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The Proceedings of the American Thoracic Society 2:78-82 (2005)
© 2005 The American Thoracic Society

Effects of Corticosteroids on Systemic Inflammation in Chronic Obstructive Pulmonary Disease

S. F. Paul Man and Don D. Sin

Department of Medicine, University of British Columbia; and the James Hogg iCAPTURE Center for Cardiovascular and Pulmonary Research, St. Paul's Hospital, Vancouver, British Columbia, Canada

Correspondence and requests for reprints should be addressed to S. F. Paul Man, M.D., Room 548, Burrard Building, St. Paul's Hospital, 1081 Burrard Street, Vancouver, BC V6Z 1Y7, Canada. E-mail: pman{at}providencehealth.bc.ca


   ABSTRACT
TOP
 ABSTRACT
COPD: More than a...
 Linking COPD to Extrapulmonary...
 CONCLUSIONS
 REFERENCES
 
Patients with chronic obstructive pulmonary disease (COPD) are predisposed to atherosclerosis and coronary artery disease, but the underlying mechanisms are unclear. Although there is wide acceptance that atherosclerosis is related to systemic inflammation, the cause(s) and mechanism(s) of pulmonary inflammation in stable COPD remain unknown. Infectious (bacterial and viral) as well as noninfectious agents can cause acute exacerbations in COPD, and they intensify local and systemic inflammation. Although it is not known how systemic inflammation develops in stable COPD, there is good evidence to suggest that it occurs and that the intensity of systemic inflammation is linked to the severity of airflow obstruction. We postulate that systemic inflammation provides the linkage between COPD and atherosclerosis. Inhaled corticosteroids have been shown to improve health outcomes in COPD, but the mechanism by which this occurs is a pivotal and challenging question that has yet to be answered. To prove the concept that inhaled corticosteroids could suppress systemic inflammation (as exemplified by serum C-reactive protein [CRP] levels), a double-blind, placebo-controlled clinical trial was conducted in a group of patients with mild to moderate COPD. We found that withdrawal of inhaled corticosteroids increased serum CRP levels, and that reintroduction of inhaled fluticasone could suppress CRP levels.

Key Words: C-reactive protein • chronic obstructive pulmonary disease • corticosteroid • systemic inflammation

Patients with chronic obstructive pulmonary disease (COPD) often have extrapulmonary organ involvement beyond that which can be explained solely as being the result of abnormal blood gases. Oxidative stress (1–3) and systemic inflammation (4) are considered to be mechanistically linked to the extrapulmonary manifestations in COPD (Figure 1). Coronary heart disease is a common cause of death in COPD. We postulate that systemic inflammation, evidenced by the presence of increased numbers of inflammatory cells and endogenous levels of proinflammatory molecules, may link COPD to extrapulmonary manifestations, such as coronary vascular disease. This article examines the presence of systemic inflammation in COPD, and provides preliminary evidence that therapy with inhaled corticosteroids may modulate such a process.



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  		Figure 1. Oxidative stress and inflammation in the lung in chronic obstructive pulmonary disease. Cigarette smoke, other environmental irritants, and infection produce oxidative stress and/or inflammation in the lung. Collectively and individually, inflammatory cells may be activated and/or recruited. Oxidants and products of inflammatory cells or airway cells may affect distant organs by their direct action, or through their action on an intermediate organ, such as the bone marrow or the liver, which in turn release blood elements or C-reactive protein (CRP) and fibrinogen, respectively, into the blood circulation.

 

   COPD: More than a Lung Disease
TOP
 ABSTRACT
 COPD: More than a...
Linking COPD to Extrapulmonary...
 CONCLUSIONS
 REFERENCES
 
COPD is recognized now as a systemic disorder, the extrapulmonary manifestations of which involve diverse organs, resulting in skeletal muscle dysfunction, muscle wasting (4), osteoporosis (5), and atherosclerosis and its associated complications (6). Current evidence suggests roles for oxidative stress (7), inflammatory mediators, including several cytokines (8), and endocrine hormones (9, 10) in these extrapulmonary manifestations in COPD. Importantly, there is a general association between the severity of the airflow obstruction and the severity of extrapulmonary end-organ damage in patients with COPD. As an example, poor lung function has been shown to be a better predictor of cardiac mortality than serum cholesterol (6). In fact, approximately 50% of patients with COPD have ischemic heart disease or stroke as the primary cause of death and approximately 20% of patients with COPD die from lung cancer or respiratory failure (6).


   Linking COPD to Extrapulmonary Manifestations
TOP
 ABSTRACT
 COPD: More than a...
 Linking COPD to Extrapulmonary...
CONCLUSIONS
 REFERENCES
 
COPD is characterized by chronic inflammation in the respiratory tract. In the early stages of disease, the inflammatory process, initiated mainly by smoke inhalation, may be self-limited and reversible. With time, however, pulmonary inflammation becomes chronic and persistent, even after the cessation of cigarette smoking (11). When COPD becomes established, extrapulmonary manifestations become increasingly evident. The exact mechanism by which local changes in the lungs result in organ damage elsewhere in the body is not known, but the connection has been postulated to occur by: (1) spilling over of reactive oxygen species and stress-induced cytokines directly into the systemic circulation (12); (2) activation of peripheral blood leukocytes or bone marrow precursors that can result in changes in extrapulmonary organs (13, 14); or (3) proinflammatory mediators liberated by inflammatory cells, and/or structural cells, during progression of the disease further amplify their effect through their action on organs, such as the bone marrow or liver. On stimulation, these organs, in turn, produce more white blood cells and platelets, and C-reactive protein (CRP) and fibrinogen (15). Although these processes can be considered independent, in reality they often interact, and more than one pathway can be operational at one time.

Elevated levels of several potent proinflammatory cytokines and other mediators have been demonstrated in the lungs of patients with COPD (8). For example, interleukin (IL)-8 and tumor necrosis factor (TNF)-{alpha} are present in induced sputum (16), and their levels increase further during exacerbation (17). IL-10, which can reduce inflammatory responses, is found in lower concentrations in smokers with COPD (18). The levels of TNF-{alpha} and IL-8 are increased in bronchoalveolar lavage fluid from chronic smokers compared to nonsmokers (19). Levels of other proinflammatory molecules, such as serum leptin, a hormone that can promote atherothrombosis, are raised in individuals with impaired lung function (10). Blood levels of IL-6, and TNF-{alpha}, as well as the soluble receptors for these cytokines, are two to three times higher in subjects with COPD than in the non-COPD population (20–22). Importantly, these levels correlate directly with the severity of airflow impairment (23).

Recent years have witnessed a better understanding of the mechanisms underlying pulmonary inflammation in COPD, one of which is bacterial colonization and/or infection, by organisms such as Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae (24). Although noninfectious particulates and nonparticulates can cause acute exacerbation in COPD (reviewed by van Eeden in this issue of PATS, pp. 61–67), the majority of exacerbations are due to bacterial or viral infections. Indeed, it has been reported that many exacerbations can be linked to a new strain of bacterial pathogen, such as H. influenzae (25), or viral infections (26–28). During acute exacerbations, levels of IL-6 and TNF-{alpha} (17), and IL-8 and TNF-{alpha} (29) increase markedly in sputum, and TNF receptors and CRP increase in the systemic circulation (30). Moreover, the rise in systemic inflammatory molecules during acute exacerbations correlates closely with the increase in sputum indices of inflammation, suggesting that there may be a link between lung and systemic inflammation (31).

An imbalance between oxidants and antioxidants plays an important role in the pathogenesis of COPD (7; reviewed by MacNee in this issue of PATS, pp. 50–60). The imbalance in oxidant production and intra- and extracellular antioxidant defense systems are responsible for some of the molecular and structural changes in the respiratory system in COPD. Interestingly, inflammation and hypoxia can trigger oxidative stress in skeletal muscles resulting in muscle dysfunction (32). Also, oxidative stress produced by inhalation of tobacco smoke can make inflammation resistant to antiinflammatory drugs, including corticosteroids (33).

Evidence that Systemic Inflammation Exists in COPD
Sin and Man (15; reviewed in this issue of PATS, pp. 78–82) have examined for the presence of systemic inflammation in the general population using the National Health and Nutrition Examination Survey-3 database. This study (15) has demonstrated that low-grade systemic inflammation was present in participants with moderate to severe airflow obstruction, and that the low-grade inflammation was associated with an increased risk of cardiac injury. Moreover, the findings also suggest an additive effect of high CRP levels and the severity of airflow obstruction on the risk of cardiac injury. One limitation of this study is that causality cannot be established.

In a recent systematic review and metaanalysis, Gan and colleagues (34) reported on systemic inflammation in individuals with stable COPD. They reviewed studies that reported on the relationship between COPD, FEV1, or FVC and levels of systemic inflammatory markers that included serum CRP, fibrinogen, TNF-{alpha}, IL-6, and IL-8, in addition to blood leukocyte counts. Overall, the standardized mean difference in the CRP level between subjects with COPD and control subjects was 0.53 units (95% confidence interval [CI], 0.34–0.72) or 1.86 mg/L (95% CI, 0.75–2.97 mg/L) using a weighted mean difference technique. The standardized mean difference in the fibrinogen level was 0.47 units (95% CI, 0.29–0.65), or 0.37 g/L (95% CI, 0.18–0.56 g/L). Blood leukocyte counts were also higher in subjects with COPD than in control subjects (standardized mean difference, 0.44 units; 95% CI, 0.20–0.67) or 0.88 x 109 cells/L (95% CI, 0.36–1.40 x 109 cells/L). Likewise, serum TNF-{alpha} levels were higher in subjects with COPD than in control subjects (standardized mean difference, 0.59 units; 95% CI, 0.29–0.89) or 2.64 pg/ml (95% CI, –0.44 to 5.72 pg/ml). It was concluded that reduced lung function is associated with elevated levels of systemic inflammatory markers that are, in turn, known to be associated with atherosclerosis.

Evidence that Corticosteroids May Be Beneficial in Stable COPD
There is considerable controversy concerning the utility of inhaled corticosteroids for the long-term treatment of patients with COPD. Recent studies have suggested that although inhaled corticosteroids do not alter the rate of decline in lung function, they may reduce bronchial hyperreactivity, decrease the frequency of exacerbations, and slow the rate of decline in the patient's health status (35).

Sin and Tu (36) reported on a population-based cohort study (n = 22,620) using administrative databases from the Province of Ontario, Canada, and showed an association between therapy with inhaled corticosteroids and the combined risk of repeat hospitalization and all-cause mortality in elderly patients with COPD. A total of 25% of the patients had a repeat hospitalization and 11% died during the study period. Patients who received inhaled corticosteroids after discharge (within 90 days) had 24% fewer repeat hospitalizations for COPD (95% CI, 22–35%) and were 29% less likely to experience mortality (95% CI, 22–35%) during 1 year of follow-up. This cohort study has suggested that inhaled corticosteroid therapy is associated with reduced COPD-related morbidity and mortality in elderly patients. Using a database from the Province of Alberta, Canada, Sin and Man (37) extended the above observations to look at the relationship between the dose of inhaled corticosteroids and mortality. For all patients aged 65 years or older hospitalized due to COPD, the relative risk (RR) for all-cause mortality was compared across different dose categories of inhaled corticosteroids (none versus low doses, medium versus high doses) after hospital discharge. The low dose was 500 µg/day or less of beclomethasone or equivalent, the medium dose was from 501–1,000 µg/day, and the high dose was greater than 1,000 µg/day. Inhaled corticosteroid therapy after discharge was associated with a 25% relative reduction in risk for all-cause mortality (RR, 0.75; 95% CI, 0.68–0.82). Patients on medium- or high-dose therapy showed lower risks for mortality than those on low doses (RR, 0.77; 95% CI, 0.69–0.86 for low dose; RR, 0.48; 95% CI, 0.37–0.63 for medium dose; and RR, 0.55; 95% CI, 0.44–0.69 for high dose). Low-dose was not as effective as medium- or high-dose therapy in protecting against mortality in COPD.

In an observational study by Jared and colleagues, it was reported that, in 272 subjects with mean FEV1 of 42.8%, inhaled corticosteroids withdrawal resulted in 38% exacerbation, whereas exacerbation occurred in 6% in those who had not been chronically treated with inhaled corticosteroids (38). To examine further the benefits of inhaled corticosteroids in COPD, van der Valk and colleagues (39) conducted a double-blind, single-center study in which inhaled fluticasone propionate (FP) was discontinued. The endpoints were exacerbations and health-related quality of life in these patients. After 4 months of treatment with FP (1,000 µg/day), 244 patients were randomized to receive either continued FP or placebo for 6 months (123 patients continued FP [FP group] and 121 received placebo [placebo group]. In the FP group, 58 patients (47%) developed at least one exacerbation compared with 69 patients (57%) in the placebo group. The hazard ratio of a first exacerbation in the placebo group compared with the FP group was 1.5 (95% CI, 1.1–2.1). In the placebo group, 26 patients (21.5%) experienced rapid recurrent exacerbations compared with 6 patients (4.9%) in the FP group (RR, 4.4; 95% CI, 1.9–10.3). Over a 6-month period, a significant difference in favor of the FP group was observed in the total score (+2.48; 95% CI 0.37–4.58), activity domain (+4.64; 95% CI, 1.60–7.68), and symptom domain (+4.58; 95% CI, 1.05–8.10) of the St. George's Respiratory Questionnaire. This study has shown that discontinuation of FP in patients with COPD is associated with a more rapid onset and higher recurrence risk of exacerbations and a significant deterioration in aspects of health-related quality of life.

Finally, Alsaeedi and colleagues (40) performed a systematic review to determine whether inhaled corticosteroids improve clinical outcomes for patients with stable COPD. All placebo-controlled randomized trials of inhaled corticosteroids for at least 6 months for stable COPD were included for the period up to 2002. Nine randomized trials (3,976 patients with COPD), including four with a systemic steroid run-in phase, were identified. Use of inhaled corticosteroids therapy reduced the rate of exacerbations (RR, 0.70; 95% CI, 0.58–0.84). No effects were seen on all-cause mortality (RR, 0.84; 95% CI, 0.60–1.18) in the five trials that measured this outcome, but these studies were not powered to examine mortality. Interestingly, in the trials where patients had a mean FEV1 of less than 2.0 L (or < 70% predicted), the use of inhaled corticosteroids had, almost uniformly, a positive effect on exacerbation, regardless of the duration of the study or the specific formulation used (41).

Can Systemic Inflammation in Stable COPD Be Modified?
It is postulated that if systemic inflammation could be reduced in COPD, this would potentially reduce mortality associated with atherosclerosis in these patients. Corticosteroids can reduce serum CRP and other circulating inflammatory cytokine levels in some acute inflammatory states (42). They can also downregulate certain (43–46), although not all (47), inflammatory cells and cytokine expression levels in the airways of patients with COPD. Whether inhaled steroids can reduce circulating CRP levels in stable COPD is unknown. Recently, Pinto-Plata and colleagues (48) reported that CRP levels were elevated in patients with COPD (mean FEV1, 1.2 L) who had no clinical evidence of ischemic heart disease. In this study, which lasted for 1 year, the authors found that CRP levels were reproducible and were about 20% lower among those who used inhaled corticosteroids.

As a proof-of-concept, we conducted a short, randomized, double-blind, placebo-controlled trial to determine the effects of oral and inhaled corticosteroids on serum markers of inflammation in patients with COPD (49). These COPD subjects were in the Global Initiative on Obstructive Lung Disease classification Stages I and II (50). A total of 41 men and women were enrolled. After 4 weeks, within which all inhaled corticosteroids were discontinued, patients were assigned to inhaled fluticasone (500 µg twice daily), oral prednisone (30 mg/day), or placebo over 2 weeks. Serum CRP level was measured using nephelometry in accordance with recommendations from Center for Disease Control and the American Heart Association (51). Withdrawal of inhaled corticosteroids increased serum CRP levels by 71% (95% CI, 16–152%). Two weeks on inhaled fluticasone reduced CRP levels by 50% (95% CI, 9–73%) and prednisone reduced it by 63% (95% CI, 29–81%). No significant changes were observed with the placebo. Inhaled fluticasone also reduced significantly the serum IL-6 levels by 26% (95% CI, 3.2–43.6%). It was concluded that inhaled or oral corticosteroids were effective in reducing serum CRP levels in patients with COPD (49).

We hypothesize that inhaled corticosteroids may reduce CRP production indirectly by downregulating the expression of IL-6. Previous studies indicate that IL-6 is a major signaling cytokine for CRP expression by hepatocytes (52). In COPD, IL-6 production in the airway cells in culture is increased upon stimulation (53). Importantly, persistent therapy with inhaled corticosteroids attenuates IL-6 expression in patients with COPD (53). Our findings have shown a significant correlation between changes in serum CRP and IL-6 levels when inhaled corticosteroids were withdrawn in this group of subjects (Figure 2). We therefore postulate that the reduction in serum CRP was likely due to a reduction in IL-6 production, which was the result of the action of inhaled fluticasone in the airway (49). Alternatively, it is possible that any fluticasone that might have been absorbed systemically could have affected hepatocyte function directly, a scenario which we believe to be less likely.



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  		Figure 2. The relationship between changes in serum interleukin-6 and CRP levels from Visit 1 (time of enrolment) to Visit 2 (after withdrawal of inhaled corticosteroids). Both changes are plotted on a logarithmic scale to achieve best fit. The r2 value for the fitted line is 53.4% (p < 0.001; n = 41). Reproduced by permission, Reference 49.

 

   CONCLUSIONS
TOP
 ABSTRACT
 COPD: More than a...
 Linking COPD to Extrapulmonary...
 CONCLUSIONS
REFERENCES
 
Although the exact mechanisms responsible for extrapulmonary manifestations in COPD remained incompletely defined, it is suggested that the increase in cardiovascular morbidity and mortality is at least in part due to the systemic inflammation associated with COPD. There are reasons why corticosteroids might not be entirely effective in reducing pulmonary inflammation in COPD (33). However, it is known that IL-6, a potent regulator of CRP generation (54), is present in high concentrations in the serum and expiratory condensate of patients with COPD (55), and that IL-6 can be downregulated by corticosteroids (52). Chronic use of inhaled corticosteroids is one treatment strategy that may potentially make a difference, but much larger and longer clinical trials involving subjects with a wider range of airflow obstruction are likely needed to address this hypothesis.


   FOOTNOTES
 
Supported by a Canada Research Chair (Obstructive Airway Disease) and a Glaxo-SmithKline/St. Paul's Hospital Foundation Professorship in COPD (D.D.S.).

Conflict of Interest Statement: S.F.P.M. received $4,000 per annum from Merck Frost Canada, Inc., for Advisory Board function from 2001–2003 and received $2,000 from GlaxoSmithKline (GSK) in 2003 and a medical school grant to attend the 2003 ATS meeting, and has received as coprincipal investigator a medical school grant from GSK $140,000 and from Merck $2.5 million until 2003; a medical school grant is being negotiated and a consultation is still in progress with GSK, and he was invited to speak at an AstraZeneca-sponsored scientific meeting in April 2004 with all travel expenses paid by the hosting company; D.D.S. received $4,000 in 2003 and $4,000 in 2004 for speaking at conferences sponsored by GSK, for which he serves as a consultant and has received grant support, and $2,000 in 2003 and $2,000 in 2004 from AstraZeneca.

(Received in original form June 3, 2004; accepted in final form October 4, 2004)


   REFERENCES
TOP
 ABSTRACT
 COPD: More than a...
 Linking COPD to Extrapulmonary...
 CONCLUSIONS
 REFERENCES
 

  1. MacNee W. Oxidative stress and lung inflammation in airways disease. Eur J Pharmacol 2001;429:195–207.[CrossRef][Medline]
  2. Paredi P, Hkaritonov SA, Leak D, Ward S,Cramer D, Barnes PJ. Exhaled ethane, a marker of lipid peroxidation, is elevated in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;162:369–373.[Abstract/Free Full Text]
  3. Montuschi P, Collins JV, Ciabattoni G, Lazzeri N, Corradi M, Kharitonov SA, Barnes PJ. Exhaled 8-isoprostane as an in vivo biomarker of lung oxidative stress in patients with COPD and healthy smokers. Am J Respir Crit Care Med 2000;162:1175–1177.[Abstract/Free Full Text]
  4. Wouters EF. Chronic obstructive pulmonary disease: 5. Systemic effects of COPD. Thorax 2002;57:1067–1070.[Abstract/Free Full Text]
  5. Sin DD, Man JP, Man SF. The risk of osteoporosis in Caucasian men and women with obstructive airways disease. Am J Med 2003;114:10–14.[CrossRef][Medline]
  6. Hole DJ, Watt GC, Davey-Smith G, Hart CL, Gillis CR, Hawthorne VM. Impaired lung function and mortality risk in men and women: findings from the Renfrew and Paisley prospective population study. BMJ. 1996;313:711–775.[Abstract/Free Full Text]
  7. Boots AW, Haenen GR, Bast A. Oxidant metabolism in chronic obstructive pulmonary disease. Eur Respir J Suppl 2003;46:14s–27s.[CrossRef][Medline]
  8. Chung KF. Cytokines in chronic obstructive pulmonary disease. Eur Respir J Suppl 2001;34:50s–59s.[CrossRef][Medline]
  9. Calikoglu M, Sahin G, Unlu A, Ozturk C, Tamer L, Ercan B, Kanik A, Atik U. Leptin and TNF-alpha levels in patients with chronic obstructive pulmonary disease and their relationship to nutritional parameters. Respiration (Herrlisheim) 2004;71:45–50.
  10. Sin DD, Man SF. Impaired lung function and serum leptin in men and women with normal body weight: a population based study. Thorax 2003;58:695–698.[Abstract/Free Full Text]
  11. Hogg JC, Macklem PT, Thurlbeck WM. Site and nature of airway obstruction in chronic obstructive lung disease. N Engl J Med 1968;278:1355–1360.[Medline]
  12. Langen RC, Korn SH, Wouters EF. ROS in the local and systemic pathogenesis of COPD. Free Radic Biol Med 2003;35:226–235.[CrossRef][Medline]
  13. Tan WC, Qiu D, Liam BL, Ng TP, Lee SH, van Eeden SF, D'Yachkova Y, Hogg JC. The human bone marrow response to acute air pollution caused by forest fires. Am J Respir Crit Care Med 2000;161:1213–1217.[Abstract/Free Full Text]
  14. Mukae H, Hogg JC, English D, Vincent R, van Eeden SF. Phagocytosis of particulate air pollutants by human alveolar macrophages stimulates the bone marrow. Am J Physiol Lung Cell Mol Physiol 2000;279:L924–L931.[Abstract/Free Full Text]
  15. Sin DD, Man SF. Why are patients with chronic obstructive pulmonary disease at increased risk of cardiovascular diseases? The potential role of systemic inflammation in chronic obstructive pulmonary disease. Circulation 2003;107:1514–1519.[Abstract/Free Full Text]
  16. Keatings VM, Collins PD, Scott DM, Barnes PJ. Differences in interleukin-8 and tumor necrosis factor-alpha in induced sputum from patients with chronic obstructive pulmonary disease or asthma. Am J Respir Crit Care Med 1996;153:530–534.[Abstract]
  17. Wedzicha JA, Seemungal TA, MacCallum PK, Paul EA, Donaldson GC, Bhowmik A, Jeffries DJ, Meade TW. Acute exacerbations of chronic obstructive pulmonary disease are accompanied by elevations of plasma fibrinogen and serum IL-6 levels. Thromb Haemost 2000;84:210–215.[Medline]
  18. Takanashi S, Hasegawa Y, Kanehira Y, Yamamoto K, Fujimoto K, Satoh K, Okamura K. Interleukin-10 level in sputum is reduced in bronchial asthma, COPD and in smokers. Eur Respir J 1999;14:309–314.[Abstract]
  19. Kuschner WG, D'Alessandro A, Wong H, Blanc PD. Dose-dependent cigarette smoking-related inflammatory responses in healthy adults. Eur Respir J 1996;9:1989–1994.[Abstract]
  20. Eid AA, Ionescu AA, Nixon LS, Lewis-Jenkins V, Matthews SB, Griffiths TL, Shale DJ. Inflammatory response and body composition in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;164:1414–1418.[Abstract/Free Full Text]
  21. Schols AM, Creutzberg EC, Buurman WA, Campfield LA, Saris WH, Wouters EF. Plasma leptin is related to proinflammatory status and dietary intake in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999;160:1220–1226.[Abstract/Free Full Text]
  22. Takabatake N, Nakamura H, Abe S, Hino T, Saito H, Yuki H, Kato S, Tomoike H. Circulating leptin in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999;159:1215–1219.[Abstract/Free Full Text]
  23. Takabatake N, Nakamura H, Abe S, Inoue S, Hino T, Saito H, Yuki H, Kato S, Tomoike H. The relationship between chronic hypoxemia and activation of the tumor necrosis factor-alpha system in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;161:1179–1184.[Abstract/Free Full Text]
  24. Sethi S, Evans N, Grant BJ, Murphy TF. New strains of bacteria and exacerbations of chronic obstructive pulmonary disease. N Engl J Med 2002;347:465–471.[Abstract/Free Full Text]
  25. Murphy TF, Brauer AL, Schiffmacher AT, Sethi S. Persistent colonization by Haemophilus influenzae in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2004;170:266–272.[Abstract/Free Full Text]
  26. Anderson HR, Limb ES, Bland JM, Ponce de Leon A, Strachan DP, Bower JS. Health effects of an air pollution episode in London, December 1991. Thorax 1995;50:1188–1193.[Abstract]
  27. Linaker CH, Coggon D, Holgate ST, Clough J, Josephs L, Chauhan AJ, Inskip HM. Personal exposure to nitrogen dioxide and risk of airflow obstruction in asthmatic children with upper respiratory infection. Thorax 2000;55:930–933.[Abstract/Free Full Text]
  28. Greenberg SB, Allen M, Wilson J, Atmar RL. Respiratory viral infections in adults with and without chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;162:167–173.[Abstract/Free Full Text]
  29. Aaron SD, Angel JB, Lunau M, Wright K, Fex C, Le Saux N, Dales RE. Granulocyte inflammatory markers and airway infection during acute exacerbation of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;163:349–355.[Abstract/Free Full Text]
  30. Dentener MA, Creutzberg EC, Schols AM, Mantovani A, van't Veer C, Buurman WA, Wouters EF. Systemic anti-inflammatory mediators in COPD: increase in soluble interleukin 1 receptor II during treatment of exacerbations. Thorax 2001;56:721–726.[Abstract/Free Full Text]
  31. Roland M, Bhowmik A, Sapsford RJ, Seemungal TA, Jeffries DJ, Warner TD, Wedzicha JA. Sputum and plasma endothelin-1 levels in exacerbations of chronic obstructive pulmonary disease. Thorax 2001;56:30–35.[Abstract/Free Full Text]
  32. Koechlin C, Couillard A, Cristol JP, Chanez P, Hayot M, Le Gallais D, Prefaut C. Does systemic inflammation trigger local exercise-induced oxidative stress in COPD? Eur Respir J 2004;23:538–544.[Abstract/Free Full Text]
  33. Barnes PJ, Ito K, Adcock IM. Corticosteroid resistance in chronic obstructive pulmonary disease: inactivation of histone deacetylase. Lancet 2004;363:731–733.[CrossRef][Medline]
  34. Gan WQ, Man SF, Senthilselvan A, Sin DD. The association between chronic obstructive pulmonary disease and systemic inflammation: a systematic review and a metaanalysis. Thorax 2004;59:574–580.[Abstract/Free Full Text]
  35. Lung Health Study Research Group. Effect of inhaled triamcinolone on the decline in pulmonary function in chronic obstructive pulmonary disease. N Engl J Med 2000;343:1902–1909.[Abstract/Free Full Text]
  36. Sin DD, Tu JV. Inhaled corticosteroids and the risk of mortality and readmission in elderly patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;164:580–584.[Abstract/Free Full Text]
  37. Sin DD, Man SF. Inhaled corticosteroids and survival in chronic obstructive pulmonary disease: does the dose matter? Eur Respir J 2003;21:260–266.[Abstract/Free Full Text]
  38. Jarad NA, Wedzicha JA, Burge PS, Calverley PMA, for the ISOLE study group. An observational study of inhaled corticosteroids withdrawal in stable chronic obstructive pulmonary disease. Respir Med 1999;93:161–166.[CrossRef][Medline]
  39. van der Valk P, Monninkhof E, van der Palen J, Zielhuis G, van Herwaarden C. Effect of discontinuation of inhaled corticosteroids in patients with chronic obstructive pulmonary disease: the COPE study. Am J Respir Crit Care Med 2002;166:1358–1363.[Abstract/Free Full Text]
  40. Alsaeedi A, Sin DD, McAlister FA. The effects of inhaled corticosteroids in chronic obstructive pulmonary disease: a systematic review of randomized placebo-controlled trials. Am J Med 2002;113:59–65.[CrossRef][Medline]
  41. Man SF, McAlister FA, Anthonisen NR, Sin DD. Contemporary management of chronic obstructive pulmonary disease: clinical applications. JAMA 2003;290:2313–2316.[Abstract/Free Full Text]
  42. Versaci F, Gaspardone A, Tomai F, Ribichini F, Russo P, Proietti I, Ghini AS, Ferrero V, Chiariello L, Gioffre PA, et al. Immunosuppressive therapy for the prevention of restenosis after coronary artery stent implantation (IMPRESS study). J Am Coll Cardiol 2002;40:1935–1942.[Abstract/Free Full Text]
  43. Hattotuwa KL, Gizycki MJ, Ansari TW, Jeffery PK, Barnes NC. The effects of inhaled fluticasone on airway inflammation in chronic obstructive pulmonary disease: a double-blind, placebo-controlled biopsy study. Am J Respir Crit Care Med 2002;165:1592–1596.[Abstract/Free Full Text]
  44. Balzano G, Stefanelli F, Iorio C, De Felice A, Melillo EM, Martucci M, Melillo G. Eosinophilic inflammation in stable chronic obstructive pulmonary disease: relationship with neutrophils and airway function. Am J Respir Crit Care Med 1999;160:1486–1492.[Abstract/Free Full Text]
  45. Confalonieri M, Mainardi E, Della Porta R, Bernorio S, Gandola L, Beghe B, Spanevello A. Inhaled corticosteroids reduce neutrophilic bronchial inflammation in patients with chronic obstructive pulmonary disease. Thorax 1998;53:583–585.[Abstract/Free Full Text]
  46. Yildiz F, Kaur AC, Ilgazli A, Celikoglu M, Kacar Ozkara S, Paksoy N, Ozkarakas O. Inhaled corticosteroids may reduce neutrophilic inflammation in patients with stable chronic obstructive pulmonary disease. Respiration (Herrlisheim) 2000;67:71–76.
  47. 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. Am J Respir Crit Care Med 1999;160:1635–1639.[Abstract/Free Full Text]
  48. Pinto-Plata V, Muellerova H, Toso J, Vessey R, Feudjo-Tepic M, Soriano J, Celli B. C-reactive protein is elevated in patients with COPD but not in smoker and non-smoker controls. CRP is influenced by the use of MDI corticosteroids. Am J Respir Crit Care Med 2004;169:A839.
  49. Sin D, Lacy P, York E, Man SFP. Effects of fluticasone on systemic markers of inflammation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2004;170:1–6.[Free Full Text]
  50. Pauwels RA, Buist AS, Calverley PM, Jenkins CR, Hurd SS. GOLD Scientific Committee. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop summary. Am J Respir Crit Care Med 2001;163:1256–1276.[Free Full Text]
  51. Pearson TA, Mensah GA, Alexander RW, Anderson JL, Cannon RO III, Criqui M, Fadl YY, Fortmann SP, Hong Y, Myers GL, et al. Centers for Disease Control and Prevention; American Heart Association. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: A statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation 2003;107:499–511.[Free Full Text]
  52. Van Snick J. Interleukin-6: an overview. Annu Rev Immunol 1990;8:253–278.[Medline]
  53. Patel IS, Roberts NJ, Lloyd-Owen SJ, Sapsford RJ, Wedzicha JA. Airway epithelial inflammatory responses and clinical parameters in COPD. Eur Respir J 2003;22:94–99.[Abstract/Free Full Text]
  54. Pepys MB, Hirschfield GM. C-reactive protein: a critical update. J Clin Invest 2003;111:1805–1812.[CrossRef][Medline]
  55. Bucchioni E, Kharitonov SA, Allegra L, Barnes PJ. High levels of interleukin-6 in the exhaled breath condensate of patients with COPD. Respir Med 2003;97:1299–1302.[CrossRef][Medline]



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