Articles on Inflammation & COPD 

Groenewegen KH. Postma DS. Hop WC. Wielders PL. Schlosser NJ. Wouters EF. COSMIC Study Group. Increased systemic inflammation is a risk factor for COPD exacerbations. Chest. 133(2):350-7, 2008 BACKGROUND: COPD is characterized by episodic increases in respiratory symptoms, so-called exacerbations. COPD exacerbations are associated with an increase in local and systemic inflammation. Data of a previously published study in a well-characterized COPD cohort were analyzed to define predictive factors of acute exacerbations, particularly focusing on systemic inflammation. OBJECTIVE: To determine if an elevated systemic inflammatory status measured at baseline is related to the occurrence of acute exacerbations in patients with COPD. METHODS: The occurrence of moderate (requiring oral prednisolone) and severe exacerbations (requiring hospitalization) was prospectively recorded over 1 year. At the beginning of the study, lung function values (FEV1, FVC, functional residual capacity, and diffusion capacity of the lung for carbon monoxide [Dlco]) and serum levels of C-reactive protein, fibrinogen, lipopolysaccharide binding protein, tumor necrosis factor (TNF)-alpha, and its soluble receptors (soluble TNF receptors 55 and 75) as markers of systemic inflammation were determined. RESULTS: Two hundred seventy-seven person-years of follow-up were analyzed in the total group of 314 patients: 186 patients were responsible for 411 exacerbations (374 moderate and 37 severe). Multivariate analyses showed that a higher initial fibrinogen level and a lower FEV1 predicted a higher rate of both moderate and severe exacerbations. Additional independent predictors of a severe exacerbation were a higher number of prestudy severe exacerbations and lower Dlco. A higher number of prestudy moderate exacerbations was the only additional independent risk factor for the rate of moderate exacerbations. CONCLUSION: This study demonstrates that besides lung function impairment systemic inflammation manifested by elevated fibrinogen levels is an independent risk factor for exacerbations of COPD. Attenuation of systemic inflammation may offer new perspectives in the management of COPD patients to reduce the burden of exacerbations.

Walter RE. Wilk JB. Larson MG. Vasan RS. Keaney JF Jr. Lipinska I. O'Connor GT. Benjamin EJ. Systemic inflammation and COPD: the Framingham Heart Study.[see comment]. Chest. 133(1):19-25, 2008 BACKGROUND: The current paradigm for the pathogenesis of COPD includes an ultimately maladaptive local inflammatory response to environmental stimuli. We examined the hypothesis that systemic inflammatory biomarkers are associated with impaired lung function, particularly among those with extensive cigarette smoking. METHODS: Using data from the Framingham Heart Study, we examined cross-sectional associations of systemic inflammatory biomarkers (CD40 ligand [CD40L], intercellular adhesion molecule [ICAM]-1, interleukin [IL]-6, monocyte chemoattractant protein-1, P-selectin, and myeloperoxidase, in addition to C-reactive protein) to impaired lung function. RESULTS: IL-6 was consistently associated with impaired lung function; a 1-SD higher concentration of IL-6 was associated with a 41-mL lower FEV(1) (95% confidence interval [CI], - 61 to - 20) and a borderline 15% higher odds of COPD (odds ratio, 1.15; 95% CI, 0.99 to 1.34). Additionally, P-selectin was associated with lower FEV(1) levels; after adjusting for the other biomarkers, a 1-SD higher concentration of P-selectin predicted an FEV(1) that was on average 19 mL lower (95% CI, - 37 to 0). Including the biomarkers individually as sole exposures in the models generally strengthened the impaired lung function/biomarker association; the relations of ICAM-1 to FEV(1), and ICAM and CD40L to COPD became significant. The observed associations did not vary significantly with smoking history, except that the association between CD40L and COPD appeared greater in individuals with more extensive smoking histories. CONCLUSIONS: Among participants in the Framingham Heart Study, systemic inflammation was associated with lower levels of pulmonary function. Further research into the role of systemic inflammation in the development of pulmonary dysfunction is merited.

van Eeden SF. Sin DD. Chronic obstructive pulmonary disease: a chronic systemic inflammatory disease.[see comment]. [Review] [141 refs] Respiration. 75(2):224-38, 2008. Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation in both the airways causing airway obstruction and the lung tissues causing emphysema. The disease is induced by inhalation of noxious gasses and particulate matter resulting in a chronic persistent inflammatory response in the lung, and the extent of the inflammatory reaction correlates with the severity of the disease. This chronic inflammatory response in the lung is also associated with a significant systemic inflammatory response with downstream adverse clinical health effects. The systemic response in COPD is associated with mortality, specifically cardiovascular mortality. This review describes the nature of the systemic inflammatory response in COPD and the clinical manifestations associated with the systemic response, with a focus on the potential mechanisms for these adverse health effects.

Karadag F. Karul AB. Cildag O. Yilmaz M. Ozcan H. Biomarkers of systemic inflammation in stable and exacerbation phases of COPD. Lung. 186(6):403-9, 2008  Apart from the deleterious effects on the lungs, chronic obstructive pulmonary disease (COPD) should be considered a complex, systemic disease involving several organs and systems. The nature and course of systemic inflammation in COPD is important since there is a potential for anti-inflammatory therapy. The objective of the current study was to assess biomarkers of systemic inflammation in stable and exacerbation phases of COPD patients as compared to healthy controls. We also investigated the course of these biomarkers after COPD exacerbation to evaluate their usefulness for disease monitoring. Eighty-three stable patients with moderate to very severe COPD, 20 patients in exacerbation phase, and 30 subjects with normal pulmonary function were included. Serum tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and nitric oxide (NO) levels were measured once in stable COPD patients and controls and three times in the COPD exacerbation group during follow-up. TNF-alpha and IL-6 levels were higher than in controls in both stable and exacerbation groups. Although NO was not higher in the stable COPD group than in controls, it was higher in the exacerbation group. In follow-up after the exacerbation period, significant alteration was not detected in cytokine or NO levels compared to admission. Raised serum levels of TNF-alpha and IL-6 support their use as biomarkers of the systemic inflammatory response in stable COPD patients. However, the circulating biomarkers we have studied are not found to be useful either as indicators of COPD exacerbation or for monitoring recovery after exacerbation.

Seemungal TA. Wilkinson TM. Hurst JR. Perera WR. Sapsford RJ. Wedzicha JA. Long-term erythromycin therapy is associated with decreased chronic obstructive pulmonary disease exacerbations.[see comment]. American Journal of Respiratory & Critical Care Medicine. 178(11):1139-47, 2008 RATIONALE: Frequent chronic obstructive pulmonary disease (COPD) exacerbations are a major cause of hospital admission and mortality and are associated with increased airway inflammation. Macrolides have airway antiinflammatory actions and may reduce the incidence of COPD exacerbations. OBJECTIVES: To determine whether regular therapy with macrolides reduces exacerbation frequency. METHODS: We performed a randomized, double-blind, placebo-controlled study of erythromycin administered at 250 mg twice daily to patients with COPD over 12 months, with primary outcome variable being the number of moderate and/or severe exacerbations (treated with systemic steroids, treated with antibiotics, or hospitalized). MEASUREMENTS AND MAIN RESULTS: We randomized 109 outpatients: 69 (63%) males, 52 (48%) current smokers, mean (SD) age 67.2 (8.6) years, FEV1 1.32 (0.53) L, FEV1% predicted 50 (18)%. Thirty-eight (35%) of the patients had three or more exacerbations in the year before recruitment, with no differences between treatment groups. There were a total of 206 moderate to severe exacerbations: 125 occurred in the placebo arm. Ten in the placebo group and nine in the macrolide group withdrew. Generalized linear modeling showed that the rate ratio for exacerbations for the macrolide-treated patients compared with placebo-treated patients was 0.648 (95% confidence interval: 0.489, 0.859; P = 0.003) and that these patients had shorter duration exacerbations compared with placebo. There were no differences between the macrolide and placebo arms in terms of stable FEV1, sputum IL-6, IL-8, myeloperoxidase, bacterial flora, serum C-reactive protein, or serum IL-6 or in changes in these parameters from baseline to first exacerbation over the 1-year study period. CONCLUSIONS: Macrolide therapy was associated with a significant reduction in exacerbations compared with placebo and may be useful in decreasing the excessive disease burden in this important patient population. Clinical trial registered with www.clinicaltrials.gov (NCT 00147667).

Bircan A. Gokirmak M. Kilic O. Ozturk O. Akkaya A. C-reactive protein levels in patients with chronic obstructive pulmonary disease: role of infection. Medical Principles & Practice. 17(3):202-8, 2008.  OBJECTIVE: To investigate the value of C-reactive protein (CRP) as a marker of chronic obstructive pulmonary disease (COPD) exacerbations or specifically bacterial exacerbations and to evaluate a correlation between raised CRP levels and other markers of inflammation in patients with an acute exacerbation (AECOPD). SUBJECTS AND METHODS: The medical records of patients with AECOPD were retrospectively analyzed. They were categorized according to the nature of sputum as mucoid or purulent and to the findings on chest radiographs as with pneumonia (PCOPD) or without pneumonia. Stable COPD (SCOPD) patients and a group of asymptomatic nonsmokers were also included in the study. RESULTS: All COPD patients (SCOPD: 30; AECOPD: 51; PCOPD: 32) and control subjects (30) were male. The mean CRP levels and WBC counts of the groups were PCOPD: 108.1 +/- 61.8 mg/l and 13.7 +/- 6.8 x 10(9)/l; AECOPD: 36.8 +/- 43.9 mg/l and 11.4 +/- 4.8 x 10(9)/l; SCOPD: 3.9 +/- 1.4 mg/l and 7.9 +/- 1.9 x 10(9)/l; control: 2.1 +/- 0.9 mg/l and 7.7 +/- 1.1 x 10(9)/l. The mean CRP level of AECOPD was statistically different from those of PCOPD and SCOPD (p = 0.0001, p = 0.002, respectively). The sensitivity and specificity of CRP to determine an acute exacerbation were 72.5 and 100%, respectively. Among the patients with AECOPD, 25 had purulent sputum and a mean CRP level of 46.4 +/- 48.6 mg/l, which is significantly higher than the CRP level (28.0 +/- 44.5 mg/l) of the 18 patients with mucoid expectoration (p = 0.015). Among the mucoid-expectorating subgroup, the patients with leukocytosis had significantly higher CRP levels than the patients without leukocytosis (p = 0.034). CONCLUSION: A high serum CRP value may indicate an infectious exacerbation in COPD patients and it correlates with sputum purulence and increased serum WBC counts.

Roth M. Pathogenesis of COPD. Part III. Inflammation in COPD. [Review] [84 refs] International Journal of Tuberculosis & Lung Disease. 12(4):375-80, 2008 Chronic obstructive pulmonary disease (COPD) is mostly caused by cigarette smoking and affects up to 25% of smokers. Air pollution and occupational exposure to dust and fumes can also induce COPD. COPD is characterised by airflow limitation that is not fully reversible and chronic inflammation of the lung. Most patients with COPD also have evidence of tissue remodelling in the smaller airways. How the different pathological features are linked remains unknown. The inflammation of the COPD lung is initially caused by cigarette smoke and the increased infiltration of immune cells into the lung, but it is not clear why the inflammation persists after smoking cessation, while other pathologies partly reverse. Furthermore, anti-inflammatory treatments are not very successful and only control the symptoms but do not cure the disease. Animal models suggest that the imbalance of proteases and antiproteases is central to the major pathologies in the COPD lung. However, this hypothesis was never fully confirmed in humans and may only explain the degenerative stage of the disease, emphysema. The role of tissue-forming cells in the pathogenesis of COPD has not been adequately studied and indicates a deregulated synthesis of growth factors and cytokines in COPD. Finally, recent studies indicate that alpha-1-antitrypsin activity plays a role in all forms of COPD.

Aniwidyaningsih W. Varraso R. Cano N. Pison C. Impact of nutritional status on body functioning in chronic obstructive pulmonary disease and how to intervene. [Review] [82 refs] Current Opinion in Clinical Nutrition & Metabolic Care. 11(4):435-42, 2008 PURPOSE OF REVIEW: Chronic obstructive pulmonary disease is the fifth leading cause of mortality in the world. This study reviews diet as a risk or protective factor for chronic obstructive pulmonary disease, mechanisms of malnutrition, undernutrition consequences on body functioning and how to modulate nutritional status of patients with chronic obstructive pulmonary disease. RECENT FINDINGS: Different dietary factors (dietary pattern, foods, nutrients) have been associated with chronic obstructive pulmonary disease and the course of the disease. Mechanical disadvantage, energy imbalance, disuse muscle atrophy, hypoxemia, systemic inflammation and oxidative stress have been reported to cause systemic consequences such as cachexia and compromise whole body functioning. Nutritional intervention makes it possible to modify the natural course of the disease provided that it is included in respiratory rehabilitation combining bronchodilators optimization, infection control, exercise and, in some patients, correction of hypogonadism. SUMMARY: Diet, as a modifiable risk factor, appears more as an option to prevent and modify the course of chronic obstructive pulmonary disease. Reduction of mechanical disadvantage, physical training and anabolic agents should be used conjointly with oral nutrition supplements to overcome undernutrition and might change the prognosis of the disease in some cases. Major research challenges address the role of systemic inflammation and the best interventions for controlling it besides smoking cessation.

Gray RD. MacGregor G. Noble D. Imrie M. Dewar M. Boyd AC. Innes JA. Porteous DJ. Greening AP. Sputum proteomics in inflammatory and suppurative respiratory diseases. American Journal of Respiratory & Critical Care Medicine. 178(5):444-52, 2008 RATIONALE: Markers of inflammatory activity are important for assessment and management of many respiratory diseases. Markers that are currently unrecognized may be more valuable than those presently believed to be useful. OBJECTIVES: To identify potential biomarkers of suppurative and inflammatory lung disease in induced sputum samples. METHODS: Induced sputum was collected from 20 healthy control subjects, 24 patients with asthma, 24 with chronic obstructive pulmonary disease, 28 with cystic fibrosis (CF), and 19 with bronchiectasis. Twelve patients with CF had sputum sampled before and after antibiotic therapy for an infective exacerbation. The fluid phase of induced sputum was analyzed by surface-enhanced laser desorption/ionization time-of-flight (SELDI-TOF) mass spectroscopy on three protein array surfaces. Some protein markers were selected for identification, and relevant ELISA assays sought. For 12 patients with CF, both SELDI-TOF and ELISA monitored changes in inflammatory responses during infective exacerbations. MEASUREMENTS AND MAIN RESULTS: SELDI-TOF identified potential biomarkers that differentiated each of the disease groups from healthy control subjects: at a significance of P < 0.01, there were 105 for asthma, 113 for chronic obstructive pulmonary disease, 381 for CF, and 377 for bronchiectasis. Peaks selected for protein identification yielded calgranulin A, calgranulin B, calgranulin C, Clara cell secretory protein, lysosyme c, proline rich salivary peptide, cystatin s, and hemoglobin alpha. On treatment of an infective CF exacerbation, SELDI-TOF determined falls in levels of calgranulin A and calgranulin B that were mirrored by ELISA-measured falls in calprotectin (heterodimer of calgranulins A and B). CONCLUSIONS: Proteomic screening of sputum yields potential biomarkers of inflammation. The early development of a clinically relevant assay from such data is demonstrated.

Calabrese F. Baraldo S. Bazzan E. Lunardi F. Rea F. Maestrelli P. Turato G. Lokar-Oliani K. Papi A. Zuin R. Sfriso P. Balestro E. Dinarello CA. Saetta M. IL-32, a novel proinflammatory cytokine in chronic obstructive pulmonary disease. American Journal of Respiratory & Critical Care Medicine. 178(9):894-901, 2008  Biswas S. Rahman I. Modulation of steroid activity in chronic inflammation: a novel anti-inflammatory role for curcumin. [Review] [57 refs] Molecular Nutrition & Food Research. 52(9):987-94, 2008 The expression of NF-kappaB (NF-kappaB)-dependent pro-inflammatory genes in response to oxidative stress is regulated by the acetylation-deacetylation status of histones bound to the DNA. It has been suggested that in severe asthma and in chronic obstructive pulmonary disease (COPD) patients, oxidative stress not only activates the NF-kappaB pathway but also alters the histone acetylation and deacetylation balance via post-translational modification of histone deacetylases (HDACs). Corticosteroids have been one of the major modes of therapy against various chronic respiratory diseases such as asthma and COPD. Failure of corticosteroids to ameliorate such disease conditions has been attributed to their inability to either recruit HDAC2 or to the presence of an oxidatively modified HDAC2 in asthmatics and COPD subjects. Naturally occurring polyphenols such as curcumin and resveratrol have been increasingly considered as safer nutraceuticals. Curcumin is a polyphenol present in the spice turmeric, which can directly scavenge free radicals such as superoxide anion and nitric oxide and modulate important signaling pathways mediated via NF-kappaB and mitogen-activated protein kinase pathways. Polyphenols also down-regulate expression of pro-inflammatory mediators, matrix metalloproteinases, adhesion molecules, and growth factor receptor genes and they up-regulate HDAC2 in the lung. Thus, curcumin may be a potential antioxidant and anti-inflammatory therapeutic agent against chronic inflammatory lung diseases.

Macnee W. Maclay J. McAllister D. Cardiovascular injury and repair in chronic obstructive pulmonary disease. [Review] [138 refs] Proceedings of the American Thoracic Society. 5(8):824-33, 2008  Cardiovascular disease represents a considerable burden in terms of both morbidity and mortality in patients with chronic obstructive pulmonary disease (COPD). For 20 years, forced expiratory volume in 1 second (FEV(1)) has been an established predictor of cardiovascular mortality among smokers, never-smokers, and patients with COPD. We review evidence for increased cardiovascular risk in COPD. In addition, we assess the emerging evidence which suggests that hypoxia, systemic inflammation, and oxidative stress in patients with COPD may cause cardiovascular disease. We also discuss alternative hypotheses that the endothelium and connective tissues in the arteries and lungs of patients with COPD and cardiovascular disease have a shared susceptibility to these factors.

Yawn BP. Kaplan A. Co-morbidities in people with COPD: a result of multiple diseases, or multiple manifestations of smoking and reactive inflammation?. [Review] [76 refs] Primary Care Respiratory Journal. 17(4):199-205, 2008  There has been increased awareness and recognition of COPD in both developed and developing nations. As people with COPD are identified and treated before they reach end-stage lung disease, the multiple morbidities associated with COPD have been recognised. These morbidities affect many areas of the body and currently are often treated with numerous different drugs. This poly-pharmacy, and the need for therapy by multiple organ-specific specialists, is not optimal and often not feasible for patients with COPD. New information on many of the common multiple morbidities suggests that it may be possible to explain--and in the future control or treat--these multiple morbidities, by addressing one common trigger and a common final pathway of inflammation. This review outlines some of the reasons why it is time to consider a 'whole body' approach to COPD, rather than clinicians continuing to address the lungs first and then each additional organ one at a time.

Kim V. Rogers TJ. Criner GJ. New concepts in the pathobiology of chronic obstructive pulmonary disease. [Review] [92 refs] Proceedings of the American Thoracic Society. 5(4):478-85, 2008 Chronic obstructive pulmonary disease (COPD) is characterized by an abnormal persistent inflammatory response to cigarette smoke. This noxious insult leads to emphysema and airway remodeling, manifested by squamous and mucous metaplasia of the epithelium, smooth muscle hypertrophy, and airway wall fibrosis. These pathologic abnormalities interact synergistically to cause progressive airflow obstruction. Although it has been accepted that the spectrum of COPD is vast, the reasons for the development of different phenotypes from the same exposure to cigarette smoke have not been determined. Furthermore, it is becoming increasingly clear that airways disease and emphysema often coexist in many patients, even with a clear clinical phenotype of either emphysema or chronic bronchitis. Recent studies have focused on the nature of the inflammatory response to cigarette smoke, the inflammatory cell lines responsible for COPD pathogenesis, and new biomarkers for disease activity and progression. New cytokines are being discovered, and the complex interactions among them are being unraveled. The inflammatory biomarker that has received the most attention is C-reactive protein, but new ones that have caught our attention are interleukin (IL)-6, tumor necrosis factor-alpha, IL-8, and IL-10. Further research should focus on how these new concepts in lung inflammation interact to cause the various aspects of COPD pathology.

de Boer WI. Alagappan VK. Sharma HS. Molecular mechanisms in chronic obstructive pulmonary disease: potential targets for therapy. [Review] [118 refs] Cell Biochemistry & Biophysics. 47(1):131-48, 2007. Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease associated with progressive airflow obstruction. Tobacco smoking is the main risk factor worldwide. In contrast to asthma, antiinflammatory therapies are rather ineffective in improving chronic symptoms and reducing inflammation, lung function decline, and airway remodeling. Specific drugs that are directed against the remodeling and chronic inflammation, thereby preventing lung tissue damage and progressive lung function decline, must be developed. Experimental models and expression studies suggest that anti-vascular endothelial growth factor (VEGF) receptor strategies may be of use in patients with emphysema, whereas anti-HER1-directed strategies may be more useful in patients with pulmonary mucus hypersecretion, as seen in chronic bronchitis and asthma. Growth factors and cytokines including VEGF, fibroblast growth factors, transforming growth factor-beta, tumor necrosis factor-alpha, CXCL1, CXCL8, and CCL2, and signal transduction proteins such as mitogen-activated protein kinase p38 and nuclear factor-kappaB, seem to be important pathogenetic molecules in COPD. Specific antagonists for these proteins may be effective for different inflammatory diseases. However, their efficacy for COPD therapy has not yet been demonstrated. Finally, other drugs such as retinoic acids may provide restoration of lung tissue structure. Such approaches, however, must await the first results of growth factor or cytokine antagonist therapy in chronic lung diseases.

Foschino Barbaro MP. Carpagnano GE. Spanevello A. Cagnazzo MG. Barnes PJ. Inflammation, oxidative stress and systemic effects in mild chronic obstructive pulmonary disease. International Journal of Immunopathology & Pharmacology. 20(4):753-63, 2007  Chronic obstructive pulmonary diseases (COPD) is a pulmonary disease characterized by systemic abnormalities. The aim of this study is to investigate inflammation and systemic effects in mild COPD. Twenty-seven mild stable smoking related COPD patients and 15 age-matched healthy subjects were enrolled in the study. IL-6, TNF-alpha and IL-4 in plasma, sputum and exhaled breath condensate were measured. We also measured exhaled nitric oxide (NO) and pH in sputum and in breath condensate. Moreover, fat-free mass, body mass index (BMI), respiratory muscle strength, plasma oxidative stress and C-reactive protein (CRP) were measured. Higher concentrations were found of CRP, of diacron reactive oxygen metabolites (DROMs) and of IL-6, TNF-alpha and IL-4 either in plasma or in supernatant of induced sputum or in exhaled breath condensate of COPD subjects compared to healthy controls. Furthermore, higher concentrations were observed of exhaled NO and lower exhaled pH in breath condensate of COPD when compared with healthy subjects. In the group of COPD patients, the subjects with airway reversibility showed an increase of sputum eosinophils and exhaled NO, whereas the subjects without airway obstruction reversibility showed an increase in sputum neutrophils, TNF-alpha and IL-6. We also found a trend towards a decrease in fat-free mass and respiratory muscle strength in COPD compared to healthy subjects and a negative correlation between these systemic indices (fat-free mass, maximal inspiratory pressure, maximal expiratory pressure) and TNF-alpha concentrations in the blood, sputum and breath condensate. We conclude that mild COPD subjects present an increase in inflammatory markers in blood and in airways of similar pattern and furthermore, the neutrophilic pattern of airway inflammation observed in the group of COPD subjects without an airway obstruction reversibility makes it more likely that systemic features are present.

Wouters EF. Groenewegen KH. Dentener MA. Vernooy JH. Systemic inflammation in chronic obstructive pulmonary disease: the role of exacerbations. [Review] [145 refs] Proceedings of the American Thoracic Society. 4(8):626-34, 2007 The systemic manifestations of chronic obstructive pulmonary disease (COPD) exacerbations are recognized, but our understanding of their etiology and importance is lacking largely due to the small number of systematic and longitudinal studies. Most of the systemic manifestations are likely the result of inflammatory processes. Serum biomarkers, such as various cytokines, adipokines, C-reactive protein, and coagulation factors, are elevated during exacerbations. Our understanding of the systemic manifestations can be greatly enhanced if we integrate what is known about the basic science of systemic mediators with the translational science of their role in COPD exacerbations. Many overlapping connections and promising avenues of future research come to light with such a viewpoint.

Wu TL. Chang PY. Tsao KC. Sun CF. Wu LL. Wu JT. A panel of multiple markers associated with chronic systemic inflammation and the risk of atherogenesis is detectable in asthma and chronic obstructive pulmonary disease. Journal of Clinical Laboratory Analysis. 21(6):367-71, 2007. Asthma and chronic obstructive pulmonary disease (COPD) are both lung diseases involving chronic inflammation of the airway. The injury is reversible in asthma whereas it is mostly irreversible in COPD. Both patients of asthma and COPD are known at risk for cardiovascular disease (CVD) and type 2 diabetes (T2DM), nephropathy, and cancer. We measured multiple risk markers for atherogenesis in 55 patients with asthma and 62 patients with COPD. We wanted to know whether risk markers for atherogenesis corresponding to sequence of events of chronic inflammation were also detectable in the airway inflammatory diseases. Elevation of almost all markers involving inflammation of the endothelial cells in the coronary artery were detectable in asthma and COPD involving the inflammation of the epithelial cell lining of the airway. Both the level and % elevation of all markers were found mostly higher in COPD, the more severe form of the lung disease. We believe that these markers are useful for predicting risk of developing clinical complications such as CVD.Remels AH. Gosker HR. van der Velden J. Langen RC. Schols AM. Systemic inflammation and skeletal muscle dysfunction in chronic obstructive pulmonary disease: state of the art and novel insights in regulation of muscle plasticity. [Review] [129 refs] Clinics in Chest Medicine. 28(3):537-52, vi, 2007 Systemic inflammation is a recognized hallmark of chronic obstructive pulmonary disease pathogenesis. Although the origin and mechanisms responsible for the persistent chronic inflammatory process remain to be elucidated, it is recognized that it plays an important role in skeletal muscle pathology as observed in chronic obstructive pulmonary disease and several other chronic inflammatory disorders. This article describes state-of-the-art knowledge and novel insights in the role of inflammatory processes on several aspects of inflammation-related skeletal muscle pathology and offers new insights in therapeutic perspectives. 

Tomaki M. Sugiura H. Koarai A. Komaki Y. Akita T. Matsumoto T. Nakanishi A. Ogawa H. Hattori T. Ichinose M. Decreased expression of antioxidant enzymes and increased expression of chemokines in COPD lung. Pulmonary Pharmacology & Therapeutics. 20(5):596-605, 2007. The involvement of inflammation in the pathogenesis of chronic obstructive pulmonary disease (COPD) has been investigated using samples from relatively central airways such as airway biopsies, but there have been fewer studies in the peripheral lung, which is thought to be the main site of the disease process. To determine the molecules that relate to the mechanisms underlying the pathogenesis of COPD, we evaluated the mRNA expression of inflammatory cytokines, chemokines, oxidant enzymes, antioxidant enzymes, proteinases and antiproteinases in peripheral lung tissues from 33 COPD and non-COPD subjects who were undergoing lung resection for lung cancer using an RT-PCR technique. Among the 42 studied candidate genes, the expressions of mRNA for catalase, glutathion S-transferase P1 (GSTP1), glutathion S-transferase M1 (GSTM1), microsomal epoxide hydrolase (mEPHX) and tissue inhibitor of metalloproteinase 2 (TIMP2) were significantly decreased in COPD lung tissues compared with those in non-COPD tissues, and most of these decreases were significantly correlated with the degree of airflow limitation. On the other hand, the expressions of mRNA for interleukin 1beta (IL-1beta), interleukin 8 (IL-8), growth-related oncogene-alpha (Gro-alpha) and monocyte chemotactic protein-1 (MCP-1) were significantly increased in COPD lungs. Most of these changes were also associated with cigarette smoking. These data suggest that an impairment of protective mechanisms against oxidants and xenobiotics, in addition to the upregulation of CXC- and CC-chemokines, may be associated with cigarette smoking and involved in the inflammatory process of COPD.

Tkacova R. Kluchova Z. Joppa P. Petrasova D. Molcanyiova A. Systemic inflammation and systemic oxidative stress in patients with acute exacerbations of COPD. Respiratory Medicine. 101(8):1670-6, 2007 BACKGROUND: In patients with chronic obstructive pulmonary disease (COPD), the inflammatory processes and oxidative stress are closely linked in the lung compartment. However, the relationships between systemic inflammation and parameters of oxidative stress in the systemic circulation during acute exacerbations of COPD remain to be explored. OBJECTIVE: To analyze relationships between erythrocytic glutathione peroxidase (GPx), a marker of systemic oxidative stress, and parameters reflecting systemic inflammation, such as circulating neutrophils, C-reactive protein (CRP), and interleukin (IL)-6, in patients with acute exacerbations of COPD. PATIENTS AND METHODS: We measured erythrocytic GPx activity, circulating neutrophil count, and serum high-sensitivity (hs) CRP and IL-6 in 177 patients admitted to the hospital due to an acute exacerbation of COPD (91 males, mean age 66.8+/-0.9 years, mean FEV1 45.3+/-1.3% predicted). RESULTS: From GOLD Stage II to Stage III and IV, erythrocytic GPx activity significantly decreased [mean+/-SEM: from 44.3+/-1.7 U/g Hb to 40.8+/-1.1 U/g Hb and to 38.4+/-1.5 U/g Hb, p = 0.037], while serum hsCRP increased [median (25th, 75th percentile): from 9.6 (3.0, 23.0) mg/l to 23.3 (6.4, 46.8) mg/l, and to 26.7 (6.5, 117.2) mg/l, p = 0.004]. Erythrocytic GPx activity was significantly inversely related to both, log neutrophil count (r = -0.219, p = 0.003) and log hsCRP (r = -0.199, p = 0.008). CONCLUSIONS: Our study suggests an association between systemic inflammation and systemic oxidative stress reflected by erythrocytic GPx in patients with acute exacerbations of COPD.

Sabit R. Bolton CE. Edwards PH. Pettit RJ. Evans WD. McEniery CM. Wilkinson IB. Cockcroft JR. Shale DJ. Arterial stiffness and osteoporosis in chronic obstructive pulmonary disease.[see comment]. American Journal of Respiratory & Critical Care Medicine. 175(12):1259-65, 2007  RATIONALE: Chronic obstructive pulmonary disease (COPD) is associated with an increased risk of cardiovascular events and osteoporosis. Increased arterial stiffness is an independent predictor of cardiovascular disease. OBJECTIVES: We tested the hypothesis that patients with COPD would have increased arterial stiffness, which would be associated with osteoporosis and systemic inflammation. METHODS: We studied 75 clinically stable patients with a range of severity of airway obstruction and 42 healthy smoker or ex-smoker control subjects, free of cardiovascular disease. All subjects underwent spirometry, measurement of aortic pulse wave velocity (PWV) and augmentation index, dual-energy X-ray absorptiometry, and blood sampling for inflammatory mediators. MEASUREMENTS AND MAIN RESULTS: Mean (SD) aortic PWV was greater in patients, 11.4 (2.7) m/s, than in control subjects, 8.95 (1.7) m/s, p < 0.0001. Inflammatory mediators and augmentation index were also greater in patients. Patients with osteoporosis at the hip had a greater aortic PWV, 13.1 (1.8) m/s, than those without, 11.2 (2.7) m/s, p < 0.05. In patients, aortic PWV was related to age (r = 0.63, p < 0.0001) and log(10) IL-6 (r = 0.31, p < 0.01), and inversely to FEV(1) (r = -0.34, p < 0.01). The strongest predictors of aortic PWV in all subjects were age (p < 0.0001), percent predicted FEV(1) (p < 0.05), mean arterial pressure (p < 0.05), and log(10) IL-6 (p < 0.05). CONCLUSIONS: Increased arterial stiffness was related to the severity of airflow obstruction and may be a factor in the excess risk for cardiovascular disease in COPD. The increased aortic PWV in patients with osteoporosis and the association with systemic inflammation suggest that age-related bone and vascular changes occur prematurely in COPD.

Bolton CE. Evans M. Ionescu AA. Edwards SM. Morris RH. Dunseath G. Luzio SD. Owens DR. Shale DJ. Insulin resistance and inflammation - A further systemic complication of COPD. Copd: Journal of Chronic Obstructive Pulmonary Disease. 4(2):121-6, 2007 Chronic obstructive pulmonary disease (COPD) is associated with a continuous systemic inflammatory response. Furthermore, COPD is associated with an excess risk for cardiovascular disease and type II diabetes. Systemic inflammation in other populations is a factor in atherogenesis and has been associated with insulin resistance. We assessed the association between systemic inflammation and insulin resistance in non-hypoxaemic patients with COPD. Fasting plasma glucose, insulin and inflammatory mediators were measured in 56 patients and 29 healthy subjects. Body mass index (BMI) and height squared fat- and fat-free-mass index were similar between subject groups. Using homeostatic modelling techniques, mean (SD) insulin resistance was greater in the patients, 1.68 (2.58) and 1.13 (2.02) in healthy subjects, p=0.032. Fasting plasma insulin was increased in patients while glucose was similar to that in healthy subjects. Patients had increased circulating inflammatory mediators. Insulin resistance was related to interleukin-6 (IL-6), r=0.276, p=0.039, and tumour necrosis factor alpha soluble receptor I, r=0.351, p=0.008. Both IL-6 and BMI were predictive variables of insulin resistance r(2)=0.288, p<0.05. We demonstrated greater insulin resistance in non-hypoxaemic patients with COPD compared with healthy subjects, which was related to systemic inflammation. This relationship may indicate a contributory factor in the excess risk of cardiovascular disease and type II diabetes in COPD.

Dourado VZ. Tanni SE. Vale SA. Faganello MM. Sanchez FF. Godoy I. Systemic manifestations in chronic obstructive pulmonary disease. [Review] [60 refs] Jornal Brasileiro De Pneumologia: Publicacao Oficial Da Sociedade Brasileira De Pneumologia E Tisilogia. 32(2):161-71, 2006 Chronic obstructive pulmonary disease is progressive and is characterized by abnormal inflammation of the lungs in response to inhalation of noxious particles or toxic gases, especially cigarette smoke. Although this infirmity primarily affects the lungs, diverse extrapulmonary manifestations have been described. The likely mechanisms involved in the local and systemic inflammation seen in this disease include an increase in the number of inflammatory cells (resulting in abnormal production of inflammatory cytokines) and an imbalance between the formation of reactive oxygen species and antioxidant capacity (leading to oxidative stress). Weakened physical condition secondary to airflow limitation can also lead to the development of altered muscle function. Chronic obstructive pulmonary disease presents diverse systemic effects including nutritional depletion and musculoskeletal dysfunction (causing a reduction in exercise tolerance), as well as other effects related to the comorbidities generally observed in these patients. These manifestations have been correlated with survival and overall health status in chronic obstructive pulmonary disease patients. In view of these facts, the aim of this review was to discuss findings in the literature related to the systemic manifestations of chronic obstructive pulmonary disease, emphasizing the role played by systemic inflammation and evaluating various therapeutic strategies.

van Helvoort HA. Heijdra YF. de Boer RC. Swinkels A. Thijs HM. Dekhuijzen PN. Six-minute walking-induced systemic inflammation and oxidative stress in muscle-wasted COPD patients. Chest. 131(2):439-45, 2007  BACKGROUND: Systemic inflammation and oxidative stress are potential mechanisms for muscle wasting in COPD patients. Six-minute walking testing (6MWT) has been suggested as simple and valid exercise test in COPD that is well tolerated, and reflective of activities of daily living. The present study investigated physiologic and systemic immunologic responses to a 6MWT in muscle-wasted patients with COPD and compared them with maximal cardiopulmonary exercise testing (CPET). METHODS: Ten patients with muscle-wasted COPD were included (fat-free mass index [FFMI]: men, < 16 kg/m2; women, < 15 kg/m2). 6MWT and CPET were performed in random order. The physiologic response was followed by a mobile oxycon. Arterial blood was obtained at rest and after exercise to measure blood gases and markers of systemic inflammation and oxidative stress. RESULTS: In these patients (FEV1 55 +/- 4% of predicted [mean +/- SE]), the 6MWT was a submaximal, albeit intense, exercise as reflected by oxygen uptake (VO2), minute ventilation, heart rate, and lactate values. Leukocytosis was less intense after 6MWT compared to CPET. Contrary, the increase in interleukin-6, free radical release by neutrophils, oxidation of proteins and lipids, and the reduction in antioxidant capacity were similar after both exercises. FFMI was inversely related to 6MWT-induced increases in protein and lipid peroxidation. CONCLUSIONS: This study shows that a 6MWT induces a systemic immunologic response in muscle-wasted patients with COPD, which is comparable to CPET-induced responses. The correlation between systemic oxidative stress and the degree of muscle wasting supports a possible causal relation between systemic inflammation, oxidative stress, and muscle wasting.

Garrod R. Ansley P. Canavan J. Jewell A. Exercise and the inflammatory response in chronic obstructive pulmonary disease (COPD)--Does training confer anti-inflammatory properties in COPD?. [Review] [59 refs] Medical Hypotheses. 68(2):291-8, 2007.  There is increasing evidence that systemic inflammation plays an important role in the pathogenesis of COPD. Inflammatory markers show relationships with exercise performance, health related quality of life and breathlessness. These are important clinical outcomes in the management of COPD. Even more so is the consideration that systemic inflammation in COPD may be directly associated with mortality and deterioration of disease. Long-term exercise training clearly has beneficial properties in healthy subjects, whether the same is true in COPD remains to be seen. This review discusses aspects of the anti-inflammatory effects of exercise in relation to patients with COPD. There is intriguing evidence that the exercise-induced cytokine response differs in COPD patients compared with healthy subjects. We consider the role of IL-6 in the manifestation of fatigue in COPD and consider the implications of raised CRP- and TNF-alpha. Early data suggests beneficial effects of polyunsaturated fatty acid PUFA supplementation and exercise training in combination with appropriate nutritional support may yield rewarding therapeutic benefits. This review raises the hypothesis that physical training in COPD is associated with immunological changes that may confer anti-inflammatory benefits and in part, explain changes seen after pulmonary rehabilitation in COPD patients.

Parr DG. White AJ. Bayley DL. Guest PJ. Stockley RA. Inflammation in sputum relates to progression of disease in subjects with COPD: a prospective descriptive study. Respiratory Research. 7:136, 2006.  BACKGROUND: Inflammation is considered to be of primary pathogenic importance in COPD but the evidence on which current understanding is based does not distinguish between cause and effect, and no single mechanism can account for the complex pathology. We performed a prospective longitudinal study of subjects with COPD that related markers of sputum inflammation at baseline to subsequent disease progression. METHODS: A cohort of 56 patients with chronic bronchitis was characterized in the stable state at baseline and after an interval of four years, using physiological measures and CT densitometry. Sputum markers of airway inflammation were quantified at baseline from spontaneously produced sputum in a sub-group (n = 38), and inflammation severity was related to subsequent disease progression. RESULTS: Physiological and CT measures indicated disease progression in the whole group. In the sub-group, sputum myeloperoxidase correlated with decline in FEV1 (rs = -0.344, p = 0.019, n = 37). LTB4 and albumin leakage correlated with TLCO decline (rs = -0.310, p = 0.033, rs = -0.401, p = 0.008, respectively, n = 35) and IL-8 correlated with progression of lung densitometric indices (rs = -0.464, p = 0.005, n = 38). CONCLUSION: The data support a principal causative role for neutrophilic inflammation in the pathogenesis of COPD and suggest that the measurement of sputum inflammatory markers may have a predictive role in clinical practice.

Joppa P. Petrasova D. Stancak B. Tkacova R. Systemic inflammation in patients with COPD and pulmonary hypertension.[see comment]. Chest. 130(2):326-33, 2006 STUDY OBJECTIVES: COPD is a systemic disorder that is associated with increases of inflammatory proteins in systemic circulation. However, no data on the potential role of systemic inflammation in pulmonary hypertension secondary to COPD are available. Therefore, our aim was to investigate the degree of systemic inflammation reflected by circulatory levels of C-reactive protein (CRP), tumor-necrosis factor (TNF)-alpha, and interleukin (IL)-6 in COPD patients with and without pulmonary hypertension. DESIGN: Cross-sectional study. SETTING: University hospital, tertiary referral setting. PATIENTS AND MEASUREMENTS: In 43 consecutive patients with COPD (mean [+/- SD] age, 65.0 +/- 10.5 years; mean FEV(1), 46.2 +/- 18.1% predicted), lung function was assessed using body plethysmography; pulmonary artery pressure (Ppa) levels were measured by echocardiography. Serum TNF-alpha and IL-6 levels were assessed by enzyme-linked immunosorbent assay, and high-sensitivity serum CRP levels were measured by chemiluminescent immunoassay. RESULTS: Pulmonary hypertension was present in 19 patients and was absent in 24 patients. In patients with pulmonary hypertension, serum CRP and TNF-alpha levels were significantly higher than in those patients without hypertension (median, 3.6 mg/L [25th to 75th percentile, 1.4 to 13.0 mg/L] vs 1.8 mg/L [25th to 75th percentile, 0.8 to 2.8 mg/L; p = 0.034]; and median, 4.2 pg/mL [25th to 75th percentile, 3.4 to 10.9 pg/mL] vs 3.1 pg/mL [25th to 75th percentile, 2.1 to 4.2 pg/mL]; p = 0.042, respectively). No differences were seen in serum IL-6 (median, 10.4 pg/mL [25th to 75th percentile, 8.8 to 12.2 pg/mL] vs 10.5 pg/mL [25th to 75th percentile, 9.4 to 39.1 pg/mL]; p = 0.651) between the groups. In multiple linear regression analysis, the following two variables were independent predictors of systolic Ppa (R(2) = 0.373): Pao(2) (p = 0.011); and log-transformed serum CRP level (p = 0.044). CONCLUSION: We conclude that increases in Ppa in patients with COPD are associated with higher serum levels of CRP and TNF-alpha, raising the possibility of a pathogenetic role for low-grade systemic inflammation in the pathogenesis of pulmonary hypertension in COPD patients.

Rahman I. Adcock IM. Oxidative stress and redox regulation of lung inflammation in COPD. [Review] [223 refs] European Respiratory Journal. 28(1):219-42, 2006 Reactive oxygen species, either directly or via the formation of lipid peroxidation products, may play a role in enhancing inflammation through the activation of stress kinases (c-Jun activated kinase, extracellular signal-regulated kinase, p38) and redox-sensitive transcription factors, such as nuclear factor (NF)-kappaB and activator protein-1. This results in increased expression of a battery of distinct pro-inflammatory mediators. Oxidative stress activates NF-kappaB-mediated transcription of pro-inflammatory mediators either through activation of its activating inhibitor of kappaB-alpha kinase or the enhanced recruitment and activation of transcriptional co-activators. Enhanced NF-kappaB-co-activator complex formation results in targeted increases in histone modifications, such as acetylation leading to inflammatory gene expression. Emerging evidence suggests the glutathione redox couple may entail dynamic regulation of protein function by reversible disulphide bond formation on kinases, phosphatases and transcription factors. Oxidative stress also inhibits histone deacetylase activity and in doing so further enhances inflammatory gene expression and may attenuate glucocorticoid sensitivity. The antioxidant/anti-inflammatory effects of thiol molecules (glutathione, N-acetyl-L-cysteine and N-acystelyn, erdosteine), dietary polyphenols (curcumin-diferuloylmethane, cathechins/quercetin and reserveratol), specific spin traps, such as alpha-phenyl-N-tert-butyl nitrone, a catalytic antioxidant (extracellular superoxide dismutase (SOD) mimetic, SOD mimetic M40419 and SOD, and catalase manganic salen compound, eukarion-8), porphyrins (AEOL 10150 and AEOL 10113) and theophylline have all been shown to play a role in either controlling NF-kappaB activation or affecting histone modifications with subsequent effects on inflammatory gene expression in lung epithelial cells. Thus, oxidative stress regulates both key signal transduction pathways and histone modifications involved in lung inflammation. Various approaches to enhance lung antioxidant capacity and clinical trials of antioxidant compounds in chronic obstructive pulmonary disease are also discussed.

Balasubramanian VP. Varkey B. Chronic obstructive pulmonary disease: effects beyond the lungs. [Review] [61 refs] Current Opinion in Pulmonary Medicine. 12(2):106-12, 2006 PURPOSE OF REVIEW: This article reviews the systemic effects of chronic obstructive pulmonary disease in general and the musculoskeletal effects and cachexia in particular. RECENT FINDINGS: Shift in muscle fiber type from I to II, reduction of capillary/mitochondria ratio, reduction of oxidative enzymes and oxidative capacity, alteration in amino acid profile, changes in respiratory muscle dynamics, activation of the ubiquitin-proteosome pathway with loss of contractile proteins are some of the factors found to cause muscle dysfunction in chronic obstructive pulmonary disease. Chemotaxis and capability to produce more reactive oxygen species and to cause extracellular proteolysis are enhanced in neutrophils of chronic obstructive pulmonary disease patients. Tumor necrosis factor-alpha is shown to cause loss of myosin chains in a time and dose-dependent fashion and to induce production of reactive oxygen species through activation of the cyclooxygenase pathway. Inflammation and oxidative stress caused by reactive oxygen species fuel each other. Weight loss due to muscle wasting (cachexia) in chronic obstructive pulmonary disease is not solely related to malnutrition and is an independent predictor of mortality. Causative factors for cachexia include cytokine effects, protein degradation enhanced by increased ubiquination, upregulation of mRNA for key enzymes, increased energy expenditure and neurohormonal effects such as leptin production and an imbalance in anabolic and catabolic hormone homeostasis. SUMMARY: The findings noted above may well have the common link of inflammation in and beyond the lungs. 

Yende S. Waterer GW. Tolley EA. Newman AB. Bauer DC. Taaffe DR. Jensen R. Crapo R. Rubin S. Nevitt M. Simonsick EM. Satterfield S. Harris T. Kritchevsky SB. Inflammatory markers are associated with ventilatory limitation and muscle dysfunction in obstructive lung disease in well functioning elderly subjects.[see comment]. Thorax. 61(1):10-6, 2006 BACKGROUND: Inflammatory markers are increased in chronic obstructive pulmonary disease (COPD) and are hypothesised to play an important part in muscle dysfunction and exercise intolerance. METHODS: The Health Aging and Body Composition (Health ABC) study is a prospective observational cohort of well functioning individuals aged 70-79 years. A cross sectional analysis of the baseline data was conducted to examine the association between inflammatory markers and ventilatory limitation, muscle strength, and exercise capacity. These associations were compared in participants with and without obstructive lung disease (OLD). RESULTS: Of the 3075 participants enrolled in the Health ABC cohort, OLD was identified by spirometric testing in 268 participants and 2005 participants had normal spirometric results. Of the participants with OLD, 35%, 38%, and 27% participants had mild, moderate, and severe OLD, respectively. Participants with OLD had lower quadriceps strength (102.5 Nm v 108.9 Nm, p = 0.02), lower maximum inspiratory pressure (64.7 cm H(2)O v 74.2 cm H(2)O, p<0.0001), higher systemic interleukin (IL)-6 levels (2.6 pg/ml v 2.2 pg/ml, p<0.0001), and higher C-reactive protein (CRP) levels (3.5 mg/l v 2.5 mg/l, p<0.0001) than those with normal spirometry. In participants with OLD and those with normal spirometry, forced expiratory volume in 1 second (FEV(1)) was associated with IL-6 (adjusted regression coefficients (beta) = -5.3 (95% CI -9.1 to-1.5) and -3.1 (95% CI -4.3 to -1.9), respectively). IL-6 and TNF were also associated with quadriceps strength among participants with OLD and those with normal spirometry (beta = -6.4 (95% CI -12.8 to -0.03) and -3.4 (95% CI -5.4 to -1.3), respectively, for IL-6 and beta = -10.1 (95% CI -18.7 to -1.5) and -3.8 (95% CI -7 to -0.6), respectively, for TNF). IL-6, quadriceps strength, and maximum inspiratory pressures were independent predictors of reduced exercise capacity in both groups. CONCLUSIONS: In well functioning elderly subjects with or without OLD, IL-6 is associated with reduced FEV(1), quadriceps strength, and exercise capacity.

Hurst JR. Perera WR. Wilkinson TM. Donaldson GC. Wedzicha JA. Systemic and upper and lower airway inflammation at exacerbation of chronic obstructive pulmonary disease. American Journal of Respiratory & Critical Care Medicine. 173(1):71-8, 2006 RATIONALE: In addition to pulmonary involvement, stable chronic obstructive pulmonary disease (COPD) is associated with nasal and systemic inflammation. Although exacerbations of COPD are associated with increased pulmonary and systemic inflammation, determinants of the systemic response remain obscure, and nor is it known whether there is nasal involvement. OBJECTIVES: To investigate upper airway, lower airway, and systemic inflammation at exacerbation of COPD. METHODS: We sampled sputum, nasal wash, and serum from 41 exacerbations (East London cohort) for analysis of pathogenic microorganisms and inflammatory indices (sputum/nasal wash leukocytes, interleukin [IL]-6, IL-8, and myeloperoxidase; serum IL-6 and C-reactive protein). Values were compared with stable COPD. MEASUREMENTS AND MAIN RESULTS: Exacerbation of COPD is associated with greater nasal, sputum, and serum inflammation than the stable state. At exacerbation, inflammatory markers were highly correlated within nasal wash and serum (all r >/= 0.62, p < 0.001), but not sputum. The degree of upper airway inflammation correlated with the degree of lower airway inflammation (e.g., nasal wash/sputum myeloperoxidase; r = 0.50, p = 0.001). The degree of systemic inflammation correlated with the degree of lower airway inflammation (e.g., serum IL-6/sputum IL-8; r = 0.35, p = 0.026), and was greater in the presence of a sputum bacterial pathogen (29.0 g/dl C-reactive protein difference, p = 0.002). We did not find relationships between the upper airway and systemic compartments. CONCLUSIONS: Exacerbation of COPD is associated with pan-airway inflammation; the systemic inflammatory response is proportional to that occurring in the lower airway and greater in the presence of a bacterial pathogen.