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ABSTRACT |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Inhaled corticosteroids are widely prescribed for the treatment of stable chronic obstructive pulmonary disease (COPD), despite lack of proven efficacy. Because COPD involves airway inflammation and probable protease-antiprotease imbalance, we examined the effect of high dose fluticasone propionate on markers of activity of both pathogenetic mechanisms. Thirteen patients with COPD were treated with fluticasone propionate (500 µg twice a day) for 4 wk, delivered via MDI and spacer, in a double-blind crossover study. There was no clinical benefit in terms of lung function or symptom scores, and induced sputum inflammatory cells, percentage neutrophils, and IL-8 levels were unchanged. Sputum supernatant elastase activity, matrix metalloproteinase (MMP)-1, MMP-9, and the antiproteases secretory leukoprotease inhibitor (SLPI) and tissue inhibitor of metalloproteinase (TIMP)-1 were similarly unaffected by treatment. These results add to previous evidence that inhaled steroids have no anti-inflammatory action in stable COPD. Furthermore, inhaled steroids do not appear to redress the protease-antiprotease imbalance that is thought to be important in the pathogenesis of airway obstruction. Culpitt SV, Maziak W, Loukidis S, Nightingale JA, Matthews JL, Barnes PJ. Effect of high dose inhaled steroid on cells, cytokines, and proteases in induced sputum in chronic obstructive pulmonary disease.
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INTRODUCTION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Chronic obstructive pulmonary disease (COPD) is characterized by progressive airflow limitation, and to date cessation of smoking is the only intervention that has been shown to slow disease progression (1). The pathogenesis of airway obstruction in COPD is multifactorial, involving neutrophilic airway inflammation (2), protease-antiprotease imbalance (3, 4), oxidative stress (5), and recurrent infection. These mechanisms are interrelated such that reducing one factor may also reduce the stimulus to others.
Airway inflammation in COPD can be demonstrated by examination of induced sputum, and it clearly differs from that seen in asthma (6). Smokers and ex-smokers with COPD have increased sputum neutrophil numbers compared with subjects without COPD (6, 7), and increased neutrophils are associated with rapid decline in FEV1 (2). Furthermore, neutrophil activation markers are elevated in the sputum supernatants of subjects with COPD (8), suggesting that neutrophils are active participants in airway inflammation. Such evidence would predict that sputum is an effective tool for assessing airway inflammation and that a reduction in neutrophilic inflammation would be a marker of therapeutic success.
The protease-antiprotease imbalance hypothesis of emphysema has seen many advances since the initial reports of Laurell and Eriksson (9) and Gross and colleagues (10). Much attention has focused on the proteolytic potential of neutrophils
(11), which includes neutrophil elastase and matrix metalloproteinases (MMPs) with collagenase and gelatinase activity.
MMPs contribute as much as 50% of the elastolytic activity of
bronchoalveolar lavage fluid in smokers (12). More recently,
the macrophage has been identified as a source of a family of
MMPs with the ability to degrade all extracellular matrix components (13, 14). The elastinolytic activity of macrophages
from subjects with emphysema is greater than that from control subjects (15), and macrophage metalloelastase is essential
in the development of cigarette-smoke-induced emphysema
in mice (16), observations that have contributed to growing
evidence of the importance of macrophages and MMPs in the pathogenesis of emphysema (17). MMP-1 and MMP-9 are
elevated in bronchoalveolar lavage fluid of subjects with emphysema, suggesting that these two MMPs may be important
in pathogenesis (18). A similar body of literature has arisen
around the inhibitors of proteolysis. The major antineutrophil
elastase shield in the lung is provided by 
1-proteinase inhibitor (1-PI) in peripheral lung and secretory leukoprotease inhibitor (SLPI) in airways (19). The MMPs are inhibited by tissue inhibitors of metalloproteinases (TIMPs) of which there
are at least three types (13). Thus, the balance of protease-
antiprotease activity remains an active area of investigation.
There is evidence that steroids increase lung defenses against neutrophil elastase (20, 21). Steroids may also modify MMP and TIMP activity (22, 23). Systemic corticosteroids reduce neutrophil recruitment and activation (24), and in vitro studies have demonstrated a reduction in neutrophil chemotaxis by fluticasone (25). Treatment with fluticasone also reduces sputum chemotactic activity and increases neutrophil elastase inhibitory capacity (26). Therefore, steroids could be expected to have an anti-inflammatory action in COPD. The effect of steroids on inflammation in COPD has been studied using the method of induced sputum (27), and no benefit was demonstrated in this 2-wk trial. We aimed to extend the latter study, using a more potent steroid and for a longer duration of 4 wk. In addition we looked at the effect of fluticasone on MMP-1, MMP-9, TIMP-1, elastase activity, and SLPI levels in the induced sputum of subjects with COPD.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Patients
Twenty-five patients (13 male, eight female) 43 to 73 yr of age, with
stable COPD were recruited from the outpatient department of the
Royal Brompton Hospital. All subjects had a smoking history of at
least 20 pack-years, 11 were current smokers, and the remainder had
ceased smoking for a minimum of 8 mo. Inclusion criteria for entry
were FEV1/FVC ratio < 0.7, postbronchodilator FEV1 < 85% predicted value, reversibility with inhaled 
2-agonist of < 15% of predicted FEV1: all three criteria were required. Subjects who had taken
inhaled or oral steroids or who had suffered an exacerbation of their
airway disease in the previous 6 wk were excluded. Three subjects had
concomitant treatment with albuterol (200 µg twice a day) and ipratropium bromide (40 µg twice a day), one subject with albuterol (200 µg as needed) alone. No other medications were taken in the 6 wk before or during the study. Subjects had no history of asthma or variability of symptoms and were nonatopic. All subjects gave written informed consent, and the study was approved by the ethics committee
of the Royal Brompton Hospital.
Study Design
The study was randomized, double-blind, placebo-controlled crossover design with a run-in period of 2 wk. Subjects received treatment with either fluticasone propionate (FP) 500 µg (Glaxo-Wellcome, Stamford, UK) twice a day or placebo, delivered by metered-dose inhaler via a spacer device, for 4-wk. Treatment periods were separated by 2 wk of washout during which no study medications were taken. Each subject kept a diary card to record diurnal peak expiratory flow rate (PEF), use of reliever inhaler (albuterol), use of study medication, and symptoms. Dyspnea was assessed daily as none, mild (one or two episodes of breathlessness), moderate (three or more episodes but not breathless most of the time), or severe (breathless most of the time). Cough was assessed daily as none, mild (one or two episodes), moderate (three or more episodes) or severe (troubled by cough most of the time). Daily sputum production was ranked as none, only on rising, less than one eggcup full, or more than one eggcup full, and the color was recorded.
Patients attended the laboratory at the end of the run-in and treatment periods. At each visit spirometry (Vitalograph, Buckingham, UK) and sputum induction were performed. Diary cards were collected, and investigators checked treatment compliance as recorded by the patients. The run-in period of 2 wk enabled assessment of PEF variability, ability to comply with filling a diary card, and assessment of the stability of spirometry on two occasions.
Sputum Induction and Processing
Subjects inhaled 3.5% saline for 15 min via an ultrasonic nebulizer (DeVilbiss 2000; DeVilbiss Co., Heston, UK) with a calibrated mass median diameter of 4.5 µm and the output set at 4.5 ml/min. Prior to inhalation and before each expectoration, subjects discarded saliva into a separate bowl and mouthwashed thoroughly. Any secretions collected during the first 5 min were discarded in order to minimize squamous epithelial cell contamination (6). Secretions expectorated over the subsequent 10 min hereafter referred to as "sputum," were analyzed. Fresh samples were kept at 4° C for no more than 2 h before further processing.
The whole sputum sample was diluted with Hank's balanced salt
solution (HBSS) containing dithiothreitol (DTT) (Sigma Chemicals, Poole, UK), with a final DTT concentration of 0.2%, and was gently vortexed at room temperature. When homogeneous, the volume was recorded and the sample was further diluted with HBSS and centrifuged at 300 × g for 10 min. The supernatant was separated and stored at 
70° C and the cell pellet resuspended in 1 ml HBSS. Cell viability was determined by exclusion of Trypan Blue. Total cell counts were
determined on a hemocytometer slide using Kimura stain, and slides
were prepared using a cytospin (Shandon, Runcorn, UK) and stained
with May-Grunwald-Giemsa. Differential cell counts were performed
by a blinded observer with 300 nonsquamous cells counted on each of
two slides for each sample. Differential cell counts were expressed as
a percentage of lower airways cells (i.e., excluding squamous epithelial cells). Squamous cell counts were expressed as a percentage of total cells. Samples were considered adequate for analysis if there was < 50% squamous cell contamination.
Sputum Assays
IL-8 assay. IL-8 was measured with an amplified sandwich-type enzyme-linked immunosorbent assay (ELISA) using a paired antibody system (Genzyme Duoset; Genzyme Diagnostics, Cambridge, MA). Plates were washed between incubations with phosphate-buffered saline (PBS) containing 0.05% vol/vol Tween. Ninety-six-well microtiter plates (Greiner Labortecnik Ltd., Dursley, UK) were coated with 100 µl of mouse antihuman IL-8 at a concentration of 2.5 µg/ml and left overnight at 4° C. Blocking buffer of 0.1 M PBS containing 1% bovine serum albumin (BSA) was applied for 2 h at 37° C. Plates were decanted, and 100 µl of samples and standards were added and incubated at 37° C for 1 h. Then 100 µl of secondary antibody, rabbit anti-human IL-8 biotinylated were added at a concentration of 0.5 µg/ml and plates were incubated at 37° C for 1 h. The plates were incubated with Streptavidin-horseradish peroxidase for 15 min and 3,3',5,5'-tetramethylbenzidine (TMB) (Pharminagen, San Diego, CA) for 20 min. The reaction was stopped with 2N sulfuric acid, and the optical density of the wells was read using a plate photometer at 450 nm within 30 min. The lower limit of sensitivity of the assay was 15.6 pg/ml. The assay was linearly affected by DTT, and all standards were prepared using an equivalent concentration of DTT to that in the samples. The upper limit of detection of the assay was 1 ng/ml, and samples containing higher levels were diluted prior to assay.
SLPI assay. SLPI was measured by ELISA using a commercially available kit (R&D Systems, Minneapolis, MN). The assay measured in the range 62.5 to 4,000 pg/ml. Similar to that of IL-8, the effect of DTT was a linear reduction in the gradient of standard curves, which was compensated for by adding an equivalent concentration of DTT to standards.
Elastase assay. Elastolytic activity was measured by a method that uses N-methoxysuccinyl-ala-ala-pro-val p-nitroanilide (Sigma Chemicals) as a substrate. Samples, substrate, and TRIS buffer (pH, 8.6) were shaken at 1,000 rpm for 2 min and incubated for a further 60 min at 37° C. The plates were read using a photometer at 405 nm. Samples were compared with standards of human sputum elastase (HSE). The lower limit of detection of the assay was 0.05 µg/ml. Elastolytic activity was not altered by the presence of DTT in standards or samples.
MMP-1, MMP-9, and TIMP-1 assays. ELISA assays were performed using commercially available kits (Amersham Life Science; Amersham, Buckinghamshire, UK) and according to manufacturers instructions. The MMP-1 assay recognizes total MMP-1, i.e., free MMP-1, pro-MMP-1, and that complexed with TIMP-1. There is no cross-reactivity with MMP-2, 3, or 9, and the measurement range is 6.25 to 100 ng/ml. The MMP-9 assay recognizes pro-MMP-9 and pro-MMP-9 complexed with TIMP-1. MMP-9 can be measured in the range 1 to 32 ng/ml. The TIMP-1 assay recognizes free TIMP-1 and that complexed with MMPs. It does not cross-react with TIMP-2, and the lower limit of detection is 3.13 ng/ml. DTT was added to standard curves at an equivalent concentration to that in the sputum samples as the assays were affected similarly to the IL-8 assay.
Statistical Analysis
Parametric data are expressed as the mean ± SEM; nonparametric
data are expressed as medians and ranges. Data are presented as baseline values followed by post-FP values. Parametric data were compared
using Student's t test. For nonparametric data comparisons were made
using Wilcoxon's signed rank sum test between two groups
baseline (start of FP treatment period) and end of FP treatment period. Two-tailed tests were performed, and a p value of < 0.05 was considered significant.
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RESULTS |
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INTRODUCTION
METHODS
RESULTS
DISCUSSION
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A total of 12 subjects were withdrawn from the study. Five subjects failed to meet the inclusion/exclusion criteria after the run-in period: two of five had postbronchodilator FEV1 of 85% predicted on retesting, and the remainder were unable to complete diary cards or were unwilling to continue with the study. Of the seven withdrawn during the treatment phase, two suffered exacerbation of their airway disease (increased dyspnea, purulent sputum, and positive sputum culture requiring antibiotic therapy), one failed to take the study medication, and four completed treatment but failed to provide adequate sputum samples so were not evaluable. All subjects tolerated the medication and sputum induction procedure. The results presented are an analysis of the 13 subjects (8/13 male, 4/13 ex-smokers) who completed the study and had provided adequate samples from each study period. The subject characteristics remain the same as those outlined in METHODS. For all results there was no effect of placebo, baseline results for the placebo and treatment periods were equivalent, and there were no carryover effects of treatment. All 13 subjects were compliant with study medication, as assessed by diary card records: none reported missing more than two doses during the study.
Clinical Parameters
Subjects were 62 ± 2 yr of age and had moderate to severe airflow limitation, with a mean FEV1 49.5 ± 4.6% predicted. There was no significant difference in daily PEF between the placebo and FP treatment periods (278 ± 22 L/min versus 295 ± 22 L/min, p > 0.05). Similarly, there were no differences in median dyspnea score, cough, sputum production, sputum color, or percentage of relief medication-free days (Table 1).
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Cell Counts
Total inflammatory cell counts (millions/ml) were unchanged after FP (1.9, range, 0.6 to 4.3 versus 1.4; range, 0.3 to 3.3). The percentage of inflammatory cells identified as neutrophils was also unchanged (85%; range, 39 to 95% versus 76%; range, 28 to 95%) (Figure 1A) as was the absolute neutrophil number (millions/ml) (1.6; range, 0.3 to 6.9 versus 1.3; range, 0.3 to 2.9) (Table 2). The percentage of macrophages (Table 2), lymphocytes (< 3%), and eosinophils (< 3%) did not differ between the treatment periods (data not shown). Cell viability was 85% (range, 82 to 91%) in all samples, with no difference between treatment periods.
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Supernatant Measurements
All samples tested contained measurable amounts of all parameters. There were no changes in sputum IL-8 (Figure 1B), MMP-1, MMP-9 (Figure 2), or TIMP-1 (Figure 3) after FP treatment. Similar results were obtained for SLPI (Figure 3A) and elastase activity (Figure 2A). Results are summarized in Table 2. There was no relationship between the non-significant changes in cell counts, cytokines, or proteases.
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DISCUSSION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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The results of this study show that FP, at a dose of 500 µg twice a day, has no effect on lung function, inflammatory indices, proteases, or antiproteases that were measured in the induced sputum of patients with COPD.
Studies on induced sputum in asthmatic subjects suggest that the technique is sensitive enough to demonstrate changes that reflect reduced inflammation (27). Induced sputum analysis can also distinguish between asthmatic and healthy subjects and subjects with COPD (6) and has been validated in these groups (28). Therefore, the lack of a demonstrable treatment effect is unlikely to be solely attributable to the methods used. FP is a potent corticosteroid and the dose of 500 µg once a day should be therapeutic, especially when delivered via a spacer device. Therefore, treatment failure is unlikely to be due to the dose used or the method of administration. A 4-wk treatment period is short in clinical terms, and this could account for the lack of clinical improvement. Many studies have used longer treatment courses and also failed to show clinical benefit (29). However, a number of published studies have shown improvement in airway inflammation (30, 31) and lung function (32). Four weeks of treatment may not be sufficient to observe reduction in cell counts, but the time course of steroid action on gene expression suggests that an effect on cytokines and MMPs would be observed in this time period. The current study included smokers and ex-smokers, but numbers were too small to identify a difference in response between them. There was no change in the smoking habit of the subjects during the study and no differences in the sputum characteristics of smokers and ex-smokers at baseline or after FP treatment. However, we cannot exclude a differential response to steroids between patients with COPD who smoke and those who abstain. This was a small study and no formal power calculation was carried out. Underpowering of the study may be responsible for the negative results.
The lack of anti-inflammatory effect may account for the failure of FP to modify elastase activity. IL-8 is a potent chemoattractant for neutrophils (33), which in turn provide elastase activity, and we have demonstrated that IL-8 levels are not reduced after treatment. MMPs are also upregulated by mediators of inflammation (34). It is possible that whereas inflammation is present it outweighs the downregulation of MMP mRNA and protein synthesis achieved by steroids (35). Oxidative stress, thought to be important in COPD (5), may also contribute to an ongoing stimulus for MMP activation. Neutrophil collagenases are activated by chlorinated oxidants, thiol-driven activation of MMPs has been demonstrated, and oxidants can inactivate the antiprotease shield (11), all of which contribute to ongoing protease-antiprotease imbalance.
In summary we have demonstrated the presence of measurable quantities of MMP-1, MMP-9, and TIMP-1 in the induced sputum of subjects with COPD. FP has no effect on the levels of these proteases, nor does it alter elastase activity or SLPI. In addition we have confirmed the results of previous studies, which demonstrated no effect of inhaled steroids on induced sputum inflammatory indices.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Professor P. J. Barnes, National Heart and Lung Institute, Department of Thoracic Medicine, Dovehouse Street, London, SW3 6LY, UK. E-mail: p.j.barnes{at}ic.ac.uk
(Received in original form November 16, 1998 and in revised form May 18, 1999).
Acknowledgments: Supported by Glaxo-Wellcome UK.
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References |
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METHODS
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DISCUSSION
REFERENCES
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D. A. Ngan, S. V. Vickerman, D. J. Granville, S. F. P. Man, and D. D. Sin The possible role of granzyme B in the pathogenesis of chronic obstructive pulmonary disease Therapeutic Advances in Respiratory Disease, June 1, 2009; 3(3): 113 - 129. [Abstract] [PDF]
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D-W. Perng, C-W. Tao, K-C. Su, C-C. Tsai, L-Y. Liu, and Y-C. Lee Anti-inflammatory effects of salmeterol/fluticasone, tiotropium/fluticasone or tiotropium in COPD Eur. Respir. J., April 1, 2009; 33(4): 778 - 784. [Abstract] [Full Text] [PDF]
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 K. K. Meja, S. Rajendrasozhan, D. Adenuga, S. K. Biswas, I. K. Sundar, G. Spooner, J. A. Marwick, P. Chakravarty, D. Fletcher, P. Whittaker, et al. Curcumin Restores Corticosteroid Function in Monocytes Exposed to Oxidants by Maintaining HDAC2 Am. J. Respir. Cell Mol. Biol., September 1, 2008; 39(3): 312 - 323. [Abstract] [Full Text] [PDF]
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K. F. Chung and I. M. Adcock Multifaceted mechanisms in COPD: inflammation, immunity, and tissue repair and destruction Eur. Respir. J., June 1, 2008; 31(6): 1334 - 1356. [Abstract] [Full Text] [PDF]
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 V. Kim, T. J. Rogers, and G. J. Criner New Concepts in the Pathobiology of Chronic Obstructive Pulmonary Disease Proceedings of the ATS, May 1, 2008; 5(4): 478 - 485. [Abstract] [Full Text] [PDF]
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M. Cazzola, W. MacNee, F. J. Martinez, K. F. Rabe, L. G. Franciosi, P. J. Barnes, V. Brusasco, P. S. Burge, P. M. A. Calverley, B. R. Celli, et al. Outcomes for COPD pharmacological trials: from lung function to biomarkers Eur. Respir. J., February 1, 2008; 31(2): 416 - 469. [Abstract] [Full Text] [PDF]
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 C. Costa, R. Rufino, S. L. Traves, J. R. Lapa e Silva, P. J. Barnes, and L. E. Donnelly CXCR3 and CCR5 Chemokines in Induced Sputum From Patients With COPD Chest, January 1, 2008; 133(1): 26 - 33. [Abstract] [Full Text] [PDF]
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D. J. Powrie, T. M. A. Wilkinson, G. C. Donaldson, P. Jones, K. Scrine, K. Viel, S. Kesten, and J. A. Wedzicha Effect of tiotropium on sputum and serum inflammatory markers and exacerbations in COPD Eur. Respir. J., September 1, 2007; 30(3): 472 - 478. [Abstract] [Full Text] [PDF]
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 P. Ernst, A. V. Gonzalez, P. Brassard, and S. Suissa Inhaled Corticosteroid Use in Chronic Obstructive Pulmonary Disease and the Risk of Hospitalization for Pneumonia Am. J. Respir. Crit. Care Med., July 15, 2007; 176(2): 162 - 166. [Abstract] [Full Text] [PDF]
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 F. Komatsu, H. Kudoh, and Y. Kagawa Evaluation of Oxidative Stress and Effectiveness of Low-Dose Glucocorticoid Therapy on Exacerbation of Chronic Obstructive Pulmonary Disease J. Gerontol. A Biol. Sci. Med. Sci., April 1, 2007; 62(4): 459 - 464. [Abstract] [Full Text] [PDF]
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P. Paredi, S. Ward, D. Cramer, P. J. Barnes, and S. A. Kharitonov Normal Bronchial Blood Flow in COPD Is Unaffected by Inhaled Corticosteroids and Correlates With Exhaled Nitric Oxide Chest, April 1, 2007; 131(4): 1075 - 1081. [Abstract] [Full Text] [PDF]
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T. Tao, J. Lan, G. L. Lukacs, R. J. G. Hache, and F. Kaplan Importin 13 Regulates Nuclear Import of the Glucocorticoid Receptor in Airway Epithelial Cells Am. J. Respir. Cell Mol. Biol., December 1, 2006; 35(6): 668 - 680. [Abstract] [Full Text] [PDF]
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P. J. Barnes Against the dutch hypothesis: asthma and chronic obstructive pulmonary disease are distinct diseases. Am. J. Respir. Crit. Care Med., August 1, 2006; 174(3): 240 - 243. [Full Text] [PDF]
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I. Rahman and I. M. Adcock Oxidative stress and redox regulation of lung inflammation in COPD. Eur. Respir. J., July 1, 2006; 28(1): 219 - 242. [Abstract] [Full Text] [PDF]
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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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O. Leclerc, V. Lagente, J-M. Planquois, C. Berthelier, M. Artola, T. Eichholtz, C. P. Bertrand, and F. Schmidlin Involvement of MMP-12 and phosphodiesterase type 4 in cigarette smoke-induced inflammation in mice Eur. Respir. J., June 1, 2006; 27(6): 1102 - 1109. [Abstract] [Full Text] [PDF]
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 M A Dentener, R Louis, R H E Cloots, M Henket, and E F M Wouters Differences in local versus systemic TNF{alpha} production in COPD: inhibitory effect of hyaluronan on LPS induced blood cell TNF{alpha} release Thorax, June 1, 2006; 61(6): 478 - 484. [Abstract] [Full Text] [PDF]
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E. F. M. Wouters Approaches to Improving Health Status in Chronic Obstructive Pulmonary Disease: One or Several? Proceedings of the ATS, May 1, 2006; 3(3): 262 - 269. [Abstract] [Full Text] [PDF]
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C. Bergeron and L.-P. Boulet Structural changes in airway diseases: characteristics, mechanisms, consequences, and pharmacologic modulation. Chest, April 1, 2006; 129(4): 1068 - 1087. [Abstract] [Full Text] [PDF]
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L.-P. Boulet, C. Lemiere, F. Archambault, G. Carrier, M. C. Descary, and F. Deschesnes Smoking and Asthma: Clinical and Radiologic Features, Lung Function, and Airway Inflammation Chest, March 1, 2006; 129(3): 661 - 668. [Abstract] [Full Text] [PDF]
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P. J. Barnes Corticosteroid effects on cell signalling Eur. Respir. J., February 1, 2006; 27(2): 413 - 426. [Abstract] [Full Text] [PDF]
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P. J. Barnes Reduced Histone Deacetylase in COPD: Clinical Implications Chest, January 1, 2006; 129(1): 151 - 155. [Abstract] [Full Text] [PDF]
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D D Sin, L Wu, J A Anderson, N R Anthonisen, A S Buist, P S Burge, P M Calverley, J E Connett, B Lindmark, R A Pauwels, et al. Inhaled corticosteroids and mortality in chronic obstructive pulmonary disease Thorax, December 1, 2005; 60(12): 992 - 997. [Abstract] [Full Text] [PDF]
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W. MacNee Pathogenesis of Chronic Obstructive Pulmonary Disease Proceedings of the ATS, November 1, 2005; 2(4): 258 - 266. [Abstract] [Full Text] [PDF]
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I. M. Adcock and K. Ito Glucocorticoid Pathways in Chronic Obstructive Pulmonary Disease Therapy Proceedings of the ATS, November 1, 2005; 2(4): 313 - 319. [Abstract] [Full Text] [PDF]
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P. J. Barnes Theophylline in Chronic Obstructive Pulmonary Disease: New Horizons Proceedings of the ATS, November 1, 2005; 2(4): 334 - 339. [Abstract] [Full Text] [PDF]
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P. A. Martorana, R. Beume, M. Lucattelli, L. Wollin, and G. Lungarella Roflumilast Fully Prevents Emphysema in Mice Chronically Exposed to Cigarette Smoke Am. J. Respir. Crit. Care Med., October 1, 2005; 172(7): 848 - 853. [Abstract] [Full Text] [PDF]
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M. A. Birrell, S. Wong, D. J. Hele, K. McCluskie, E. Hardaker, and M. G. Belvisi Steroid-resistant Inflammation in a Rat Model of Chronic Obstructive Pulmonary Disease Is Associated with a Lack of Nuclear Factor-{kappa}B Pathway Activation Am. J. Respir. Crit. Care Med., July 1, 2005; 172(1): 74 - 84. [Abstract] [Full Text] [PDF]
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P. J. Barnes and R. A. Stockley COPD: current therapeutic interventions and future approaches Eur. Respir. J., June 1, 2005; 25(6): 1084 - 1106. [Abstract] [Full Text] [PDF]
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 L. de Garavilla, M. N. Greco, N. Sukumar, Z.-W. Chen, A. O. Pineda, F. S. Mathews, E. Di Cera, E. C. Giardino, G. I. Wells, B. J. Haertlein, et al. A Novel, Potent Dual Inhibitor of the Leukocyte Proteases Cathepsin G and Chymase: MOLECULAR MECHANISMS AND ANTI-INFLAMMATORY ACTIVITY IN VIVO J. Biol. Chem., May 6, 2005; 280(18): 18001 - 18007. [Abstract] [Full Text] [PDF]
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S. F. P. Man and D. D. Sin Effects of Corticosteroids on Systemic Inflammation in Chronic Obstructive Pulmonary Disease Proceedings of the ATS, April 1, 2005; 2(1): 78 - 82. [Abstract] [Full Text] [PDF]
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M. Alvarez-Mon, M. Miravitlles, J. Morera, L. Callol, and J. L. Alvarez-Sala Treatment With the Immunomodulator AM3 Improves the Health-Related Quality of Life of Patients With COPD Chest, April 1, 2005; 127(4): 1212 - 1218. [Abstract] [Full Text] [PDF]
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P. J. Barnes, I. M. Adcock, and K. Ito Histone acetylation and deacetylation: importance in inflammatory lung diseases Eur. Respir. J., March 1, 2005; 25(3): 552 - 563. [Abstract] [Full Text] [PDF]
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C E Brightling, S McKenna, B Hargadon, S Birring, R Green, R Siva, M Berry, D Parker, W Monteiro, I D Pavord, et al. Sputum eosinophilia and the short term response to inhaled mometasone in chronic obstructive pulmonary disease Thorax, March 1, 2005; 60(3): 193 - 198. [Abstract] [Full Text] [PDF]
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A. Linden, M. Laan, and G. P. Anderson Neutrophils, interleukin-17A and lung disease Eur. Respir. J., January 1, 2005; 25(1): 159 - 172. [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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P. Chanez, A. Bourdin, I. Vachier, P. Godard, J. Bousquet, and A. M. Vignola Effects of Inhaled Corticosteroids on Pathology in Asthma and Chronic Obstructive Pulmonary Disease Proceedings of the ATS, November 1, 2004; 1(3): 184 - 190. [Abstract] [Full Text] [PDF]
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M. G. Belvisi Regulation of Inflammatory Cell Function by Corticosteroids Proceedings of the ATS, November 1, 2004; 1(3): 207 - 214. [Abstract] [Full Text] [PDF]
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R. P. Schleimer Glucocorticoids Suppress Inflammation but Spare Innate Immune Responses in Airway Epithelium Proceedings of the ATS, November 1, 2004; 1(3): 222 - 230. [Abstract] [Full Text] [PDF]
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I. M. Adcock, K. Ito, and P. J. Barnes Glucocorticoids: Effects on Gene Transcription Proceedings of the ATS, November 1, 2004; 1(3): 247 - 254. [Abstract] [Full Text] [PDF]
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P. J. Barnes Corticosteroid Resistance in Airway Disease Proceedings of the ATS, November 1, 2004; 1(3): 264 - 268. [Abstract] [Full Text] [PDF]
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D. D. Sin, P. Lacy, E. York, and S. F. P. Man Effects of Fluticasone on Systemic Markers of Inflammation in Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., October 1, 2004; 170(7): 760 - 765. [Abstract] [Full Text] [PDF]
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 S. Lam, J. C. leRiche, A. McWilliams, C. MacAulay, Y. Dyachkova, E. Szabo, J. Mayo, R. Schellenberg, A. Coldman, E. Hawk, et al. A Randomized Phase IIb Trial of Pulmicort Turbuhaler (Budesonide) in People with Dysplasia of the Bronchial Epithelium Clin. Cancer Res., October 1, 2004; 10(19): 6502 - 6511. [Abstract] [Full Text] [PDF]
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 L. E. Donnelly, R. Newton, G. E. Kennedy, P. S. Fenwick, R. H. F. Leung, K. Ito, R. E. K. Russell, and P. J. Barnes Anti-inflammatory effects of resveratrol in lung epithelial cells: molecular mechanisms Am J Physiol Lung Cell Mol Physiol, October 1, 2004; 287(4): L774 - L783. [Abstract] [Full Text] [PDF]
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A. Barczyk, E. Sozanska, M. Trzaska, and W. Pierzchala Decreased Levels of Myeloperoxidase in Induced Sputum of Patients With COPD After Treatment With Oral Glucocorticoids Chest, August 1, 2004; 126(2): 389 - 393. [Abstract] [Full Text] [PDF]
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 S. L. Traves, S. J. Smith, P. J. Barnes, and L. E. Donnelly Specific CXC but not CC chemokines cause elevated monocyte migration in COPD: a role for CXCR2 J. Leukoc. Biol., August 1, 2004; 76(2): 441 - 450. [Abstract] [Full Text] [PDF]
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D. W. Mapel Treatment Implications on Morbidity and Mortality in COPD Chest, August 1, 2004; 126(2_suppl_1): 150S - 158S. [Abstract] [Full Text] [PDF]
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M. Cazzola and R. Dahl Inhaled Combination Therapy With Long-Acting {beta}2-Agonists and Corticosteroids in Stable COPD Chest, July 1, 2004; 126(1): 220 - 237. [Abstract] [Full Text] [PDF]
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D. Banerjee, O.A. Khair, and D. Honeybourne Impact of sputum bacteria on airway inflammation and health status in clinical stable COPD Eur. Respir. J., May 1, 2004; 23(5): 685 - 691. [Abstract] [Full Text] [PDF]
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M.N. de Melo, P. Ernst, and S. Suissa Inhaled corticosteroids and the risk of a first exacerbation in COPD patients Eur. Respir. J., May 1, 2004; 23(5): 692 - 697. [Abstract] [Full Text] [PDF]
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P.N.R. Dekhuijzen Antioxidant properties of N-acetylcysteine: their relevance in relation to chronic obstructive pulmonary disease Eur. Respir. J., April 1, 2004; 23(4): 629 - 636. [Abstract] [Full Text] [PDF]
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 D. D. Sin, F. A. McAlister, S. F. P. Man, and N. R. Anthonisen Contemporary Management of Chronic Obstructive Pulmonary Disease: Scientific Review JAMA, November 5, 2003; 290(17): 2301 - 2312. [Abstract] [Full Text] [PDF]
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E{-}J.D. Oudijk, J{-}W.J. Lammers, and L. Koenderman Systemic inflammation in chronic obstructive pulmonary disease Eur. Respir. J., November 2, 2003; 22(46_suppl): 5s - 13s. [Abstract] [Full Text] [PDF]
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E R Sutherland, H Allmers, N T Ayas, A J Venn, and R J Martin Inhaled corticosteroids reduce the progression of airflow limitation in chronic obstructive pulmonary disease: a meta-analysis Thorax, November 1, 2003; 58(11): 937 - 941. [Abstract] [Full Text] [PDF]
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E. Gamble, D. C. Grootendorst, C. E. Brightling, S. Troy, Y. Qiu, J. Zhu, D. Parker, D. Matin, S. Majumdar, A. M. Vignola, et al. Antiinflammatory Effects of the Phosphodiesterase-4 Inhibitor Cilomilast (Ariflo) in Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., October 15, 2003; 168(8): 976 - 982. [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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K. Kostikas, G. Papatheodorou, K. Psathakis, P. Panagou, and S. Loukides Oxidative Stress in Expired Breath Condensate of Patients With COPD Chest, October 1, 2003; 124(4): 1373 - 1380. [Abstract] [Full Text] [PDF]
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 P. J. Barnes and I. M. Adcock How Do Corticosteroids Work in Asthma? Ann Intern Med, September 2, 2003; 139(5_Part_1): 359 - 370. [Full Text] [PDF]
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N. A. Hanania, P. Darken, D. Horstman, C. Reisner, B. Lee, S. Davis, and T. Shah The Efficacy and Safety of Fluticasone Propionate (250 {micro}g)/Salmeterol (50 {micro}g) Combined in the Diskus Inhaler for the Treatment of COPD Chest, September 1, 2003; 124(3): 834 - 843. [Abstract] [Full Text] [PDF]
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B. Suki, K. R. Lutchen, and E. P. Ingenito On the Progressive Nature of Emphysema: Roles of Proteases, Inflammation, and Mechanical Forces Am. J. Respir. Crit. Care Med., September 1, 2003; 168(5): 516 - 521. [Full Text] [PDF]
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The pharmacoepidemiology of COPD: Recent advances and methodological discussion Eur. Respir. J., September 1, 2003; 22(43_suppl): 1s - 44s. [Full Text] [PDF]
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P J Barnes Chronic obstructive pulmonary disease * 12: New treatments for COPD Thorax, September 1, 2003; 58(9): 803 - 808. [Full Text] [PDF]
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J. Bourbeau, P. Ernst, D. Cockcoft, and S. Suissa Inhaled corticosteroids and hospitalisation due to exacerbation of COPD Eur. Respir. J., August 1, 2003; 22(2): 286 - 289. [Abstract] [Full Text] [PDF]
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R.O. Crapo, R.L. Jensen, and F.E. Hargreave Airway inflammation in COPD: physiological outcome measures and induced sputum Eur. Respir. J., June 1, 2003; 21(41_suppl): 19S - 28s. [Abstract] [Full Text] [PDF]
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S. Escotte, O. Tabary, D. Dusser, C. Majer-Teboul, E. Puchelle, and J. Jacquot Fluticasone reduces IL-6 and IL-8 production of cystic fibrosis bronchial epithelial cells via IKK-{beta} kinase pathway Eur. Respir. J., April 1, 2003; 21(4): 574 - 581. [Abstract] [Full Text] [PDF]
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P.G. Gibson, P.A.B. Wark, J.L. Simpson, C. Meldrum, S. Meldrum, N. Saltos, and M. Boyle Induced sputum IL-8 gene expression, neutrophil influx and MMP-9 in allergic bronchopulmonary aspergillosis Eur. Respir. J., April 1, 2003; 21(4): 582 - 588. [Abstract] [Full Text] [PDF]
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J. Domagala-Kulawik, M. Maskey-Warzechowska, I. Kraszewska, and R. Chazan The Cellular Composition and Macrophage Phenotype in Induced Sputum in Smokers and Ex-Smokers With COPD Chest, April 1, 2003; 123(4): 1054 - 1059. [Abstract] [Full Text] [PDF]
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K. M. Beeh, O. Kornmann, R. Buhl, S. V. Culpitt, M. A. Giembycz, and P. J. Barnes Neutrophil Chemotactic Activity of Sputum From Patients With COPD: Role of Interleukin 8 and Leukotriene B4 Chest, April 1, 2003; 123(4): 1240 - 1247. [Abstract] [Full Text] [PDF]
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P. J. Barnes Theophylline: New Perspectives for an Old Drug Am. J. Respir. Crit. Care Med., March 15, 2003; 167(6): 813 - 818. [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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H. Garn, A. Siese, S. Stumpf, P. J. Barth, B. Muller, and D. Gemsa Shift Toward an Alternatively Activated Macrophage Response in Lungs of NO2-Exposed Rats Am. J. Respir. Cell Mol. Biol., March 1, 2003; 28(3): 386 - 396. [Abstract] [Full Text] [PDF]
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K. M. Beeh, J. Beier, O. Kornmann, A. Mander, and R. Buhl Long-term Repeatability of Induced Sputum Cells and Inflammatory Markers in Stable, Moderately Severe COPD Chest, March 1, 2003; 123(3): 778 - 783. [Abstract] [Full Text] [PDF]
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D.D. Sin and S.F.P. Man Inhaled corticosteroids and survival in chronic obstructive pulmonary disease: does the dose matter? Eur. Respir. J., February 1, 2003; 21(2): 260 - 266. [Abstract] [Full Text] [PDF]
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S. V. Culpitt, D. F. Rogers, P. Shah, C. De Matos, R. E. K. Russell, L. E. Donnelly, and P. J. Barnes Impaired Inhibition by Dexamethasone of Cytokine Release by Alveolar Macrophages from Patients with Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., January 1, 2003; 167(1): 24 - 31. [Abstract] [Full Text] [PDF]
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S L Traves, S V Culpitt, R E K Russell, P J Barnes, and L E Donnelly Increased levels of the chemokines GRO{alpha} and MCP-1 in sputum samples from patients with COPD Thorax, July 1, 2002; 57(7): 590 - 595. [Abstract] [Full Text] [PDF]
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Leader of the Working Group: M.M. Kelly, Members of the Working Group:, V. Keatings, R. Leigh, C. Peterson, J. Shute, P. Venge, and R. Djukanovic Analysis of fluid{-}phase mediators Eur. Respir. J., July 1, 2002; 20(37_suppl): 24S - 39s. [Full Text] [PDF]
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S. V. Culpitt, C. de Matos, R. E. Russell, L. E. Donnelly, D. F. Rogers, and P. J. Barnes Effect of Theophylline on Induced Sputum Inflammatory Indices and Neutrophil Chemotaxis in Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., May 15, 2002; 165(10): 1371 - 1376. [Abstract] [Full Text] [PDF]
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G. Sturton and M. Fitzgerald Phosphodiesterase 4 Inhibitors for the Treatment of COPD* Chest, May 1, 2002; 121 (2009): 192S - 196S. [Abstract] [Full Text] [PDF]
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W. I. de Boer Cytokines and Therapy in COPD* : A Promising Combination? Chest, May 1, 2002; 121 (2009): 209S - 218S. [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. PILETTE, V. GODDING, R. KISS, M. DELOS, E. VERBEKEN, C. DECAESTECKER, K. DE PAEPE, J.-P. VAERMAN, M. DECRAMER, and Y. SIBILLE Reduced Epithelial Expression of Secretory Component in Small Airways Correlates with Airflow Obstruction in Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., January 1, 2001; 163(1): 185 - 194. [Abstract] [Full Text]
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A. Hill, S. Gompertz, and R. Stockley Factors influencing airway inflammation in chronic obstructive pulmonary disease Thorax, November 1, 2000; 55(11): 970 - 977. [Full Text]
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 P. J. Barnes Chronic Obstructive Pulmonary Disease N. Engl. J. Med., July 27, 2000; 343(4): 269 - 280. [Full Text] [PDF]
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P. J. BARNES Inhaled Corticosteroids Are Not Beneficial in Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., February 1, 2000; 161(2): 342 - 344. [Full Text]
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P. J. Barnes Mechanisms in COPD : Differences From Asthma Chest, February 1, 2000; 117 (2009): 10S - 14S. [Abstract] [Full Text] [PDF]
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