Induction of Epithelial-Mesenchymal Transition in Alveolar Epithelial Cells by Transforming Growth Factor-β1

Abstract

The hallmark of idiopathic pulmonary fibrosis (IPF) is the myofibroblast, the cellular origin of which in the lung is unknown. We hypothesized that alveolar epithelial cells (AECs) may serve as a source of myofibroblasts through epithelial-mesenchymal transition (EMT). Effects of chronic exposure to transforming growth factor (TGF)-beta1 on the phenotype of isolated rat AECs in primary culture and a rat type II cell line (RLE-6TN) were evaluated. Additionally, tissue samples from patients with IPF were evaluated for cells co-expressing epithelial (thyroid transcription factor (TTF)-1 and pro-surfactant protein-B (pro-SP-B), and mesenchymal (alpha-smooth muscle actin (alpha-SMA)) markers. RLE-6TN cells exposed to TGF-beta1 for 6 days demonstrated increased expression of mesenchymal cell markers and a fibroblast-like morphology, an effect augmented by tumor necrosis factor-alpha (TNF-alpha). Exposure of rat AECs to TGF-beta1 (100 pmol/L) resulted in increased expression of alpha-SMA, type I collagen, vimentin, and desmin, with concurrent transition to a fibroblast-like morphology and decreased expression of TTF-1, aquaporin-5 (AQP5), zonula occludens-1 (ZO-1), and cytokeratins. Cells co-expressing epithelial markers and alpha-SMA were abundant in lung tissue from IPF patients. These results suggest that AECs undergo EMT when chronically exposed to TGF-beta1, raising the possibility that epithelial cells may serve as a novel source of myofibroblasts in IPF.

HIF‐1α regulates EMT via the Snail and β‐catenin pathways in paraquat poisoning‐induced early pulmonary fibrosis

“…The excessive activation of fibroblasts and the collagen deposition in the extracellular matrix coincide with the occurrence of EMT 39. It has been demonstrated that alveolar epithelial cells, especially type II alveolar epithelial cells, acquire the phenotype of fibroblasts through EMT to promote the development of pulmonary fibrosis 40, 41. A549 cells retain the features of type II alveolar epithelial cells although they are a type of cancer cells 42, and this cell line is widely used to study the mechanism of pulmonary fibrosis 43, 44, 45.…”

Matrix Metalloproteinase 3 Is a Mediator of Pulmonary Fibrosis

“…Epithelial cells acquire phenotypic mesenchymal (fibroblast) markers when exposed to TGF-␤. 43 With respect to the importance of MMPs in EMT, Illman et al 44 reported that epilysin (MMP-28) can induce EMT, leading to cell invasion in lung adenocarcinoma cells through a TGF-␤-dependent mechanism. Additionally, there is strong evidence that MMP-3 can induce EMT in mouse mammary epithelial cells though alteration in Rac1b, a splice variant of Rac1, leading to increases in reactive oxygen species resulting in EMT.…”

A positive feedback loop promotes HIF‐1α stability through miR‐210‐mediated suppression of RUNX3 in paraquat‐induced EMT

“…Type II alveolar epithelial cells have been shown to acquire a fibroblast‐like phenotype through EMT to promote the progression of pulmonary fibrosis 3, 4. These cells promote collagen deposition in the extracellular matrix.…”