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ABSTRACT |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Chronic obstructive pulmonary disease (COPD) is characterized by progressive airflow obstruction
and a neutrophilic inflammation. Exhaled nitric oxide (NO) may be a marker of disease activity in a
variety of lung diseases. We measured exhaled NO in patients with documented COPD and investigated whether the concentration of exhaled NO is related to the severity of disease as defined by
lung function. We also investigated whether concentration of exhaled NO was different in COPD patients who received inhaled steroids compared with steroid-naïve patients. We studied 13 current
smokers with COPD, eight exsmokers with COPD, 12 patients with unstable COPD (exacerbation or
severe disease), and 10 smokers with chronic bronchitis without airflow limitation. Exhaled NO levels
were significantly higher in patients with unstable COPD (12.7 ± 1.5 ppb) than in other groups (p < 0.01). Exhaled NO levels were significantly higher in smokers with COPD than in smokers with
chronic bronchitis (4.3 ± 0.5 versus 2.5 ± 0.5 ppb, p < 0.05), and were even higher in patients with
COPD who had stopped smoking (6.3 ± 0.6 ppb, p < 0.01). Exhaled NO levels showed a significant negative correlation with their lung function assessed by % predicted FEV1 values (r = 
0.6, p < 0.001). Exhaled NO levels in patients treated with inhaled steroids were significantly higher compared with steroid-naïve patients (8.2 ± 1.2 ppb versus 5 ± 0.4 ppb, p < 0.05), but the first group included more severe patients as assessed by lung function. We conclude that exhaled NO could serve as a useful, practical marker for monitoring disease activity in COPD.
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Chronic obstructive pulmonary disease (COPD) is defined as a disease state characterized by the presence of airflow obstruction due to chronic bronchitis or emphysema; the airflow obstruction is generally progressive, may be accompanied by airflow hyperreactivity, and may be partially reversible (1). The main risk factor is smoking. Smokers have higher death rates for chronic bronchitis and emphysema and they also have a higher prevalence of lung function abnormalities, respiratory symptoms, and all forms of chronic obstructive airway disease (2).
There is increasing evidence that endogenous nitric oxide
(NO) plays a key role in the physiological regulation of airways and is implicated in the pathophysiology of airway disease (3). NO is derived endogenously from the amino acid
L-arginine by three isoforms of the enzyme NO synthase (NOS);
two constitutive NO synthase (cNOS) are involved in physiological regulation of airways function and an inducible form of
the enzyme (iNOS) is involved in inflammatory diseases of the
airways and in host defence against infections (4, 5). Tumor
necrosis factor-alpha (TNF-
), a proinflammatory cytokine that
is known to increase the expression of iNOS in airway epithelial cells (6), is increased in patients with COPD compared with
normal smokers suggesting that iNOS may be contributing to
disease progression (7).
Since COPD involves chronic inflammation in the airways with the presumed release of proinflammatory cytokines, we investigated whether exhaled NO might be elevated in these patients and whether any elevation in NO might be related to the extent of the disease as measured by lung function. We also investigated whether levels of exhaled NO were different in patients who received inhaled steroids compared with steroid-naïve patients.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Subjects
Four groups of subjects were studied (Table 1). Patients were recruited from clinics at the Royal Brompton Hospital. Group 1 consisted of 13 current smokers with COPD (10 males, mean age 54 ± 2 yr,
FEV1 70 ± 4% predicted). Two of them were not receiving any treatment. Three of them were on inhaled steroids (beclomethasone 500 µg/d) and the other eight were using 
2 agonists as a relief medication.
Group 2 consisted of eight exsmokers (i.e., discontinuation of smoking for at least 6 mo) with COPD (three males, age 64 ± 3 yr, and
FEV1 48 ± 5% pred). One of them was on inhaled steroids (fluticasone propionate 500 µg/d). The other seven were on anticholinergics (n = 3) and 2 agonists (n = 4). Group 3 consisted of 12 patients (9 males, age 63 ± 2 yr, FEV1 25 ± 3% pred) with "unstable" COPD, in
which patients either had exacerbation (n = 6, FEV1 27 ± 4% pred,
PaO2 59 ± 2 mm Hg), as defined as the American Thoracic Society
(ATS) criteria (8), or severe disease (n = 6, FEV1 23 ± 3% pred)
judged by FEV1 of less than 35% predicted (9). Patients with exacerbation were studied at the onset of the exacerbation. All were on oral
steroids (prednisolone 25 ± 5 mg/d), two were on theophylline (250 mg
bid), and all were using 2 agonists as a regular treatment. Five patients with severe disease were on inhaled steroids (fluticasone propionate 500 µg/d) and all of them were using 2 agonists as a regular
treatment. All patients were diagnosed as COPD using the ATS criteria (1) for the diagnosis and management of COPD. Group 4 consisted of 10 normal smokers (five males, age 48 ± 1 yr, FEV1 94 ± 3%
predicted) who had chronic bronchitis with absence of airflow limitation. None of them received any regular medication. All groups were
matched according to smoking history (36 of 43 studied subjects, had a
smoking history of > 30 pack-yr). None of the subjects had pulmonary
hypertension or echocardiography. The person measured exhaled NO
was not aware of the patient's clinical and functional status.
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NO Measurements
Exhaled NO was measured using a chemiluminescence analyzer (Model LR2000; Logan Research, Rochester, UK), with sensitivity from 1 ppb to 500 ppb (by volume) of NO, accuracy ± 0.5 ppb and response time of < 2 s to 90% of full scale. In addition, the analyzer also measured CO2 (range 0-10% CO2, accuracy ± 0.1%, response time 200 ms to 90% of full scale), expiratory flow and pressure, and exhaled volume in real-time. The analyzer was fitted with a biofeedback display unit to provide visual guidance for the subject to maintain the pressure and expiratory flow within a certain range (3 ± 0.4 mm Hg and 5-6 L/min for end-exhaled NO measurements), hence, improving test repeatability, and enhancing patients cooperation. Sampling rate through the reaction chamber of the analyzer was 250 ml/min for all measurements. The analyzer was calibrated daily using NO-free certified compressed air to set absolute zero and then a certified concentration of NO in nitrogen of 90 ppb and 500 ppb (BOC Special Gases; Surrey Research Park, Guilford, UK), and certified 5% CO2 (BOC). Ambient air NO level was recorded and the absolute zero was adjusted prior to all measurements. For the end-exhaled NO measurements subjects were exhaling slowly from TLC over 30-35 s with exhalation flow of 5-6 L/min by-passing the analyzer. The subjects exhaled against a mild resistance, thereby creating the positive pressure 3 ± 0.4 mm Hg, which was necessary to close the soft palate (10, 11). Expiratory flow rate and positive pressure created during exhalation were similar to those recommended by the European guidelines on exhaled NO measurements (12). There is no apparent influence of exhaled volume on NO levels, provided that dead space volume is discarded. In a single exhalation exhaled NO almost reaches a plateau after 5-10 s of exhalation, while the CO2 and exhaled volume continue to increase (13). There is no difference in NO concentration between mixed expired air collected into a reservoir after a full VC exhalation and an exhalation form one tidal breath above FRC to RV either in normal or asthmatic subjects (14, 15).
Fractional analysis of expired gas collected during exhalation
against a low resistance, also has shown no significant difference in exhaled NO between the first 40-45% (6.9 ± 1.9 ng L
1) and the remaining part (5.1 ± 1.0 ng L1) of an exhalation (16). However, the
first exhalation fraction is usually associated with a transient NO peak,
which represents the portion of exhaled air contaminated mostly with
the nasal (17, 18), oropharyngeal, and ambient NO in the dead space. The detection of this peak depends on the response time of the analyzer and should be discarded from the analysis, unless there is a particular need to analyze NO in this part of exhalation. The phenomena
of "sequential" lung emptying cannot be overestimated in interpretation of the conventional forced exhalation maneuvers, as forceful exhalation leads to dynamic narrowing of the intrathoracic airways. In
patients with COPD reduction in lung recoil pressure and peripheral
airway narrowing both enhance dynamic narrowing of the large intrathoracic airways on expiration. However, during slow expiration
airway pressures fall progressively from alveoli to the mouth, so that
the pressure distending the airway is less than during forceful expiration. As exhaled NO has been measured during gentle (5-6 L/min)
and slow (over 20 s) exhalation against mild resistance (3 ± 0.4 mm
Hg of positive pressure), the dynamic narrowing of the large intrathoracic airways and consequent gas trapping have been avoided. The
mean value of the last 100 measurements, acquired with 0.04 s interval, was taken from the point corresponding to the plateau of end-
exhaled CO2 reading (5-6% CO2) and represents the lower respiratory tract sample (13). Results of the analyses were computed and
graphically displayed on a plot of NO and CO2 concentration pressure
and flow against time.
Statistical Analysis
The data are expressed as mean ± SEM. The significance of difference between groups was assessed by two-way analysis of variance (ANOVA). Regression analysis was performed by Pearson's rank correlation coefficients. A p value < 0.05 was considered to be significant.
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RESULTS |
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INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Exhaled NO was highest in the "unstable" COPD group (12 ± 1.5 ppb) (Table ). NO levels in this group were significantly higher than in smokers with COPD (p < 0.001), the exsmokers with COPD group (p < 0.01) and in normal smokers group (p < 0.0001). Also, exhaled NO was significantly higher in the exsmoker group with COPD (6 ± 0.6 ppb) than in the smokers with COPD group (4 ± 0.4 ppb) and the normal smokers group (3 ± 0.5) (p < 0.02, p < 0.01, respectively). Exhaled NO was higher in the smoking COPD (4 ± 0.4 ppb) than in normal smokers (3 ± 0.5 ppb, p < 0.05) (Figure 1). Separating the subgroup of unstable COPD patients we found that NO levels in patients with exacerbation were higher than levels in patients with severe disease, but this difference was not statistically significant (14.5 ± 2 ppb versus 11 ± 1.5 ppb, p > 0.05).
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There was significant negative correlation (r = 0.6, p < 0.001) between FEV1 and exhaled NO levels (Figure 2). No
correlation was found between arterial oxygen tension and exhaled NO in patients with exacerbation (r = 0.3, p > 0.05).
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NO levels were significantly higher in COPD patients treated with inhaled steroids (8.2 ± 1.2 ppb) than in patients not treated with inhaled steroids (5 ± 0.4 ppb, p < 0.05) (Figure 3), but the first group included more severe patients as assessed by FEV1 (37% pred versus 67% pred).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Our results show a significant increase in the concentration of exhaled NO in patients with severe or exacerbated COPD. Levels of exhaled NO were significantly correlated with lung function as assessed by FEV1.
Chronic cigarette smoking itself decreases exhaled NO,
and the decrease correlates with the amount smoked (19, 20).
This effect could result from downregulation of nitric oxide
synthase (NOS) by the high NO concentration in cigarette
smoke (21), from inactivation of NO by oxidants in cigarette
smoke like superoxide anions (O2·) (22), or finally from tobacco-induced toxic damage to NO-producing epithelial cells
(20). A decrease in NO formation might be relevant in COPD.
First, inhibition of endogenous NO production may contribute to reduced mucociliary clearance and bactericidal activity of phagocytes (23, 24), thus increasing susceptibility to recurrent respiratory infections, a pattern seen in smokers as well as
COPD patients. Second, reduced NO may increase bronchial
tone, since NO acts as an endogenous neurotransmitter of
bronchodilator nerves in human airways (25), although clinical trials using NO as a bronchodilator in COPD demonstrated little efficacy (26, 27). Finally reduced synthesis of NO
by the endothelial cells of pulmonary arteries may contribute
to pulmonary hypertension in COPD patients (28).
Exhaled NO measurement may offer a simple and noninvasive mean of monitoring disease activity in the respiratory tract and its place in various diseases affecting the lungs is now under intensive evaluation by many research groups (6). In contrast to asthma, we found that exhaled NO was not elevated compared to normal values, in patients with stable COPD, in either current or exsmokers. However, exhaled NO levels in both smoker and exsmoker COPD groups were higher than those of smoking controls. The finding that NO levels in exsmokers with stable COPD were relatively normal, is in agreement with previous observations made by Robbins and coworkers (29).
In patients with greater disease severity (FEV1 < 35% pred), and during acute exacerbations, NO levels showed a significant increase in comparison to the other groups. This suggests that exhaled NO may be a method of assessing disease activity in COPD and could also be used to monitor response to treatment in these patients.
The significant inverse correlation between % predicted FEV1 and NO levels, regardless of smoking status, could also support the use of exhaled NO as a mean of monitoring disease activity. In patients with severe disease the increase in exhaled NO outweighs the decrease in NO levels due to cigarette smoking.
Studying similar populations of stable and unstable COPD patients and healthy controls, Dekhuijzen and coworkers found a significant increase in the concentration of hydrogen peroxide (H2O2) in the expired breath condensate of patients with COPD compared with controls, with significantly greater increase in the unstable patients compared with the stable patients with COPD (30). This supports the hypothesis of an increase in airway inflammation as the severity of airway obstruction increases in patients with COPD. However, our findings contradict the conclusions of Kanazawa and coworkers, who studied exhaled NO in smokers with mild obstruction (mean FEV1 82% predicted) and compared it to NO levels in a healthy non-smoking group. They suggest that the reduced NO in the smoking obstructed group could be the important factor leading to airway obstruction (31).
Keatings and Stanescu and associates (7, 32), finding that neutrophil counts in induced sputum are increased as obstruction progresses (percent-predicted FEV1 declines), favor the hypothesis of neutrophilic inflammation as an important factor in the development of airway obstruction. The activated state that characterizes these intraluminal neutrophils may account for the increase in NO production that were are detecting in severe COPD patients.
The finding that NO levels in patients with inhaled steroids were not significantly higher than those in steroid naïve COPD patients was not surprising, since the steroid-treated group included most of the unstable patients. This also supports earlier observations made by Robbins and coworkers, who found no difference in relation to treatment with corticosteroids in COPD patients (25). The theoretically plausible explanation for this phenomenon could lie within the known lack of effect of steroids on neutrophils, as was recently demonstrated using induced sputum (33).
In conclusion, exhaled NO could serve as a useful, practical surrogate marker for monitoring disease activity in COPD patients. Future work should concentrate on the relation between exhaled NO and other direct inflammatory markers in sputum, BAL and biopsies. It would be interesting also to look at NO response to different treatment regimens used in COPD, including theophylline and antioxidants, which may interfere with the neutrophil inflammatory response.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Professor P. J. Barnes, Department of Thoracic Medicine, National Heart and Lung Institute, Dovehouse St., London SW3 6LY, UK. E-mail: p.j.barnes{at}ic.ac.uk
(Received in original form May 5, 1997 and in revised form September 5, 1997).
Acknowledgments: Supported by Karim Rida Said Foundation and British Lung Foundation.
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References |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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 P. J. Barnes, B. Chowdhury, S. A. Kharitonov, H. Magnussen, C. P. Page, D. Postma, and M. Saetta Pulmonary Biomarkers in Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., July 1, 2006; 174(1): 6 - 14. [Abstract] [Full Text] [PDF]
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 J. Vestbo Clinical Assessment, Staging, and Epidemiology of Chronic Obstructive Pulmonary Disease Exacerbations Proceedings of the ATS, May 1, 2006; 3(3): 252 - 256. [Abstract] [Full Text] [PDF]
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 W. Cao and Y. Duan Breath Analysis: Potential for Clinical Diagnosis and Exposure Assessment Clin. Chem., May 1, 2006; 52(5): 800 - 811. [Abstract] [Full Text] [PDF]
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 J. Choi, L. A. Hoffman, G. W. Rodway, and J. M. Sethi Markers of lung disease in exhaled breath: nitric oxide. Biol Res Nurs, April 1, 2006; 7(4): 241 - 255. [Abstract] [PDF]
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A. Bhowmik, T. A. R. Seemungal, G. C. Donaldson, and J. A. Wedzicha Effects of exacerbations and seasonality on exhaled nitric oxide in COPD Eur. Respir. J., December 1, 2005; 26(6): 1009 - 1015. [Abstract] [Full Text] [PDF]
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Y.-H. Chen, W.-Z. Yao, B. Geng, Y.-L. Ding, M. Lu, M.-W. Zhao, and C.-S. Tang Endogenous Hydrogen Sulfide in Patients With COPD Chest, November 1, 2005; 128(5): 3205 - 3211. [Abstract] [Full Text] [PDF]
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 W. MacNee Treatment of stable COPD: antioxidants Eur. Respir. Rev., September 1, 2005; 14(94): 12 - 22. [Abstract] [Full Text] [PDF]
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C. Brindicci, K. Ito, O. Resta, N. B. Pride, P. J. Barnes, and S. A. Kharitonov Exhaled nitric oxide from lung periphery is increased in COPD Eur. Respir. J., July 1, 2005; 26(1): 52 - 59. [Abstract] [Full Text] [PDF]
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H. Yasuda, M. Yamaya, K. Nakayama, S. Ebihara, T. Sasaki, S. Okinaga, D. Inoue, M. Asada, M. Nemoto, and H. Sasaki Increased Arterial Carboxyhemoglobin Concentrations in Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., June 1, 2005; 171(11): 1246 - 1251. [Abstract] [Full Text] [PDF]
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N Berkman, A Avital, R Breuer, E Bardach, C Springer, and S Godfrey Exhaled nitric oxide in the diagnosis of asthma: comparison with bronchial provocation tests Thorax, May 1, 2005; 60(5): 383 - 388. [Abstract] [Full Text] [PDF]
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ATS/ERS Recommendations for Standardized Procedures for the Online and Offline Measurement of Exhaled Lower Respiratory Nitric Oxide and Nasal Nitric Oxide, 2005 Am. J. Respir. Crit. Care Med., April 15, 2005; 171(8): 912 - 930. [Full Text] [PDF]
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W. MacNee Pulmonary and Systemic Oxidant/Antioxidant Imbalance in Chronic Obstructive Pulmonary Disease Proceedings of the ATS, April 1, 2005; 2(1): 50 - 60. [Abstract] [Full Text] [PDF]
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 P. J. Barnes Mediators of Chronic Obstructive Pulmonary Disease Pharmacol. Rev., December 1, 2004; 56(4): 515 - 548. [Abstract] [Full Text] [PDF]
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S. A. Kharitonov and P. J. Barnes Effects of Corticosteroids on Noninvasive Biomarkers of Inflammation in Asthma and Chronic Obstructive Pulmonary Disease Proceedings of the ATS, November 1, 2004; 1(3): 191 - 199. [Abstract] [Full Text] [PDF]
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C Lane, D Knight, S Burgess, P Franklin, F Horak, J Legg, A Moeller, and S Stick Epithelial inducible nitric oxide synthase activity is the major determinant of nitric oxide concentration in exhaled breath Thorax, September 1, 2004; 59(9): 757 - 760. [Abstract] [Full Text] [PDF]
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 F. L. M. Ricciardolo, P. J. Sterk, B. Gaston, and G. Folkerts Nitric Oxide in Health and Disease of the Respiratory System Physiol Rev, July 1, 2004; 84(3): 731 - 765. [Abstract] [Full Text] [PDF]
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B.W.M. Willemse, D.S. Postma, W. Timens, and N.H.T. ten Hacken The impact of smoking cessation on respiratory symptoms, lung function, airway hyperresponsiveness and inflammation Eur. Respir. J., March 1, 2004; 23(3): 464 - 476. [Abstract] [Full Text] [PDF]
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 S. D. Message and S. L. Johnston Host defense function of the airway epithelium in health and disease: clinical background J. Leukoc. Biol., January 1, 2004; 75(1): 5 - 17. [Abstract] [Full Text] [PDF]
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D. C. Tornberg, H. Bjorne, J. O. Lundberg, and E. Weitzberg Multiple Single-breath Measurements of Nitric Oxide in the Intubated Patient Am. J. Respir. Crit. Care Med., November 15, 2003; 168(10): 1210 - 1215. [Abstract] [Full Text] [PDF]
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A.W. Boots, G.R.M.M. Haenen, and A. Bast Oxidant metabolism in chronic obstructive pulmonary disease Eur. Respir. J., November 2, 2003; 22(46_suppl): 14s - 27s. [Abstract] [Full Text] [PDF]
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P.J. Barnes, S.D. Shapiro, and R.A. Pauwels Chronic obstructive pulmonary disease: molecular and cellularmechanisms Eur. Respir. J., October 1, 2003; 22(4): 672 - 688. [Abstract] [Full Text] [PDF]
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G. I. Snell, L. Holsworth, Z. L. Borrill, K. R. Thomson, V. Kalff, J. A. Smith, and T. J. Williams The Potential for Bronchoscopic Lung Volume Reduction Using Bronchial Prostheses: A Pilot Study Chest, September 1, 2003; 124(3): 1073 - 1080. [Abstract] [Full Text] [PDF]
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M. Corradi, I. Rubinstein, R. Andreoli, P. Manini, A. Caglieri, D. Poli, R. Alinovi, and A. Mutti Aldehydes in Exhaled Breath Condensate of Patients with Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., May 15, 2003; 167(10): 1380 - 1386. [Abstract] [Full Text] [PDF]
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H Sugiura, M Ichinose, S Yamagata, A Koarai, K Shirato, and T Hattori Correlation between change in pulmonary function and suppression of reactive nitrogen species production following steroid treatment in COPD Thorax, April 1, 2003; 58(4): 299 - 305. [Abstract] [Full Text] [PDF]
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P. Paredi, G. Caramori, D. Cramer, S. Ward, A. Ciaccia, A. Papi, S.A. Kharitonov, and P.J. Barnes Slower rise of exhaled breath temperature in chronic obstructive pulmonary disease Eur. Respir. J., March 1, 2003; 21(3): 439 - 443. [Abstract] [Full Text] [PDF]
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P. Paredi, S. A. Kharitonov, and P. J. Barnes Analysis of Expired Air for Oxidation Products Am. J. Respir. Crit. Care Med., December 15, 2002; 166(12): S31 - 37. [Abstract] [Full Text] [PDF]
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B-;M. Sundblad, B-;M. Larsson, L. Palmberg, and K. Larsson Exhaled nitric oxide and bronchial responsiveness in healthy subjects exposed to organic dust Eur. Respir. J., August 1, 2002; 20(2): 426 - 431. [Abstract] [Full Text] [PDF]
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K. Kostikas, G. Papatheodorou, K. Ganas, K. Psathakis, P. Panagou, and S. Loukides pH in Expired Breath Condensate of Patients with Inflammatory Airway Diseases Am. J. Respir. Crit. Care Med., May 15, 2002; 165(10): 1364 - 1370. [Abstract] [Full Text] [PDF]
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K. W. Tsang, R. Leung, P. Chin-wan Fung, S. L. Chan, G. L. Tipoe, G. C. Ooi, and W. K. Lam Exhaled and Sputum Nitric Oxide in Bronchiectasis : Correlation With Clinical Parameters Chest, January 1, 2002; 121(1): 88 - 94. [Abstract] [Full Text] [PDF]
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I. M. FERREIRA, M. S. HAZARI, C. GUTIERREZ, N. ZAMEL, and K. R. CHAPMAN Exhaled Nitric Oxide and Hydrogen Peroxide in Patients with Chronic Obstructive Pulmonary Disease . Effects of Inhaled Beclomethasone Am. J. Respir. Crit. Care Med., September 15, 2001; 164(6): 1012 - 1015. [Abstract] [Full Text] [PDF]
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D. H. YATES, H. BREEN, and P. S. THOMAS Passive Smoke Inhalation Decreases Exhaled Nitric Oxide in Normal Subjects Am. J. Respir. Crit. Care Med., September 15, 2001; 164(6): 1043 - 1046. [Abstract] [Full Text] [PDF]
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P. Montuschi, S. A. Kharitonov, and P. J. Barnes Exhaled Carbon Monoxide and Nitric Oxide in COPD Chest, August 1, 2001; 120(2): 496 - 501. [Abstract] [Full Text] [PDF]
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 G. Cella, A. Sbarai, G. Mazzaro, B. Vanzo, S. Romano, D. Hoppensteadt, and J. Fareed Plasma Markers of Endothelial Dysfunction in Chronic Obstructive Pulmonary Disease Clinical and Applied Thrombosis/Hemostasis, July 1, 2001; 7(3): 205 - 208. [Abstract] [PDF]
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E Clini, L Bianchi, K Foglio, R Porta, M Vitacca, and N Ambrosino Effect of pulmonary rehabilitation on exhaled nitric oxide in patients with chronic obstructive pulmonary disease Thorax, July 1, 2001; 56(7): 519 - 523. [Abstract] [Full Text] [PDF]
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S. A. KHARITONOV and P. J. BARNES Exhaled Markers of Pulmonary Disease Am. J. Respir. Crit. Care Med., June 1, 2001; 163(7): 1693 - 1722. [Full Text] [PDF]
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K. Ansarin, J.M. Chatkin, I.M. Ferreira, C.A. Gutierrez, N. Zamel, and K.R. Chapman Exhaled nitric oxide in chronic obstructive pulmonary disease: relationship to pulmonary function Eur. Respir. J., May 1, 2001; 17(5): 934 - 938. [Abstract] [Full Text] [PDF]
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R. Wilson Bacteria, antibiotics and COPD Eur. Respir. J., May 1, 2001; 17(5): 995 - 1007. [Abstract] [Full Text] [PDF]
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P. E. Silkoff, D. Martin, J. Pak, J. Y. Westcott, and R. J. Martin Exhaled Nitric Oxide Correlated With Induced Sputum Findings in COPD Chest, April 1, 2001; 119(4): 1049 - 1055. [Abstract] [Full Text] [PDF]
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C. ADRIE, M. MONCHI, A. TUAN DINH-XUAN, J. DALL'AVA-SANTUCCI, J.-F. DHAINAUT, and M. R. PINSKY Exhaled and Nasal Nitric Oxide as a Marker of Pneumonia in Ventilated Patients Am. J. Respir. Crit. Care Med., April 1, 2001; 163(5): 1143 - 1149. [Abstract] [Full Text]
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B. Ulvestad, M.B. Lund, B. Bakke, P.G. Djupesland, J. Kongerud, and J. Boe Gas and dust exposure in underground construction is associated with signs of airway inflammation Eur. Respir. J., March 1, 2001; 17(3): 416 - 421. [Abstract] [Full Text] [PDF]
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A. PAPI, M. ROMAGNOLI, S. BARALDO, F. BRACCIONI, I. GUZZINATI, M. SAETTA, A. CIACCIA, and L. M. FABBRI Partial Reversibility of Airflow Limitation and Increased Exhaled NO and Sputum Eosinophilia in Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., November 1, 2000; 162(5): 1773 - 1777. [Abstract] [Full Text]
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P. PAREDI, S. A. KHARITONOV, D. LEAK, S. WARD, D. CRAMER, and P. J. BARNES Exhaled Ethane, a Marker of Lipid Peroxidation, Is Elevated in Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., August 1, 2000; 162(2): 369 - 373. [Abstract] [Full Text] [PDF]
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E. CLINI, G. CREMONA, M. CAMPANA, C. SCOTTI, M. PAGANI, L. BIANCHI, A. GIORDANO, and N. AMBROSINO Production of Endogenous Nitric Oxide in Chronic Obstructive Pulmonary Disease and Patients with Cor Pulmonale . Correlates with Echo-Doppler Assessment Am. J. Respir. Crit. Care Med., August 1, 2000; 162(2): 446 - 450. [Abstract] [Full Text] [PDF]
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M. ICHINOSE, H. SUGIURA, S. YAMAGATA, A. KOARAI, and K. SHIRATO Increase in Reactive Nitrogen Species Production in Chronic Obstructive Pulmonary Disease Airways Am. J. Respir. Crit. Care Med., August 1, 2000; 162(2): 701 - 706. [Abstract] [Full Text] [PDF]
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W. MacNee Oxidants/Antioxidants and COPD Chest, May 1, 2000; 117 (2009): 303S - 317S. [Abstract] [Full Text] [PDF]
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 M B Lund, P I Øksne, R Hamre, and J Kongerud Increased nitric oxide in exhaled air: an early marker of asthma in non-smoking aluminium potroom workers? Occup. Environ. Med., April 1, 2000; 57(4): 274 - 278. [Abstract] [Full Text]
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F. M. Delen, J. M. Sippel, M. L. Osborne, S. Law, N. Thukkani, and W. E. Holden Increased Exhaled Nitric Oxide in Chronic Bronchitis: Comparison With Asthma and COPD Chest, March 1, 2000; 117(3): 695 - 701. [Abstract] [Full Text] [PDF]
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E. Clini, L. Bianchi, M. Vitacca, R. Porta, K. Foglio, and N. Ambrosino Exhaled Nitric Oxide and Exercise in Stable COPD Patients Chest, March 1, 2000; 117(3): 702 - 707. [Abstract] [Full Text] [PDF]
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P. Silkoff Recommendations for Standardized Procedures for the Online and Offline Measurement of Exhaled Lower Respiratory Nitric Oxide and Nasal Nitric Oxide in Adults and Children---1999 . THIS OFFICIAL STATEMENT OF THE AMERICAN THORACIC SOCIETY WAS ADOPTED BY THE ATS BOARD OF DIRECTORS, JULY 1999 Am. J. Respir. Crit. Care Med., December 1, 1999; 160(6): 2104 - 2117. [Full Text]
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B. D. Johnson, K. C. Beck, R. J. Zeballos, and I. M. Weisman Advances in Pulmonary Laboratory Testing Chest, November 1, 1999; 116(5): 1377 - 1387. [Abstract] [Full Text] [PDF]
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W. MACNEE and I. RAHMAN Oxidants and Antioxidants as Therapeutic Targets in Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., November 1, 1999; 160(5): S58 - 65. [Abstract] [Full Text] [PDF]
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 G. Cucchiaro, A. H. Tatum, M. C. Brown, E. M. Camporesi, J. W. Daucher, and T. S. Hakim Inducible nitric oxide synthase in the lung and exhaled nitric oxide after hyperoxia Am J Physiol Lung Cell Mol Physiol, September 1, 1999; 277(3): L636 - L644. [Abstract] [Full Text] [PDF]
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 J. Tamaoki, M. Kondo, K. Kohri, K. Aoshiba, E. Tagaya, and A. Nagai Macrolide Antibiotics Protect Against Immune Complex-Induced Lung Injury in Rats: Role of Nitric Oxide from Alveolar Macrophages J. Immunol., September 1, 1999; 163(5): 2909 - 2915. [Abstract] [Full Text] [PDF]
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P J STERK, H W F M DE GOUW, F L M RICCIARDOLO, and K F RABE Exhaled nitric oxide in COPD: glancing through a smoke screen Thorax, July 1, 1999; 54(7): 565 - 567. [Full Text]
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M. Corradi, M. Majori, G. C. Cacciani, G. F. Consigli, E. de'Munari, and A. Pesci Increased exhaled nitric oxide in patients with stable chronic obstructive pulmonary disease Thorax, July 1, 1999; 54(7): 572 - 575. [Abstract] [Full Text]
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S R Rutgers, T. W van der Mark, W Coers, H Moshage, W Timens, H F Kauffman, G H Koëter, and D S Postma Markers of nitric oxide metabolism in sputum and exhaled air are not increased in chronic obstructive pulmonary disease Thorax, July 1, 1999; 54(7): 576 - 580. [Abstract] [Full Text]
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E. Clini, L. Bianchi, M. Pagani, and N. Ambrosino Endogenous nitric oxide in patients with stable COPD: correlates with severity of disease Thorax, October 1, 1998; 53(10): 881 - 883. [Abstract] [Full Text]
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P Paredi, S Loukides, S Ward, D Cramer, M Spicer, S A Kharitonov, and P J Barnes Exhalation flow and pressure-controlled reservoir collection of exhaled nitric oxide for remote and delayed analysis Thorax, September 1, 1998; 53(9): 775 - 779. [Abstract] [Full Text]
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