Autophagy inhibition-mediated epithelial–mesenchymal transition augments local myofibroblast differentiation in pulmonary fibrosis

作者：Charlotte Hill, Juanjuan Li, Dian Liu, Franco Conforti, Christopher J. Brereton, Liudi Yao, Yilu Zhou, Aiman Alzetani, Serena Chee, Ben G. Marshall, Sophie Fletcher, David C. Hancock, Christian H. Ottensmeier, Andrew J. Steele, Julian Downward, Luca Richeldi, Xin Lü, Donna E. Davies, Mark G. Jones, Yihua Wang · 发表于：Cell Death and Disease · 年份：2019 · DOI：10.1038/s41419-019-1820-x · 被引用次数：181 · 研究领域：Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis、Medical Imaging and Pathology Studies、Chronic Obstructive Pulmonary Disease (COPD) Research

Idiopathic pulmonary fibrosis (IPF), the prototypic progressive fibrotic interstitial lung disease, is thought to be a consequence of repetitive micro-injuries to an ageing, susceptible alveolar epithelium. Ageing is a risk factor for IPF and incidence has been demonstrated to increase with age. Decreased (macro)autophagy with age has been reported extensively in a variety of systems and diseases, including IPF. However, it is undetermined whether the role of faulty autophagy is causal or coincidental in the context of IPF. Here, we report that in alveolar epithelial cells inhibition of autophagy promotes epithelial-mesenchymal transition (EMT), a process implicated in embryonic development, wound healing, cancer metastasis and fibrosis. We further demonstrate that this is attained, at least in part, by increased p62/SQSTM1 expression that promotes p65/RELA mediated-transactivation of an EMT transcription factor, Snail2 (SNAI2), which not only controls EMT but also regulates the production of locally acting profibrogenic mediators. Our data suggest that reduced autophagy induces EMT of alveolar epithelial cells and can contribute to fibrosis via aberrant epithelial-fibroblast crosstalk.