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

Abstract

COPD is a common and highly destructive disease with huge impacts on people and health services throughout the world. It is mainly caused by cigarette smoking though environmental pollution is also significant. There are no current treatments that affect the overall course of COPD; current drugs focus on symptomatic relief and to some extent reducing exacerbation rates. There is an urgent need for in-depth studies of the fundamental pathogenic mechanisms that underpin COPD. This is vital, given the fact that nearly 40%-60% of the small airway and alveolar damage occurs in COPD well before the first measurable changes in lung function are detected. These individuals are also at a high risk of lung cancer. Current COPD research is mostly centered around late disease and/or innate immune activation within the airway lumen, but the actual damage to the airway wall has early onset. COPD is the end result of complex mechanisms, possibly triggered through initial epithelial activation. To change the disease trajectory, it is crucial to understand the mechanisms in the epithelium that are switched on early in smokers. One such mechanism we believe is the process of epithelial to mesenchymal transition. This article highlights the importance of this profound epithelial cell plasticity in COPD and also its regulation. We consider that understanding early changes in COPD will open new windows for therapy.

Downregulation of epithelial DUOX1 in chronic obstructive pulmonary disease

“…Consistent with observations of reduced DUOX1 mRNA expression in the airways of smokers ( 22 ), chronic exposure of C57BL/6J mice to acrolein (5 ppm; 4 hours/day, for 2 weeks) resulted in reduced lung DUOX1 protein ( Supplemental Figure 2A ; see complete unedited blots in the supplemental material) and Duox1 mRNA expression ( Supplemental Figure 2B ). Acrolein exposure also enhanced production of TGF-β1 ( Supplemental Figure 2C ), a profibrotic growth factor that is thought to contribute to features of EMT and subepithelial fibrosis in COPD ( 37 – 39 ). To address the potential impact of Duox1 downregulation for such EMT features, we isolated mouse tracheal epithelial cells (MTECs) from C57BL/6J mice and exposed them to either acrolein or TGF-β, over a 2-week period.…”

Effect of sub-chronic exposure to cigarette smoke, electronic cigarette and waterpipe on human lung epithelial barrier function

“…There is increasing recognition that CS can disrupt the epithelial barrier due to the toxicity of the mixture of chemicals acting through several molecular mechanisms that include MAPK (mitogen-activated protein kinase), TGFβ (transforming growth factor beta-1), and reactive oxygen species [ 25 – 29 ]. EC aerosol produced from e-liquid (propylene-glycol and glycerol) and smoke from TW contain many of the same toxicants found in CS; therefore, it is not surprising that similar pathways may be activated by exposure to EC and TW [ 10 , 30 – 33 ].…”

Canonical WNT pathway is activated in the airway epithelium in chronic obstructive pulmonary disease

“…This prevents its migration to the nucleus, where expression of WNT target genes is constitutively repressed by a complex consisting of T-cell factor/lymphoid enhancer-binding factor (TCF/LEF) and transducing-like enhancer of split protein (TLE/Groucho). The binding of a canonical WNT ligand to one of the Frizzled receptors (FZD 1–10 ) leads to the inactivation of the destruction complex and to the accumulation of intracytoplasmic, unphosphorylated β-catenin, whose migration to the nucleus will transactivate its target genes [16] , including epithelial-to-mesenchymal (EMT)-promoting transcription factors [17] .…”