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Pulmonary and Systemic Oxidant/Antioxidant Imbalance in Chronic Obstructive Pulmonary Disease

ELEGI, Colt Research Laboratories, MRC Centre for Inflammation Research, Medical School, University of Edinburgh, Edinburgh, Scotland, United Kingdom

Correspondence and requests for reprints should be addressed to W. MacNee, M.B. Ch.B., M.D., ELEGI, Colt Research Laboratories, Wilkie Building, Medical School, Teviot Place, Edinburgh EH8 9AG, Scotland, UK. E-mail: w.macnee{at}ed.ac.uk

	ABSTRACT

TOP ABSTRACT HOW IS OXIDATIVE STRESS... EVIDENCE OF LOCAL OXIDATIVE... ANTIOXIDANTS AND COPD IS OXIDATIVE STRESS IMPORTANT... OXIDATIVE STRESS AND... OXIDANTS AND MUCUS... OXIDATIVE STRESS AND AIRSPACE... OXIDATIVE STRESS AND NEUTROPHIL... OXIDATIVE STRESS AND LUNG... SYSTEMIC OXIDATIVE STRESS REFERENCES

 
An imbalance between oxidants and antioxidants is considered to play a role in the pathogenesis of chronic obstructive pulmonary disease (COPD). There is considerable evidence that an increased oxidative burden occurs in the lungs of patients with this disorder, and this may be involved in many of the pathogenic processes, such as direct injury to lung cells, mucus hypersecretion, inactivation of antiproteases, and enhancing lung inflammation through activation of redox-sensitive transcription factors. COPD is now recognized to have multiple systemic consequences, such as weight loss and skeletal muscle dysfunction. Moreover, it is appreciated that oxidative stress extends beyond the lung and may, through similar oxidative stress mechanisms as those in the lung, contribute to several of the systemic manifestations in COPD.

Key Words: chronic obstructive pulmonary disease • oxidant/antioxidant imbalance • oxidative stress • smoking • systemic inflammation

The lungs are exposed continuously to oxidants generated either endogenously from phagocytes and other cell types or exogenously from air pollutants or cigarette smoke. In addition, intracellular oxidants, such as those derived from mitochondrial electron transport, are involved in many cellular signaling pathways. Lung cells are protected against this oxidative challenge by well-developed enzymatic and nonenzymatic antioxidant systems (1). When the balance between oxidants and antioxidants shifts in favor of the former, from either an excess of oxidants and/or depletion of antioxidants, oxidative stress occurs. Oxidative stress produces not only direct injurious effects in the lungs but also activates molecular mechanisms that initiate lung inflammation (2).

Smoking is the main etiologic factor in chronic obstructive pulmonary disease (COPD). Cigarette smoke contains around 10¹⁷ oxidant molecules per puff, and this, together with a large body of evidence demonstrating increased oxidative stress in smokers with and without COPD, has led to the proposed role of oxidant/antioxidant imbalance in the pathogenesis of this condition (3). Increasingly, COPD is recognized to affect not only the lungs but also to have significant systemic consequences, such as muscle dysfunction and weight loss (4). Oxidative stress is also believed to play an important role in the systemic manifestations of COPD (5).

	HOW IS OXIDATIVE STRESS MEASURED?

TOP ABSTRACT HOW IS OXIDATIVE STRESS... EVIDENCE OF LOCAL OXIDATIVE... ANTIOXIDANTS AND COPD IS OXIDATIVE STRESS IMPORTANT... OXIDATIVE STRESS AND... OXIDANTS AND MUCUS... OXIDATIVE STRESS AND AIRSPACE... OXIDATIVE STRESS AND NEUTROPHIL... OXIDATIVE STRESS AND LUNG... SYSTEMIC OXIDATIVE STRESS REFERENCES

 
Oxidative stress can be measured in several different ways, either by direct measurements of the oxidative burden, as the responses to oxidative stress, or by the effects of oxidative stress on target molecules (Table 1). Direct measurements of the oxidative burden in airspaces can be derived from measurement of hydrogen peroxide (H₂O₂) in bronchoalveolar lavage (BAL) fluid or in exhaled breath condensate. Airspace leukocytes derived from BAL can also be assessed ex vivo for their ability to produce reactive oxygen species (ROS). Nitric oxide (NO) is produced in the lungs by the catalytic activity of NO synthase (NOS), which exists in both constitutive isoforms (cNOS) and an inducible isoform (iNOS) (6). The latter is induced by inflammatory stimuli, and NO in exhaled breath is considered a marker of inflammation and indirectly as a marker of oxidative stress.

Oxidized proteins can be measured as protein carbonyls, nitrotyrosine, or oxidative damage to DNA producing 8-hydroxydeoxyguanine. The reaction of NO and superoxide anion produces peroxynitrite (Figure 1), which can then cause the nitration of tyrosine to produce nitrotyrosine, a marker of peroxynitrite that can be measured in blood, breath condensate, BAL, and lung tissue as an indicator of free-radical protein damage (11). NO may form stable nitrosothiols with low-molecular-weight thiols, such as glutathione, to enhance its bioactivity (12). Nitrite is a further end-product of NO.

View larger version (17K): [in this window] [in a new window]   Figure 1. Nitric oxide (NO) and NO-related products. FAD = flavin adenine dinucleotide; FMN = flavin mononucleotide; NADP = nicotinamide adenine dinucleotide phosphate; NADPH = reduced form of NADP; S-GSNO = S-nitrosoglutathione. Adapted from Reference 6.

	EVIDENCE OF LOCAL OXIDATIVE STRESS IN THE LUNGS

TOP ABSTRACT HOW IS OXIDATIVE STRESS... EVIDENCE OF LOCAL OXIDATIVE... ANTIOXIDANTS AND COPD IS OXIDATIVE STRESS IMPORTANT... OXIDATIVE STRESS AND... OXIDANTS AND MUCUS... OXIDATIVE STRESS AND AIRSPACE... OXIDATIVE STRESS AND NEUTROPHIL... OXIDATIVE STRESS AND LUNG... SYSTEMIC OXIDATIVE STRESS REFERENCES

 
Numerous studies have shown that oxidative stress is increased in the lungs of patients with COPD compared with healthy subjects, but also compared with smokers with similar smoking history but who have not developed airways obstruction (3). Smokers and patients with COPD have higher levels of H₂O₂ in exhaled breath condensate, a direct measurement of airspace oxidative burden, than ex-smokers with COPD or nonsmokers (14, 15). H₂O₂ levels are even higher during exacerbations of COPD (Figure 2) (14). The elevated level of H₂O₂ in the exhaled breath of smokers is believed to derive partly from increased release of superoxide anion (O₂^–) by alveolar macrophages (16, 17).

View larger version (13K): [in this window] [in a new window]   Figure 2. Individual data for hydrogen peroxide (H2O2) concentrations in breath condensate in control subjects and in patients with stable and unstable chronic obstructive pulmonary disease (COPD). Modified from Reference 14 by permission.

NO has been used as a marker of airway inflammation and indirectly as a measure of oxidative stress. Increased NO levels in exhaled breath occurs in some studies of COPD but are not as high as the NO levels reported in asthma (21–23). Other studies have found either normal or even lower exhaled NO in patients with stable COPD, compared with normal subjects (24, 25).

The rapid reaction of NO with O₂^–, as described previously, or with thiols may alter breath NO levels. Nitrosothiol levels have been shown to be higher in breath condensate in smokers and patients with COPD compared with subjects who do not smoke (Figure 3) (6). Smoking increases directly exhaled NO levels, which limits the usefulness of this marker in COPD. Peroxynitrite, formed by the reaction of NO with superoxide anion, can cause nitrosylation of tyrosine to produce nitrotyrosine (11). Nitrotyrosine levels are elevated in sputum leukocytes of patients with COPD (Figure 3) and are correlated negatively with the FEV₁ (26).

View larger version (16K): [in this window] [in a new window]   Figure 3. Left: nitrosothiols, breath condensate in smokers and patients with COPD. Right: increased inducible NO (iNOS) and nitrotyrosine immunoreactivity in sputum leukocytes in COPD. *p < 0.05. Modified by permission from Reference 26.

View larger version (13K): [in this window] [in a new window]   Figure 4. Hemeoxygenase system-synthesis of carbon monoxide (CO).

View larger version (15K): [in this window] [in a new window]   Figure 5. Exhaled CO in patients with COPD with and without corticosteroid therapy. ns = not significant. Modified by permission from Reference 27.

2

View larger version (15K): [in this window] [in a new window]   Figure 6. Isoprostane levels in exhaled breath condensate (EBC) in smokers with COPD (left). Significant correlation between 8-isoprostane levels in EBC and percentage of neutrophils in induced sputum (right). Adapted from Reference 32.

There is increasing evidence that these markers of oxidative stress are also reflected in lung tissue in patients with COPD. Increased nitrotyrosine immunoreactivity has been shown in sputum leukocytes and lung tissue in patients with COPD compared with healthy subjects (26). The lipid peroxidation product 4-HNE reacts quickly with cellular proteins to form adducts. These adducts have been shown to be present in greater quantities in airway epithelial and endothelial cells in the lungs of patients with COPD, compared with smokers with a similar smoking history who have not developed the disease (Figure 7) (36). Lipid peroxidation products, such as 8-isoprostane, can act as signaling molecules and cause release of inflammatory mediators, such as interleukin 8 (IL-8) from lung cells (37). 4-HNE can cause the upregulation of transforming growth factor ß (TGF-ß) (38) and oxidant enzyme gene expression (39).

View larger version (36K): [in this window] [in a new window]   Figure 7. Immunostaining for lipid peroxidation product 4-hydroxy-2-nonenal (4-HNE) adduct in the lungs of smokers with and without COPD. (A) Immunohistochemistry showing increased staining in both bronchial and alveolar epithelium in patients with COPD who have the same smoking history as a group of smokers without COPD. (B) Staining score showing increased staining in COPD. (C) Correlation between 4-HNE staining score in the lungs and percent predicted FEV1. Modified by permission from Reference 36.

	ANTIOXIDANTS AND COPD

TOP ABSTRACT HOW IS OXIDATIVE STRESS... EVIDENCE OF LOCAL OXIDATIVE... ANTIOXIDANTS AND COPD IS OXIDATIVE STRESS IMPORTANT... OXIDATIVE STRESS AND... OXIDANTS AND MUCUS... OXIDATIVE STRESS AND AIRSPACE... OXIDATIVE STRESS AND NEUTROPHIL... OXIDATIVE STRESS AND LUNG... SYSTEMIC OXIDATIVE STRESS REFERENCES

 
Several studies have investigated a relationship between antioxidants, pulmonary function, and the development of COPD (40, 41). The National Health and Nutrition Examination Survey (NHANES) and the Dutch Monitoring Project for the Risk Factors for Chronic Diseases (MORGEN) suggested relationships between dietary intake and airflow limitation. In NHANES I, lower dietary vitamin C related directly to lower FEV₁ levels in a population survey study and, in addition, the protective effect of vitamin C was even greater in subjects with bronchitis (40). Data from NHANES II showed an inverse relationship between both dietary and serum vitamin C and chronic respiratory symptoms (41). Moreover, in NHANES III, the levels of dietary vitamin C, vitamin E, selenium, and beta-carotene were positively associated with lung function (42). Analysis of the data obtained in the MORGEN study also shows higher intake of vitamin C and beta-carotene is associated with a higher level FEV₁, compared with a low intake of these antioxidants (43). The association between dietary vitamin E intake and lung function is less consistent (43–45). Several studies, including the MORGEN study, have shown associations between fruit intake and higher FEV₁ and lower symptoms in patients with COPD (46–49). Data from the MORGEN study have also shown the beneficial effects of flavonoids on FEV₁ (50).

	IS OXIDATIVE STRESS IMPORTANT IN THE PATHOGENESIS OF COPD?

TOP ABSTRACT HOW IS OXIDATIVE STRESS... EVIDENCE OF LOCAL OXIDATIVE... ANTIOXIDANTS AND COPD IS OXIDATIVE STRESS IMPORTANT... OXIDATIVE STRESS AND... OXIDANTS AND MUCUS... OXIDATIVE STRESS AND AIRSPACE... OXIDATIVE STRESS AND NEUTROPHIL... OXIDATIVE STRESS AND LUNG... SYSTEMIC OXIDATIVE STRESS REFERENCES

 
Biomarkers of oxidative stress have been related to the development of airflow limitation, and many studies have shown higher oxidant levels in patients with COPD, compared with healthy smokers. Furthermore, several studies show relationships between oxidative stress markers and the degree of airflow limitation in COPD (3, 5, 51). However, the presence of oxidative stress and its relationship to airflow limitation may be epiphenomena, because it occurs in inflammation, a characteristic feature of COPD (10). There are as yet no longitudinal studies showing that the presence of enhanced oxidative stress relates to the decline in FEV₁ or to the progression of the disease.

	OXIDATIVE STRESS AND PROTEASE/ANTIPROTEASE IMBALANCE

TOP ABSTRACT HOW IS OXIDATIVE STRESS... EVIDENCE OF LOCAL OXIDATIVE... ANTIOXIDANTS AND COPD IS OXIDATIVE STRESS IMPORTANT... OXIDATIVE STRESS AND... OXIDANTS AND MUCUS... OXIDATIVE STRESS AND AIRSPACE... OXIDATIVE STRESS AND NEUTROPHIL... OXIDATIVE STRESS AND LUNG... SYSTEMIC OXIDATIVE STRESS REFERENCES

 
An increased protease burden in the lungs occurs as a result of the influx and activation of inflammatory leukocytes. It has been proposed that a relative "deficiency" of antiproteases, such as ₁-antitrypsin, because of their inactivation by oxidants, creates a protease/antiprotease imbalance in the lungs. This forms the basis of the protease/antiprotease theory of the pathogenesis of emphysema (52, 53). Inactivation of ₁-antitrypsin occurs by oxidation of a critical methionine residue at its active site by oxidants from cigarette smoke or released from inflammatory leukocytes, resulting in a dramatic reduction in its inhibitory capacity in vitro (54, 55). The acute effects of cigarette smoke on functional activity of ₁-antitrypsin have been studied in vivo, and show a transient, but nonsignificant, fall in the antiprotease activity of BAL fluid 1 hour after smoking (56). However, a protease/antiprotease imbalance involving ₁-antitrypsin and neutrophil elastase is likely an oversimplification, because other proteases and other antiproteases are likely to have a role in the pathogenesis of COPD.

	OXIDANTS AND MUCUS HYPERSECRETION

TOP ABSTRACT HOW IS OXIDATIVE STRESS... EVIDENCE OF LOCAL OXIDATIVE... ANTIOXIDANTS AND COPD IS OXIDATIVE STRESS IMPORTANT... OXIDATIVE STRESS AND... OXIDANTS AND MUCUS... OXIDATIVE STRESS AND AIRSPACE... OXIDATIVE STRESS AND NEUTROPHIL... OXIDATIVE STRESS AND LUNG... SYSTEMIC OXIDATIVE STRESS REFERENCES

 
Oxidant-generating systems, such as xanthine/xanthine oxidase, can cause airway epithelial mucus secretion (57). Oxidants are also involved in the signaling pathways for epidermal growth factor, which has an important role in mucus production (58). H₂O₂ or HOCl, in relatively low concentrations (100 µM), causes significant impairment of ciliary beating and even complete stasis (59). Oxidant-mediated hypersecretion and impaired mucociliary clearance may result in airway mucus accumulation contributing to airflow limitation (60).

	OXIDATIVE STRESS AND AIRSPACE EPITHELIAL INJURY

TOP ABSTRACT HOW IS OXIDATIVE STRESS... EVIDENCE OF LOCAL OXIDATIVE... ANTIOXIDANTS AND COPD IS OXIDATIVE STRESS IMPORTANT... OXIDATIVE STRESS AND... OXIDANTS AND MUCUS... OXIDATIVE STRESS AND AIRSPACE... OXIDATIVE STRESS AND NEUTROPHIL... OXIDATIVE STRESS AND LUNG... SYSTEMIC OXIDATIVE STRESS REFERENCES

 
Because of their direct contact with the environment, the lung epithelial surfaces are especially vulnerable to the effects of oxidative stress. Injury to the airway epithelium is an important early event after exposure to cigarette smoke as shown by an increase in airspace epithelial permeability. This increased permeability can be shown to result from cigarette smoke exposure both in vitro and in vivo (61–63) and is partially reversible by antioxidants. Extra- and intracellular glutathione appears to be critical to the maintenance of epithelial integrity after exposure to smoke. This has been shown in studies of the permeability of epithelial cell monolayers in vitro and in animal models in vivo after exposure to cigarette smoke condensate, which is associated with profound changes in the homeostasis of the antioxidant glutathione (63–66). Depletion of lung glutathione alone can induce increased airspace epithelial permeability (63, 66). Interindividual variability in antioxidant defenses may be one factor in determining whether COPD develops after cigarette smoking.

	OXIDATIVE STRESS AND NEUTROPHIL INFLUX IN THE LUNGS

TOP ABSTRACT HOW IS OXIDATIVE STRESS... EVIDENCE OF LOCAL OXIDATIVE... ANTIOXIDANTS AND COPD IS OXIDATIVE STRESS IMPORTANT... OXIDATIVE STRESS AND... OXIDANTS AND MUCUS... OXIDATIVE STRESS AND AIRSPACE... OXIDATIVE STRESS AND NEUTROPHIL... OXIDATIVE STRESS AND LUNG... SYSTEMIC OXIDATIVE STRESS REFERENCES

 
The lungs contain a large pool of noncirculating (marginated) neutrophils, which either are retained or move only slowly within the pulmonary microcirculation (67). This is because of the smaller average diameter of the neutrophil ( 7 µm) compared with the pulmonary capillary diameter ( 5 µm), and results in a proportion of the circulating neutrophils having to deform and thus move slowly to negotiate the small capillaries. In normal subjects, there is a correlation between neutrophil deformability, measured in vitro, and their subsequent sequestration in the pulmonary microcirculation after reinjection—the less deformable the cells, the greater their sequestration (68). This mechanism of neutrophil sequestration in the pulmonary bed allows time to interact and adhere to capillary endothelium before their subsequent migration across the alveolar–capillary membrane to the interstitial airspaces. During smoking, there is a transient increase in neutrophil sequestration in the lungs (69) because of a decrease in circulating neutrophil deformability (67, 70). Studies in vitro show that the decreased neutrophil deformability induced by cigarette smoke is abolished by antioxidants (71). Oxidative stress occurs systemically during smoking as shown by a profound decrease in the antioxidant capacity of plasma (Figure 8), which may reduce neutrophil deformability because of actin polymerization (71). These may be the initial events that cause the influx of neutrophils into the lungs of cigarette smokers, and variability in this effect (69, 70) may be one reason why not all smokers develop enhanced lung inflammation and therefore COPD. It is possible that activation of neutrophils sequestered in the pulmonary microvasculature could also induce the release of ROS and proteases within a microenvironment, which limits access for free-radical scavengers and antiproteases. Thus, destruction of the alveolar wall, as occurs in emphysema, could result from a proteolytic/oxidant insult derived from the intravascular space without the need for the neutrophils to migrate into the airspaces.

View larger version (17K): [in this window] [in a new window]   Figure 8. Oxidative stress in exacerbations of COPD. Superoxide anion release from peripheral blood neutrophils (PMN; spontaneous and phorbol myristate acetate [PMA] activated) in normal subjects and in patients with acute and stable COPD (left). Plasma antioxidant capacity (Trolox equivalent antioxidant capacity [TEAC]) in normal subjects, and in those with stable and exacerbated COPD (right). ROS = reactive oxygen species. *p < 0.05; **p < 0.01. Adapted from Reference 108.

	OXIDATIVE STRESS AND LUNG INFLAMMATION

TOP ABSTRACT HOW IS OXIDATIVE STRESS... EVIDENCE OF LOCAL OXIDATIVE... ANTIOXIDANTS AND COPD IS OXIDATIVE STRESS IMPORTANT... OXIDATIVE STRESS AND... OXIDANTS AND MUCUS... OXIDATIVE STRESS AND AIRSPACE... OXIDATIVE STRESS AND NEUTROPHIL... OXIDATIVE STRESS AND LUNG... SYSTEMIC OXIDATIVE STRESS REFERENCES

Oxidative stress may have a fundamental role enhancing inflammation through the upregulation of redox-sensitive transcription factors, such as nuclear factor B (NF-B) and activating protein 1 (AP-1), and also the extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase pathways. Cigarette smoke has been shown to activate all of these signaling mechanisms (2, 80–82). Genes for many inflammatory mediators are regulated by NF-B, which is present in the cytosol in an inactive form linked to its inhibitory protein IB. Many stimuli, including cytokines and oxidants, result in activation of IB kinase, resulting in phosphorylation of IB, cleaving of IB from NF-B, and the destruction of IB in the proteasome. This critical event in the inflammatory response is redox-sensitive (83, 84). Studies in macrophage cell lines and alveolar and bronchial epithelial cells show that oxidants cause the release of inflammatory mediators, such as IL-8, IL-1, and NO, and that these events are associated with increased expression of the genes for these inflammatory mediators and increased nuclear binding or activation of NF-B (85, 86). The linking of NF-B to its consensus site in the nucleus leads to enhanced transcription of proinflammatory genes and therefore inflammation, which itself will produce more oxidative stress, creating a vicious circle of enhanced inflammation resulting from the increased oxidative stress (Figure 9). Animal models of smoke exposure show that neutrophil influx in the lungs is associated with increased IL-8 gene expression and protein release and with NF-B activation (87). All of these events are associated with oxidative stress because they can be abrogated by antioxidant therapy (Figure 10). NF-B can be activated and translocated to the nucleus in lung tissue in smokers and in patients with COPD compared with healthy subjects (88). NF-B activation in lung tissue has been shown to correlate with the FEV₁ (89).

View larger version (23K): [in this window] [in a new window]   Figure 9. Activation of signal pathways by oxidative stress. AP-1 = activating protein 1; ERK = extracellular signal-related kinase; ikK = inhibitor kB kinase; JNK = c-Jun N-terminal kinase; NF-B = nuclear factor B; P = phosphate.

View larger version (24K): [in this window] [in a new window]   Figure 10. Effect of recombinant superoxide dismutase (rhSOD) on cigarette smoke (CS-)–induced neutrophil influx, interleukin (IL-)-8 gene expression, and NF-B nuclear binding in guinea pig lungs. *p < 0.05; **p < 0.01. Modified by permission from Reference 86.

View larger version (33K): [in this window] [in a new window]   Figure 11. Model of histone acetylation/deacetylation. HAT = histone acetyltransferase.

View larger version (40K): [in this window] [in a new window]   Figure 12. Histone deacetylase (HDAC) activity (left) and immunoreactivity (right) in alveolar macrophages from smokers and nonsmokers. Modified by permission from Reference 90.

Recent evidence suggests that latent adenoviral infection may be associated with the pathogenesis of COPD by enhancing lung inflammation (95). E1A protein derived from latent adenoviral infection interacts with transcription factor cofactors and enhances nuclear binding of transcription factors (95). E1A has been noted to be more prevalent in the lungs of smokers who develop COPD than in smokers who do not develop the disease (96). Cells transfected with the E1A protein have also been shown to have increased IL-8 release in response to oxidants, such as H₂O₂, and enhanced NF-B activation (97). Latent adenoviral infection may, therefore, render lung cells more susceptible to oxidative stress, thus enhancing the release of proinflammatory mediators. The presence of E1A also enhances smoke-induced inflammation and emphysema in animal models (98).

The pathogenesis of emphysema has been proposed recently to result from loss of alveolar endothelial cells via apoptosis, and this may be as an initial event in the development of emphysema (99). Apoptosis occurs to a greater extent in emphysematous lungs than in lungs of nonsmokers (100). The process of endothelial apoptosis is believed to be under the influence of vascular endothelial growth factor (VEGF) R2 receptors. Downregulation of VEGF-R2 has been shown in animals to produce emphysema (100), and reduced expression of VEGF-R2 is evident in emphysematous human lungs (100). Studies have also shown that the "apoptosis/emphysema" produced by VEGF inhibition in animal models is associated with increased markers of oxidative stress and prevented by antioxidants (101).

Ablation in mice of nuclear factor, erythroid-derived 2, like 2 (Nrf2), a redox-sensitive transcription factor that is involved in the regulation of many antioxidant genes results in more extensive cigarette smoke–induced emphysema than occurs in wild-type mice (102), and this was associated with increased markers of oxidative stress and increased apoptosis in the lungs, suggesting a role for the Nrf2 pathway in determining the susceptibility to tobacco smoke–induced emphysema through a mechanism involving upregulation of antioxidant defenses.

Other events involving oxidative stress and epithelial cells may be relevant to the development of COPD. For example, TGF-ß₁ expression is increased in small airway epithelial cells of smokers compared with nonsmokers and increased even more in patients with COPD (101, 102). TGF-ß mRNA levels correlated positively with smoking history and the degree of airway obstruction (103, 104).

Furthermore, TGF-ß₁ itself may increase oxidative stress because this substance produces profound changes in endothelial and epithelial cell glutathione (105, 106) by a mechanism involving the downregulation of -glutamylcysteine synthetase (GCS) RNA in alveolar epithelial cells (39, 106). In addition, oxidative stress has been shown to activate TGF-ß.

Studies in vitro show that the lipid peroxidation product 4-HNE is present in increased amounts in lung tissue in patients with COPD (36). 4-HNE increases TGF-ß expression by a mechanism dependent on the activation of macrophage AP-1 (38). Furthermore, 4-HNE induces GCS in alveolar epithelial cells (39), and increased GCS expression has been demonstrated in the lungs of patients with COPD (107). Thus, it has been suggested that 4-HNE can act as a second messenger in the regulation of protective antioxidant genes, such as GCS, and a variety of other genes, such as TGF-ß (107).

Thus, as a response to oxidative stress induced by cigarette smoke, there appears to be upregulation of protective antioxidant genes. Glutathione is concentrated in epithelial lining fluid compared with plasma (108). Human studies have shown that glutathione is elevated in the epithelial lining fluid in chronic cigarette smokers compared with nonsmokers, an increase that does not occur during acute cigarette smoking (61). The effects of chronic cigarette smoking can be mimicked by exposure of airspace epithelial cells to cigarette smoke condensate in vitro. This produces an initial decrease in intracellular glutathione (GSH) with a rebound increase after 24 hours (64, 109). This effect is mimicked by a similar change in glutathione in rat lungs in vivo after exposure to cigarette smoke (109), associated with an increase in the oxidized form of glutathione (GSSG). The increase in glutathione after cigarette smoke exposure is caused by transcriptional upregulation of GCS mRNA, the rate-limiting enzyme in GSH synthesis (109). The mechanism of the upregulation of GCS mRNA is by the activation by cigarette smoke of the redox-sensitive transcription factor AP-1 (108, 110). These events likely account for the increased glutathione levels seen in epithelial lining fluid in chronic cigarette smokers, a protective mechanism. The injurious effects of cigarette smoke may occur repeatedly during and immediately after cigarette smoking when the lung is depleted of antioxidants, including glutathione. TNF-, which is believed to have a role in the lung inflammation of COPD, also decreases intracellular glutathione levels initially in epithelial cells by a mechanism involving intracellular oxidative stress, which is followed 24 hours thereafter by a rebound increase in intracellular glutathione as a result of AP-1 activation and increased GCS expression (108). Animals exposed to whole cigarette smoke for up to 14 days also show increased expression of a number of antioxidant genes, including manganese superoxide dismutase, metallothionine, and glutathione peroxidase (111).

Sensitivity to oxidative stress may also be a cofactor in the development of a protease/antiprotease imbalance and consequent emphysema. Strains of mice that decreased their lung antioxidant defenses developed emphysema when exposed chronically to cigarette smoke, whereas emphysema did not develop in strains of mice that showed upregulation of antioxidants in response to smoke (112).

	SYSTEMIC OXIDATIVE STRESS

TOP ABSTRACT HOW IS OXIDATIVE STRESS... EVIDENCE OF LOCAL OXIDATIVE... ANTIOXIDANTS AND COPD IS OXIDATIVE STRESS IMPORTANT... OXIDATIVE STRESS AND... OXIDANTS AND MUCUS... OXIDATIVE STRESS AND AIRSPACE... OXIDATIVE STRESS AND NEUTROPHIL... OXIDATIVE STRESS AND LUNG... SYSTEMIC OXIDATIVE STRESS REFERENCES

 
An increased systemic oxidative burden has been shown to occur in smokers. In COPD, peripheral blood neutrophils have been shown to release more ROS than in normal subjects and this is enhanced still further in exacerbation, being associated with marked depletion of the plasma antioxidant capacity, indicating increased systemic oxidative stress (Figure 8) (113). Products of lipid peroxidation are also increased in plasma in smokers with COPD, particularly during exacerbations (113). Increased levels of nitrotyrosine have also been shown to occur in the plasma of patients with COPD (25).

Exacerbations of COPD result from increased levels of air pollutants, specifically particulate air pollution (see article in this issue by van Eeden and coworkers, pp. 61–67) (114). Particulate air pollution causes oxidative stress in the airways (115), and enhanced inflammation by mechanisms similar to those described previously, through oxidative stress–induced NF-B activation, decreased histone deacetylation, and increased histone acetylation (72, 86). Air pollution has also been associated with increased cardiovascular deaths. The mechanism of this effect may involve oxidative stress–induced changes in fibrinolytic balance, resulting in enhanced plasminogen activator inhibitor type 1 and decreased tissue-type plasminogen activator, both of which would reduce fibrinolysis of clots forming on ruptured atherosclerotic plaques and therefore lead to acute cardiac events, such as myocardial infarction and death (discussed in detail in the articles in this issue by MacCallum, pp. 34–43, and Tapson, pp. 71–77) (116). Furthermore, COPD is an independent risk factor for the development of ischemic heart disease and death from myocardial infarction, as reviewed by Sin and Man in this issue, pp. 8–11 (117).

It is now recognized that COPD is not only a disease that affects the lungs but has important systemic consequences, such as cachexia of skeletal muscle function (118). Increasing evidence suggests that similar mechanisms involving oxidative stress and inflammation in the lungs may also be responsible for many of the systemic effects of COPD (5, 118).

Patients with COPD often display weight loss, which is seen as an independent predictor of outcome (119, 120). Loss of fat-free mass also results in peripheral muscle dysfunction, decreased exercise capacity, and reduced health status (121–123). There are several factors that influence the loss of weight and fat-free mass in patients with COPD, including malnutrition, imbalance in overall protein turnover and hormones involved in this process, tissue hypoxia, and pulmonary inflammation (118, 122, 124, 125). The roles of body weight and fat-free mass in the pathogenesis and morbidity of COPD are reviewed by Wouters in this issue (pp. 26–33).

The cachexia and loss of fat-free mass that occur in COPD may involve oxidative stress. Skeletal muscle is exposed continuously to changes in the redox environment as occurs during exercise. There is increased ROS production by the mitochondrial respiratory chain after exercise in patients with COPD. It has been shown that lipid peroxidation products increase in serum during exercise accompanied by an increase in GSSG/GSH ratio (125–128). The increased oxidative stress was much greater than in healthy individuals. Thus, although redox homeostasis seems to be conserved in COPD, it requires only a little stress to disturb this balance. Skeletal muscle cells adapt to oxidative stress by upregulating antioxidant enzymes, such as manganese, copper, and zinc superoxide dismutase (SOD), catalase, and glutathione peroxidase (129). In patients with COPD submitted to a training protocol, GSSG/GSH ratios increased, whereas no such increase was seen in healthy individuals (130). This finding suggests that the adaptor response of skeletal muscle to oxidative stress may be impaired in COPD. There is also evidence of disturbed redox homeostasis in the phenotype of COPD associated with emphysema, in which glutathione levels in the vastus lateralis muscle were decreased. This was associated with reduced concentrations of glutamate, an important substrate in the synthesis of glutamine and glutathione (Figure 13) (131). This suggests that glutathione metabolism may be impaired in COPD, which is supported further by studies that demonstrate a decrease in glutathione peroxidase activity, elevated glutathione reductase activity, and increased lipid peroxidation indicative of oxidative damage in skeletal muscle of experimental emphysema in hamsters (132).

View larger version (16K): [in this window] [in a new window]   Figure 13. Altered glutamate metabolism associated with reduced muscle glutathione levels in patients with emphysema. **p < 0.01; ***p < 0.001. Adapted from Reference 125.

In conclusion, there is now considerable evidence of both local and systemic oxidative stress in patients with COPD. There is also increasing evidence that oxidative stress is involved in the pathogenesis of local lung inflammation as well as in systemic phenomena, such as skeletal muscle dysfunction, and perhaps even the increased cardiovascular risk of mortality that results from COPD.

	FOOTNOTES

 
Conflict of Interest Statement: W.M. has been reimbursed for travel by GlaxoSmithKline, Zambon, AstraZeneca, Boehringer Ingelheim, Pfizer, and Micromet for attending conferences and has received honoraria from GlaxoSmtihKline, AstraZeneca, Zambon, and Pfizer for participating as a speaker in scientific meetings, and serves on advisory boards for GlaxoSmithKline, Pfizer, Almirall, Amgen, Bayer, and Micromet, and serves as a consultant for Pfizer and SMB Pharmaceuticals, and research grants to support work carried out in his laboratory come from SMB, Pfizer, Ceremedix, GlaxoSmithKline, Chugi, and Novartis.

(Received in original form November 11, 2004; accepted in final form December 21, 2004)

	REFERENCES

TOP ABSTRACT HOW IS OXIDATIVE STRESS... EVIDENCE OF LOCAL OXIDATIVE... ANTIOXIDANTS AND COPD IS OXIDATIVE STRESS IMPORTANT... OXIDATIVE STRESS AND... OXIDANTS AND MUCUS... OXIDATIVE STRESS AND AIRSPACE... OXIDATIVE STRESS AND NEUTROPHIL... OXIDATIVE STRESS AND LUNG... SYSTEMIC OXIDATIVE STRESS REFERENCES

 

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