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

Abstract

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.

Bioinformatics Approach to Identify Common Gene Signatures of Patients With Coronavirus 2019 and Lung Adenocarcinoma

“…Airway epithelial reprogramming or the epithelial-mesenchymal transformation (EMT) contributes to the remodelling changes in lung brosis (Eapen et al 2019), one of the main respiratory signs of COVID-19. HBEGF is a key driver of the EMT and in uences the outcomes of treatment of lung cancer (Stawowczyk et al 2017;Wu et al 2021).…”

<p>Epithelial–mesenchymal transition is driven by transcriptional and post transcriptional modulations in COPD: implications for disease progression and new therapeutics</p>

“…Other potential interactive pathways were demonstrated to enhance EMT changes, for example, TGF-β1 and p38 MAPK/PI3K/Akt signaling pathways complement each other and are known to activate SMAD2/3 signaling in in vivo models of COPD and in lung cancer 56. Further, an increase in EGFR ligand HB-EGF in smokers and COPD was also observed to potentiate EMT-related and airway modeling changes possibly by interacting and modulating TGFβ pathways 57,58. Considering the complexity in the number of pathways involved would indeed be hard to pinpoint one pathway which could be specifically targeted to inhibit this profound epithelial plasticity.…”

The Correlation of EMT-related Genes in the Pathogenesis of Non-Small Cell Lung Cancer and Chronic Obstructive Pulmonary Disease

“…EMT is regulated by EMT-related genes [13] .The fundamental alterations in epithelial cells are caused by genomic and transcriptomic reprogramming [14,16] .In lung cancer, these changes have been associated with the initiation and metastasis oftumor cells [3] . On the other hand, EMT has been associated with airway remodeling and obliteration in COPD [10] .…”