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Clinical Investigations: TECHNIQUES |

Exhaled Carbon Monoxide and Nitric Oxide in COPD* FREE TO VIEW

Paolo Montuschi, MD; Sergei A. Kharitonov, MD, PhD; Peter J. Barnes, DM
Author and Funding Information

*From the Department of Thoracic Medicine, Imperial College School of Medicine, National Heart and Lung Institute, London, UK.

Correspondence to: Paolo Montuschi, MD, Department of Pharmacology, Catholic University of the Sacred Heart, Largo F. Vito, 1, 00168 Roma, Italy; e-mail: p.montuschi@ic.ac.uk



Chest. 2001;120(2):496-501. doi:10.1378/chest.120.2.496
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Study objectives: To investigate whether exhaled carbon monoxide (CO) and nitric oxide (NO) could be used as noninvasive in vivo biomarkers of oxidative stress in the lungs of patients with COPD.

Design: Single-center cross-sectional study.

Patients: Ten healthy nonsmokers, 12 smokers, 15 stable ex-smokers with COPD, and 15 stable current smokers with COPD.

Interventions: Subjects attended the outpatient clinic on one occasion for pulmonary function tests and exhaled CO and NO measurements.

Measurements and results: Mean (± SEM) CO levels in ex-smokers with COPD were higher (7.4 ± 1.9 ppm; p < 0.05) than in nonsmoking control subjects (3.0 ± 0.3 ppm) but were lower than in current smokers with COPD (20.0 ± 2.6 ppm; p < 0.001). There was no correlation between exhaled CO and NO. There was no correlation between CO and lung function tests in any group of patients. Exhaled NO was higher in ex-smokers with COPD (12.0 ± 1.0 parts per billion [ppb]; p < 0.001) than in healthy nonsmokers (6.5 ± 0.6 ppb) and in current smokers with COPD (7.6 ± 1.1 ppb; p < 0.01) compared to healthy smokers (3.3 ± 0.4 ppb). Ex-smokers with COPD had higher exhaled NO levels than did current smokers with COPD (p < 0.001) There was a negative correlation between exhaled NO and FEV1 in both ex-smokers with COPD (r = −0.60; p < 0.02) and current smokers with COPD (r = −0.59; p < 0.02).

Conclusion: The measurement of exhaled CO and NO may represent a new method for the noninvasive monitoring of airway inflammation and oxidant stress in COPD ex-smokers. Exhaled CO and NO are strongly affected by cigarette smoking, which limits their usefulness as biomarkers in current smokers.

Figures in this Article

Oxidative stress is a major pathogenetic component of airway inflammation that characterizes COPD.1 Oxidants decrease the activity of elastase inhibitors,1and an imbalance between oxidants and antioxidants may play an important role in the pathophysiology of COPD.2Plasma antioxidant capacity is decreased in the patients with acute exacerbations of COPD3and returns toward normal values during treatment.4Oxidative stress also is increased in chronic healthy smokers.5 Recently,6 we have demonstrated that lung oxidative stress is increased in stable COPD patients by measuring 8-isoprostane, a prostaglandin analog reflecting in vivo arachidonic acid peroxidation in breath condensate.

Carbon monoxide (CO) is produced ubiquitously in the body by heme oxygenase (HO) as a breakdown product of heme.7 The following two HO isoforms have been characterized: the constitutive isoform HO-2, which is the major isoform present under physiologic conditions; and HO-1, the stress-induced isoform.7HO-1 is up-regulated by oxidative stress,8proinflammatory cytokines,9and nitric oxide (NO).10HO has been found in the pulmonary vascular endothelium11and in alveolar macrophages.12CO causes bronchodilatation in vivo.13 These findings suggest a role for endogenous CO in inflammatory airway diseases. Exhaled CO has been used to quantify oxidative stress in stable asthma and bronchiectasis patients who have higher CO levels than healthy subjects.1415 Exhaled CO also is increased in stable cystic fibrosis patients and, to a greater extent, during exacerbations.16

Exhaled NO is a well-studied marker of airway inflammation and oxidative stress and is increased in lung diseases such as asthma17and bronchiectasis.18In contrast, exhaled NO is decreased in healthy chronic smokers.19Exhaled NO also is increased during COPD exacerbations,20whereas conflicting results have been reported in stable COPD patients. One study21showed increased NO levels in ex-smokers with COPD compared to healthy nonsmokers and in current smokers with COPD compared to healthy current smokers. Two studies did not show any difference in NO concentrations between subjects with COPD and healthy subjects.2223 Both NO and CO may be modulated by inhaled steroid treatment.14,17,24

Most of the studies linking COPD with oxidative stress were performed in vitro, using invasive techniques such as examination of BAL fluid or measurement of systemic rather than oxidative stress.1 The aim of this study was to quantify lung oxidative stress in stable COPD patients (current and ex-smokers) by measuring exhaled CO levels. This may contribute to the understanding of the pathophysiology of COPD and may suggest a potential new noninvasive method to monitor airway inflammation in this disease. We also measured exhaled NO to study possible differences in the biological significance of these two biomarkers of airway inflammation and oxidative stress.

Study Subjects

The following four groups of subjects were studied: 10 healthy nonsmokers; 12 healthy smokers; 15 patients with COPD who were ex-smokers; and 15 patients with COPD who were current smokers (Table 1 ). Patients with COPD attended the outpatient clinic at the Royal Brompton Hospital in London. Informed consent was obtained from all subjects. This study was approved by the Ethics Committee of the Royal Brompton Hospital and Harefield Trust. Study groups were matched for age (Table 1). The diagnosis of COPD was based on the British Thoracic Society guidelines.25All the patients had airways obstruction with an FEV1 < 80% of predicted, an FEV1/FVC ratio of < 70% that did not change markedly for > 2 months, no spirometric response to bronchodilators (ie, an FEV1 increase of < 200 mL and 15% of baseline values), a history of chronic progressive symptoms such as dyspnea, cough, and wheeze, and a history of smoking. Patients with a history of atopy or positive results of skin prick testing for common inhaled allergens, and a history of asthma or other respiratory diseases were excluded from the study. Chest radiography was carried out to exclude other respiratory diseases. Patients with systemic diseases, vascular disease, thrombosis, alcoholism, renal disease, and hepatic disease were excluded from the study. Patients with COPD were clinically stable with no worsening of symptoms and no increase in wheeze, dyspnea, sputum volume, or sputum purulence within the previous 8 weeks. The FEV1/FVC ratio was unchanged over a period of at least 8 weeks before NO and CO measurements. Eight current smokers with COPD and 8 ex-smokers with COPD were at stage 1 (ie, FEV1 ≥ 50% of predicted) according to the American Thoracic Society guidelines for COPD,26 and the others were at stage 2 (ie, FEV1 35 to 49% of predicted). Healthy smokers, ex-smokers with COPD, and current smokers with COPD were matched for smoking habits and had a history of > 20 pack-years (Table 1). The mean (± SEM) daily consumption of cigarettes was similar in healthy smokers (25 ± 5 pack-years) and in current smokers with COPD (26 ± 4 pack-years). Smoking habit was checked by the measurement of urinary cotinine levels (data not shown). Ex-smokers had stopped smoking for at least 6 months. Healthy smokers and current smokers with COPD refrained from smoking for at least 12 h before NO and CO measurements. Thirteen ex-smokers with COPD were treated with inhaled glucocorticoids (eg, beclomethasone dipropionate, 0.5 to 2 mg/d; budesonide, 0.8 mg/d; or fluticasone, 1 mg/d) and/or oral glucocorticoids (eg, prednisolone, 7.5 to 10 mg/d). Twelve current smokers with COPD were treated with inhaled glucocorticoids (eg, beclomethasone dipropionate, 0.4 to 1 mg/d; budesonide, 0.4 to 1.6 mg/d; or fluticasone, 1 mg/d) and/or oral corticosteroids (eg, prednisolone, 5 to 10 mg/d). Inhaled β-adrenergic agonists and theophylline also were used (Table 1).

Study Design

The type of study was cross-sectional. Subjects attended the outpatient clinic at the Royal Brompton Hospital in London for clinical examination, spirometry, and exhaled CO and NO measurements

Methods
Pulmonary Function:

Pulmonary function tests were performed on the same day as the measurement of exhaled markers. Spirometry was measured using a dry spirometer (Vitalograph Ltd; Buckingham, UK), and the best value from three maneuvers was expressed as an absolute value (in liters) and as a percentage of the predicted value.

Exhaled CO Measurement:

Exhaled CO was measured by an electrochemical CO monitor sensitive to CO levels from 0.1 to 500 ppm (by volume), which adapted for online recording of CO concentration and was integrated with a chemiluminescence analyzer (model LR2000; Logan Research; Rochester, UK) to control the exhalation parameters. The subjects exhaled slowly from total lung capacity with a constant flow (5 to 6 L/min) against resistance (3 ± 0.4 mm Hg) for > 20 to 30 s into the analyzer. Two successive recordings were made, and mean values were used in all calculations. Ambient CO levels were recorded before each measurement and were subtracted from the exhaled values.

Exhaled NO Measurement:

Exhaled NO was measured using a chemiluminescence analyzer (model LR2000; Logan Research), which was sensitive to NO levels from 1 to 5,000 parts per billion (ppb, by volume) and had a resolution of 0.3 ppb, which was designed for the online recording of exhaled NO concentrations, as previously described.17 The analyzer was calibrated using certified NO mixture (90 ppb) in nitrogen (BOC Special Gases; Guilford, UK). Measurements of exhaled NO were made by single-breath slow exhalation (5 to 6 L/min) from total lung capacity for 20 to 30 s against a resistance (3 ± 0.4 mm Hg) to prevent nasal contamination. Two successive recordings were made and mean values were used in all calculations.

Statistical Analysis

One-way analysis of variance with a Newman-Keuls test for multiple comparisons was used to compare groups. For comparing two groups, an unpaired Student’s t test was used for parametric data and a Mann-Whitney U test was used for nonparametric data. Linear regression analysis was used to assess the relationship between exhaled gases and between exhaled gases and FEV1. All data were expressed as the mean± SEM, and significance was defined as a p value of < 0.05.

The clinical data for healthy subjects and patients with COPD are summarized in Table 1.

Exhaled CO

Exhaled CO levels were higher in ex-smokers with COPD (7.4 ± 1.9 ppm; p < 0.05; 95% confidence interval [CI], 3.3 to 11.5) compared to healthy nonsmokers (3.0 ± 0.3 ppm; 95% CI, 2.3 to 3.8), and in current smokers with COPD (20.0 ± 2.6 ppm; p < 0.001; 95% CI, 14.4 to 25.6) compared to healthy smokers (7.9 ± 1.4 ppm; 95% CI, 4.9 to 11.1) [Fig 1 ] . Current smokers with COPD had higher exhaled CO levels than ex-smokers with COPD (p < 0.001) [Fig 1]. Exhaled CO levels were higher in healthy smokers than in healthy nonsmokers (p < 0.05)[ Fig 1]. Current smokers with COPD did not show any difference in exhaled CO levels based on lung function (20.2 ± 1.5 ppm; 95% CI, 16.6 to 23.8; FEV1 < 60% vs 19.7 ± 5.6 ppm; 95% CI, 6.1 to 33.4; FEV1> 60%, respectively). There was no correlation between exhaled CO and NO levels. There was no correlation between CO levels and the results of lung function tests in any group of patients.

Exhaled NO

The exhaled NO level was higher in ex-smokers with COPD (12.0 ± 1.0 ppb; 95% CI, 9.9 to 14.0; p < 0.001) than in healthy nonsmokers (6.5 ± 0.6 ppb; 95% CI, 5.2 to 7.8), and in current smokers with COPD (7.6 ± 1.1 ppb; 95% CI, 5.2 to 9.9; p < 0.01) compared to healthy smokers (3.3 ± 0.4 ppb; 95% CI, 2.5 to 4.1)[ Fig 2 ] . Ex-smokers with COPD had higher exhaled NO levels than did current smokers with COPD (p < 0.001) [Fig 2 ] . NO was lower in healthy smokers than in healthy nonsmokers (p < 0.05) [Fig 2]. As shown in Figure 3, exhaled NO values in current smokers with COPD had a clear dual distribution. These patients were divided into two groups according to FEV1 values that were lower or higher than 60% of the predicted value to investigate possible differences in exhaled NO and CO levels according to the lung function of the patients. Current smokers with COPD who had poor lung function (ie, FEV1 < 60% of predicted) had higher exhaled NO levels (ie, 9.9 ± 1.6 ppb; 95% CI, 6.0 to 13.8; p < 0.02) than those smokers with better lung function (ie, FEV1> 60%) [4.8 ± 0.5 ppb; 95% CI, 3.6 to 6.2] (Fig 3). A negative correlation was found between exhaled NO and FEV1 in both ex-smokers with COPD (r = −0.60; p < 0.02)[ Fig 4, top, A] and current smokers with COPD (r = −0.59; p < 0.02) [Fig 4, bottom, B].

Oxidative stress is a major component of airway inflammation in patients with COPD.1 In this study, we have suggested a potential new noninvasive method to monitor airway inflammation and oxidative stress in stable ex-smokers with COPD that is based on exhaled NO and CO measurements. Since the levels of exhaled CO and NO are strongly affected by cigarette smoking, their usefulness in current smokers is limited. We found a 2.5-fold increase in the level of exhaled CO in ex-smokers with COPD compared to healthy nonsmokers. Since ex-smokers with COPD had stopped smoking for at least 6 months, increased CO levels in these patients are likely to be the result of enhanced oxidant stress in their lungs. A similar relative increase in CO was observed in current smokers with COPD compared to healthy smokers matched for age and smoking habits. This may indicate higher oxidative stress in the former group. However, higher exhaled CO levels in patients with COPD may partially reflect a decreased CO clearance due to the presence of significant airflow obstruction and limited alveolar ventilation. We found higher CO levels in current smokers with COPD than in ex-smokers with COPD, but comparisons between the two groups are not possible because of the influence of cigarette smoke on exhaled CO levels. In current smokers with COPD, it is difficult to discriminate between the amount of increased exhaled CO due to lung oxidative stress and that due to CO contained in cigarette smoke. Despite similar patterns in COPD patients, exhaled CO and NO levels seem to have different biological significance. In contrast to NO, there was no negative correlation between CO levels and lung function, and there was no difference in CO levels based on FEV1 values higher or lower than 60% predicted. This may indicate that CO reflects primarily oxidant damage, which is only a component, albeit an important one, of the inflammatory process, with NO being a more general marker of airway inflammation on which the degree of obstruction depends. CO has a protective role in conditions of increased oxidant stress,,2728 whereas the biological role (beneficial or deleterious) of increased NO levels in inflammatory airway diseases is still unclear.

Exhaled NO is increased in many inflammatory airway diseases including COPD, although to a much lesser extent than in asthma.20 We found an increase in exhaled NO of about twofold in ex-smokers with COPD compared to healthy nonsmokers. This relative increase was consistent with that reported in a previous study,21 although the absolute NO values that we measured in ex-smokers with COPD were significantly lower (7.4 ± 1.9 vs 25.7 ± 3 ppb, respectively) and were similar to those previously reported by Maziak et al20 (7.4 ± 1.9 vs 6.3 ± 0.6 ppb, respectively). This could be due to differences in the analytic technique used to measure NO levels. Alternatively, the lower NO levels that we observed could be accounted for by the less severe degree of obstruction of the ex-smokers with COPD who were selected for our study (ie, FEV1, 54.5 ± 3.9 vs 42.8 ± 4, respectively). Consistent with previous studies showing an inhibitory effect of NO contained in cigarette smoke on endogenous NO production,,19,29 healthy smokers had lower NO levels than did healthy nonsmokers. Current smokers with COPD had higher NO values than did healthy smokers, but in the former group the NO level was lower than that in ex-smokers with COPD, as was previously reported.2021 In current smokers with COPD, the increase in exhaled NO due to airway inflammation is likely to be counteracted by the inhibitory effect of smoking on NO endogenous production. In this group of patients, there was a clear double distribution of the NO values, which can be explained on the basis of the different degrees of severity of airway obstruction within the group of current smokers with COPD. Airway inflammation is concomitant with the decrease in lung function, as shown by the negative correlation between NO levels and FEV1 values in both ex-smokers with COPD and current smokers with COPD, as was previously reported.,21However, this does not necessarily imply that airway inflammation is responsible for the decrease in lung function, since long-term changes both in the parenchyma and in the airways contribute markedly to airflow obstruction in patients with COPD. Our results differ from two studies that showed similar exhaled NO concentrations in stable patients with COPD and in healthy subjects.2223 These discrepancies could be explained partly by methodological differences such as the chemiluminescence analyzer used, the sampling flow (0.6 L/min vs 5 to 6 L/min), and response time (< 7 s vs 20 to 30 s). In one study,23 NO, expressed as excretion rates, was measured by tidal breathing and COPD patients had better lung function compared to our study groups (mean FEV1, 63% vs 54% of predicted). Moreover, although matched for smoking habits, COPD and healthy subject study groups included current smokers, ex-smokers, and never-smokers.,23

Most of the COPD patients in our study were treated with steroids. This made it impossible to investigate any effect of steroids on CO and NO in COPD patients. In patients with moderate asthma (ie, FEV1 67 ± 3% of predicted), an open study14 has shown that CO is sensitive to inhaled steroid treatment. In contrast, in a cross-sectional study24 in patients with severe asthma (ie, FEV1 49 ± 6% of predicted), we found that exhaled CO is relatively resistant to oral steroid treatment. In another study,,30 exhaled CO and NO levels were similar in COPD patients treated and not treated with inhaled and/or oral steroids. A lack of effect of steroids on neutrophil inflammation in patients with COPD has been reported.31This may result in persistent activation of the stress-induced enzyme isoforms (HO-1 and inducible NO-synthase) and in increased exhaled CO and NO levels. However, double-blind, placebo-controlled studies are required to definitively establish the effects of steroid treatment on exhaled CO in COPD. Our approach was unable to ascertain the cellular source of CO in the airways. A previous study in asthma patients has demonstrated that increased exhaled CO levels are associated with the overexpression of HO-1 in airway macrophages.32 Further studies are required to characterize the modulation of HO-1 activity and the cell subtypes involved in COPD.

In conclusion, we have shown that exhaled CO and NO may be used to quantify lung oxidative stress and inflammation in ex-smokers with COPD. Measurements of these biomarkers in the exhaled air may provide a noninvasive, sensitive approach with which to monitor lung inflammation and to assess the response to drug treatment. Due to the high dependence of exhaled CO and NO levels on smoking, their usefulness as markers in current smokers with COPD is limited.

Abbreviations: CI = confidence interval; CO = carbon monoxide; HO = heme oxygenase; NO = nitric oxide; ppb = parts per billion

Dr. Montuschi was the recipient of Research Fellowship from the National Research Council of Italy.

Table Graphic Jump Location
Table 1. Subject Characteristics *
* 

Values given as No. or mean ± SEM. Values in parentheses are the range.

 

p < 0.01 compared to healthy nonsmokers.

 

p < 0.05 compared to healthy nonsmokers.

Figure Jump LinkFigure 1. CO concentrations in the exhaled air of healthy nonsmokers, healthy smokers, patients with COPD who are ex-smokers, and patients with COPD who are current smokers. Mean values are shown by horizontal bars.Grahic Jump Location
Figure Jump LinkFigure 2. NO concentrations in the exhaled air of healthy nonsmokers, healthy smokers, patients with COPD who are ex-smokers, and patients with COPD who are current smokers. Mean values are shown by horizontal bars.Grahic Jump Location
Figure Jump LinkFigure 3. NO concentrations in the exhaled air of patients with COPD who are current smokers with FEV1 values higher or lower than 60% predicted. Mean values are shown by horizontal bars.Grahic Jump Location
Figure Jump LinkFigure 4. Top, A: correlation between NO levels in exhaled air and FEV1 in patients with COPD who are ex-smokers (r = −0.60; p < 0.02). Bottom, B: correlation between NO levels in exhaled air and FEV1 in patients with COPD who are current smokers (r = −0.59; p < 0.02).Grahic Jump Location
Repine, JE, Bast, A, Lankhorst, I (1997) Oxidative stress in chronic obstructive pulmonary disease: Oxidative Stress Study Group.Am J Respir Crit Care Med156,341-357. [PubMed]
 
Taylor, JC, Madison, R, Kosinska, D Is antioxidant deficiency related to chronic obstructive pulmonary disease?Am Rev Respir Dis1986;134,285-289. [PubMed]
 
Rahman, I, Morrison, D, Donaldson, K, et al Systemic oxidative stress in asthma, COPD, and smokers.Am J Respir Crit Care Med1996;154,1055-1060. [PubMed]
 
Rahman, I, Skwarska, E, McNee, W Attenuation of oxidant/antioxidant imbalance during treatment of exacerbations of chronic obstructive pulmonary disease.Thorax1997;52,565-568. [PubMed] [CrossRef]
 
Morrow, JD, Frei, B, Longmire, AW, et al Increase in circulating products of lipid peroxidation (F2-isoprostanes) in smokers.N Engl J Med1995;332,1198-1203. [PubMed]
 
Montuschi, P, Collins, JV, Ciabattoni, G, et al Exhaled 8-isoprostane as anin vivobiomarker of lung oxidative stress in patients with COPD and healthy smokers.Am J Respir Crit Care Med2000;162,1175-1177. [PubMed]
 
Maines, MD The heme oxygenase system: a regulator of second messenger gases.Annu Rev Pharmacol Toxicol1997;37,517-554. [PubMed]
 
Poss, KD, Tonegawa, S Reduced stress defense in heme oxygenase 1-deficient cells.Proc Natl Acad Sci USA1997;94,10925-10930. [PubMed]
 
Cantoni, L, Rossi, C, Rizzardini, M, et al Interleukin-1 and tumour necrosis factor induce hepatic heme oxygenase: feedback regulation by glucocorticoids.Biochem J1991;279,891-894. [PubMed]
 
Kim, Y, Bergonia, HA, Muller, C, et al Loss and degradation of enzyme-bound heme induced by cellular nitric oxide synthesis.J Biol Chem1995;270,5710-5713. [PubMed]
 
Otterbein, L, Sylvester, SL, Choi, AMK Hemoglobin provides protection against lethal endotoxemia in rats: the role of heme oxygenase-1.Am J Respir Crit Care Med1995;13,595-601
 
Fukushima, T, Okinaga, S, Sekizawa, T, et al The role of carbon monoxide in lucigenin-dependent chemiluminescence of rat alveolar macrophages.Eur J Pharmacol1995;289,103-107. [PubMed]
 
Cardell, LO, Ueki, IF, Stjarne, P, et al Bronchodilatationin vivoby carbon monoxide, a cyclic GMP related messenger.Br J Pharmacol1998;124,1065-1068. [PubMed]
 
Zayasu, K, Sekidawa, K, Okinaga, S, et al Increased carbon monoxide in exhaled air of asthmatic patients.Am J Respir Crit Care Med1997;156,1140-1143. [PubMed]
 
Horwath, I, Loukides, S, Wodehouse, T, et al Increased levels of exhaled carbon monoxide in bronchiectasis: a new marker of oxidative stress.Thorax1998;53,867-870. [PubMed]
 
Antuni, JD, Kharitonov, SA, Hughes, D, et al Increase in exhaled carbon monoxide during exacerbations of cystic fibrosis.Thorax2000;55,138-142. [PubMed]
 
Kharitonov, SA, Yates, DH, Barnes, PJ Inhaled glucocorticoids decrease nitric oxide in exhaled air of asthmatic patients.Am J Respir Crit Care Med1996;153,454-457. [PubMed]
 
Kharitonov, SA, Wells, AU, O’Connor, BJ, et al Elevated levels of exhaled nitric oxide in bronchiectasis.Am J Respir Crit Care Med1995;151,1889-1893. [PubMed]
 
Kharitonov, SA, Robbins, RA, Yates, D, et al Acute and chronic effect of cigarette smoking on exhaled nitric oxide.Am J Respir Cell Mol Biol1995;52,609-612
 
Maziak, W, Loukides, S, Culpitt, S, et al Exhaled nitric oxide in chronic obstructive pulmonary disease.Am J Respir Crit Care Med1998;157,998-1002. [PubMed]
 
Corradi, M, Majori, M, Cacciani, GC, et al Increased exhaled nitric oxide in patients with stable chronic obstructive pulmonary disease.Thorax1999;54,572-575. [PubMed]
 
Rutgers, SR, Meijer, RJ, Kerstjens, HAM, et al Nitric oxide measured with single-breath and tidal-breathing methods in asthma and COPD.Eur Respir J1998;12,816-819. [PubMed]
 
Rutgers, SR, van der Mark, ThW, Coers, W, et al Markers of nitric oxide metabolism in sputum and exhaled air are not increased in chronic obstructive pulmonary disease.Thorax1999;54,576-580. [PubMed]
 
Montuschi, P, Corradi, M, Ciabattoni, G, et al Increased 8-isoprostane, a biomarker of oxidative stress, in exhaled condensate of asthma patients.Am J Respir Crit Care Med1999;160,216-220. [PubMed]
 
British Thoracic Society.. BTS guidelines for the management of chronic pulmonary disease. Thorax. 1997;;52(suppl) ,.:S4
 
American Thoracic Society.. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease.Am J Respir Crit Care Med1995;152,S77-S120. [PubMed]
 
Choi, AM, Alam, J Heme oxygenase-1: function, regulation, and implication of a novel stress-inducible protein in oxidant-induced lung injury.Am J Respir Cell Mol Biol1996;15,9-19. [PubMed]
 
Otterbein, LE, Bach, FH, Alam, J, et al Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway.Nat Med2000;6,422-428. [PubMed]
 
Schilling, J, Holzer, P, Guggenbach, M, et al Reduced endogenous nitric oxide in the exhaled air of smokers and hypertensives.Eur Respir J1994;7,467-471. [PubMed]
 
Paredi, P, Kharitonov, SA, Leak, D, et al Exhaled ethane, a marker of lipid peroxidation, is elevated in chronic obstructive pulmonary disease.Am J Respir Crit Care Med2000;162,369-373. [PubMed]
 
Keatings, VM, Jatakanon, A, Worsdell, YM, et al Effects of inhaled and oral glucocorticoids in inflammatory indices in asthma and COPD.Am J Respir Crit Care Med1997;155,542-548. [PubMed]
 
Horvath, I, Donnelly, LE, Kiss, A, et al Raised levels of exhaled carbon monoxide are associated with an increased expression of heme oxygenase-1 in airway macrophages in asthma: a new marker of oxidative stress.Thorax1998;53,668-672. [PubMed]
 

Figures

Figure Jump LinkFigure 1. CO concentrations in the exhaled air of healthy nonsmokers, healthy smokers, patients with COPD who are ex-smokers, and patients with COPD who are current smokers. Mean values are shown by horizontal bars.Grahic Jump Location
Figure Jump LinkFigure 2. NO concentrations in the exhaled air of healthy nonsmokers, healthy smokers, patients with COPD who are ex-smokers, and patients with COPD who are current smokers. Mean values are shown by horizontal bars.Grahic Jump Location
Figure Jump LinkFigure 3. NO concentrations in the exhaled air of patients with COPD who are current smokers with FEV1 values higher or lower than 60% predicted. Mean values are shown by horizontal bars.Grahic Jump Location
Figure Jump LinkFigure 4. Top, A: correlation between NO levels in exhaled air and FEV1 in patients with COPD who are ex-smokers (r = −0.60; p < 0.02). Bottom, B: correlation between NO levels in exhaled air and FEV1 in patients with COPD who are current smokers (r = −0.59; p < 0.02).Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1. Subject Characteristics *
* 

Values given as No. or mean ± SEM. Values in parentheses are the range.

 

p < 0.01 compared to healthy nonsmokers.

 

p < 0.05 compared to healthy nonsmokers.

References

Repine, JE, Bast, A, Lankhorst, I (1997) Oxidative stress in chronic obstructive pulmonary disease: Oxidative Stress Study Group.Am J Respir Crit Care Med156,341-357. [PubMed]
 
Taylor, JC, Madison, R, Kosinska, D Is antioxidant deficiency related to chronic obstructive pulmonary disease?Am Rev Respir Dis1986;134,285-289. [PubMed]
 
Rahman, I, Morrison, D, Donaldson, K, et al Systemic oxidative stress in asthma, COPD, and smokers.Am J Respir Crit Care Med1996;154,1055-1060. [PubMed]
 
Rahman, I, Skwarska, E, McNee, W Attenuation of oxidant/antioxidant imbalance during treatment of exacerbations of chronic obstructive pulmonary disease.Thorax1997;52,565-568. [PubMed] [CrossRef]
 
Morrow, JD, Frei, B, Longmire, AW, et al Increase in circulating products of lipid peroxidation (F2-isoprostanes) in smokers.N Engl J Med1995;332,1198-1203. [PubMed]
 
Montuschi, P, Collins, JV, Ciabattoni, G, et al Exhaled 8-isoprostane as anin vivobiomarker of lung oxidative stress in patients with COPD and healthy smokers.Am J Respir Crit Care Med2000;162,1175-1177. [PubMed]
 
Maines, MD The heme oxygenase system: a regulator of second messenger gases.Annu Rev Pharmacol Toxicol1997;37,517-554. [PubMed]
 
Poss, KD, Tonegawa, S Reduced stress defense in heme oxygenase 1-deficient cells.Proc Natl Acad Sci USA1997;94,10925-10930. [PubMed]
 
Cantoni, L, Rossi, C, Rizzardini, M, et al Interleukin-1 and tumour necrosis factor induce hepatic heme oxygenase: feedback regulation by glucocorticoids.Biochem J1991;279,891-894. [PubMed]
 
Kim, Y, Bergonia, HA, Muller, C, et al Loss and degradation of enzyme-bound heme induced by cellular nitric oxide synthesis.J Biol Chem1995;270,5710-5713. [PubMed]
 
Otterbein, L, Sylvester, SL, Choi, AMK Hemoglobin provides protection against lethal endotoxemia in rats: the role of heme oxygenase-1.Am J Respir Crit Care Med1995;13,595-601
 
Fukushima, T, Okinaga, S, Sekizawa, T, et al The role of carbon monoxide in lucigenin-dependent chemiluminescence of rat alveolar macrophages.Eur J Pharmacol1995;289,103-107. [PubMed]
 
Cardell, LO, Ueki, IF, Stjarne, P, et al Bronchodilatationin vivoby carbon monoxide, a cyclic GMP related messenger.Br J Pharmacol1998;124,1065-1068. [PubMed]
 
Zayasu, K, Sekidawa, K, Okinaga, S, et al Increased carbon monoxide in exhaled air of asthmatic patients.Am J Respir Crit Care Med1997;156,1140-1143. [PubMed]
 
Horwath, I, Loukides, S, Wodehouse, T, et al Increased levels of exhaled carbon monoxide in bronchiectasis: a new marker of oxidative stress.Thorax1998;53,867-870. [PubMed]
 
Antuni, JD, Kharitonov, SA, Hughes, D, et al Increase in exhaled carbon monoxide during exacerbations of cystic fibrosis.Thorax2000;55,138-142. [PubMed]
 
Kharitonov, SA, Yates, DH, Barnes, PJ Inhaled glucocorticoids decrease nitric oxide in exhaled air of asthmatic patients.Am J Respir Crit Care Med1996;153,454-457. [PubMed]
 
Kharitonov, SA, Wells, AU, O’Connor, BJ, et al Elevated levels of exhaled nitric oxide in bronchiectasis.Am J Respir Crit Care Med1995;151,1889-1893. [PubMed]
 
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