circulating cytokines can contribute to this protein catabolic state.

As shown in several experimental animal and in vitro studies, both components of the energy balance, i.e. dietary intake and energy or substrate metabolism, can be influenced by inflammation 118. Skeletal muscle proteins can become mobilised during inflammation in order to deliver the increased amount of amino acids necessary for acute phase protein synthesis. Increased levels of acute phase proteins in COPD patients are indeed correlated with an enhanced resting metabolic rate and FFM loss 157.


   Carcinogenesis and chronic obstructive pulmonary disease
TOP
 ABSTRACT
 Indicators of oxidative stress...
 Antioxidant capacity in chronic...
 Body composition and chronic...
 Carcinogenesis and chronic...
Conclusion
 REFERENCES
 
Since both lung cancer and pulmonary impairment are linked to tobacco smoke, it can be expected that these diseases frequently occur together 162, 163. Forty­nine per cent of lung cancer patients have COPD and as many as 12% of COPD patients between the age of 65–69 yrs die as a consequence of lung cancer 164, 165. Most studies have found that, even after standardisation for the smoking habits, impaired pulmonary function increases the risk for lung cancer 166–169. However, the strength of this relationship differs among the various studies from very weak 170 to quite strong 168. When the relationship of pulmonary impairment with lung cancer is investigated by its histological type or tumour location, it displays a somewhat stronger association with squamous­ or small­cell carcinoma than with adenocarcinoma 162, 171.

Furthermore, COPD is not only a risk factor for lung cancer, but also for death from lung cancer and death from any cause after matching for smoking habits 172. However, a direct link between COPD and other primary forms of cancer has not been established 173.

The predisposition of COPD to lung cancer may occur by several mechanisms including impaired mucociliary clearance, genetic predisposition and oxidative stress­mediated processes like inflammation and stimulation of the carcinogenesis process 149, 167, 174, 175.

Mucociliary clearance
The predisposition of COPD to lung cancer may partly result from the impaired mucociliary clearance in smokers and even more in COPD patients 172, 176, 177. In the more central airways, i.e. the sites where smoking­related cancers occur, microparticles are deposited. During the clearing process, the particles tend to assemble in areas that display the most impaired mucociliary clearance. These areas will, as a result of the pooling, be exposed longer to carcinogens from the smoke 178.

Genetic predisposition
A common denominator of the effects mediated by tobacco smoke could be pulmonary dysfunction, since preservation of other organs depends on a normal pulmonary function. Furthermore, ventilatory impairment is associated with mortality from COPD, ischaemic heart disease and overall mortality 179–186. Impaired ventilatory function is more present in first­degree relatives of lung cancer patients and COPD patients than in control subjects or relatives of nonpulmonary patients 174, 187. Since this difference could not be ascribed to the tested genetic markers or to the adjustment factors like age, sex, alcohol and smoking, it is suggested that COPD and lung cancer share a common familial pathogenetic factor associated with ventilatory impairment 174, 187.

Oxidative stress­mediated carcinogenesis
As shown in figure 3Go, oxidative stress may be implicated in carcinogenesis via several pathways like inflammation and disruption of genomic integrity.


Figure 3
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  		Oxidative­stress mediated effects on carcinogenesis in chronic obstructive pulmonary disease. DNA: deoxyribonucleic acid; PAH: polycyclic aromatic hydrocarbons.

 
Inflammation
The risk for cancer in several organs like lungs, pancreas, esophagus and skin is increased in chronic inflammatory disorders 188. Several epidemiological studies show that asthma, a disease characterised by persistent lung inflammation, elevates the risk of lung cancer 189–192. In vitro, leucocytes can induce sister chromatid exchanges in hamster ovary cells 193. Athymic mice injected with fibroblasts that were exposed to activated neutrophils, developed both benign and malign tumours whereas injection of control cells did not mediate tumour development 194. Neutrophils can also induce deoxyribonucleic acid (DNA) base damage in naked DNA 195, 196 as well as in target cellular DNA 197. Furthermore both neutrophils and macrophages are able to induce target cellular DNA strand breakage 198, 199.

The influence of inflammation on cancer may be mediated by inflammatory cell­derived ROS and RNS. Granulocytes and lymphocytes can generate at least four types of genotoxic or mutagenic products, namely H2O2, nitric oxide, malondialdehyde and 4-hydroxy-2,3-nonenal 155, 200–215. H2O2 can function as a progenitor of ROS like the highly reactive hydroxyl radical 196, 197, 216. The fact that the induction of ex vivo mutagenesis by alveolar macrophages is significantly lower than by neutrophils could be explained by the fact that neutrophils have a higher potential to increase the ROS-generation after activation than macrophages 217–219.

Since lung inflammatory response can also be initiated and mediated by increased levels of ROS, it can be expected that in COPD patients the inflammation­induced risk of lung cancer will be further elevated.

Stimulation of cancer development
ROS can cause disruption of genomic integrity, a process required for neoplastic progression, in both a direct and an indirect way 220. Directly they can introduce oncogenic mutations by causing DNA strand breaks or DNA adducts, whereas indirectly they may suppress genomic repair processes by modulating gene transcription and nuclear transcription factor activities 175, 220–225. LPO-products like malondialdehyde and 4-hydroxy-2,3-nonenal can also directly react with DNA bases, forming exocyclic DNA adducts like propano­ and etheno({epsilon})­ DNA adducts 175. Moreover, ROS can contribute to the formation of DNA adducts by activating polycyclic aromatic hydrocarbons (PAH's) to a DNA binding metabolite 226, 227. The mainly tobacco­derived PAH benzo­a­pyrene (B43P) for example can be activated through a one­electron oxidation 228. The generated B[a]P.+­radical cation predominantly forms labile guanine or adenine DNA adducts, but can also induce some stable DNA adducts 229, 230. Furthermore, the cation can also function as an intermediate metabolite which upon auto­oxidation ultimately results in the formation of reactive quinones 231.

Finally, ROS can also contribute to carcinogenesis by modifying intracellular proteins, inducing mitogen­activated protein kinases and increasing mitosis 220, 232, 233. However, ROS are also capable of inducing permanent growth arrest and activating several caspases as well as the release of cytochrome c in order to induce cell death by apoptosis 232–234.


   Conclusion
TOP
 ABSTRACT
 Indicators of oxidative stress...
 Antioxidant capacity in chronic...
 Body composition and chronic...
 Carcinogenesis and chronic...
 Conclusion
REFERENCES
 
It is evident that local (pulmonary) and systemic aberrant metabolism of oxidants occur in COPD patients. The resulting chronic metabolic stress may have far­reaching consequences ranging from exacerbations to muscle wasting and carcinogenesis. Therapeutic intervention should therefore include three approaches: 1) prevention of oxidant formation, 2) inhibition of oxidant effects and 3) repair of oxidant­mediated damage.

Adequate anti­inflammatory pharmacotherapy may prevent the formation of oxidant generation. Optimal treatment to diminish the neutrophilic inflammation in COPD has not yet been achieved with either classical or new drugs such as corticosteroids, chemokine inhibitors, leukotriene B4 inhibitors, adhesion molecule inhibitors, phosphodiesterase inhibitors or neutrophil function blockers 235.

Attempts to attenuate other possible pathways for ROS generation have only been explored in a limited way. An interesting recent finding is the inhibition of ROS-generating enzyme xanthine oxidase by allopurinol in COPD 15.

Antioxidants might be used to combat the oxidant effects. The antioxidant N-acetylcysteine has been shown to reduce acute exacerbations in COPD 236. Intervention studies with other antioxidants have not been performed. It is now known that enzymatic and nonenzymatic antioxidants form an intricate network that functions as a shield against ROS 237. Knowledge on the functioning of this network is slowly emerging. It appears that the network differs between various tissues. This becomes clear when the composition of two extracellular fluids, i.e. the pulmonary epithelial lining fluid and blood plasma, are compared 238. Rational supplementation in this antioxidant network is only possible when the changes that occur as a result of COPD are known. Until now only general dietary intake of antioxidants has been associated with improvement of lung function. It might be anticipated that a more specific supplementation may result in better results.

Finally, it might be speculated that enhancement of repair of pulmonary or systemic oxidative damage may lead to new therapeutic avenues. An example of this approach is the stimulated repair of the oxidised {alpha}1-antiprotease. It has been shown that it is possible to reduce oxidised methionine in oxidatively damaged {alpha}1-antiprotease thus restoring its activity 239.

The chronic and systemic oxidant burden in chronic obstructive pulmonary disease warrants a continuous elevated antioxidant level to circumvent oxidative damage. The diet forms the major source of antioxidants in the body. The joint activity of the antioxidant ingredients in the diet is probably superior to the classical pharmacotherapeutic antioxidant action of individual compounds, which act in isolation. Moreover, the chronic and systemic character of chronic obstructive pulmonary disease asks for a nutritional rather than a pharmacological intervention. Optimising the antioxidant content of the diet might therefore be utilised to avert or treat chronic metabolic stress in chronic obstructive pulmonary disease.


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 Indicators of oxidative stress...
 Antioxidant capacity in chronic...
 Body composition and chronic...
 Carcinogenesis and chronic...
 Conclusion
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