Inhaled corticosteroid normalizes some but not all airway vascular remodeling in COPD

et al. 2017

Developmental Dynamics

Self Cite

204

156

Epithelial-mesenchymal transition (EMT) plays key roles during lung development and many lung diseases such as chronic obstructive pulmonary disease (COPD), lung cancer, and pulmonary fibrosis. Here, integrating morphological observations with underlying molecular mechanisms, we highlight the functional role of EMT in lung development and injury repair, and discuss how it can contribute to pathogenesis of chronic lung disease. We discuss the evidence of manifestation of EMT and its potential driving role in COPD, idiopathic pulmonary fibrosis (IPF), bronchiolitis obliterans syndrome (BOS), and lung cancer, while noting that all cells need not display a full EMT in any of these contexts, i.e., often cells co-express epithelial and mesenchymal markers but do not fully convert to extracellular matrix (ECM) -producing fibroblasts. Finally, we discuss recent therapeutic attempts to restrict EMT in chronic lung disease. Developmental Dynamics 247:346-358, 2018. V C 2017 Wiley Periodicals, Inc.

Section: Emt In Chronic Lung Diseasementioning

confidence: 99%

Epithelial–mesenchymal transition, a spectrum of states: Role in lung development, homeostasis, and disease

Jolly

Ward

et al. 2017

Developmental Dynamics

Self Cite

204

156

“…This is the first clinical study to show the anti-EMT effects of ICS. We also observed effects on vascular remodelling in COPD patients (45), angiogenesis (46) is also major part of EMT when associated with the formation of pro-cancer stroma (47). In epidemiological studies, it is observed that ICS treatment of COPD patients significantly reduces lung cancer risk but the underlying mechanisms are not clear (48).…”

Section: Potential Emt Treatmentsmentioning

confidence: 69%

“…Other studies, including in vivo mouse models that replicate the pathologic features of EMT and fibrosis (81), and potentially exacerbations (82)(83)(84)(85)(86)(87)(88)(89)(90), could be valuable in elucidating mechanisms identifying therapeutic targets and test new therapies (91). Validation using combinations of in vivo and ex vivo human studies (45,(92)(93)(94)(95)(96) will provide powerful evidence for their roles and potential targeting in COPD (82,97). There could be wider implications for other lung diseases such as idiopathic pulmonary fibrosis (IPF) and lung cancer where EMT activity and fibrosis are prevalent (26,81,98).…”

Section: Discussionmentioning

confidence: 99%

Heparin-binding epidermal growth factor (HB-EGF) drives EMT in patients with COPD: implications for disease pathogenesis and novel therapies

Laboratory Investigation

Sharma

Thompson

et al. 2019

Chronic obstructive pulmonary disease (COPD) is a progressive and devastating chronic lung condition that has a significant global burden, both medically and financially. Currently there are no medications that can alter the course of disease. At best, the drugs in clinical practice provide symptomatic relief to suffering patients by alleviating acute exacerbations. Most of current clinical research activities are in late severe disease with lesser attention given to early disease manifestations. There is as yet, a lack of understanding of the underlying mechanisms of disease progression and the molecular switches that are involved in their manifestation. Small airway fibrosis and obliteration are known to cause fixed airflow obstruction in COPD, and the consequential damage to the lung has an early onset. So far, there is little evidence of the mechanisms that underlie this aspect of pathology. However, emerging research confirms that airway epithelial reprogramming or epithelial to mesenchymal transition (EMT) is a key mechanism that drives fibrotic remodelling changes in smokers and patients with COPD. A recent study by Lai et al, further highlights the importance of EMT in smoking-related COPD pathology. The authors identify HB-EGF, an EGFR ligand, as a key driver of EMT and a potential new therapeutic target for the amelioration of EMT and airway remodelling. There are also wider implications in lung cancer prophylaxis, which is another major comorbidity associated with COPD. We consider that improved molecular understanding of the intricate pathways associated with epithelial cell plasticity in smokers and patients with COPD will have major therapeutic implications.

“…We have previously reported an increase in vessels in general, and VEGF and TGF-β1 positive vessels, in particular, in the reticular basement membrane (Rbm) of smokers and patients with COPD, they were also seen encroaching into the epithelium [182][183][184][185][186]. It is quite possible that these two growth factors actively promote neoangiogenesis of both the Rbm and the epithelium itself, supporting formation of a pro-cancer stroma with associated active EMT [183,187]. In a separate study, we also reported effects of inhaled fluticasone propionate on vascular remodelling in patients with COPD [187].…”

Section: Angiogenesismentioning

confidence: 98%

Chronic Obstructive Pulmonary Disease and Lung Cancer: Underlying Pathophysiology and New Therapeutic Modalities

Hansbro

Larsson‐Callerfelt

et al. 2018

Drugs

COPD and lung cancer are major lung diseases affecting millions worldwide. Both diseases have links to cigarette smoking, and exert a considerable societal burden. People suffering from COPD are at a higher risk of developing lung cancer than those without COPD and are more susceptible to poor outcomes after diagnosis and treatment. Lung cancer and COPD are closely associated, possibly sharing common traits such as an underlying genetic predisposition, epithelial and endothelial cell plasticity, dysfunctional inflammatory mechanisms including the deposition of excessive extracellular matrix, angiogenesis, susceptibility to DNA damage and cellular mutagenesis. In fact, COPD could be the driving factor for lung cancer, providing a conducive environment that propagates its evolution. In the early stages of smoking, body defences provide a combative immune/oxidative response and DNA repair mechanisms are likely to subdue these changes to a certain extent; however, in patients with COPD with lung cancer the consequences could be devastating, potentially contributing to slower post-operative recovery after lung resection and increased resistance to radiotherapy and chemotherapy. Vital to the development of new-targeted therapies is an in-depth understanding of various molecular mechanisms that are associated with both pathologies. In this comprehensive review, we shall provide a detailed overview of possible underlying factors that link COPD and lung cancer and current therapeutic advances from both human and pre-clinical animal models that can effectively mitigate this unholy relationship. Running head-COPD and lung cancer: understanding and treatments