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      International Journal of COPD (submit here)

      This international, peer-reviewed Open Access journal by Dove Medical Press focuses on pathophysiological processes underlying Chronic Obstructive Pulmonary Disease (COPD) interventions, patient focused education, and self-management protocols. Sign up for email alerts here.

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      Increased matrix metalloproteinase-9 to tissue inhibitor of metalloproteinase-1 ratio in smokers with airway hyperresponsiveness and accelerated lung function decline

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          Abstract

          Background

          Airway hyperresponsiveness (AHR) is associated with airway inflammation and a rapid decline in lung function and is a predictor of future risk of COPD among smokers. Alveolar macrophages (AMs) from patients with COPD release a greater amount of matrix metalloproteinase (MMP)-9. We hypothesized that the imbalance between MMP-9 and tissue inhibitor of metalloproteinase-1 (TIMP-1) is related to AHR in smokers.

          Patients and methods

          Healthy smokers with AHR (AHR + S) or smokers without AHR (AHR − S; divided according to a methacholine challenge test) and nonsmokers without AHR (AHR − NS) were enrolled. Spirometry was performed during enrollment and repeated after 5 years. Initially, AMs recovered from bronchoalveolar lavage (BAL) fluid were cultured in the presence of p38 mitogen-activated protein kinase (MAPK) inhibitor (SB203580), MAPK kinase (MEK) 1/2 (the MEK of extracellular signal-regulated kinase [ERK] inhibitor, PD98059), or medium alone for 24 h. The release of MMP-9 and TIMP-1 in culture supernatants was measured by enzyme-linked immunosorbent assay.

          Results

          A greater reduction in forced expiratory volume in 1 s (FEV 1)/forced vital capacity (FVC), FEV 1 (as a percentage of the predicted value [%pred]), and maximal mid-expiratory flow (MMEF) was observed among AHR + S in the 5-year period. There was a higher proportion of neutrophils and a lower proportion of AMs in BAL fluid recovered from AHR + S. Compared to AMs from AHR − NS and AHR − S, AMs from nonsmokers with AHR (AHR + NS) released more MMP-9 and less TIMP-1, with an increase in MMP-9/TIMP-1 ratios. The MMP-9/TIMP-1 ratio in smokers was positively correlated with the annual decline in FEV 1%pred, FVC%pred, and MMEF%pred. Both SB203580 and PD98059 significantly reduced MMP-9, but not TIMP-1, from AMs of smokers.

          Conclusion

          AMs of AHR + NS produce excessive MMP-9 over TIMP-1, which may be a predictor of the development of airway obstruction. Inhibition of p38 MAPK and ERK suppresses the generation of MMP-9 by AMs from smokers.

          Most cited references47

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          Multifaceted mechanisms in COPD: inflammation, immunity, and tissue repair and destruction.

          Chronic obstructive pulmonary disease is a leading global cause of morbidity and mortality that is characterised by inexorable deterioration of small airways obstruction with emphysema associated with cellular inflammation and structural remodelling. Other features include apoptosis as well as proliferation of cells, and both tissue repair and lack of tissue repair. Metalloprotease release, together with that of apoptotic factors, may underlie the emphysema, and, conversely, fibrosis of the small airways may be accounted for by the effects of growth factor activation. In advanced disease, influential factors include the development of autoimmunity, with activation of dendritic cells and T-helper cells of both type 1 and 2, and the senescence response. An inability of macrophages to ingest apoptosed cells and bacteria may exacerbate inflammatory responses. Systemic inflammation with concomitant cardiovascular disease and metabolic syndrome may reflect the effect of cigarette smoke on nonpulmonary cells. Corticosteroid resistance may be secondary to oxidative stress mechanisms, such as inactivation of histone deacetylases. The mechanisms of chronic obstructive pulmonary disease may be heterogeneous, according to severity, and clinical phenotypes need to be correlated with cellular and pathological processes. Treatments may be targeted to patients with specific mechanisms.
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            The Asthma-COPD Overlap Syndrome.

            Although in textbooks asthma and chronic obstructive pulmonary disease (COPD) are viewed as distinct disorders, there is increasing awareness that many patients have features of both. This article reviews the asthma-COPD overlap syndrome.
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              Prevalence and incidence of COPD in smokers and non-smokers: the Rotterdam Study

              COPD is the third leading cause of death in the world and its global burden is predicted to increase further. Even though the prevalence of COPD is well studied, only few studies examined the incidence of COPD in a prospective and standardized manner. In a prospective population-based cohort study (Rotterdam Study) enrolling subjects aged ≥45, COPD was diagnosed based on a pre-bronchodilator obstructive spirometry (FEV1/FVC < 0.70). In absence of an interpretable spirometry within the Rotterdam Study, cases were defined as having COPD diagnosed by a physician on the basis of clinical presentation and obstructive lung function measured by the general practitioner or respiratory physician. Incidence rates were calculated by dividing the number of incident cases by the total number of person years of subjects at risk. In this cohort of 14,619 participants, 1993 subjects with COPD were identified of whom 689 as prevalent ones and 1304 cases as incident ones. The overall incidence rate (IR) of COPD was 8.9/1000 person-years (PY); 95 % Confidence Interval (CI) 8.4–9.4. The IR was higher in males and in smokers. The proportion of female COPD participants without a history of smoking was 27.2 %, while this proportion was 7.3 % in males. The prevalence of COPD in the Rotterdam Study is 4.7 % and the overall incidence is approximately 9/1000 PY, with a higher incidence in males and in smokers. The proportion of never-smokers among female COPD cases is substantial. Electronic supplementary material The online version of this article (doi:10.1007/s10654-016-0132-z) contains supplementary material, which is available to authorized users.
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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
                2018
                11 April 2018
                : 13
                : 1135-1144
                Affiliations
                [1 ]Department of Thoracic Medicine, Chang Gung Medical Foundation, College of Medicine, Chang Gung University, Taipei, Taiwan
                [2 ]Airways Disease Section, National Heart and Lung Institute, Imperial College London, London, UK
                Author notes
                Correspondence: Chun-Hua Wang, Department of Thoracic Medicine, Chang Gung Medical Foundation, Chang Gung University College of Medicine, 199 Tun-Hwa North Road, Taipei, Taiwan, Republic of China, Tel +886 3 328 1200 ext 8467, Email wchunhua@ 123456ms7.hinet.net
                Article
                copd-13-1135
                10.2147/COPD.S161257
                5903494
                29692608
                bf6ce95e-bd9e-4efc-9ebc-6cb025e2ff65
                © 2018 Lo et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                History
                Categories
                Original Research

                Respiratory medicine
                smoking,airway hyperresponsiveness,alveolar macrophage,matrix metalloproteinase-9,tissue inhibitor of metalloproteinase-1,p38 mitogen-activated protein kinase,extracellular signal-regulated kinase

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