EMT and Interstitial Lung Disease
Historically, disruption of cell contacts, hypoxia and inflammation have been proposed as potential triggers of EMT. In recent years, progress has been made in understanding the relationship between endoplasmic reticulum (ER) stress and IPF. The ER is an organelle in which secreted and membrane proteins fold and mature, and ER stress refers to activation of signaling pathways in response to relative insufficiency in protein folding capacity. In the lung, mutations in genes encoding surfactant proteins SP-A2 and SP-C are associated with ILDs, and ER stress due to mutant protein accumulation has been the proposed underlying mechanism leading to apoptosis and fibrosis. Recently, there have been two articles that both link ER stress to EMT. Induction of ER stress by either tunicamycin or overexpression of mutant SP-C resulted in loss of epithelial markers, induction of α-smooth muscle actin (α-SMA), and transition to a spindle-shaped morphology indicating EMT. Src-dependent signaling was implicated as the link between ER stress and EMT. In addition, Zhong et al. found that mild and extensive ER stress resulted in EMT and apoptosis, respectively, indicating that different levels of ER stress may have different consequences for cell survival.
Two articles have reported on interactions between epithelial cells and extracellular matrix, which in turn lead to EMT. It had been known that matrix metalloproteinases (MMPs), a group of proteolytic enzymes that degrade extracellular matrix, could paradoxically promote collagen deposition. Yamashita et al. used intratracheal adenoviral MMP-3, MMP-3-null mice, and in vitro studies to show that MMP-3 promotes lung fibrosis, possibly through EMT involving β-catenin nuclear translocation. DeMaio et al. found that mouse cells cultured on collagen I acquired spindle-shaped morphology and expressed α-SMA. Smad signaling was activated by collagen I, indicating transforming growth factor-β (TGFb) receptor-dependent signaling.
Oxidative stress from cigarette smoke extract, radiation, and hydrogen peroxide (in H358, RLE-6TN, and A549 and human primary bronchial epithelial cells, respectively), β-galactosidase binding lectin galectin-3 (using primary AEC from galectin-3−/− mice), mechanical stretch (in mice and primary mouse alveolar epithelial type II cells), Epstein Barr virus protein LMP1 (in A549 and HPL1D cells) [24], interleukin (IL)-17A (in MLE-12 cells), and mutant ATP-binding cassette transporter A3 (ABCA3) (in A549 cells) [26] have also been reported as inducers of EMT. Of note, instillation of galectin-3 inhibitor beginning 18 days after bleomycin instillation and intravenous administration of IL-17A-neutralizing antibody beginning 14 days after bleomycin or silica instillation attenuated fibrosis, suggestive of possible novel therapies. The role of these pathways awaits further mechanistic studies.
Potential Causes of Epithelial-Tomesenchymal Transition
Historically, disruption of cell contacts, hypoxia and inflammation have been proposed as potential triggers of EMT. In recent years, progress has been made in understanding the relationship between endoplasmic reticulum (ER) stress and IPF. The ER is an organelle in which secreted and membrane proteins fold and mature, and ER stress refers to activation of signaling pathways in response to relative insufficiency in protein folding capacity. In the lung, mutations in genes encoding surfactant proteins SP-A2 and SP-C are associated with ILDs, and ER stress due to mutant protein accumulation has been the proposed underlying mechanism leading to apoptosis and fibrosis. Recently, there have been two articles that both link ER stress to EMT. Induction of ER stress by either tunicamycin or overexpression of mutant SP-C resulted in loss of epithelial markers, induction of α-smooth muscle actin (α-SMA), and transition to a spindle-shaped morphology indicating EMT. Src-dependent signaling was implicated as the link between ER stress and EMT. In addition, Zhong et al. found that mild and extensive ER stress resulted in EMT and apoptosis, respectively, indicating that different levels of ER stress may have different consequences for cell survival.
Two articles have reported on interactions between epithelial cells and extracellular matrix, which in turn lead to EMT. It had been known that matrix metalloproteinases (MMPs), a group of proteolytic enzymes that degrade extracellular matrix, could paradoxically promote collagen deposition. Yamashita et al. used intratracheal adenoviral MMP-3, MMP-3-null mice, and in vitro studies to show that MMP-3 promotes lung fibrosis, possibly through EMT involving β-catenin nuclear translocation. DeMaio et al. found that mouse cells cultured on collagen I acquired spindle-shaped morphology and expressed α-SMA. Smad signaling was activated by collagen I, indicating transforming growth factor-β (TGFb) receptor-dependent signaling.
Oxidative stress from cigarette smoke extract, radiation, and hydrogen peroxide (in H358, RLE-6TN, and A549 and human primary bronchial epithelial cells, respectively), β-galactosidase binding lectin galectin-3 (using primary AEC from galectin-3−/− mice), mechanical stretch (in mice and primary mouse alveolar epithelial type II cells), Epstein Barr virus protein LMP1 (in A549 and HPL1D cells) [24], interleukin (IL)-17A (in MLE-12 cells), and mutant ATP-binding cassette transporter A3 (ABCA3) (in A549 cells) [26] have also been reported as inducers of EMT. Of note, instillation of galectin-3 inhibitor beginning 18 days after bleomycin instillation and intravenous administration of IL-17A-neutralizing antibody beginning 14 days after bleomycin or silica instillation attenuated fibrosis, suggestive of possible novel therapies. The role of these pathways awaits further mechanistic studies.
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