Epithelial mesenchymal transition (EMT) in small airways of COPD patients

Sohal, Sukhwinder Singh; Walters, E. Haydn

doi:10.1136/thoraxjnl-2013-203373

Cited by 35 publications

(33 citation statements)

References 6 publications

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“…Recent papers by Milara et al27 and Wang et al28 have confirmed the potential for EMT as a major mechanism for small airway fibrosis (EMT Type II) in COPD. We have hypothesized that large airway EMT, which we have found is also associated with Rbm hypervascularity, may be important in both fibrosis and cancer pathogenesis and progression, as this is typical of what has been described as procancerous for epithelial tumors elsewhere 5–8,15. In this pilot randomized controlled trial, we have provided consistent but still provisional evidence that ICS over 6 months suppresses such EMT-related changes.…”

Section: Discussionsupporting

confidence: 66%

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

Sohal¹,

Soltani²,

Reid³

et al. 2014

COPD

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BackgroundWe 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.MethodsAssessment 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).ResultsEpithelial 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.ConclusionAlthough 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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Section: Discussionsupporting

confidence: 66%

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

Sohal¹,

Soltani²,

Reid³

et al. 2014

COPD

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“…EMT when associated with increased angiogenesis of the reticular basement membrane (Rbm) and indeed epithelium itself (Figure 1), leads to the formation of a pro-cancer stroma (EMT-type-3) in contrast to mainly fibrosis-associated EMT-type-2 which lacks angiogenesis [2-4,7-9,12]. It is thought that this aberrant vessel plexus gives immune protection to developing malignant cells by preventing egress and local activity of natural killer (NK) cells [13,14].…”

Section: Letter To the Editormentioning

confidence: 99%

Role of epithelial mesenchymal transition (EMT) in chronic obstructive pulmonary disease (COPD)

Sohal¹,

Walters²

2013

Respir Res

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Small airway fibrosis is the main contributor to physiological airway dysfunction in COPD. One potential mechanism contributing to small airway fibrosis is epithelial mesenchymal transition (EMT). When associated with angiogenesis (so called EMT-Type-3) it may well also be the link with the development of cancer, which is closely associated with COPD and predominantly in large airways. In a recent study published in Respiratory Research, Qin Wang and colleagues investigated the role of urokinase plasminogen activator receptor (uPAR) in EMT in small airway epithelium of COPD patients. However, there are some issues with the paper which we wish to comment on.

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“…The classically described process of EMT involves phenotypic change and migration of epithelial cells into the sub-epithelial mesenchyme in the lamina propria (LP) to function as extracellular-matrix producing fibroblasts/ myofibroblasts [7][8][9][10][11]. EMT is a vital process during embryogenesis (Type I EMT), but can also be induced as a result of persistent damage and tissue inflammation [1,12,13].…”

Section: Introductionmentioning

confidence: 99%

“…EMT is a vital process during embryogenesis (Type I EMT), but can also be induced as a result of persistent damage and tissue inflammation [1,12,13]. There are then two subsequent outcome possibilities with active EMT: severe and even complete organ fibrosis (Type II EMT), development of a premalignant stroma when associated with angiogenesis (Type III EMT) [1,[7][8][9][10][11][12][13][14][15][16].…”

Section: Introductionmentioning

confidence: 99%

Clinical significance of epithelial mesenchymal transition (EMT) in chronic obstructive pulmonary disease (COPD): potential target for prevention of airway fibrosis and lung cancer

Sohal

Mahmood

Walters

2014

Clinical & Translational Med

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Unfortunately, the research effort directed into chronic obstructive pulmonary disease (COPD) has been disproportionately weak compared to its social importance, and indeed it is the least researched of all common chronic conditions. Tobacco smoking is the major etiological factor. Only 25% of smokers will develop “classic” COPD; in these vulnerable individuals the progression of airways disease to symptomatic COPD occurs over two or more decades. We know surprisingly little about the pathobiology of COPD airway disease, though small airway fibrosis and obliteration are likely to be the main contributors to physiological airway dysfunction and these features occur earlier than any subsequent development of emphysema. One potential mechanism contributing to small airway fibrosis/obliteration and change in extracellular matrix (ECM) is epithelial mesenchymal transition (EMT), so called Type-II EMT. When associated with angiogenesis (Type-III EMT) it may well also be a link with the development of lung (airway) cancer which is closely associated with COPD. Active EMT in COPD may help to explain why lung cancer is so common in smokers and also the core pathophysiology of small airway fibrosis. Better understanding may lead to new markers for incipient neoplasia, and better preventive management of patients. There is serious need to understand key components of airway EMT in smokers and COPD, and to demarcate novel drug targets for the prevention of lung cancer and airway fibrosis, as well as better secondary management of COPD. Since over 90% of human cancer arises in epithelia and the involvement of EMT in all of these may be a central paradigm, insights gained in COPD may have important generalizable value.

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Epithelial mesenchymal transition (EMT) in small airways of COPD patients

Cited by 35 publications

References 6 publications

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

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

Role of epithelial mesenchymal transition (EMT) in chronic obstructive pulmonary disease (COPD)

Clinical significance of epithelial mesenchymal transition (EMT) in chronic obstructive pulmonary disease (COPD): potential target for prevention of airway fibrosis and lung cancer

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Epithelial mesenchymal transition (EMT) in small airways of COPD patients

Cited by 35 publications

References 6 publications

A randomized controlled trial of inhaled corticosteroids (ICS) on markers of epithelial&ndash;mesenchymal transition (EMT) in large airway samples in COPD: an exploratory proof of concept study

A randomized controlled trial of inhaled corticosteroids (ICS) on markers of epithelial&ndash;mesenchymal transition (EMT) in large airway samples in COPD: an exploratory proof of concept study

Role of epithelial mesenchymal transition (EMT) in chronic obstructive pulmonary disease (COPD)

Clinical significance of epithelial mesenchymal transition (EMT) in chronic obstructive pulmonary disease (COPD): potential target for prevention of airway fibrosis and lung cancer

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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

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