{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T01:15:08Z","timestamp":1790644508323,"version":"4.1.0"},"reference-count":56,"publisher":"American Society for Clinical Investigation","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2018,2,8]]},"abstract":"<jats:p>Chronic obstructive pulmonary disease (COPD) is a highly prevalent and devastating condition for which no curative treatment is available. Exaggerated lung cell senescence may be a major pathogenic factor. Here, we investigated the potential role for mTOR signaling in lung cell senescence and alterations in COPD using lung tissue and derived cultured cells from patients with COPD and from age- and sex-matched control smokers. Cell senescence in COPD was linked to mTOR activation, and mTOR inhibition by low-dose rapamycin prevented cell senescence and inhibited the proinflammatory senescence-associated secretory phenotype. To explore whether mTOR activation was a causal pathogenic factor, we developed transgenic mice exhibiting mTOR overactivity in lung vascular cells or alveolar epithelial cells. In this model, mTOR activation was sufficient to induce lung cell senescence and to mimic COPD lung alterations, with the rapid development of lung emphysema, pulmonary hypertension, and inflammation. These findings support a causal relationship between mTOR activation, lung cell senescence, and lung alterations in COPD, thereby identifying the mTOR pathway as a potentially new therapeutic target in COPD.<\/jats:p>","DOI":"10.1172\/jci.insight.93203","type":"journal-article","created":{"date-parts":[[2018,2,7]],"date-time":"2018-02-07T11:01:03Z","timestamp":1518001263000},"source":"Crossref","is-referenced-by-count":210,"title":["mTOR pathway activation drives lung cell senescence and emphysema"],"prefix":"10.1172","volume":"3","author":[{"given":"Amal","family":"Houssaini","sequence":"first","affiliation":[{"name":"INSERM U955, D\u00e9partement de Physiologie-Explorations Fonctionnelles, and DHU A-TVB H\u00f4pital Henri Mondor, AP-HP, Cr\u00e9teil, France."},{"name":"Comprehensive Pneumology Center (CPC), University Hospital, Ludwig-Maximilians University, Helmholtz Zentrum M\u00fcnchen, Member of the German Center for Lung Research (DZL), Munich, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marielle","family":"Breau","sequence":"additional","affiliation":[{"name":"INSERM U955, D\u00e9partement de Physiologie-Explorations Fonctionnelles, and DHU A-TVB H\u00f4pital Henri Mondor, AP-HP, Cr\u00e9teil, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanny","family":"Kebe","sequence":"additional","affiliation":[{"name":"INSERM U955, D\u00e9partement de Physiologie-Explorations Fonctionnelles, and DHU A-TVB H\u00f4pital Henri Mondor, AP-HP, Cr\u00e9teil, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shariq","family":"Abid","sequence":"additional","affiliation":[{"name":"INSERM U955, D\u00e9partement de Physiologie-Explorations Fonctionnelles, and DHU A-TVB H\u00f4pital Henri Mondor, AP-HP, Cr\u00e9teil, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth","family":"Marcos","sequence":"additional","affiliation":[{"name":"INSERM U955, D\u00e9partement de Physiologie-Explorations Fonctionnelles, and DHU A-TVB H\u00f4pital Henri Mondor, AP-HP, Cr\u00e9teil, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Larissa","family":"Lipskaia","sequence":"additional","affiliation":[{"name":"INSERM U955, D\u00e9partement de Physiologie-Explorations Fonctionnelles, and DHU A-TVB H\u00f4pital Henri Mondor, AP-HP, Cr\u00e9teil, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominique","family":"Rideau","sequence":"additional","affiliation":[{"name":"INSERM U955, D\u00e9partement de Physiologie-Explorations Fonctionnelles, and DHU A-TVB H\u00f4pital Henri Mondor, AP-HP, Cr\u00e9teil, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aurelien","family":"Parpaleix","sequence":"additional","affiliation":[{"name":"INSERM U955, D\u00e9partement de Physiologie-Explorations Fonctionnelles, and DHU A-TVB H\u00f4pital Henri Mondor, AP-HP, Cr\u00e9teil, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Huang","sequence":"additional","affiliation":[{"name":"INSERM U955, D\u00e9partement de Physiologie-Explorations Fonctionnelles, and DHU A-TVB H\u00f4pital Henri Mondor, AP-HP, Cr\u00e9teil, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerie","family":"Amsellem","sequence":"additional","affiliation":[{"name":"INSERM U955, D\u00e9partement de Physiologie-Explorations Fonctionnelles, and DHU A-TVB H\u00f4pital Henri Mondor, AP-HP, Cr\u00e9teil, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nora","family":"Vienney","sequence":"additional","affiliation":[{"name":"INSERM U955, D\u00e9partement de Physiologie-Explorations Fonctionnelles, and DHU A-TVB H\u00f4pital Henri Mondor, AP-HP, Cr\u00e9teil, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"Validire","sequence":"additional","affiliation":[{"name":"Institut Mutualiste Montsouris, D\u00e9partement anatomopathologie, Paris, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernard","family":"Maitre","sequence":"additional","affiliation":[{"name":"INSERM U955, D\u00e9partement de Physiologie-Explorations Fonctionnelles, and DHU A-TVB H\u00f4pital Henri Mondor, AP-HP, Cr\u00e9teil, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aya","family":"Attwe","sequence":"additional","affiliation":[{"name":"INSERM U955, D\u00e9partement de Physiologie-Explorations Fonctionnelles, and DHU A-TVB H\u00f4pital Henri Mondor, AP-HP, Cr\u00e9teil, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Lukas","sequence":"additional","affiliation":[{"name":"Comprehensive Pneumology Center (CPC), University Hospital, Ludwig-Maximilians University, Helmholtz Zentrum M\u00fcnchen, Member of the German Center for Lung Research (DZL), Munich, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Vindrieux","sequence":"additional","affiliation":[{"name":"Centre de Recherche en Canc\u00e9rologie de Lyon, UMR INSERM U1052\/CNRS 5286, Universit\u00e9 de Lyon, Centre L\u00e9on B\u00e9rard, Lyon, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge","family":"Boczkowski","sequence":"additional","affiliation":[{"name":"INSERM U955, D\u00e9partement de Physiologie-Explorations Fonctionnelles, and DHU A-TVB H\u00f4pital Henri Mondor, AP-HP, Cr\u00e9teil, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Genevieve","family":"Derumeaux","sequence":"additional","affiliation":[{"name":"INSERM U955, D\u00e9partement de Physiologie-Explorations Fonctionnelles, and DHU A-TVB H\u00f4pital Henri Mondor, AP-HP, Cr\u00e9teil, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Pende","sequence":"additional","affiliation":[{"name":"INSERM U845, Universit\u00e9 Paris Descartes, 75015, Paris, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Bernard","sequence":"additional","affiliation":[{"name":"Centre de Recherche en Canc\u00e9rologie de Lyon, UMR INSERM U1052\/CNRS 5286, Universit\u00e9 de Lyon, Centre L\u00e9on B\u00e9rard, Lyon, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silke","family":"Meiners","sequence":"additional","affiliation":[{"name":"Comprehensive Pneumology Center (CPC), University Hospital, Ludwig-Maximilians University, Helmholtz Zentrum M\u00fcnchen, Member of the German Center for Lung Research (DZL), Munich, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serge","family":"Adnot","sequence":"additional","affiliation":[{"name":"INSERM U955, D\u00e9partement de Physiologie-Explorations Fonctionnelles, and DHU A-TVB H\u00f4pital Henri Mondor, AP-HP, Cr\u00e9teil, France."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2018,2,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(11)60990-2"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.04.00014304"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201209-1665OC"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200912-1843CC"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2015.06.007"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/nrg3246"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3823"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathol-121808-102144"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/35106045"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/0014-4827(65)90211-9"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201105-0802OC"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201208-1361OC"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.111.241299"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2013.01.004"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1172\/JCI64099"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2011.394"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2008.11.003"},{"issue":"7253","key":"B18","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1038\/nature08221","article-title":"Rapamycin fed late in life extends lifespan in genetically heterogeneous mice","volume":"460","author":"Harrison","year":"2009","journal-title":"Nature"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2006.01.016"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.R109.094003"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.03.017"},{"issue":"2","key":"B22","doi-asserted-by":"crossref","first-page":"231","DOI":"10.18632\/aging.100872","article-title":"Reversal of phenotypes of cellular senescence by pan-mTOR inhibition","volume":"8","author":"Walters","year":"2016","journal-title":"Aging (Albany NY)"},{"issue":"11","key":"B23","doi-asserted-by":"crossref","first-page":"986","DOI":"10.18632\/aging.100845","article-title":"Screening of a kinase library reveals novel pro-senescence kinases and their common NF-\u03baB-dependent transcriptional program","volume":"7","author":"Ferrand","year":"2015","journal-title":"Aging (Albany NY)"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2015-0339OC"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1002\/dvg.20367"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.152238499"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceb.2011.09.003"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.trecan.2016.03.008"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.110.973750"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.113.302302"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.113.004581"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200809-1398OC"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2003-0290OC"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2012.06.007"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201503-0593OC"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200906-0937OC"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2157"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2008.03.038"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2010.03.003"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1038\/ncb3195"},{"issue":"1, Part 2","key":"B41","first-page":"67","article-title":"Pulmonary emphysema with special reference to vascular changes","volume":"80","author":"Liebow","year":"1959","journal-title":"Am Rev Respir Dis"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.08.035"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00047.2015"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2013.166"},{"issue":"2","key":"B45","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1016\/j.cell.2017.03.035","article-title":"mTOR Signaling in Growth, Metabolism, and Disease","volume":"169","author":"Saxton","year":"2017","journal-title":"Cell"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1172\/JCI60132"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0712145105"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1172\/JCI41376"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2013-0023OC"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1172\/JCI78554"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200509-1374OC"},{"issue":"23","key":"B52","first-page":"5582","article-title":"MUC1 is a novel marker for the type II pneumocyte lineage during lung carcinogenesis","volume":"58","author":"Jarrard","year":"1998","journal-title":"Cancer Res"},{"issue":"4","key":"B53","doi-asserted-by":"crossref","first-page":"1004","DOI":"10.18632\/oncotarget.1681","article-title":"Repression of PLA2R1 by c-MYC and HIF-2alpha promotes cancer growth","volume":"5","author":"Vindrieux","year":"2014","journal-title":"Oncotarget"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.114.013258"},{"issue":"3","key":"B55","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1289\/EHP54","article-title":"Combined Effects of in Utero and Adolescent Tobacco Smoke Exposure on Lung Function in C57Bl\/6J Mice","volume":"125","author":"Drummond","year":"2017","journal-title":"Environ Health Perspect"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.01100.2009"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/93203\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T13:15:05Z","timestamp":1779196505000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/93203"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,2,8]]},"references-count":56,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2018,2,8]]},"published-print":{"date-parts":[[2018,2,8]]}},"alternative-id":["10.1172\/jci.insight.93203"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.93203","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,2,8]]},"article-number":"e93203"}}