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      Systemic signs of neutrophil mobilization during clinically stable periods and during exacerbations in smokers with obstructive pulmonary disease

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          Abstract

          Background

          It is still unclear whether signs of neutrophil mobilization in the blood of patients with chronic obstructive pulmonary disease represent true systemic events and how these relate to bacterial colonization in the airways. In this study, we evaluated these issues during clinically stable periods and during exacerbations in smokers with obstructive pulmonary disease and chronic bronchitis (OPD-CB).

          Methods

          Over a period of 60 weeks for each subject, blood samples were repeatedly collected from 60 smokers with OPD-CB during clinically stable periods, as well as during and after exacerbations. Myeloperoxidase (MPO) and neutrophil elastase (NE) protein and mRNA, growth of bacteria in sputum, and clinical parameters were analyzed. Ten asymptomatic smokers and ten never-smokers were included as controls.

          Results

          We found that, during clinically stable periods, neutrophil and NE protein concentrations were increased in smokers with OPD-CB and in the asymptomatic smokers when compared with never-smokers. During exacerbations, neutrophil and MPO protein concentrations were further increased in smokers with OPD-CB, without a detectable increase in the corresponding mRNA during exacerbations. However, MPO and NE protein and mRNA displayed positive correlations. During exacerbations, only increased neutrophil concentrations were associated with growth of bacteria in sputum. Among patients with low transcutaneous oxygen saturation during exacerbations, PaO 2 (partial oxygen pressure) correlated with concentrations of MPO and NE protein and neutrophils in a negative manner.

          Conclusion

          There are signs of systemic neutrophil mobilization during clinically stable periods and even more so during exacerbations in chronic obstructive pulmonary disease. In this condition, MPO and NE may share a cellular origin, but its location remains uncertain. Factors other than local bacteria, including hypoxemia, may be important for driving systemic signs of neutrophil mobilization.

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          Most cited references 27

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          New insights into the immunology of chronic obstructive pulmonary disease.

          Chronic obstructive pulmonary disease (COPD) is a heterogeneous syndrome associated with abnormal inflammatory immune responses of the lung to noxious particles and gases. Cigarette smoke activates innate immune cells such as epithelial cells and macrophages by triggering pattern recognition receptors, either directly or indirectly via the release of damage-associated molecular patterns from stressed or dying cells. Activated dendritic cells induce adaptive immune responses encompassing T helper (Th1 and Th17) CD4+ T cells, CD8+ cytotoxicity, and B-cell responses, which lead to the development of lymphoid follicles on chronic inflammation. Viral and bacterial infections not only cause acute exacerbations of COPD, but also amplify and perpetuate chronic inflammation in stable COPD via pathogen-associated molecular patterns. We discuss the role of autoimmunity (autoantibodies), remodelling, extracellular matrix-derived fragments, impaired innate lung defences, oxidative stress, hypoxia, and dysregulation of microRNAs in the persistence of the pulmonary inflammation despite smoking cessation. Copyright © 2011 Elsevier Ltd. All rights reserved.
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            C-reactive protein in patients with COPD, control smokers and non-smokers.

            Patients with chronic obstructive pulmonary disease (COPD) have raised serum levels of C reactive protein (CRP). This may be related directly to COPD and its associated systemic inflammation or secondary to other factors such as concomitant ischaemic heart disease (IHD) or smoking status. The aim of this study was to evaluate IHD and smoking as potential causes of raised CRP levels in COPD and to test the association between inhaled corticosteroid (ICS) use and serum CRP levels. Cross sectional analyses comparing cohorts of 88 patients with COPD, 33 smokers (S), and 38 non-smoker (NS) controls were performed. Clinical assessments included a complete medical history, pulmonary function, 6 minute walk test (6MWT), cardiopulmonary exercise test, and high sensitivity serum CRP measurements. Serum CRP levels were significantly higher in patients with COPD (5.03 (1.51) mg/l) than in controls (adjusted odds ratio 9.51; 95% confidence interval 2.97 to 30.45) but were similar in the two control groups (S: 2.02 (1.04) mg/l; NS: 2.24 (1.04) mg/l). There was no clinical or exercise evidence of unstable IHD in any of the subjects. CRP levels were lower in COPD patients treated with ICS than in those not treated (3.7 (3.0) mg/l v 6.3 (3.6) mg/l); this association was confirmed in an adjusted regression model (p<0.05). CRP levels are raised in COPD patients without clinically relevant IHD and independent of cigarette smoking, and reduced in patients with COPD using ICS. CRP may be a systemic marker of the inflammatory process that occurs in patients with COPD.
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              Systemic inflammation and comorbidity in COPD: a result of 'overspill' of inflammatory mediators from the lungs? Review of the evidence.

              Chronic obstructive pulmonary disease (COPD) is characterised by an inflammatory response by the lungs to inhaled substances such as cigarette smoking and air pollutants. In addition to the pulmonary features of COPD, several systemic effects have been recognised even after controlling for common aetiological factors such as smoking or steroid use. These include skeletal muscle dysfunction, cardiovascular disease, osteoporosis and diabetes. Individuals with COPD have significantly raised levels of several circulating inflammatory markers indicating the presence of systemic inflammation. This raises the issue of cause and effect. The role of tumour necrosis factor α in COPD is thought to be central to both lung and systemic inflammation and has been implicated in skeletal muscle dysfunction, osteoporosis and type 2 diabetes. It has been hypothesised that inflammation in the lung results in 'overspill' into the circulation causing systemic inflammation. There is supportive evidence that protein movement can occur from the lung surface to the systemic circulation. Evidence from inhaled substances such as air pollutants and cigarette smoke has demonstrated a temporal link between the inflammatory process in the lung and systemic inflammation. Also, studies have shown alterations in circulating inflammatory cells in patients with COPD compared with controls which may reflect the effects of inflammatory mediators (derived from the lung) on circulating cells or the bone marrow. This paper considers the concept of 'overspill' in depth, reviews the current evidence and highlights problems in generating direct evidence to support or refute this concept.
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                Author and article information

                Journal
                Int J Chron Obstruct Pulmon Dis
                Int J Chron Obstruct Pulmon Dis
                International Journal of COPD
                International Journal of Chronic Obstructive Pulmonary Disease
                Dove Medical Press
                1176-9106
                1178-2005
                2015
                30 June 2015
                : 10
                : 1253-1263
                Affiliations
                [1 ]Department of Internal Medicine and Clinical Nutrition, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
                [2 ]Department of Pediatrics, Dokkyo Medical University, Japan
                [3 ]Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
                [4 ]Department of Bacteriology, Institute of Laboratory Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
                [5 ]Unit for Lung and Airway Research, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
                Author notes
                Correspondence: Anders Lindén, Unit for Lung and Airway Research, Institute of Environmental Medicine, Karolinska Institutet, PO Box 210, SE-171 77 Stockholm, Sweden, Tel +467 0090 2286, Email anders.linden@ 123456ki.se
                Article
                copd-10-1253
                10.2147/COPD.S77274
                4493974
                © 2015 Andelid et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Original Research

                Respiratory medicine

                oxygen, c-reactive protein, myeloperoxidase, infection, elastase, copd

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