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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Autophagy inhibition-mediated epithelial–mesenchymal transition augments local myofibroblast differentiation in pulmonary fibrosis</title><author><name sortKey="Hill, Charlotte" sort="Hill, Charlotte" uniqKey="Hill C" first="Charlotte" last="Hill">Charlotte Hill</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9297</institution-id><institution-id institution-id-type="GRID">grid.5491.9</institution-id><institution>Biological Sciences, Faculty of Environmental and Life Sciences,</institution><institution>University of Southampton,</institution></institution-wrap>Southampton, SO17 1BJ UK</nlm:aff></affiliation></author><author><name sortKey="Li, Juanjuan" sort="Li, Juanjuan" uniqKey="Li J" first="Juanjuan" last="Li">Juanjuan Li</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9297</institution-id><institution-id institution-id-type="GRID">grid.5491.9</institution-id><institution>Biological Sciences, Faculty of Environmental and Life Sciences,</institution><institution>University of Southampton,</institution></institution-wrap>Southampton, SO17 1BJ UK</nlm:aff></affiliation></author><author><name sortKey="Liu, Dian" sort="Liu, Dian" uniqKey="Liu D" first="Dian" last="Liu">Dian Liu</name><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0368 7223</institution-id><institution-id institution-id-type="GRID">grid.33199.31</institution-id><institution>Department of Oncology, Tongji Hospital, Tongji Medical College,</institution><institution>Huazhong University of Science and Technology,</institution></institution-wrap>Wuhan, China</nlm:aff></affiliation></author><author><name sortKey="Conforti, Franco" sort="Conforti, Franco" uniqKey="Conforti F" first="Franco" last="Conforti">Franco Conforti</name><affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9297</institution-id><institution-id institution-id-type="GRID">grid.5491.9</institution-id><institution>Clinical and Experimental Sciences, Faculty of Medicine,</institution><institution>University of Southampton,</institution></institution-wrap>Southampton, SO16 6YD UK</nlm:aff></affiliation><affiliation><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="ISNI">0000000103590315</institution-id><institution-id institution-id-type="GRID">grid.123047.3</institution-id><institution>NIHR Southampton Biomedical Research Centre,</institution><institution>University Hospital Southampton,</institution></institution-wrap>Southampton, SO16 6YD UK</nlm:aff></affiliation></author><author><name sortKey="Brereton, Christopher J" sort="Brereton, Christopher J" uniqKey="Brereton C" first="Christopher J." last="Brereton">Christopher J. Brereton</name><affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9297</institution-id><institution-id institution-id-type="GRID">grid.5491.9</institution-id><institution>Clinical and Experimental Sciences, Faculty of Medicine,</institution><institution>University of Southampton,</institution></institution-wrap>Southampton, SO16 6YD UK</nlm:aff></affiliation><affiliation><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="ISNI">0000000103590315</institution-id><institution-id institution-id-type="GRID">grid.123047.3</institution-id><institution>NIHR Southampton Biomedical Research Centre,</institution><institution>University Hospital Southampton,</institution></institution-wrap>Southampton, SO16 6YD UK</nlm:aff></affiliation></author><author><name sortKey="Yao, Liudi" sort="Yao, Liudi" uniqKey="Yao L" first="Liudi" last="Yao">Liudi Yao</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9297</institution-id><institution-id institution-id-type="GRID">grid.5491.9</institution-id><institution>Biological Sciences, Faculty of Environmental and Life Sciences,</institution><institution>University of Southampton,</institution></institution-wrap>Southampton, SO17 1BJ UK</nlm:aff></affiliation></author><author><name sortKey="Zhou, Yilu" sort="Zhou, Yilu" uniqKey="Zhou Y" first="Yilu" last="Zhou">Yilu Zhou</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9297</institution-id><institution-id institution-id-type="GRID">grid.5491.9</institution-id><institution>Biological Sciences, Faculty of Environmental and Life Sciences,</institution><institution>University of Southampton,</institution></institution-wrap>Southampton, SO17 1BJ UK</nlm:aff></affiliation></author><author><name sortKey="Alzetani, Aiman" sort="Alzetani, Aiman" uniqKey="Alzetani A" first="Aiman" last="Alzetani">Aiman Alzetani</name><affiliation><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="ISNI">0000000103590315</institution-id><institution-id institution-id-type="GRID">grid.123047.3</institution-id><institution>NIHR Southampton Biomedical Research Centre,</institution><institution>University Hospital Southampton,</institution></institution-wrap>Southampton, SO16 6YD UK</nlm:aff></affiliation><affiliation><nlm:aff id="Aff5"><institution-wrap><institution-id institution-id-type="ISNI">0000000103590315</institution-id><institution-id institution-id-type="GRID">grid.123047.3</institution-id><institution>University Hospital Southampton,</institution></institution-wrap>Southampton, SO16 6YD UK</nlm:aff></affiliation></author><author><name sortKey="Chee, Serena J" sort="Chee, Serena J" uniqKey="Chee S" first="Serena J." last="Chee">Serena J. Chee</name><affiliation><nlm:aff id="Aff5"><institution-wrap><institution-id institution-id-type="ISNI">0000000103590315</institution-id><institution-id institution-id-type="GRID">grid.123047.3</institution-id><institution>University Hospital Southampton,</institution></institution-wrap>Southampton, SO16 6YD UK</nlm:aff></affiliation><affiliation><nlm:aff id="Aff6"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9297</institution-id><institution-id institution-id-type="GRID">grid.5491.9</institution-id><institution>Cancer Sciences Unit,</institution><institution>University of Southampton,</institution></institution-wrap>Somers Building, Southampton General Hospital, Southampton, SO16 6YD UK</nlm:aff></affiliation></author><author><name sortKey="Marshall, Ben G" sort="Marshall, Ben G" uniqKey="Marshall B" first="Ben G." last="Marshall">Ben G. Marshall</name><affiliation><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="ISNI">0000000103590315</institution-id><institution-id institution-id-type="GRID">grid.123047.3</institution-id><institution>NIHR Southampton Biomedical Research Centre,</institution><institution>University Hospital Southampton,</institution></institution-wrap>Southampton, SO16 6YD UK</nlm:aff></affiliation><affiliation><nlm:aff id="Aff5"><institution-wrap><institution-id institution-id-type="ISNI">0000000103590315</institution-id><institution-id institution-id-type="GRID">grid.123047.3</institution-id><institution>University Hospital Southampton,</institution></institution-wrap>Southampton, SO16 6YD UK</nlm:aff></affiliation></author><author><name sortKey="Fletcher, Sophie V" sort="Fletcher, Sophie V" uniqKey="Fletcher S" first="Sophie V." last="Fletcher">Sophie V. Fletcher</name><affiliation><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="ISNI">0000000103590315</institution-id><institution-id institution-id-type="GRID">grid.123047.3</institution-id><institution>NIHR Southampton Biomedical Research Centre,</institution><institution>University Hospital Southampton,</institution></institution-wrap>Southampton, SO16 6YD UK</nlm:aff></affiliation><affiliation><nlm:aff id="Aff5"><institution-wrap><institution-id institution-id-type="ISNI">0000000103590315</institution-id><institution-id institution-id-type="GRID">grid.123047.3</institution-id><institution>University Hospital Southampton,</institution></institution-wrap>Southampton, SO16 6YD UK</nlm:aff></affiliation></author><author><name sortKey="Hancock, David" sort="Hancock, David" uniqKey="Hancock D" first="David" last="Hancock">David Hancock</name><affiliation><nlm:aff id="Aff7"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1795 1830</institution-id><institution-id institution-id-type="GRID">grid.451388.3</institution-id><institution>Oncogene Biology,</institution><institution>The Francis Crick Institute,</institution></institution-wrap>London, NW1 1AT UK</nlm:aff></affiliation></author><author><name sortKey="Ottensmeier, Christian H" sort="Ottensmeier, Christian H" uniqKey="Ottensmeier C" first="Christian H." last="Ottensmeier">Christian H. Ottensmeier</name><affiliation><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="ISNI">0000000103590315</institution-id><institution-id institution-id-type="GRID">grid.123047.3</institution-id><institution>NIHR Southampton Biomedical Research Centre,</institution><institution>University Hospital Southampton,</institution></institution-wrap>Southampton, SO16 6YD UK</nlm:aff></affiliation><affiliation><nlm:aff id="Aff6"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9297</institution-id><institution-id institution-id-type="GRID">grid.5491.9</institution-id><institution>Cancer Sciences Unit,</institution><institution>University of Southampton,</institution></institution-wrap>Somers Building, Southampton General Hospital, Southampton, SO16 6YD UK</nlm:aff></affiliation></author><author><name sortKey="Steele, Andrew J" sort="Steele, Andrew J" uniqKey="Steele A" first="Andrew J." last="Steele">Andrew J. Steele</name><affiliation><nlm:aff id="Aff6"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9297</institution-id><institution-id institution-id-type="GRID">grid.5491.9</institution-id><institution>Cancer Sciences Unit,</institution><institution>University of Southampton,</institution></institution-wrap>Somers Building, Southampton General Hospital, Southampton, SO16 6YD UK</nlm:aff></affiliation></author><author><name sortKey="Downward, Julian" sort="Downward, Julian" uniqKey="Downward J" first="Julian" last="Downward">Julian Downward</name><affiliation><nlm:aff id="Aff7"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1795 1830</institution-id><institution-id institution-id-type="GRID">grid.451388.3</institution-id><institution>Oncogene Biology,</institution><institution>The Francis Crick Institute,</institution></institution-wrap>London, NW1 1AT UK</nlm:aff></affiliation></author><author><name sortKey="Richeldi, Luca" sort="Richeldi, Luca" uniqKey="Richeldi L" first="Luca" last="Richeldi">Luca Richeldi</name><affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9297</institution-id><institution-id institution-id-type="GRID">grid.5491.9</institution-id><institution>Clinical and Experimental Sciences, Faculty of Medicine,</institution><institution>University of Southampton,</institution></institution-wrap>Southampton, SO16 6YD UK</nlm:aff></affiliation><affiliation><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="ISNI">0000000103590315</institution-id><institution-id institution-id-type="GRID">grid.123047.3</institution-id><institution>NIHR Southampton Biomedical Research Centre,</institution><institution>University Hospital Southampton,</institution></institution-wrap>Southampton, SO16 6YD UK</nlm:aff></affiliation><affiliation><nlm:aff id="Aff8"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0941 3192</institution-id><institution-id institution-id-type="GRID">grid.8142.f</institution-id><institution>Unità Operativa Complessa di Pneumologia,</institution><institution>Università Cattolica del Sacro Cuore, Fondazione Policlinico A Gemelli IRCCS,</institution></institution-wrap>Rome, Italy</nlm:aff></affiliation></author><author><name sortKey="Lu, Xin" sort="Lu, Xin" uniqKey="Lu X" first="Xin" last="Lu">Xin Lu</name><affiliation><nlm:aff id="Aff9"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 8948</institution-id><institution-id institution-id-type="GRID">grid.4991.5</institution-id><institution>Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine,</institution><institution>University of Oxford,</institution></institution-wrap>Oxford, OX3 7DQ UK</nlm:aff></affiliation></author><author><name sortKey="Davies, Donna E" sort="Davies, Donna E" uniqKey="Davies D" first="Donna E." last="Davies">Donna E. Davies</name><affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9297</institution-id><institution-id institution-id-type="GRID">grid.5491.9</institution-id><institution>Clinical and Experimental Sciences, Faculty of Medicine,</institution><institution>University of Southampton,</institution></institution-wrap>Southampton, SO16 6YD UK</nlm:aff></affiliation><affiliation><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="ISNI">0000000103590315</institution-id><institution-id institution-id-type="GRID">grid.123047.3</institution-id><institution>NIHR Southampton Biomedical Research Centre,</institution><institution>University Hospital Southampton,</institution></institution-wrap>Southampton, SO16 6YD UK</nlm:aff></affiliation><affiliation><nlm:aff id="Aff10"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9297</institution-id><institution-id institution-id-type="GRID">grid.5491.9</institution-id><institution>Institute for Life Sciences,</institution><institution>University of Southampton,</institution></institution-wrap>Southampton, SO17 1BJ UK</nlm:aff></affiliation></author><author><name sortKey="Jones, Mark G" sort="Jones, Mark G" uniqKey="Jones M" first="Mark G." last="Jones">Mark G. Jones</name><affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9297</institution-id><institution-id institution-id-type="GRID">grid.5491.9</institution-id><institution>Clinical and Experimental Sciences, Faculty of Medicine,</institution><institution>University of Southampton,</institution></institution-wrap>Southampton, SO16 6YD UK</nlm:aff></affiliation><affiliation><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="ISNI">0000000103590315</institution-id><institution-id institution-id-type="GRID">grid.123047.3</institution-id><institution>NIHR Southampton Biomedical Research Centre,</institution><institution>University Hospital Southampton,</institution></institution-wrap>Southampton, SO16 6YD UK</nlm:aff></affiliation><affiliation><nlm:aff id="Aff10"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9297</institution-id><institution-id institution-id-type="GRID">grid.5491.9</institution-id><institution>Institute for Life Sciences,</institution><institution>University of Southampton,</institution></institution-wrap>Southampton, SO17 1BJ UK</nlm:aff></affiliation></author><author><name sortKey="Wang, Yihua" sort="Wang, Yihua" uniqKey="Wang Y" first="Yihua" last="Wang">Yihua Wang</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9297</institution-id><institution-id institution-id-type="GRID">grid.5491.9</institution-id><institution>Biological Sciences, Faculty of Environmental and Life Sciences,</institution><institution>University of Southampton,</institution></institution-wrap>Southampton, SO17 1BJ UK</nlm:aff></affiliation><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0368 7223</institution-id><institution-id institution-id-type="GRID">grid.33199.31</institution-id><institution>Department of Oncology, Tongji Hospital, Tongji Medical College,</institution><institution>Huazhong University of Science and Technology,</institution></institution-wrap>Wuhan, China</nlm:aff></affiliation><affiliation><nlm:aff id="Aff10"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9297</institution-id><institution-id institution-id-type="GRID">grid.5491.9</institution-id><institution>Institute for Life Sciences,</institution><institution>University of Southampton,</institution></institution-wrap>Southampton, SO17 1BJ UK</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31391462</idno><idno type="pmc">6685977</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685977</idno><idno type="RBID">PMC:6685977</idno><idno type="doi">10.1038/s41419-019-1820-x</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000067</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000067</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Autophagy inhibition-mediated epithelial–mesenchymal transition augments local myofibroblast differentiation in pulmonary fibrosis</title><author><name sortKey="Hill, Charlotte" sort="Hill, Charlotte" uniqKey="Hill C" first="Charlotte" last="Hill">Charlotte Hill</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9297</institution-id><institution-id institution-id-type="GRID">grid.5491.9</institution-id><institution>Biological Sciences, Faculty of Environmental and Life Sciences,</institution><institution>University of Southampton,</institution></institution-wrap>Southampton, SO17 1BJ UK</nlm:aff></affiliation></author><author><name sortKey="Li, Juanjuan" sort="Li, Juanjuan" uniqKey="Li J" first="Juanjuan" last="Li">Juanjuan Li</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9297</institution-id><institution-id institution-id-type="GRID">grid.5491.9</institution-id><institution>Biological Sciences, Faculty of Environmental and Life Sciences,</institution><institution>University of Southampton,</institution></institution-wrap>Southampton, SO17 1BJ UK</nlm:aff></affiliation></author><author><name sortKey="Liu, Dian" sort="Liu, Dian" uniqKey="Liu D" first="Dian" last="Liu">Dian Liu</name><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0368 7223</institution-id><institution-id institution-id-type="GRID">grid.33199.31</institution-id><institution>Department of Oncology, Tongji Hospital, Tongji Medical College,</institution><institution>Huazhong University of Science and Technology,</institution></institution-wrap>Wuhan, China</nlm:aff></affiliation></author><author><name sortKey="Conforti, Franco" sort="Conforti, Franco" uniqKey="Conforti F" first="Franco" last="Conforti">Franco Conforti</name><affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9297</institution-id><institution-id institution-id-type="GRID">grid.5491.9</institution-id><institution>Clinical and Experimental Sciences, Faculty of Medicine,</institution><institution>University of Southampton,</institution></institution-wrap>Southampton, SO16 6YD UK</nlm:aff></affiliation><affiliation><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="ISNI">0000000103590315</institution-id><institution-id institution-id-type="GRID">grid.123047.3</institution-id><institution>NIHR Southampton Biomedical Research Centre,</institution><institution>University Hospital Southampton,</institution></institution-wrap>Southampton, SO16 6YD UK</nlm:aff></affiliation></author><author><name sortKey="Brereton, Christopher J" sort="Brereton, Christopher J" uniqKey="Brereton C" first="Christopher J." last="Brereton">Christopher J. Brereton</name><affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9297</institution-id><institution-id institution-id-type="GRID">grid.5491.9</institution-id><institution>Clinical and Experimental Sciences, Faculty of Medicine,</institution><institution>University of Southampton,</institution></institution-wrap>Southampton, SO16 6YD UK</nlm:aff></affiliation><affiliation><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="ISNI">0000000103590315</institution-id><institution-id institution-id-type="GRID">grid.123047.3</institution-id><institution>NIHR Southampton Biomedical Research Centre,</institution><institution>University Hospital Southampton,</institution></institution-wrap>Southampton, SO16 6YD UK</nlm:aff></affiliation></author><author><name sortKey="Yao, Liudi" sort="Yao, Liudi" uniqKey="Yao L" first="Liudi" last="Yao">Liudi Yao</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9297</institution-id><institution-id institution-id-type="GRID">grid.5491.9</institution-id><institution>Biological Sciences, Faculty of Environmental and Life Sciences,</institution><institution>University of Southampton,</institution></institution-wrap>Southampton, SO17 1BJ UK</nlm:aff></affiliation></author><author><name sortKey="Zhou, Yilu" sort="Zhou, Yilu" uniqKey="Zhou Y" first="Yilu" last="Zhou">Yilu Zhou</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9297</institution-id><institution-id institution-id-type="GRID">grid.5491.9</institution-id><institution>Biological Sciences, Faculty of Environmental and Life Sciences,</institution><institution>University of Southampton,</institution></institution-wrap>Southampton, SO17 1BJ UK</nlm:aff></affiliation></author><author><name sortKey="Alzetani, Aiman" sort="Alzetani, Aiman" uniqKey="Alzetani A" first="Aiman" last="Alzetani">Aiman Alzetani</name><affiliation><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="ISNI">0000000103590315</institution-id><institution-id institution-id-type="GRID">grid.123047.3</institution-id><institution>NIHR Southampton Biomedical Research Centre,</institution><institution>University Hospital Southampton,</institution></institution-wrap>Southampton, SO16 6YD UK</nlm:aff></affiliation><affiliation><nlm:aff id="Aff5"><institution-wrap><institution-id institution-id-type="ISNI">0000000103590315</institution-id><institution-id institution-id-type="GRID">grid.123047.3</institution-id><institution>University Hospital Southampton,</institution></institution-wrap>Southampton, SO16 6YD UK</nlm:aff></affiliation></author><author><name sortKey="Chee, Serena J" sort="Chee, Serena J" uniqKey="Chee S" first="Serena J." last="Chee">Serena J. Chee</name><affiliation><nlm:aff id="Aff5"><institution-wrap><institution-id institution-id-type="ISNI">0000000103590315</institution-id><institution-id institution-id-type="GRID">grid.123047.3</institution-id><institution>University Hospital Southampton,</institution></institution-wrap>Southampton, SO16 6YD UK</nlm:aff></affiliation><affiliation><nlm:aff id="Aff6"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9297</institution-id><institution-id institution-id-type="GRID">grid.5491.9</institution-id><institution>Cancer Sciences Unit,</institution><institution>University of Southampton,</institution></institution-wrap>Somers Building, Southampton General Hospital, Southampton, SO16 6YD UK</nlm:aff></affiliation></author><author><name sortKey="Marshall, Ben G" sort="Marshall, Ben G" uniqKey="Marshall B" first="Ben G." last="Marshall">Ben G. Marshall</name><affiliation><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="ISNI">0000000103590315</institution-id><institution-id institution-id-type="GRID">grid.123047.3</institution-id><institution>NIHR Southampton Biomedical Research Centre,</institution><institution>University Hospital Southampton,</institution></institution-wrap>Southampton, SO16 6YD UK</nlm:aff></affiliation><affiliation><nlm:aff id="Aff5"><institution-wrap><institution-id institution-id-type="ISNI">0000000103590315</institution-id><institution-id institution-id-type="GRID">grid.123047.3</institution-id><institution>University Hospital Southampton,</institution></institution-wrap>Southampton, SO16 6YD UK</nlm:aff></affiliation></author><author><name sortKey="Fletcher, Sophie V" sort="Fletcher, Sophie V" uniqKey="Fletcher S" first="Sophie V." last="Fletcher">Sophie V. Fletcher</name><affiliation><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="ISNI">0000000103590315</institution-id><institution-id institution-id-type="GRID">grid.123047.3</institution-id><institution>NIHR Southampton Biomedical Research Centre,</institution><institution>University Hospital Southampton,</institution></institution-wrap>Southampton, SO16 6YD UK</nlm:aff></affiliation><affiliation><nlm:aff id="Aff5"><institution-wrap><institution-id institution-id-type="ISNI">0000000103590315</institution-id><institution-id institution-id-type="GRID">grid.123047.3</institution-id><institution>University Hospital Southampton,</institution></institution-wrap>Southampton, SO16 6YD UK</nlm:aff></affiliation></author><author><name sortKey="Hancock, David" sort="Hancock, David" uniqKey="Hancock D" first="David" last="Hancock">David Hancock</name><affiliation><nlm:aff id="Aff7"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1795 1830</institution-id><institution-id institution-id-type="GRID">grid.451388.3</institution-id><institution>Oncogene Biology,</institution><institution>The Francis Crick Institute,</institution></institution-wrap>London, NW1 1AT UK</nlm:aff></affiliation></author><author><name sortKey="Ottensmeier, Christian H" sort="Ottensmeier, Christian H" uniqKey="Ottensmeier C" first="Christian H." last="Ottensmeier">Christian H. Ottensmeier</name><affiliation><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="ISNI">0000000103590315</institution-id><institution-id institution-id-type="GRID">grid.123047.3</institution-id><institution>NIHR Southampton Biomedical Research Centre,</institution><institution>University Hospital Southampton,</institution></institution-wrap>Southampton, SO16 6YD UK</nlm:aff></affiliation><affiliation><nlm:aff id="Aff6"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9297</institution-id><institution-id institution-id-type="GRID">grid.5491.9</institution-id><institution>Cancer Sciences Unit,</institution><institution>University of Southampton,</institution></institution-wrap>Somers Building, Southampton General Hospital, Southampton, SO16 6YD UK</nlm:aff></affiliation></author><author><name sortKey="Steele, Andrew J" sort="Steele, Andrew J" uniqKey="Steele A" first="Andrew J." last="Steele">Andrew J. Steele</name><affiliation><nlm:aff id="Aff6"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9297</institution-id><institution-id institution-id-type="GRID">grid.5491.9</institution-id><institution>Cancer Sciences Unit,</institution><institution>University of Southampton,</institution></institution-wrap>Somers Building, Southampton General Hospital, Southampton, SO16 6YD UK</nlm:aff></affiliation></author><author><name sortKey="Downward, Julian" sort="Downward, Julian" uniqKey="Downward J" first="Julian" last="Downward">Julian Downward</name><affiliation><nlm:aff id="Aff7"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1795 1830</institution-id><institution-id institution-id-type="GRID">grid.451388.3</institution-id><institution>Oncogene Biology,</institution><institution>The Francis Crick Institute,</institution></institution-wrap>London, NW1 1AT UK</nlm:aff></affiliation></author><author><name sortKey="Richeldi, Luca" sort="Richeldi, Luca" uniqKey="Richeldi L" first="Luca" last="Richeldi">Luca Richeldi</name><affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9297</institution-id><institution-id institution-id-type="GRID">grid.5491.9</institution-id><institution>Clinical and Experimental Sciences, Faculty of Medicine,</institution><institution>University of Southampton,</institution></institution-wrap>Southampton, SO16 6YD UK</nlm:aff></affiliation><affiliation><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="ISNI">0000000103590315</institution-id><institution-id institution-id-type="GRID">grid.123047.3</institution-id><institution>NIHR Southampton Biomedical Research Centre,</institution><institution>University Hospital Southampton,</institution></institution-wrap>Southampton, SO16 6YD UK</nlm:aff></affiliation><affiliation><nlm:aff id="Aff8"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0941 3192</institution-id><institution-id institution-id-type="GRID">grid.8142.f</institution-id><institution>Unità Operativa Complessa di Pneumologia,</institution><institution>Università Cattolica del Sacro Cuore, Fondazione Policlinico A Gemelli IRCCS,</institution></institution-wrap>Rome, Italy</nlm:aff></affiliation></author><author><name sortKey="Lu, Xin" sort="Lu, Xin" uniqKey="Lu X" first="Xin" last="Lu">Xin Lu</name><affiliation><nlm:aff id="Aff9"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 8948</institution-id><institution-id institution-id-type="GRID">grid.4991.5</institution-id><institution>Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine,</institution><institution>University of Oxford,</institution></institution-wrap>Oxford, OX3 7DQ UK</nlm:aff></affiliation></author><author><name sortKey="Davies, Donna E" sort="Davies, Donna E" uniqKey="Davies D" first="Donna E." last="Davies">Donna E. Davies</name><affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9297</institution-id><institution-id institution-id-type="GRID">grid.5491.9</institution-id><institution>Clinical and Experimental Sciences, Faculty of Medicine,</institution><institution>University of Southampton,</institution></institution-wrap>Southampton, SO16 6YD UK</nlm:aff></affiliation><affiliation><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="ISNI">0000000103590315</institution-id><institution-id institution-id-type="GRID">grid.123047.3</institution-id><institution>NIHR Southampton Biomedical Research Centre,</institution><institution>University Hospital Southampton,</institution></institution-wrap>Southampton, SO16 6YD UK</nlm:aff></affiliation><affiliation><nlm:aff id="Aff10"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9297</institution-id><institution-id institution-id-type="GRID">grid.5491.9</institution-id><institution>Institute for Life Sciences,</institution><institution>University of Southampton,</institution></institution-wrap>Southampton, SO17 1BJ UK</nlm:aff></affiliation></author><author><name sortKey="Jones, Mark G" sort="Jones, Mark G" uniqKey="Jones M" first="Mark G." last="Jones">Mark G. Jones</name><affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9297</institution-id><institution-id institution-id-type="GRID">grid.5491.9</institution-id><institution>Clinical and Experimental Sciences, Faculty of Medicine,</institution><institution>University of Southampton,</institution></institution-wrap>Southampton, SO16 6YD UK</nlm:aff></affiliation><affiliation><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="ISNI">0000000103590315</institution-id><institution-id institution-id-type="GRID">grid.123047.3</institution-id><institution>NIHR Southampton Biomedical Research Centre,</institution><institution>University Hospital Southampton,</institution></institution-wrap>Southampton, SO16 6YD UK</nlm:aff></affiliation><affiliation><nlm:aff id="Aff10"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9297</institution-id><institution-id institution-id-type="GRID">grid.5491.9</institution-id><institution>Institute for Life Sciences,</institution><institution>University of Southampton,</institution></institution-wrap>Southampton, SO17 1BJ UK</nlm:aff></affiliation></author><author><name sortKey="Wang, Yihua" sort="Wang, Yihua" uniqKey="Wang Y" first="Yihua" last="Wang">Yihua Wang</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9297</institution-id><institution-id institution-id-type="GRID">grid.5491.9</institution-id><institution>Biological Sciences, Faculty of Environmental and Life Sciences,</institution><institution>University of Southampton,</institution></institution-wrap>Southampton, SO17 1BJ UK</nlm:aff></affiliation><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0368 7223</institution-id><institution-id institution-id-type="GRID">grid.33199.31</institution-id><institution>Department of Oncology, Tongji Hospital, Tongji Medical College,</institution><institution>Huazhong University of Science and Technology,</institution></institution-wrap>Wuhan, China</nlm:aff></affiliation><affiliation><nlm:aff id="Aff10"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9297</institution-id><institution-id institution-id-type="GRID">grid.5491.9</institution-id><institution>Institute for Life Sciences,</institution><institution>University of Southampton,</institution></institution-wrap>Southampton, SO17 1BJ UK</nlm:aff></affiliation></author></analytic><series><title level="j">Cell Death & Disease</title><idno type="eISSN">2041-4889</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="Par1">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 (<italic>SNAI2</italic>), 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.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Hutchinson, J" uniqKey="Hutchinson J">J Hutchinson</name></author><author><name sortKey="Fogarty, A" uniqKey="Fogarty A">A Fogarty</name></author><author><name sortKey="Hubbard, R" uniqKey="Hubbard R">R Hubbard</name></author><author><name sortKey="Mckeever, T" uniqKey="Mckeever T">T McKeever</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Richeldi, L" uniqKey="Richeldi L">L Richeldi</name></author><author><name sortKey="Collard, Hr" uniqKey="Collard H">HR Collard</name></author><author><name sortKey="Jones, Mg" uniqKey="Jones M">MG Jones</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Raghu, G" uniqKey="Raghu G">G Raghu</name></author><author><name sortKey="Weycker, D" uniqKey="Weycker D">D Weycker</name></author><author><name sortKey="Edelsberg, J" uniqKey="Edelsberg J">J Edelsberg</name></author><author><name sortKey="Bradford, Wz" uniqKey="Bradford W">WZ Bradford</name></author><author><name sortKey="Oster, G" uniqKey="Oster G">G Oster</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Martinez Lopez, N" uniqKey="Martinez Lopez N">N Martinez-Lopez</name></author><author><name sortKey="Athonvarangkul, D" uniqKey="Athonvarangkul D">D Athonvarangkul</name></author><author><name sortKey="Singh, R" uniqKey="Singh R">R Singh</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Romero, Y" uniqKey="Romero Y">Y Romero</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Patel, As" uniqKey="Patel A">AS Patel</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Rangarajan, S" uniqKey="Rangarajan S">S Rangarajan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Araya, J" uniqKey="Araya J">J Araya</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ghavami, S" uniqKey="Ghavami S">S Ghavami</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bento, Cf" uniqKey="Bento C">CF Bento</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Singh, Kk" uniqKey="Singh K">KK Singh</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Nieto, A" uniqKey="Nieto A">A Nieto</name></author><author><name sortKey="Huang, R" uniqKey="Huang R">R Huang</name></author><author><name sortKey="Jackson, R" uniqKey="Jackson R">R Jackson</name></author><author><name sortKey="Thiery, J" uniqKey="Thiery J">J Thiery</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Peinado, H" uniqKey="Peinado H">H Peinado</name></author><author><name sortKey="Olmeda, D" uniqKey="Olmeda D">D Olmeda</name></author><author><name sortKey="Cano, A" uniqKey="Cano A">A Cano</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Nieto, Ma" uniqKey="Nieto M">MA Nieto</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Rusten, Te" uniqKey="Rusten T">TE Rusten</name></author><author><name sortKey="Stenmark, H" uniqKey="Stenmark H">H Stenmark</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Xu, Y" uniqKey="Xu Y">Y Xu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Moscat, J" uniqKey="Moscat J">J Moscat</name></author><author><name sortKey="Diaz Meco, Mt" uniqKey="Diaz Meco M">MT Diaz-Meco</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yao, Liudi" uniqKey="Yao L">Liudi Yao</name></author><author><name sortKey="Conforti, Franco" uniqKey="Conforti F">Franco Conforti</name></author><author><name sortKey="Hill, Charlotte" uniqKey="Hill C">Charlotte Hill</name></author><author><name sortKey="Bell, Joseph" uniqKey="Bell J">Joseph Bell</name></author><author><name sortKey="Drawater, Leena" uniqKey="Drawater L">Leena Drawater</name></author><author><name sortKey="Li, Juanjuan" uniqKey="Li J">Juanjuan Li</name></author><author><name sortKey="Liu, Dian" uniqKey="Liu D">Dian Liu</name></author><author><name sortKey="Xiong, Hua" uniqKey="Xiong H">Hua Xiong</name></author><author><name sortKey="Alzetani, Aiman" uniqKey="Alzetani A">Aiman Alzetani</name></author><author><name sortKey="Chee, Serena J" uniqKey="Chee S">Serena J. Chee</name></author><author><name sortKey="Marshall, Ben G" uniqKey="Marshall B">Ben G. Marshall</name></author><author><name sortKey="Fletcher, Sophie V" uniqKey="Fletcher S">Sophie V. Fletcher</name></author><author><name sortKey="Hancock, David" uniqKey="Hancock D">David Hancock</name></author><author><name sortKey="Coldwell, Mark" uniqKey="Coldwell M">Mark Coldwell</name></author><author><name sortKey="Yuan, Xianglin" uniqKey="Yuan X">Xianglin Yuan</name></author><author><name sortKey="Ottensmeier, Christian H" uniqKey="Ottensmeier C">Christian H. Ottensmeier</name></author><author><name sortKey="Downward, Julian" uniqKey="Downward J">Julian Downward</name></author><author><name sortKey="Collins, Jane E" uniqKey="Collins J">Jane E. Collins</name></author><author><name sortKey="Ewing, Rob M" uniqKey="Ewing R">Rob M. Ewing</name></author><author><name sortKey="Richeldi, Luca" uniqKey="Richeldi L">Luca Richeldi</name></author><author><name sortKey="Skipp, Paul" uniqKey="Skipp P">Paul Skipp</name></author><author><name sortKey="Jones, Mark G" uniqKey="Jones M">Mark G. Jones</name></author><author><name sortKey="Davies, Donna E" uniqKey="Davies D">Donna E. Davies</name></author><author><name sortKey="Wang, Yihua" uniqKey="Wang Y">Yihua Wang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Molina Arcas, M" uniqKey="Molina Arcas M">M Molina-Arcas</name></author><author><name sortKey="Hancock, Dc" uniqKey="Hancock D">DC Hancock</name></author><author><name sortKey="Sheridan, C" uniqKey="Sheridan C">C Sheridan</name></author><author><name sortKey="Kumar, Ms" uniqKey="Kumar M">MS Kumar</name></author><author><name sortKey="Downward, J" uniqKey="Downward J">J Downward</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Coelho, Ma" uniqKey="Coelho M">MA Coelho</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Thiery, Jp" uniqKey="Thiery J">JP Thiery</name></author><author><name sortKey="Sleeman, Jp" uniqKey="Sleeman J">JP Sleeman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ballou, Lm" uniqKey="Ballou L">LM Ballou</name></author><author><name sortKey="Lin, Rz" uniqKey="Lin R">RZ Lin</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wang, Yihua" uniqKey="Wang Y">Yihua Wang</name></author><author><name sortKey="Xiong, Hua" uniqKey="Xiong H">Hua Xiong</name></author><author><name sortKey="Liu, Dian" uniqKey="Liu D">Dian Liu</name></author><author><name sortKey="Hill, Charlotte" uniqKey="Hill C">Charlotte Hill</name></author><author><name sortKey="Ertay, Ayse" uniqKey="Ertay A">Ayse Ertay</name></author><author><name sortKey="Li, Juanjuan" uniqKey="Li J">Juanjuan Li</name></author><author><name sortKey="Zou, Yanmei" uniqKey="Zou Y">Yanmei Zou</name></author><author><name sortKey="Miller, Paul" uniqKey="Miller P">Paul Miller</name></author><author><name sortKey="White, Eileen" uniqKey="White E">Eileen White</name></author><author><name sortKey="Downward, Julian" uniqKey="Downward J">Julian Downward</name></author><author><name sortKey="Goldin, Robert D" uniqKey="Goldin R">Robert D Goldin</name></author><author><name sortKey="Yuan, Xianglin" uniqKey="Yuan X">Xianglin Yuan</name></author><author><name sortKey="Lu, Xin" uniqKey="Lu X">Xin Lu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Thannickal, Vj" uniqKey="Thannickal V">VJ Thannickal</name></author><author><name sortKey="Zhou, Y" uniqKey="Zhou Y">Y Zhou</name></author><author><name sortKey="Gaggar, A" uniqKey="Gaggar A">A Gaggar</name></author><author><name sortKey="Duncan, Sr" uniqKey="Duncan S">SR Duncan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wynn, Ta" uniqKey="Wynn T">TA Wynn</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wynn, Ta" uniqKey="Wynn T">TA Wynn</name></author><author><name sortKey="Ramalingam, Tr" uniqKey="Ramalingam T">TR Ramalingam</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Pardo, A" uniqKey="Pardo A">A Pardo</name></author><author><name sortKey="Selman, M" uniqKey="Selman M">M Selman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Raghu, G" uniqKey="Raghu G">G Raghu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Minagawa, S" uniqKey="Minagawa S">S Minagawa</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tsakiri, Kd" uniqKey="Tsakiri K">KD Tsakiri</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Alder, Jk" uniqKey="Alder J">JK Alder</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bueno, M" uniqKey="Bueno M">M Bueno</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Fingerlin, Te" uniqKey="Fingerlin T">TE Fingerlin</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Spagnolo, P" uniqKey="Spagnolo P">P Spagnolo</name></author><author><name sortKey="Tzouvelekis, A" uniqKey="Tzouvelekis A">A Tzouvelekis</name></author><author><name sortKey="Bonella, F" uniqKey="Bonella F">F Bonella</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hill, C" uniqKey="Hill C">C Hill</name></author><author><name sortKey="Jones, Mg" uniqKey="Jones M">MG Jones</name></author><author><name sortKey="Davies, De" uniqKey="Davies D">DE Davies</name></author><author><name sortKey="Wang, Y" uniqKey="Wang Y">Y Wang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chilosi, M" uniqKey="Chilosi M">M Chilosi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Park, Js" uniqKey="Park J">JS Park</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lomas, Nj" uniqKey="Lomas N">NJ Lomas</name></author><author><name sortKey="Watts, Kl" uniqKey="Watts K">KL Watts</name></author><author><name sortKey="Akram, Km" uniqKey="Akram K">KM Akram</name></author><author><name sortKey="Forsyth, Nr" uniqKey="Forsyth N">NR Forsyth</name></author><author><name sortKey="Spiteri, Ma" uniqKey="Spiteri M">MA Spiteri</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Willis, Bc" uniqKey="Willis B">BC Willis</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Harada, T" uniqKey="Harada T">T Harada</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Marmai, C" uniqKey="Marmai C">C Marmai</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Rock, Jr" uniqKey="Rock J">JR Rock</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Humphreys, Bd" uniqKey="Humphreys B">BD Humphreys</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tanjore, H" uniqKey="Tanjore H">H 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contrib-id-type="orcid">http://orcid.org/0000-0001-5561-0648</contrib-id><name><surname>Wang</surname><given-names>Yihua</given-names></name><address><email>yihua.wang@soton.ac.uk</email></address><xref ref-type="aff" rid="Aff1">1</xref><xref ref-type="aff" rid="Aff2">2</xref><xref ref-type="aff" rid="Aff10">10</xref></contrib><aff id="Aff1"><label>1</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9297</institution-id><institution-id institution-id-type="GRID">grid.5491.9</institution-id><institution>Biological Sciences, Faculty of Environmental and Life Sciences,</institution><institution>University of Southampton,</institution></institution-wrap>Southampton, SO17 1BJ UK</aff><aff id="Aff2"><label>2</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0368 7223</institution-id><institution-id institution-id-type="GRID">grid.33199.31</institution-id><institution>Department of Oncology, Tongji Hospital, Tongji Medical College,</institution><institution>Huazhong University of Science and Technology,</institution></institution-wrap>Wuhan, China</aff><aff id="Aff3"><label>3</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9297</institution-id><institution-id institution-id-type="GRID">grid.5491.9</institution-id><institution>Clinical and Experimental Sciences, Faculty of Medicine,</institution><institution>University of Southampton,</institution></institution-wrap>Southampton, SO16 6YD UK</aff><aff id="Aff4"><label>4</label><institution-wrap><institution-id institution-id-type="ISNI">0000000103590315</institution-id><institution-id institution-id-type="GRID">grid.123047.3</institution-id><institution>NIHR Southampton Biomedical Research Centre,</institution><institution>University Hospital Southampton,</institution></institution-wrap>Southampton, SO16 6YD UK</aff><aff id="Aff5"><label>5</label><institution-wrap><institution-id institution-id-type="ISNI">0000000103590315</institution-id><institution-id institution-id-type="GRID">grid.123047.3</institution-id><institution>University Hospital Southampton,</institution></institution-wrap>Southampton, SO16 6YD UK</aff><aff id="Aff6"><label>6</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9297</institution-id><institution-id institution-id-type="GRID">grid.5491.9</institution-id><institution>Cancer Sciences Unit,</institution><institution>University of Southampton,</institution></institution-wrap>Somers Building, Southampton General Hospital, Southampton, SO16 6YD UK</aff><aff id="Aff7"><label>7</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1795 1830</institution-id><institution-id institution-id-type="GRID">grid.451388.3</institution-id><institution>Oncogene Biology,</institution><institution>The Francis Crick Institute,</institution></institution-wrap>London, NW1 1AT UK</aff><aff id="Aff8"><label>8</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0941 3192</institution-id><institution-id institution-id-type="GRID">grid.8142.f</institution-id><institution>Unità Operativa Complessa di Pneumologia,</institution><institution>Università Cattolica del Sacro Cuore, Fondazione Policlinico A Gemelli IRCCS,</institution></institution-wrap>Rome, Italy</aff><aff id="Aff9"><label>9</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 8948</institution-id><institution-id institution-id-type="GRID">grid.4991.5</institution-id><institution>Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine,</institution><institution>University of Oxford,</institution></institution-wrap>Oxford, OX3 7DQ UK</aff><aff id="Aff10"><label>10</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9297</institution-id><institution-id institution-id-type="GRID">grid.5491.9</institution-id><institution>Institute for Life Sciences,</institution><institution>University of Southampton,</institution></institution-wrap>Southampton, SO17 1BJ UK</aff></contrib-group><pub-date pub-type="epub"><day>7</day><month>8</month><year>2019</year></pub-date><pub-date pub-type="pmc-release"><day>7</day><month>8</month><year>2019</year></pub-date><pub-date pub-type="collection"><month>8</month><year>2019</year></pub-date><volume>10</volume><issue>8</issue><elocation-id>591</elocation-id><history><date date-type="received"><day>2</day><month>5</month><year>2019</year></date><date date-type="rev-recd"><day>28</day><month>6</month><year>2019</year></date><date date-type="accepted"><day>18</day><month>7</month><year>2019</year></date></history><permissions><copyright-statement>© The Author(s) 2019</copyright-statement><license license-type="OpenAccess"><license-p><bold>Open Access</bold> This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>.</license-p></license></permissions><abstract id="Abs1"><p id="Par1">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 (<italic>SNAI2</italic>), 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.</p></abstract><kwd-group kwd-group-type="npg-subject"><title>Subject terms</title><kwd>Macroautophagy</kwd><kwd>Respiratory tract diseases</kwd></kwd-group><funding-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">https://doi.org/10.13039/501100000691</institution-id><institution>Academy of Medical Sciences</institution></institution-wrap></funding-source><award-id>SBF002/1038</award-id><award-id>SBF002/1038</award-id><principal-award-recipient><name><surname>Li</surname><given-names>Juanjuan</given-names></name><name><surname>Wang</surname><given-names>Yihua</given-names></name></principal-award-recipient></award-group></funding-group><funding-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">https://doi.org/10.13039/501100008176</institution-id><institution>Wessex Medical Research (Wessex Medical Trust)</institution></institution-wrap></funding-source></award-group></funding-group><funding-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">https://doi.org/10.13039/501100005188</institution-id><institution>AAIR Charity (Asthma, Allergy and Inflammation Research Charity)</institution></institution-wrap></funding-source></award-group></funding-group><funding-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">https://doi.org/10.13039/100012166</institution-id><institution>Gerald Kerkut Charitable Trust</institution></institution-wrap></funding-source></award-group></funding-group><funding-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">https://doi.org/10.13039/501100001809</institution-id><institution>National Natural Science Foundation of China (National Science Foundation of China)</institution></institution-wrap></funding-source><award-id>81772827</award-id><principal-award-recipient><name><surname>Li</surname><given-names>Juanjuan</given-names></name></principal-award-recipient></award-group></funding-group><funding-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">https://doi.org/10.13039/501100000265</institution-id><institution>RCUK | Medical Research Council (MRC)</institution></institution-wrap></funding-source><award-id>MRF-091-0003-RG-CONFO</award-id><principal-award-recipient><name><surname>Conforti</surname><given-names>Franco</given-names></name></principal-award-recipient></award-group></funding-group><funding-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">https://doi.org/10.13039/501100004543</institution-id><institution>China Scholarship Council (CSC)</institution></institution-wrap></funding-source></award-group></funding-group><funding-group><award-group><funding-source><institution>YZ was supported by an Institute for Life Sciences PhD Studentship.</institution></funding-source></award-group></funding-group><funding-group><award-group><funding-source><institution>JD was supported by the Francis Crick Institute which receives its core funding from Cancer Research UK (FC001070), the UK Medical Research Council (FC001070), and the Wellcome Trust (FC001070).</institution></funding-source></award-group></funding-group><funding-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">https://doi.org/10.13039/100004440</institution-id><institution>Wellcome Trust (Wellcome)</institution></institution-wrap></funding-source><award-id>100638/Z/12/Z</award-id><principal-award-recipient><name><surname>Jones</surname><given-names>Mark G.</given-names></name></principal-award-recipient></award-group></funding-group><custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name><meta-value>© The Author(s) 2019</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec id="Sec1" sec-type="introduction"><title>Introduction</title><p id="Par2">Idiopathic pulmonary fibrosis (IPF) is the most common type of chronic, progressive fibrotic interstitial lung disease. It occurs with comparable incidence to that of stomach, brain and testicular cancer<sup><xref ref-type="bibr" rid="CR1">1</xref></sup>, and the median survival of patients with IPF is only 3 years<sup><xref ref-type="bibr" rid="CR2">2</xref>,<xref ref-type="bibr" rid="CR3">3</xref></sup>. IPF is characterised by aberrant extracellular matrix (ECM) deposition, which leads to decreased lung compliance, disrupted gas-exchange and ultimately respiratory failure and death. As approved therapies only slow disease progression there is significant unmet medical need.</p><p id="Par3">Evidence suggests that interacting genetic and environmental factors are crucial for the development of IPF, with repetitive injuries to aged alveolar epithelium thought to play an important role<sup><xref ref-type="bibr" rid="CR2">2</xref></sup>. Ageing is a risk factor for IPF, with disease incidence increasing with age<sup><xref ref-type="bibr" rid="CR3">3</xref></sup>. Decreased (macro)autophagy with age has been reported extensively in a variety of systems and diseases<sup><xref ref-type="bibr" rid="CR4">4</xref></sup>, including IPF<sup><xref ref-type="bibr" rid="CR5">5</xref>–<xref ref-type="bibr" rid="CR9">9</xref></sup>. Autophagy is a tightly controlled, evolutionarily conserved process for the lysosomal degradation of cytoplasmic cargo, long-lived proteins and organelles. Growing evidence suggests that autophagy acts as an adaptive response to facilitate cell survival and limit cell death following exposure to stressful stimuli<sup><xref ref-type="bibr" rid="CR10">10</xref></sup>.</p><p id="Par4">Tissues from IPF patients are characterised by defective autophagy responses<sup><xref ref-type="bibr" rid="CR5">5</xref>–<xref ref-type="bibr" rid="CR8">8</xref></sup>, although it is unclear whether faulty autophagy exerts an effect directly, or if this change is merely coincident with IPF. Loss of <italic>autophagy-related protein 7 (ATG7)</italic>, a ubiquitin-activating enzyme that is essential for autophagy, has been demonstrated both in vivo and in vitro to induce endothelial-to-mesenchymal transition (EndMT). Autophagy inhibition, by loss of <italic>ATG7</italic>, has been associated with changes in endothelial cell (EC) architecture, reduced endothelial markers and increased mesenchymal markers, whilst EC-specific <italic>Atg7</italic> knockout mice had increased susceptibility to bleomycin induced-fibrosis<sup><xref ref-type="bibr" rid="CR11">11</xref></sup>. Furthermore, inhibition of autophagy is sufficient to induce acceleration of both bronchial epithelial cell senescence and differentiation of lung fibroblasts into myofibroblasts<sup><xref ref-type="bibr" rid="CR8">8</xref></sup>. Here, we report that autophagy inhibition promotes epithelial–mesenchymal transition (EMT) in alveolar epithelial cells. EMT is a reversible biological process where epithelial cells gain migratory and invasive abilities through loss of cell polarity and cadherin-mediated cell–cell adhesion; this process has been implicated in embryonic development, wound healing, cancer metastasis and organ fibrosis<sup><xref ref-type="bibr" rid="CR12">12</xref></sup>. Specific transcription factors, EMT transcription factors (EMT-TFs), including Snail, ZEB and TWIST are able to promote the repression of epithelial features and induction of mesenchymal features<sup><xref ref-type="bibr" rid="CR13">13</xref>,<xref ref-type="bibr" rid="CR14">14</xref></sup>. We show that promotion of EMT by autophagy inhibition in alveolar epithelial cells is attained, at least in part, by increased p62/SQSTM1 expression that induces p65/RELA mediated-transactivation of Snail2 (<italic>SNAI2</italic>), which not only controls EMT but also regulates the production of locally acting profibrogenic mediators. This suggests that autophagy inhibition-induced EMT of alveolar epithelial cells contributes to fibrosis not only by affecting the epithelial phenotype but also via aberrant epithelial–fibroblast crosstalk.</p></sec><sec id="Sec2" sec-type="results"><title>Results</title><sec id="Sec3"><title>Autophagic activity is downregulated in IPF lungs</title><p id="Par5">Defective autophagy responses in tissues from IPF patients have been reported previously<sup><xref ref-type="bibr" rid="CR6">6</xref>,<xref ref-type="bibr" rid="CR8">8</xref></sup>. Similarly, we observed evidence of autophagy inhibition as determined by p62/SQSTM1 accumulation in lung epithelial cells in IPF samples (Fig. <xref rid="Fig1" ref-type="fig">1</xref>; Supplementary Fig. <xref rid="MOESM1" ref-type="media">S1a</xref>). p62/SQSTM1 is a key protein involved in autophagy that recognises cellular waste, which is then sequestered and degraded by autophagy<sup><xref ref-type="bibr" rid="CR15">15</xref></sup>. A strong staining for p62/SQSTM1 was detected in IPF tissue within epithelial cells of thickened alveoli septae where collagen deposition in the interstitium was demonstrated (Fig. <xref rid="Fig1" ref-type="fig">1b</xref>; Supplementary Fig. <xref rid="MOESM1" ref-type="media">S1a</xref>), as well as within fibroblastic foci (Fig. <xref rid="Fig1" ref-type="fig">1a</xref>). In contrast, there was weak p62/SQSTM1 expression and little collagen deposition detected in alveoli of control lung tissue (Fig. <xref rid="Fig1" ref-type="fig">1c</xref>). Using a publicly available dataset<sup><xref ref-type="bibr" rid="CR16">16</xref></sup>, the mRNA level of <italic>SQSTM1</italic> (p62) in IPF epithelial cells was evaluated. It was found that <italic>SQSTM1</italic> (p62) mRNA expression level was reduced in IPF lungs (Supplementary Fig. <xref rid="MOESM1" ref-type="media">S1b</xref>) whilst its protein level as assessed by immunohistochemistry was increased in IPF (Fig. <xref rid="Fig1" ref-type="fig">1b</xref>; Supplementary Fig. <xref rid="MOESM1" ref-type="media">S1a</xref>). Given that p62/SQSTM1 protein levels are predominantly regulated by autophagic activity<sup><xref ref-type="bibr" rid="CR17">17</xref></sup>, these results suggest that autophagic activity is downregulated in IPF epithelial cells.<fig id="Fig1"><label>Fig. 1</label><caption><title>p62/SQSTM1 is highly expressed in IPF fibroblastic foci and epithelial cells of thickened alveoli septae where collagen deposition in the interstitium is also evident.</title><p>Serial sections of IPF (fibroblastic foci in (<bold>a</bold>), and epithelial cells of thickened alveoli septae in (<bold>b</bold>)) or control lung tissue (<bold>c</bold>) were stained for p62/SQSTM1 (top panel), with H&E (middle panel) or Masson’s trichrome stain (bottom panel, collagen shown in blue). <italic>n</italic> = 3. *a fibroblastic focus. Scale bars: 50 μm</p></caption><graphic xlink:href="41419_2019_1820_Fig1_HTML" id="d29e713"></graphic></fig></p></sec><sec id="Sec4"><title>Alteration of autophagic activity affects cellular plasticity of alveolar epithelial cells</title><p id="Par6">To investigate its role in alveolar epithelial cells, autophagic activity was first modified using chemical inhibitors. We treated human alveolar epithelial type II (ATII) cells<sup><xref ref-type="bibr" rid="CR18">18</xref>–<xref ref-type="bibr" rid="CR20">20</xref></sup> with an autophagy inhibitor, hydroxychloroquine (HCQ), which is a lysosomotropic autophagy inhibitor. HCQ treatment of ATII cells inhibited autophagic activity, demonstrated by the accumulation of p62/SQSTM1 (Fig. <xref rid="Fig2" ref-type="fig">2a</xref>), inhibition of lysosomal degradation by HCQ also caused accumulation of LC3-II (Fig. <xref rid="Fig2" ref-type="fig">2a</xref>). Autophagy inhibition with HCQ resulted in a downregulation of E-cadherin in a time-dependent manner (Fig. <xref rid="Fig2" ref-type="fig">2a</xref>). Morphology changes were also observed following HCQ treatment with ATII cells developing an elongated mesenchymal cell phenotype; this was accompanied by actin cytoskeleton reorganisation demonstrated using filamentous actin (F-actin) staining with Phalloidin (Fig. <xref rid="Fig2" ref-type="fig">2c</xref>), suggesting induction of a cellular reprogramming process, EMT. A group of transcription factors, termed EMT-TFs, are capable of inducing EMT, these include Snail1 (<italic>SNAI1</italic>), Snail2 (<italic>SNAI2</italic>), TWIST1, ZEB1 and ZEB2<sup><xref ref-type="bibr" rid="CR13">13</xref></sup>, which act by binding E-boxes in the proximal promoter of the <italic>CDH1</italic> (E-cadherin) gene to repress its expression. We thus investigated the impact of HCQ treatment on the mRNA expression levels of E-cadherin (<italic>CDH1</italic>) and EMT-TFs in ATII cells. Following HCQ treatment of ATII cells, we observed a downregulation of E-cadherin (<italic>CDH1</italic>), increased levels of a mesenchymal marker Vimentin (<italic>VIM</italic>) and an EMT-TF Snail2 (<italic>SNAI2</italic>), but not others (Fig. <xref rid="Fig2" ref-type="fig">2b</xref>).<fig id="Fig2"><label>Fig. 2</label><caption><title>Autophagic activity altered by chemicals affects cellular plasticity of ATII cells.</title><p><bold>a</bold> Protein expression of E-Cadherin, Snail2, p62/SQSTM1 and LC3 in ATII cells treated with HCQ (25 μM) at indicated times. β-actin was used as a loading control. <bold>b</bold> Fold change in mRNA levels of <italic>CDH1</italic> (E-cadherin), <italic>VIM</italic> (Vimentin), <italic>SNAI1</italic> (Snail1), <italic>SNAI2</italic> (Snail2), <italic>TWIST1</italic>, <italic>ZEB1</italic> and <italic>ZEB2</italic> in ATII cells cultured in the absence or presence of HCQ (25 μM) for 24 hours. GAPDH-normalised mRNA levels in control cells were used to set the baseline value at unity. Data are mean ± s.d. <italic>n</italic> = 3 samples per group. ***<italic>P</italic> < 0.001. <bold>c</bold> Immunofluorescence staining of Snail2 (green) and F-actin (red) in ATII cells cultured in the absence or presence of HCQ (25 μM) for 24 h. Rhodamine-phalloidin was used to stain F-actin. DAPI (blue) was used to stain nuclei. Scale bar: 40 μm</p></caption><graphic xlink:href="41419_2019_1820_Fig2_HTML" id="d29e814"></graphic></fig></p><p id="Par7">To confirm our observations with HCQ, we treated ATII cells with another autophagy inhibitor, Bafilomycin-A1 (Baf-A1), which inhibits autophagy by disrupting vesicular acidification leading to an accumulation of mature, undigested autophagosomes<sup><xref ref-type="bibr" rid="CR21">21</xref></sup>. Autophagy inhibition by Baf-A1 treatment of ATII cells resulted in a similar induction of EMT, evidenced by a reduction in E-cadherin (Supplementary Fig. <xref rid="MOESM1" ref-type="media">S2a</xref>), an increase of Vimentin (<italic>VIM</italic>) (Supplementary Fig. <xref rid="MOESM1" ref-type="media">S2b</xref>), and an upregulation of EMT-TF Snail2 (<italic>SNAI2</italic>) (Supplementary Fig. <xref rid="MOESM1" ref-type="media">S2b</xref>). Morphology changes were observed following Baf-A1 treatment of ATII cells, with cells developing invasive phenotype when cultured in Matrigel (Supplementary Fig. <xref rid="MOESM1" ref-type="media">S2c</xref>).</p><p id="Par8">We further used small interfering RNAs (siRNAs) against <italic>autophagy-related protein 5</italic> (<italic>ATG5</italic>) to study the effects of inhibition of autophagic activity in ATII cells. ATG5, a ubiquitin-protein ligase (E3)-like enzyme, is essential for autophagy due to its role in autophagosome elongation. <italic>ATG5</italic> siRNA-transfection of ATII cells inhibited autophagic activity, evidenced by the accumulation of p62/SQSTM1 (Fig. <xref rid="Fig3" ref-type="fig">3a, c</xref>). As a result, <italic>ATG5</italic> depletion led to a downregulation of E-cadherin at both the mRNA and protein levels (Fig. <xref rid="Fig3" ref-type="fig">3a, b</xref>), an increase in <italic>VIM</italic> (Vimentin) at mRNA level (Fig. <xref rid="Fig3" ref-type="fig">3b</xref>), and a rearrangement of the F-actin cytoskeleton (Fig. <xref rid="Fig3" ref-type="fig">3c</xref>). Similar results were observed in A549 alveolar epithelial cells where autophagy inhibition by <italic>ATG5</italic> depletion down regulated E-cadherin levels and increased Snail2 (<italic>SNAI2</italic>) expression (Supplementary Fig. <xref rid="MOESM1" ref-type="media">S3a–c</xref>).<fig id="Fig3"><label>Fig. 3</label><caption><title>Autophagy inhibition by <italic>ATG5</italic> depletion induces EMT and cell migration in ATII cells.</title><p><bold>a</bold> Protein expression of E-cadherin, p62/SQSTM and ATG12–ATG5 in ATII cells transfected with indicated siRNAs. β-tubulin was used as a loading control. <bold>b</bold> Fold change in the mRNA levels of <italic>CDH1</italic> (E-cadherin), <italic>SNAI2</italic> (Snail2) and <italic>VIM</italic> (Vimentin) in ATII cells transfected with indicated siRNAs. GAPDH-normalised mRNA levels in control cells were used to set the baseline value at unity. Data are mean ± s.d. <italic>n</italic> = 3 samples per group. **<italic>P</italic> < 0.01. <bold>c</bold> Immunofluorescence staining of p62/SQSTM (green) and F-actin (red) in ATII cells transfected with control or <italic>ATG5</italic> siRNAs. Rhodamine-phalloidin was used to stain F-actin. DAPI (blue) was used to stain nuclei. Scale bar: 40 μm. <bold>d</bold> Scratch wound assay of ATII cells transfected with control or <italic>ATG5</italic> siRNAs. Representative images of ATII cells with the indicated treatments at time 0 or 20 h after the scratch wound. Wounds have been artificially coloured red to aid visualisation. Scale bar: 200 μm. The graph shows the area of a wound evaluated with ImageJ, and data are mean ± s.d. <italic>n</italic> = 3. ***<italic>P</italic> < 0.001. <bold>e</bold> Transwell migration assays in control or <italic>ATG5</italic>-depleted ATII cells. Cells were stained with crystal violet. Scale bar: 100 μm. Data are mean ± s.d. <italic>n</italic> = 3. ***<italic>P</italic> <italic><</italic> 0.001</p></caption><graphic xlink:href="41419_2019_1820_Fig3_HTML" id="d29e948"></graphic></fig></p><p id="Par9">In a wound healing context, the EMT process allows epithelial cells to adopt a more migratory mesenchymal phenotype in order to spread rapidly and cover the wounded area<sup><xref ref-type="bibr" rid="CR22">22</xref></sup>. Therefore, a wound scratch assay was utilised to test whether <italic>ATG5</italic> depletion using <italic>ATG5</italic> siRNA was sufficient to augment cell mobility. This showed that 20 hours after creating the scratch wound, <italic>ATG5</italic> siRNA-transfected ATII cells had more completely repaired the wound compared to control siRNA-transfected cells (Fig. <xref rid="Fig3" ref-type="fig">3d</xref>; <italic>P</italic> < 0.001). In addition, we found in both the Transwell migration (Fig. <xref rid="Fig3" ref-type="fig">3e</xref>) and Matrigel invasion assays (Supplementary Fig. <xref rid="MOESM1" ref-type="media">S3d</xref>), knockdown of <italic>ATG5</italic> promoted cell migration and invasion respectively.</p><p id="Par10">Having examined the effects of autophagy inhibition in ATII cells, we next evaluated the effect of autophagy induction using Rapamycin, which inhibits mammalian Target Of Rapamycin (mTOR)<sup><xref ref-type="bibr" rid="CR23">23</xref></sup>. As predicted, following Rapamycin treatment of ATII cells, phosphorylation levels of mTOR were reduced (Supplementary Fig. <xref rid="MOESM1" ref-type="media">S4a</xref>), and autophagy activity was induced, indicated by a downregulation of p62/SQSTM1 and an increase in LC3-II (Supplementary Fig. <xref rid="MOESM1" ref-type="media">S4a</xref>). We also found an increase in <italic>CDH1</italic> (E-cadherin), and reductions in <italic>VIM</italic> (Vimentin) and <italic>SNAI2</italic> (Snail2) mRNA levels in ATII cells treated with Rapamycin (Supplementary Fig. <xref rid="MOESM1" ref-type="media">S4b</xref>), and these effects were mainly via the induction of autophagy, since knockdown of <italic>ATG5</italic> completely abolished the changes (Supplementary Fig. <xref rid="MOESM1" ref-type="media">S4b</xref>).</p><p id="Par11">Together, our results demonstrate that autophagic activity is an important regulator of cellular plasticity in alveolar epithelial cells.</p></sec><sec id="Sec5"><title>Autophagy inhibition induces EMT via p62/SQSMT1-NFκB-Snail2 pathway in alveolar epithelial cells</title><p id="Par12">We recently reported that in colorectal and pancreatic cancer cells, inhibition of autophagy induces EMT via p62/SQSMT1-NFκB pathway<sup><xref ref-type="bibr" rid="CR24">24</xref></sup>. Therefore, we investigated if this pathway is involved in initiating autophagy inhibition-induced EMT in ATII cells. Comparison of control and HCQ-treated cells revealed that p65/RELA accumulated in the nuclei of treated cells (Fig. <xref rid="Fig4" ref-type="fig">4a</xref>), indicating that the NF-κB pathway is activated in ATII cells when autophagy is inhibited. Functionally, p62/<italic>SQSTM1</italic> or p65/<italic>RELA</italic> knockdown abolished the increase in Snail2 following autophagy inhibition by HCQ treatment in ATII cells (Fig. <xref rid="Fig4" ref-type="fig">4b</xref>). Similar results were observed in A549 cells (Supplementary Fig. <xref rid="MOESM6" ref-type="media">S5</xref>). While knockdown of <italic>ATG5</italic> induced EMT, as evidenced by a reduction in <italic>CDH1</italic> (E-cadherin) mRNA levels and increased <italic>SNAI2</italic> (Snail2) mRNA levels, subsequent depletion of <italic>RELA</italic> (p65) or <italic>SQSTM1</italic> (p62) (Supplementary Fig. <xref rid="MOESM1" ref-type="media">S5a</xref>) partially or completely abolished the increase in <italic>SNAI2</italic> (Snail2), and restored <italic>CDH1</italic> (E-cadherin) expression (Supplementary Fig. <xref rid="MOESM1" ref-type="media">S5b</xref>). These data suggest that autophagy inhibition in alveolar epithelial cells promotes EMT via the p62/SQSMT1-NFκB-Snail2 pathway.<fig id="Fig4"><label>Fig. 4</label><caption><title>Autophagy inhibition induces EMT via p62/SQSTM1-NF-κB-Snail2 pathway in ATII cells.</title><p><bold>a</bold> Immunofluorescence staining of p62/SQSTM1 (red) and p65/RELA (green) in ATII cells treated with hydroxychloroquine (HCQ, 25 μM) for 24 h. DAPI (blue) was used to stain nuclei. Scale bar: 40 μm. <bold>b</bold> Protein expression of Snail2, p65/RELA and p62/SQSTM1 in ATII cells transfected with the indicated siRNAs followed by treatment of HCQ (25 μM) for 24 h. For protein expression of p62/SQSTM1, both short and long exposures (respectively) are shown. β-tubulin was used as a loading control</p></caption><graphic xlink:href="41419_2019_1820_Fig4_HTML" id="d29e1081"></graphic></fig></p></sec><sec id="Sec6"><title>ATII cells undergoing autophagy inhibition-induced EMT induce fibroblast activation via Snail2-regulated paracrine signalling</title><p id="Par13">Given that autophagy inhibition is able to induce EMT in ATII cells, we wanted to determine the role of these cells in the context of fibrosis, and whether they were contributing to the fibroblast population directly. Comparison of ECM components in control or <italic>ATG5</italic> siRNA ATII cells demonstrated that ATII cells after autophagy inhibition-induced EMT did not express significantly more ECM genes (Supplementary Fig. <xref rid="MOESM7" ref-type="media">S6</xref>). This suggested ECM production in IPF lung tissue (Fig. <xref rid="Fig1" ref-type="fig">1</xref>) was unlikely due directly to EMT but rather epithelial cells exhibiting an indirect effect on fibrogenesis. Therefore, we investigated whether <italic>ATG5</italic>-depleted ATII cells could produce secreted factors that activate fibroblasts. We treated primary human lung fibroblasts from IPF patients (IPF fibroblasts, IPFFs) with conditioned media (CM) from ATII cells transfected with control or <italic>ATG5</italic> siRNA (Fig. <xref rid="Fig5" ref-type="fig">5a</xref>) without or with addition of transforming growth factor-β (TGF-β), and assessed levels of α-smooth muscle actin (α-SMA), a marker of myofibroblast differentiation. CM from ATII cells transfected with <italic>ATG5</italic> siRNA without TGF-β had minimal effect on the activation of fibroblasts (Fig. <xref rid="Fig5" ref-type="fig">5b</xref>). However in IPFFs, CM from <italic>ATG5</italic>-depleted ATII cells together with TGF-β achieved a synergistic effect in activating fibroblasts as assessed by α-SMA protein levels (Fig. <xref rid="Fig5" ref-type="fig">5b</xref>). Notably, levels of phospho-Smad2 (p-Smad2) did not significantly change between different CM with TGF-β treatment, suggesting α-SMA increase may be Smad2-independent (Fig. <xref rid="Fig5" ref-type="fig">5b</xref>). Given the importance of Snail2 (<italic>SNAI2</italic>) in mediating EMT by autophagy inhibition (Fig. <xref rid="Fig5" ref-type="fig">5a</xref>), we hypothesised that Snail2 (<italic>SNAI2</italic>) may facilitate crosstalk by mediating paracrine signalling from ATII cells undergoing autophagy inhibition-induced EMT. Snail2 (<italic>SNAI2</italic>) depletion (Fig. <xref rid="Fig5" ref-type="fig">5a</xref>) in ATII cells eliminated the effects of CM from <italic>ATG5</italic>-depleted ATII cells on activation of fibroblasts in the presence of TGF-β (Fig. <xref rid="Fig5" ref-type="fig">5c</xref>), highlighting the importance of Snail2 (<italic>SNAI2</italic>) as a key regulator of paracrine signalling between alveolar cells and fibroblasts in IPF under conditions where autophagy is defective.<fig id="Fig5"><label>Fig. 5</label><caption><title>ATII cells undergoing autophagy inhibition-induced EMT induce fibroblast activation via Snail2-regulated paracrine signalling.</title><p><bold>a</bold> Protein expression of E-cadherin, ATG12–ATG5 and Snail2 in ATII cells transfected with indicated siRNAs. β-tubulin was used as a loading control. <bold>b, c</bold> Protein expression of α-SMA, Smad2 and phospho-Smad2 (p-Smad2) in IPFFs with indicated treatments. β-tubulin was used as a loading control. Scores under the bands are relative levels when compared with indicated controls (1.0). The graphs show relative α-SMA protein levels evaluated with ImageJ, and data are mean ± s.d. <italic>n</italic> = 3. *<italic>P</italic> < 0.05. ***<italic>P</italic> < 0.001</p></caption><graphic xlink:href="41419_2019_1820_Fig5_HTML" id="d29e1171"></graphic></fig></p></sec></sec><sec id="Sec7" sec-type="discussion"><title>Discussion</title><p id="Par14">Fibrotic diseases are poorly characterised and lack effective treatment<sup><xref ref-type="bibr" rid="CR25">25</xref></sup>, with fibrosis presenting as a pathological feature in a range of diseases affecting many organs<sup><xref ref-type="bibr" rid="CR25">25</xref>,<xref ref-type="bibr" rid="CR26">26</xref></sup>. A rise in the incidence of some fibrotic diseases<sup><xref ref-type="bibr" rid="CR1">1</xref>,<xref ref-type="bibr" rid="CR3">3</xref></sup> and with fibrogenesis being accepted as a major cause of death<sup><xref ref-type="bibr" rid="CR27">27</xref></sup>; it is evident that they are becoming an increasing healthcare burden, requiring further research to elucidate underlying mechanisms which drive fibrogenesis. IPF is an aging-associated chronic, interstitial lung disease<sup><xref ref-type="bibr" rid="CR2">2</xref>,<xref ref-type="bibr" rid="CR28">28</xref>–<xref ref-type="bibr" rid="CR34">34</xref></sup>. Treatment options for patients are limited<sup><xref ref-type="bibr" rid="CR35">35</xref></sup> and the underlying mechanisms for fibrosis are still debated<sup><xref ref-type="bibr" rid="CR36">36</xref></sup>. EMT has been suggested to have a direct role in IPF, with studies showing co-localisation of epithelial and mesenchymal markers<sup><xref ref-type="bibr" rid="CR37">37</xref>–<xref ref-type="bibr" rid="CR41">41</xref></sup>, and laser capture micro-dissection isolated RNA from epithelial cells in IPF lungs confirmed expression of mesenchymal markers<sup><xref ref-type="bibr" rid="CR42">42</xref></sup>. However, lineage tracing studies found the number of fibroblasts derived from epithelial cells to be small<sup><xref ref-type="bibr" rid="CR43">43</xref>,<xref ref-type="bibr" rid="CR44">44</xref></sup>, and these cells were not found to co-localise with α-SMA suggesting they did not transition to myofibroblasts<sup><xref ref-type="bibr" rid="CR45">45</xref>,<xref ref-type="bibr" rid="CR46">46</xref></sup>. It also been proposed in a number of systems that epithelial cells that have undergone EMT may secrete a range of fibrogenic growth factors and cytokines, with impaired epithelial repair leading to aberrant epithelial–mesenchymal communication contributing to the recruitment and activation of myofibroblasts<sup><xref ref-type="bibr" rid="CR18">18</xref>,<xref ref-type="bibr" rid="CR47">47</xref>,<xref ref-type="bibr" rid="CR48">48</xref></sup>. Here, we show that autophagy inhibition in ATII cells can induce EMT, and this contributes to fibrosis via aberrant epithelial–fibroblast crosstalk, rather than as a direct contribution to the fibroblast population.</p><p id="Par15">Autophagy is a tightly controlled, evolutionarily conserved biological process where long-lived proteins and damaged organelles are degraded. Manipulation of autophagy is now being utilised as a therapeutic approach in a number of fields, such as, neurodegenerative diseases and cancer<sup><xref ref-type="bibr" rid="CR49">49</xref>,<xref ref-type="bibr" rid="CR50">50</xref></sup>. On the other hand, decreased autophagic activity has been reported in many human diseases<sup><xref ref-type="bibr" rid="CR51">51</xref></sup>, including IPF<sup><xref ref-type="bibr" rid="CR5">5</xref>–<xref ref-type="bibr" rid="CR8">8</xref></sup>. In IPF, ageing is a main risk factor in its development with patients under the age of 50 being rare<sup><xref ref-type="bibr" rid="CR29">29</xref></sup>. Ageing has been linked to reduced autophagy in many contexts, including IPF<sup><xref ref-type="bibr" rid="CR5">5</xref>,<xref ref-type="bibr" rid="CR52">52</xref></sup>. Consistent with these findings<sup><xref ref-type="bibr" rid="CR6">6</xref>,<xref ref-type="bibr" rid="CR8">8</xref></sup> we demonstrated strong immunostaining for p62/SQSTM1 in IPF epithelial cells of thickened alveolar septae whilst identifying only very weak signals in the control lung. We found significantly lower levels of <italic>SQSTM1</italic> (p62) mRNA in IPF epithelial cells compared to control epithelial cells, which indicated that the increase in p62/SQSTM1 protein levels was due to reduced autophagic activity. Taken with previous findings<sup><xref ref-type="bibr" rid="CR6">6</xref>,<xref ref-type="bibr" rid="CR8">8</xref></sup>, these results indicate that autophagic activity is downregulated in IPF epithelial cells.</p><p id="Par16">Whilst the concept of EMT is well established in the context of embryonic development, it also plays a role in in wound healing, cancer metastasis and fibrosis<sup><xref ref-type="bibr" rid="CR12">12</xref></sup>. EMT requires a complex orchestration of multiple signalling pathways, including TGF-β, fibroblast growth factor, Wnt/β-catenin, epidermal growth factor (EGF) and others. Loss of E-cadherin is considered to be a fundamental event in EMT. Snail1/2, ZEB1/2 and some basic helix-loop-helix factors are potent repressors of E-cadherin expression<sup><xref ref-type="bibr" rid="CR53">53</xref>,<xref ref-type="bibr" rid="CR54">54</xref></sup>. The role of EMT in cancer is detrimental whereas in wound healing, EMT as a response to injury can be beneficial, however, if the wound healing process is exaggerated it may lead to fibrosis. The interplay between autophagy and EMT have been reported in other disease contexts<sup><xref ref-type="bibr" rid="CR55">55</xref>–<xref ref-type="bibr" rid="CR57">57</xref></sup>, with a recent study demonstrating inhibition of autophagy induces EMT via p62/SQSMT1-NFκB/RELA pathway in <italic>RAS</italic>-mutated cancer cells<sup><xref ref-type="bibr" rid="CR24">24</xref></sup>. This is mainly via upregulation of ZEB1 and to a lesser extent via Snail2<sup><xref ref-type="bibr" rid="CR24">24</xref></sup>. In contrast, in lung alveolar epithelial cells, autophagy inhibition induces EMT in the absence of RAS activation and is exclusively via up-regulation of Snail2 (Fig. <xref rid="Fig6" ref-type="fig">6a</xref>), indicating this effect is likely dependent on the cellular context. The importance of Snail2 in IPF has been demonstrated with Snail2 being upregulated in IPF lung epithelial cells, but not Snail1 or TWIST1, compared to control epithelial cells<sup><xref ref-type="bibr" rid="CR16">16</xref>,<xref ref-type="bibr" rid="CR18">18</xref></sup>. Jayachandran et al.<sup><xref ref-type="bibr" rid="CR54">54</xref></sup> reported that Snail2-mediated EMT may contribute to the fibroblast pool. However, in this study, we found ATII cells undergoing autophagy inhibition-induced EMT induce fibroblast activation via Snail2-regulated paracrine signalling.<fig id="Fig6"><label>Fig. 6</label><caption><title>Autophagy inhibition-mediated epithelial–mesenchymal transition augments local myofibroblast differentiation in pulmonary fibrosis.</title><p>Diagrams showing autophagy inhibition induces EMT via p62/SQSMT1-NFκB-Snail2 pathway in alveolar epithelial cells (<bold>a</bold>) and local micro-injuries to ageing alveolar epithelium causes persistent activation of alveolar epithelial cells, which secrete numerous profibrogenic factors, driving local myofibroblast differentiation (<bold>b</bold>)</p></caption><graphic xlink:href="41419_2019_1820_Fig6_HTML" id="d29e1365"></graphic></fig></p><p id="Par17">In IPF it was recently reported that micro-injuries could lead to the activation of the EGFR-RAS-ERK pathway, and ZEB1 was demonstrated to mediate paracrine signalling<sup><xref ref-type="bibr" rid="CR18">18</xref></sup>. Similarly in renal fibrosis, tubular epithelial cells are able to promote myofibroblast differentiation and fibrogenesis without directly contributing to the fibroblast population by relaying signals to the interstitium. For example, in a murine model, damage-mediated Snail1 reactivation-induced partial EMT and resulted in renal fibrosis, but these cells did not contribute to myofibroblast or interstitial cell population<sup><xref ref-type="bibr" rid="CR47">47</xref></sup>. Conversely, EMT was inhibited and interstitial fibrosis attenuated upon conditional deletion of <italic>Snail1</italic> or <italic>Twist1</italic><sup><xref ref-type="bibr" rid="CR48">48</xref></sup>.</p><p id="Par18">Taken together, we believe that repetitive local micro-injuries to ageing alveolar epithelium cause persistent activation of alveolar epithelial cells, which secrete numerous profibrogenic factors, driving local myofibroblast differentiation (Fig. <xref rid="Fig6" ref-type="fig">6b</xref>). Thus, targeting of EMT inducers might have therapeutic potential in fibrotic conditions, with such therapies currently undergoing development in the context of malignancy<sup><xref ref-type="bibr" rid="CR58">58</xref>,<xref ref-type="bibr" rid="CR59">59</xref></sup>.</p></sec><sec id="Sec8"><title>Methods</title><sec id="Sec9"><title>Lung tissue sampling</title><p id="Par19">All human lung experiments were approved by the Southampton and South West Hampshire and the Mid and South Buckinghamshire Local Research Ethics Committees, and all subjects gave written informed consent. Clinically indicated IPF lung biopsy tissue samples and non-fibrotic control tissue samples (macroscopically normal lung sampled remote from a cancer site) were assessed as surplus to clinical diagnostic requirements. All IPF samples were from patients subsequently receiving a multidisciplinary diagnosis of IPF according to international consensus guidelines<sup><xref ref-type="bibr" rid="CR29">29</xref></sup>.</p></sec><sec id="Sec10"><title>Cell culture, reagents and transfections</title><p id="Par20">Primary parenchymal lung fibroblast cultures were established from IPF tissues as described previously<sup><xref ref-type="bibr" rid="CR60">60</xref>,<xref ref-type="bibr" rid="CR61">61</xref></sup>. Fibroblasts were cultured in Dulbecco’s Modified Eagle’s Medium (DMEM) supplemented with 10% foetal bovine serum (FBS), 50 units/ml penicillin, 50 μg/ml streptomycin, 2 mM <sc>l</sc>-glutamine, 1 mM sodium pyruvate and 1× non-essential amino acids (DMEM/FBS) (all from Life Technologies). ATII cells<sup><xref ref-type="bibr" rid="CR18">18</xref>–<xref ref-type="bibr" rid="CR20">20</xref></sup> were cultured in DCCM-1 (Biological Industries Ltd.) supplemented with 10% NBCS (Life Technologies), 1% penicillin, 1% streptomycin and 1% <sc>l</sc>-glutamine (all from Sigma Aldrich). A549 cells were cultured in DMEM (Fisher Scientific UK, 11594446) supplemented with 10% FBS (Invitrogen) and antibiotics. All cells were kept at 37 °C and 5% CO<sub>2</sub>. For 3D culture, ATII cells were cultured as previously described<sup><xref ref-type="bibr" rid="CR62">62</xref></sup> in Matrigel (BD Biosciences). Bafilomycin-A1 (Baf-A1) was from Enzo Life Sciences. HCQ and Rapamycin were from Sigma Aldrich. No mycoplasma contamination was detected in the cell lines used.</p><p id="Par21">siRNA oligos against <italic>ATG5</italic> (MU-004374-04-0002), <italic>SQSTM1</italic> (p62) (MU-010230-00-0002), <italic>SNAI2</italic> (Snail2) (MU-017386-00-0002) and <italic>RELA</italic> (p65) (MU-003533-02-0002) were purchased from Dharmacon. Sequences are available from Dharmacon, or on request. As a negative control we used siGENOME RISC-Free siRNA (Dharmacon, D-001220-01). ATII and A549 cells were transfected with the indicated siRNA oligos at a final concentration of 35 nM using DharmaFECT 2 reagent (Dharmacon).</p></sec><sec id="Sec11"><title>Western blot analysis</title><p id="Par22">Western blot analysis was performed with lysates from cells with urea buffer (8 M Urea, 1 M Thiourea, 0.5% CHAPS, 50 mM DTT, and 24 mM Spermine). Primary antibodies were from: Santa Cruz (β-actin, sc-47778; E-cadherin, sc-21791; Snail2, sc-10436), Abcam (β-tubulin, ab6046), Cell Signalling Technology (α-SMA, 14968; Snail2, 9585; Smad2, 5339; Phospho-Smad2, 3104; β-tubulin, 86298; LC3, 2775; p62/SQSTM1, 5114; p65/RELA, 8242; ATG5, 2630; mTOR, 2972; Phospho-mTOR Ser2448, 5536), and BD Transduction Laboratories (E-cadherin, 610405). Signals were detected using an ECL detection system (GE Healthcare) or Odyssey imaging system (LI-COR), and evaluated by ImageJ 1.42q software (National Institutes of Health).</p></sec><sec id="Sec12"><title>qRT-PCR</title><p id="Par23">Total RNA was isolated using RNeasy mini kit (Qiagen) according to manufacturer’s instructions and quantified using a Nanodrop Spectophotometer 2000c (Thermo Fisher Scientific). Real-time quantitative RT-PCR was carried out using gene-specific primers (QuantiTect Primer Assays, Qiagen) for <italic>CDH1</italic> (E-cadherin) (QT00080143), <italic>SNAI1</italic> (Snail1) (QT00010010), <italic>SNAI2</italic> (Snail2) (QT00044128), <italic>ZEB1</italic> (QT00008555), <italic>ZEB2</italic> (QT00008554), <italic>TWIST1</italic> (QT00011956), <italic>COL1A1</italic> (QT00037793), <italic>ACTA2</italic> (α-SMA) (QT00088102), <italic>COL3A1</italic> (QT00058233)<italic>, FN1</italic> (QT00038024<italic>), VIM</italic> (QT00095795)<italic>, GAPDH</italic> (QT01192646) or <italic>ACTB</italic> (β-actin) (QT01680476) with QuantiNova SYBR Green RT-PCR kits (Qiagen). Relative transcript levels of target genes were normalised to <italic>GAPDH</italic> or <italic>ACTB</italic> (β-actin).</p></sec><sec id="Sec13"><title>Immunofluorescence microscopy</title><p id="Par24">Cells were fixed in 4% phosphate-buffered saline (PBS)–paraformaldehyde for 15 min, incubated in 0.1% Triton X-100 for 5 min on ice, then in 0.2% fish skin gelatine in PBS for 1 h and stained for 1 h with an anti-E-cadherin (1:100, BD Biosciences, 610182) or anti-p62/SQSTM1 (1:100, BD Biosciences, 610833) or anti-Snail2 (1:100, Cell Signalling Technology, 9585), p65/RELA (1:100, Cell Signalling Technology, 8242). Protein expression was detected using Alexa Fluor (1:400, Molecular Probes) for 20 min. DAPI or TO-PRO-3 (Invitrogen) was used to stain nuclei (1:1000). Rhodamine phalloidin was used to visualise filamentous actin (F-actin) (Molecular Probes). For immunofluorescence staining of 3D cultures from ATII cells, spheres were fixed with 4% PBS–paraformaldehyde for 40 min, permeabilised in 0.5% Triton X-100 for 10 min on ice and stained with rhodamine phalloidin for 1 h at room temperature. Spheres were counterstained with DAPI. Samples were observed using a confocal microscope system (Leica SP8). Acquired images were analysed using Photoshop (Adobe Systems) according to the guidelines of the journal.</p></sec><sec id="Sec14"><title>Wound-healing migration assay</title><p id="Par25">The wound-healing migration assays were done in conjunction with siRNA transfections in ATII cells. Seventy-two hours after siRNA transfections, confluent monolayers of cells were wounded with a p20 pipette tip (time 0). Phase-contrast images were taken using an Olympus inverted microscope at time 0 or 20 h after the scratch wound, invasive cells were evaluated by ImageJ software (National Institutes of Health).</p></sec><sec id="Sec15"><title>Transwell migration and Matrigel invasion assay</title><p id="Par26">For the Transwell migration assay, Transwell membranes (8-μm pore size, 6.5-mm diameter; Corning Costar, 3422) were used. The bottom chambers of the Transwell were filled with migration-inducing medium (with 50% FBS). The top chambers were seeded with 1.5 × 10<sup>5</sup> live serum-starved control or <italic>ATG5</italic>-depleted ATII cells per well. After 24 h, the filters were fixed with 4% paraformaldehyde for 10 min at room temperature; subsequently, the cells on the upper side of the membrane were scraped with a cotton swab. Similar inserts coated with Matrigel (Corning, 354480) were used to determine invasive potential in invasion assays. Filters were stained with crystal violet for light microscopy. Images were taken using an Olympus inverted microscope and migratory cells were evaluated by ImageJ 1.42q software (National Institutes of Health).</p></sec><sec id="Sec16"><title>Immunohistochemistry, haematoxylin and eosin (H/E) and tinctorial stains</title><p id="Par27">Control or IPF lung tissues were fixed and embedded in paraffin wax; tissue sections (4 µm) were processed and stained as previously described<sup><xref ref-type="bibr" rid="CR18">18</xref></sup>. Briefly, the tissue sections were de-waxed, rehydrated and incubated with 3% hydrogen peroxide in methanol for 10 min to block endogenous peroxidase activity. Sections were then blocked with normal goat serum and incubated at room temperature with a primary antibody against p62/SQSTM1 (1:100, Progen, GP62_C), followed by a biotinylated secondary antibody (1:500, Vector Laboratories Ltd., UK); antibody binding was detected using streptavidin-conjugated horse-radish peroxidase and visualised using DAB (DAKO) before counterstaining with Mayer’s Haematoxylin. For H/E stain, Shandon Varistain 24-4 automatic slide stainer (Thermo Fisher Scientific) was used. For tinctorial stain, Trichrome stain (Abcam ab150686) was used according to the manufacturers’ instructions. Images were acquired using an Olympus Dotslide Scanner VS110.</p></sec><sec id="Sec17"><title>Statistical analysis and repeatability of experiments</title><p id="Par28">Each experiment was repeated at least twice. Unless otherwise noted, data are presented as mean and s.d., and a two-tailed, unpaired or paired Student’s <italic>t</italic> test was used to compare two groups for independent samples. <italic>P</italic> < 0.05 was considered statistically significant.</p></sec></sec><sec sec-type="supplementary-material"><title>Supplementary information</title><sec id="Sec18"><p><supplementary-material content-type="local-data" id="MOESM1"><media xlink:href="41419_2019_1820_MOESM1_ESM.docx"><caption><p>Supplementary Text.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="MOESM2"><media xlink:href="41419_2019_1820_MOESM2_ESM.pdf"><caption><p>Supplementary Figure S1.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="MOESM3"><media xlink:href="41419_2019_1820_MOESM3_ESM.pdf"><caption><p>Supplementary Figure S2.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="MOESM4"><media xlink:href="41419_2019_1820_MOESM4_ESM.pdf"><caption><p>Supplementary Figure S3.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="MOESM5"><media xlink:href="41419_2019_1820_MOESM5_ESM.pdf"><caption><p>Supplementary Figure S4.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="MOESM6"><media xlink:href="41419_2019_1820_MOESM6_ESM.pdf"><caption><p>Supplementary Figure S5.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="MOESM7"><media xlink:href="41419_2019_1820_MOESM7_ESM.pdf"><caption><p>Supplementary Figure S6.</p></caption></media></supplementary-material></p></sec></sec></body><back><fn-group><fn><p>Edited by B. Zhivotovsky</p></fn><fn><p><bold>Publisher’s note:</bold> Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.</p></fn><fn><p>These authors contributed equally: Charlotte Hill, Juanjuan Li</p></fn></fn-group><sec><title>Supplementary information</title><p><bold>Supplementary Information</bold> accompanies this paper at (10.1038/s41419-019-1820-x).</p></sec><ack><title>Acknowledgements</title><p>This project was supported by an Academy of Medical Sciences/the Wellcome Trust Springboard Award [SBF002/1038], the Wessex Medical Trust and AAIR Charity. C.H. was supported by Gerald Kerkut Charitable Trust and University of Southampton Central VC Scholarship Scheme. D.L. was supported by the National Natural Science Foundation of China [81772827]. F.C. was supported by Medical Research Foundation [MRF-091-0003-RG-CONFO]. L.Y. was supported by China Scholarship Council. Y.Z. was supported by an Institute for Life Sciences PhD Studentship. A.J.S. was supportd by Bloodwise grant 12044. J.D. was supported by the Francis Crick Institute which receives its core funding from Cancer Research UK (FC001070), the UK Medical Research Council (FC001070) and the Wellcome Trust (FC001070). X.L. was supported by the Ludwig Institute for Cancer Research and the NIHR Oxford Biomedical Research Centre. M.G.J. was supported by the Wellcome Trust [100638/Z/12/Z]. 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