EMT and Interstitial Lung Disease
EMT and Interstitial Lung Disease
Purpose of review Pathogenesis of interstitial lung diseases (ILD) has largely been investigated in the context of the most frequent ILD, idiopathic pulmonary fibrosis (IPF). We review studies of epithelial-to-mesenchymal transition (EMT) and discuss its potential contribution to collagen-producing (myo)fibroblasts in IPF.
Recent findings Endoplasmic reticulum (ER) stress leading to epithelial apoptosis has been reported as a potential etiologic factor in fibrosis. Recent studies further suggest EMT as a link between ER stress and fibrosis. Combinatorial interactions among Smad3, β-catenin and other transcriptional co-activators at the a-smooth muscle actin (α-SMA) promoter provide direct evidence for crosstalk between transforming growth factor-β (TGFβ) and β-catenin pathways during EMT. Lineage tracing yielded conflicting results, with two recent studies supporting and one opposing a role for EMT in lung fibrosis.
Summary Advances have been made in elucidating causes and mechanisms of EMT, potentially leading to new treatment options, although contributions of EMT to lung fibrosis in vivo remain controversial. In addition to EMT providing a direct source of (myo)fibroblasts, expression of mesenchymal markers may reflect epithelial injury, in which case inhibition of EMT might be deleterious. EMT-derived cells may also contribute to aberrant epithelial–mesenchymal crosstalk that promotes fibrogenesis.
Interstitial lung diseases (ILD) refer to a collection of disorders characterized by varying degrees of inflammation and fibrosis in the lung interstitium. The cause of ILD is sometimes known (e.g., environmental factors, drugs, collagen vascular disease, and sarcoidosis). When the cause is unknown, it is labeled as idiopathic and further classified into the currently recognized single disease entities. Research on pathogenesis has been conducted mostly in the context of the most frequent idiopathic ILD, idiopathic pulmonary fibrosis (IPF). In the currently accepted paradigm, a major factor in IPF pathogenesis is thought to be recurrent alveolar epithelial cell (AEC) injury. Initial injury leads to aberrant activation of AECs, creating a profibrotic environment with accumulation of collagen-producing fibroblasts and myofibroblasts. To date, (myo)fibroblasts have been suggested to accumulate via three mechanisms: proliferation and differentiation of resident lung fibroblasts; epithelial-to-mesenchymal transition (EMT), in which AECs undergo transition to (myo)fibroblasts; and transition of bone marrow-derived fibrocytes or circulating progenitors to fibroblasts. The significance and relative contribution of each pathway to fibrosis have not been definitively established, hampering development of novel therapies. We first review the latest advances on causes and underlying mechanisms of EMT and then focus on the ongoing controversy of whether and how EMT contributes to lung fibrosis and whether inhibition of EMT would be of benefit therapeutically.
Abstract and Introduction
Abstract
Purpose of review Pathogenesis of interstitial lung diseases (ILD) has largely been investigated in the context of the most frequent ILD, idiopathic pulmonary fibrosis (IPF). We review studies of epithelial-to-mesenchymal transition (EMT) and discuss its potential contribution to collagen-producing (myo)fibroblasts in IPF.
Recent findings Endoplasmic reticulum (ER) stress leading to epithelial apoptosis has been reported as a potential etiologic factor in fibrosis. Recent studies further suggest EMT as a link between ER stress and fibrosis. Combinatorial interactions among Smad3, β-catenin and other transcriptional co-activators at the a-smooth muscle actin (α-SMA) promoter provide direct evidence for crosstalk between transforming growth factor-β (TGFβ) and β-catenin pathways during EMT. Lineage tracing yielded conflicting results, with two recent studies supporting and one opposing a role for EMT in lung fibrosis.
Summary Advances have been made in elucidating causes and mechanisms of EMT, potentially leading to new treatment options, although contributions of EMT to lung fibrosis in vivo remain controversial. In addition to EMT providing a direct source of (myo)fibroblasts, expression of mesenchymal markers may reflect epithelial injury, in which case inhibition of EMT might be deleterious. EMT-derived cells may also contribute to aberrant epithelial–mesenchymal crosstalk that promotes fibrogenesis.
Introduction
Interstitial lung diseases (ILD) refer to a collection of disorders characterized by varying degrees of inflammation and fibrosis in the lung interstitium. The cause of ILD is sometimes known (e.g., environmental factors, drugs, collagen vascular disease, and sarcoidosis). When the cause is unknown, it is labeled as idiopathic and further classified into the currently recognized single disease entities. Research on pathogenesis has been conducted mostly in the context of the most frequent idiopathic ILD, idiopathic pulmonary fibrosis (IPF). In the currently accepted paradigm, a major factor in IPF pathogenesis is thought to be recurrent alveolar epithelial cell (AEC) injury. Initial injury leads to aberrant activation of AECs, creating a profibrotic environment with accumulation of collagen-producing fibroblasts and myofibroblasts. To date, (myo)fibroblasts have been suggested to accumulate via three mechanisms: proliferation and differentiation of resident lung fibroblasts; epithelial-to-mesenchymal transition (EMT), in which AECs undergo transition to (myo)fibroblasts; and transition of bone marrow-derived fibrocytes or circulating progenitors to fibroblasts. The significance and relative contribution of each pathway to fibrosis have not been definitively established, hampering development of novel therapies. We first review the latest advances on causes and underlying mechanisms of EMT and then focus on the ongoing controversy of whether and how EMT contributes to lung fibrosis and whether inhibition of EMT would be of benefit therapeutically.
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