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      Essential need for rethink of COPD airway pathology: implications for new drug approaches for prevention of lung cancer as well as small airway fibrosis

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          Abstract

          Dear editor We read with interest the recent comprehensive review by Sowmya P Lakshmi et al on potential new therapies for COPD in the International Journal of Chronic Obstructive Pulmonary Disease.1 The review says that only by understanding the core pathological processes, new therapeutics emerge, and it encourages that leading respiratory journals are recognizing this. However, we would suggest that, in this review, the overall view of the pathology of COPD airway disease does not reflect the current literature. In particular, the airway wall in at least mild to moderate COPD is hypo-cellular and hypo-vascular, with markedly active epithelial–mesenchymal transition (EMT)2 as part of epithelial activation and reprogramming.3 This process is closely related to small airway fibrosis and airflow obstruction. Inhaled corticosteroids (ICSs) affect these key epithelial cellular activation and vascular aspects of COPD,2 and more research on alternatives to corticosteroid on these aspects is urgently needed. It is of interest that the peroxisome proliferator-activated receptor system that the reviewers mention has implication for EMT induction,1 as has the TGF/Activin family and the Wnt system; these pathways are replete with potential drug targets. There is certainly marked innate cellular activation within the airway lumen in COPD, due to oxidant attack or chronic infection or indeed both. We have shown that the airways in COPD are especially vulnerable to rhinovirus infection and bacterial infection by non-typeable Haemophilus influenzae and Pneumococci, because of marked upregulation of their respective major epithelial cell–surface adhesion sites, intercellular adhesion molecule-1, and platelet-activating factor receptor.4 Blocking these receptors could potentially have great positive effect on airway luminal inflammation, acute exacerbations, and the downhill natural history of COPD.4 Lung cancer is strongly related to COPD and not only smoking. In epidemiological studies, there is a strong suggestion that patients on ICSs at high doses are associated with an appreciable (50%) reduction in the cancer risk. Epithelia with active EMT are highly vulnerable to malignant transition, and EMT in COPD airways may well be the link between airway fibrosis and cancer development that is inhibited by ICS. Recently, we showed strong correlations between EMT activity in the leading edge of invasive cancer and EMT activity even in the non-malignant airways from which the tumor originated.5 Such a link would have huge implications for therapeutic and public health policy, since drugs acting on epithelial activation, and the EMT system would need to be given early in the natural history of COPD, not just to suppress airway luminal inflammation, but also to suppress epithelial activation, EMT, and related fibrotic and malignant consequences. In summary, better insights into core airway pathologies in COPD are vital, and of those EMT may well represent a fundamentally important aspect for airway wall fibrosis and cancer development. Finally, we may get an integrated understanding of this airway disease translatable into a new paradigm for attacking fundamental disease mechanisms early, rather than only symptoms and luminal “inflammation” in later-stage patients.

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          Most cited references 7

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          Epithelial to mesenchymal transition is increased in patients with COPD and induced by cigarette smoke.

          Cigarette smoking contributes to lung remodelling in chronic obstructive pulmonary disease (COPD). As part of remodelling, peribronchiolar fibrosis is observed in the small airways of patients with COPD and contributes to airway obstruction. Epithelial to mesenchymal transition (EMT) appears to be involved in the formation of peribronchiolar fibrosis. This study examines the EMT process in human bronchial epithelial cells (HBECs) from non-smokers, smokers and patients with COPD as well as the in vitro effect of cigarette smoke extract (CSE) on EMT. HBECs from non-smokers (n=5), smokers (n=12) and patients with COPD (n=15) were collected to measure the mesenchymal markers α-smooth muscle actin, vimentin and collagen type I and the epithelial markers E-cadherin, ZO-1 and cytokeratin 5 and 18 by real time-PCR and protein array. In vitro differentiated bronchial epithelial cells were stimulated with CSE. Mesenchymal markers were upregulated in HBECs of smokers and patients with COPD compared with non-smokers. In contrast, epithelial cell markers were downregulated. In vitro differentiated HBECs underwent EMT after 72 h of CSE exposure through the activation of intracellular reactive oxygen species, the release and autocrine action of transforming growth factor β1, the phosphorylation of ERK1/2 and Smad3 and by the downregulation of cyclic monophosphate. The EMT process is present in bronchial epithelial cells of the small bronchi of smokers and patients with COPD and is activated by cigarette smoke in vitro.
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            A randomized controlled trial of inhaled corticosteroids (ICS) on markers of epithelial–mesenchymal transition (EMT) in large airway samples in COPD: an exploratory proof of concept study

            Background We recently reported that epithelial–mesenchymal transition (EMT) is active in the airways in chronic obstructive pulmonary disease (COPD), suggesting presence of an active profibrotic and promalignant stroma. With no data available on potential treatment effects, we undertook a blinded analysis of inhaled corticosteroids (ICS) effects versus placebo on EMT markers in previously obtained endobronchial biopsies in COPD patients, as a “proof of concept” study. Methods Assessment of the effects of inhaled fluticasone propionate (FP; 500 μg twice daily for 6 months) versus placebo in 34 COPD patients (23 on fluticasone propionate and eleven on placebo). The end points were epidermal growth factor receptor (EGFR; marker of epithelial activation) and the biomarkers of EMT: reticular basement membrane (Rbm) fragmentation (“hallmark” structural marker), matrix metalloproteinase-9 (MMP-9) cell expression, and S100A4 expression in basal epithelial and Rbm cells (mesenchymal transition markers). Results Epithelial activation, “clefts/fragmentation” in the Rbm, and changes in the other biomarkers all regressed on ICS, at or close to conventional levels of statistical significance. From these data, we have been able to nominate primary and secondary end points and develop power calculations that would be applicable to a definitive prospective study. Conclusion Although only a pilot “proof of concept” study, this trial provided strong suggestive support for an anti-EMT effect of ICS in COPD airways. A larger and fully powered prospective study is now indicated as this issue is likely to be extremely important. Such studies may clarify the links between ICS use and better clinical outcomes and protection against lung cancer in COPD.
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              Early events in the pathogenesis of chronic obstructive pulmonary disease. Smoking-induced reprogramming of airway epithelial basal progenitor cells.

              The airway epithelium is the primary site of the earliest pathologic changes induced by smoking, contributing to the development of chronic obstructive pulmonary disease (COPD). The normal human airway epithelium is composed of several major cell types, including differentiated ciliated and secretory cells, intermediate undifferentiated cells, and basal cells (BC). BC contain the stem/progenitor cell population responsible for maintenance of the normally differentiated airway epithelium. Although inflammatory and immune processes play a significant role in the pathogenesis of COPD, the earliest lesions include hyperplasia of the BC population, suggesting that the disease may start with this cell type. Apart from BC hyperplasia, smoking induces a number of COPD-relevant airway epithelial remodeling phenotypes that are likely initiated in the BC population, including mucous cell hyperplasia, squamous cell metaplasia, epithelial-mesenchymal transition, altered ciliated and nonmucous secretory cell differentiation, and suppression of junctional barrier integrity. Significant progress has been recently made in understanding the biology of human airway BC, including gene expression features, stem/progenitor, and other functions, including interaction with other airway cell types. Accumulating evidence suggests that human airway BC function as both sensors and cellular sources of various cytokines and growth factors relevant to smoking-associated airway injury, as well as the origin of various molecular and histological phenotypes relevant to the pathogenesis of COPD. In the context of these considerations, we suggest that early BC-specific smoking-induced molecular changes are critical to the pathogenesis of COPD, and these represent a candidate target for novel therapeutic approaches to prevent COPD progression in susceptible individuals.
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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
                2017
                07 September 2017
                : 12
                : 2677-2679
                Affiliations
                School of Health Sciences, University of Tasmania, Launceston, TAS, Australia
                [1 ]Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine
                [2 ]Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA, USA
                Author notes
                Correspondence: Sukhwinder Singh Sohal, School of Health Sciences, University of Tasmania, Locked Bag – 1322, Newnham Drive, Launceston, TAS 7248, Australia, Tel +61 3 6324 5434, Email sssohal@ 123456utas.edu.au
                Correspondence: Raju C Reddy, Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine 3459 Fifth Avenue, Pittsburgh, PA 15213, USA, Tel +1 412 360 6823, Fax +1 412 360 1919, Email reddyrc@ 123456upmc.edu
                Article
                copd-12-2677
                10.2147/COPD.S149092
                5593405
                © 2017 Sohal and Walters. 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.

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                Respiratory medicine

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