TGF-β-induced EMT: mechanisms and implications for fibrotic lung disease

Abstract

Epithelial-mesenchymal transition (EMT), a process whereby fully differentiated epithelial cells undergo transition to a mesenchymal phenotype giving rise to fibroblasts and myofibroblasts, is increasingly recognized as playing an important role in repair and scar formation following epithelial injury. The extent to which this process contributes to fibrosis following injury in the lung is a subject of active investigation. Recently, it was demonstrated that transforming growth factor (TGF)-β induces EMT in alveolar epithelial cells (AEC) in vitro and in vivo, and epithelial and mesenchymal markers have been colocalized to hyperplastic type II (AT2) cells in lung tissue from patients with idiopathic pulmonary fibrosis (IPF), suggesting that AEC may exhibit extreme plasticity and serve as a source of fibroblasts and/or myofibroblasts in lung fibrosis. In this review, we describe the characteristic features of EMT and its mechanistic underpinnings. We further describe the contribution of EMT to fibrosis in adult tissues following injury, focusing especially on the critical role of TGF-β and its downstream mediators in this process. Finally, we highlight recent descriptions of EMT in the lung and the potential implications of this process for the treatment of fibrotic lung disease. Treatment for fibrosis of the lung in diseases such as IPF has heretofore focused largely on amelioration of potential inciting processes such as inflammation. It is hoped that this review will stimulate further consideration of the cellular mechanisms of fibrogenesis in the lung and especially the role of the epithelium in this process, potentially leading to innovative avenues of investigation and treatment.

Matrix Metalloproteinase 3 Is a Mediator of Pulmonary Fibrosis

“…32,33 Although multiple complex signaling pathways are likely to contribute to end-stage tissue fibrosis, a prominent role of TGF-␤ in both experimental animal and human studies has been established. 28,29,49,50 Among its various properties, TGF-␤ has been shown to induce myofibroblast differentiation, EMT in pulmonary epithelial cells, and extracellular matrix gene transcription promoting collagen and fibronectin deposition. As noted above, however, there was no difference in the TGF-␤ levels in BALF between wild-type and MMP-3-null mice at early or later time points after bleomycin administration, despite considerable differences in physiological and histological measures of fibrosis.…”

“…Given that TGF-␤ is a central mediator of pulmonary fibrosis, 28,29 we assessed the levels of this growth factor in BALF from bleomycin-treated wild-type and MMP-3-null mice. This analysis revealed no difference in the levels of TGF-␤ in BALF samples collected from wild-type and MMP-3-null mice at early (48 hours) or at late (21 days; Figure 4D) time points after bleomycin administration.…”

The Inflammatory Tumor Microenvironment, Epithelial Mesenchymal Transition and Lung Carcinogenesis

“…Upon ligand binding, TβRII dimerizes with TβRI, activating its serine/ threonine kinase and allowing for phosphorylation of Smad2 and Smad3. Activated Smad2/Smad3 can then bind with Smad4, enter the nucleus and act with other transcription factors to initiate downstream TGF-β target genes [21,22]. In addition to this canonical Smad-mediated signaling, TGF-β can also signal via Smad-independent pathways including various MAP kinase, Rho-like GTPase and phosphatidylinositol-3-kinase/AKT signaling pathways [23].…”

“…Chronic overexpression of TGF-β1 in the pulmonary microenvironment often leads to fibrosis, a common precursor to lung cancer [19,22]. Adamson et al established that epithelial injury is sufficient to promote fibrosis in explanted mouse lung in the absence of inflammation, and that TGF-β1 is expressed at these sites following injury [24].…”

“…Alveolar epithelial type II cells, which are believed to be the progenitor cells of the lung epithelium following injury, as well as differentiated alveolar epithelial cells, can respond to mediators of fibrosis. Both cell types have been shown to undergo EMT following chronic exposure to TGF-β1 in vitro and in vivo, leading to the loss of epithelial proteins, such as cytokeratins and zonula occludens-1, and the gain of expression of mesenchymal proteins, including vimentin and collagen type I [22].…”