Epithelial-mesenchymal transition as a fundamental underlying pathogenic process in COPD airways: fibrosis, remodeling and cancer

Abstract

Chronic obstructive pulmonary disease (COPD) is a complex condition, frequently with a mix of airway and lung parenchymal damage. However, the earliest changes are in the small airways, where most of the airflow limitation occurs. The pathology of small airway damage seems to be wall fibrosis and obliteration, but the whole airway is involved in a ‘field effect’. Our novel observations on active epithelial-mesenchymal transition (EMT) in the airways of smokers, particularly in those with COPD, are changing the understanding of this airway pathology and the aetiology of COPD. EMT involves a cascade of regulatory changes that destabilise the epithelium with a motile and mesenchymal epithelial cell phenotype emerging. One important manifestation of EMT activity involves up-regulation of specific key transcription factors (TFs), such as Smads, Twist, and β-catenin. Such TFs can be used as EMT biomarkers, in recognisable patterns reflecting the potential major drivers of the process; for example, TGFβ, Wnt, and integrin-linked kinase systems. Thus, understanding the relative changes in TF activity during EMT may provide rich information on the mechanisms driving this whole process, and how they may change over time and with therapy. We have sought to review the current literature on EMT and the relative expression of specific TF activity, to define the networks likely to be involved in a similar process in the airways of patients with smoking-related COPD.

Keywords::

• COPD
• epithelial-mesenchymal transition
• Smads
• smoking
• transcription factors
• β-catenin

Acknowledgements

I would like to acknowledge Jo-Maree Courtney for her generous contribution for scientific figures in this article.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Current literature on airway fibrosis, remodeling and epithelial–mesenchymal transition (EMT) in smoking-related chronic obstructive pulmonary disease is still sparse, and further study is urgently required to confirm and extend this.

• Presence of EMT in the airways of smokers, especially in those with chronic obstructive pulmonary disease, needs to be correlated with lung function loss and indeed malignant transformation.

• The drivers of EMT in the airways and the pathways and transcription factors they use need to be defined.

• Transcription factor profiles, closely associated with EMT, can be of potential use in identifying these major drivers.

• There may be different pathways within the broad EMT machinery in large versus small airway, and in fibrosis versus malignant change; these also need to be defined.

• What are the potential impacts of pharmacological interventions on EMT, and if beneficial, which pathway do they work through to inhibit EMT?

Notes