Epithelial mesenchymal transition (EMT): a universal process in lung diseases with implications for cystic fibrosis pathophysiology

Abstract

Cystic Fibrosis (CF) is a genetic disorder that arises due to mutations in the Cystic Fibrosis Transmembrane Conductance Regulator gene, which encodes for a protein responsible for ion transport out of epithelial cells. This leads to a disruption in transepithelial Cl-, Na + and HCO3− ion transport and the subsequent dehydration of the airway epithelium, resulting in infection, inflammation and development of fibrotic tissue. Unlike in CF, fibrosis in other lung diseases including asthma, chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis has been well characterised. One of the driving forces behind fibrosis is Epithelial Mesenchymal Transition (EMT), a process where epithelial cells lose epithelial proteins including E-Cadherin, which is responsible for tight junctions. The cell moves to a more mesenchymal phenotype as it gains mesenchymal markers such as N-Cadherin (providing the cells with migration potential), Vimentin and Fibronectin (proteins excreted to help form the extracellular matrix), and the fibroblast proliferation transcription factors Snail, Slug and Twist. This review paper explores the EMT process in a range of lung diseases, details the common links that these have to cystic fibrosis, and explores how understanding EMT in cystic fibrosis may open up novel methods of treating patients with cystic fibrosis.

Role of the arecoline/YAP1/BMP4 pathway in promoting endothelial‐mesenchymal transition in oral submucous fibrosis

“…Some of these EMT-stimulating factors are RUNX1, endothelial NOX2, and transforming growth factor-beta (TGFβ), of which TGFβ is the major EMT-inducing factor. [5][6][7] The TGFβ signaling pathway is involved in many cellular processes in both mature and developing embryos, including cell growth, cell differentiation, apoptosis, and cell homeostasis. 8,9 Some of the important downstream molecules of the TGFβ pathway are receptor-regulated SMAD protein (R-SMAD) and coS-MAD/SMAD4.…”

Function of cAMP scaffolds in obstructive lung disease: Focus on epithelial‐to‐mesenchymal transition and oxidative stress

“…Type III EMT is characterized by a phenotypical change of secondary epithelial cells into carcinoma cells with a high degree of migratory and invasive properties and malignant growth subsequently creating a novel tumour nodule (Kim et al, 2017). Tight junctions play an important role in type III EMT; particularly, E-cadherin downregulation leads to a loss of cell-cell adhesion and thus facilitates migration and colonization of cancer cells (Rout-Pitt, Farrow, Parsons, & Donnelley, 2018;Thiery et al, 2009). A recent study in A549 lung cancer cells demonstrated that the novel TGF-β1 inhibitor compound 67 inhibited TGF-β1-induced down-regulation of E-cadherin mRNA and up-regulation of N-cadherin mRNA, with findings further confirmed on the protein level by using immunofluorescence (Jeong et al, 2019).…”

“…The field of compartmentalized cAMP signalling may also offer answers to yet unresolved questions underlying the distinct stages of the EMT process that is linked to a diverse subset of lung responses. Certainly, EMT plays a vital role during organ fibrosis, including pulmonary fibrosis (Jolly et al, 2018;Rout-Pitt et al, 2018). In addition, accumulating evidence indicates that an active EMT process is operational in experimental models of COPD, asthma, and IPF.…”

The role and mechanism of lncRNA NEAT1 in the fibrosis of pulmonary epithelial cell

“…The mechanism of its pathogenesis and progression is complicated. Nonetheless, it is generally believed that epithelial-mesenchymal transition (EMT) plays an important role in the development and progression of pulmonary fibrosis (Horowitz and Thannickal 2006;Rout-Pitt et al 2018). Furthermore, the activation of several signaling pathways such as transforming growth factorbeta (TGF-beta) and Wnt/beta-catenin signaling pathways were suggested to play an important role in the EMT process (Willis and Borok 2007;Saito et al 2018;Juan et al 2017).…”