{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T21:50:41Z","timestamp":1793397041636,"version":"4.5.0"},"reference-count":60,"publisher":"American Society for Clinical Investigation","issue":"1","license":[{"start":{"date-parts":[[2021,1,11]],"date-time":"2021-01-11T00:00:00Z","timestamp":1610323200000},"content-version":"vor","delay-in-days":34,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Heart, Lung and Blood Institute of the National Institutes of Health","award":["HL140595,HL147860,HL135156,HL128439,HL107202,HL117004"],"award-info":[{"award-number":["HL140595,HL147860,HL135156,HL128439,HL107202,HL117004"]}]},{"DOI":"10.13039\/100000738","name":"U.S. Department of Veterans Affairs","doi-asserted-by":"crossref","award":["BX003471,BX00240"],"award-info":[{"award-number":["BX003471,BX00240"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"crossref"}]},{"name":"U.S. Department of Defense","award":["W81WH-16-2-0018"],"award-info":[{"award-number":["W81WH-16-2-0018"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,1,11]]},"abstract":"<jats:p>Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible fibrotic disease of the distal lung alveoli that culminates in respiratory failure and reduced lifespan. Unlike normal lung repair in response to injury, IPF is associated with the accumulation and persistence of fibroblasts and myofibroblasts, as well as continued production of collagen and other extracellular matrix (ECM) components. Prior in vitro studies have led to the hypothesis that the development of resistance to Fas-induced apoptosis by lung fibroblasts and myofibroblasts contributes to their accumulation in the distal lung tissues of IPF patients. Here, we test this hypothesis in vivo in the resolving model of bleomycin-induced pulmonary fibrosis in mice. Using genetic loss-of-function approaches to inhibit Fas signaling in fibroblasts, potentially novel flow cytometry strategies to quantify lung fibroblast subsets, and transcriptional profiling of lung fibroblasts by bulk and single cell RNA sequencing, we show that Fas is necessary for lung fibroblast apoptosis during homeostatic resolution of bleomycin-induced pulmonary fibrosis in vivo. Furthermore, we show that loss of Fas signaling leads to the persistence and continued profibrotic functions of lung fibroblasts. Our studies provide insights into the mechanisms that contribute to fibroblast survival, persistence, and continued ECM deposition in the context of IPF and how failure to undergo Fas-induced apoptosis impairs fibrosis resolution.<\/jats:p>","DOI":"10.1172\/jci.insight.141618","type":"journal-article","created":{"date-parts":[[2020,12,8]],"date-time":"2020-12-08T12:58:36Z","timestamp":1607432316000},"source":"Crossref","is-referenced-by-count":63,"title":["Loss of Fas signaling in fibroblasts impairs homeostatic fibrosis resolution and promotes persistent pulmonary fibrosis"],"prefix":"10.1172","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8075-4325","authenticated-orcid":true,"given":"Elizabeth F.","family":"Redente","sequence":"first","affiliation":[{"name":"Program in Cell Biology, Department of Pediatrics, National Jewish Health, Denver, Colorado, USA."},{"name":"Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA."},{"name":"Department of Research, Veterans Affairs Eastern Colorado Health Care System, Denver, Colorado, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sangeeta","family":"Chakraborty","sequence":"additional","affiliation":[{"name":"Program in Cell Biology, Department of Pediatrics, National Jewish Health, Denver, Colorado, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satria","family":"Sajuthi","sequence":"additional","affiliation":[{"name":"Center for Genes, Environment and Health, National Jewish Health, Denver, Colorado, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bart P.","family":"Black","sequence":"additional","affiliation":[{"name":"Program in Cell Biology, Department of Pediatrics, National Jewish Health, Denver, Colorado, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ben L.","family":"Edelman","sequence":"additional","affiliation":[{"name":"Program in Cell Biology, Department of Pediatrics, National Jewish Health, Denver, Colorado, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8685-4263","authenticated-orcid":true,"given":"Max A.","family":"Seibold","sequence":"additional","affiliation":[{"name":"Program in Cell Biology, Department of Pediatrics, National Jewish Health, Denver, Colorado, USA."},{"name":"Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA."},{"name":"Center for Genes, Environment and Health, National Jewish Health, Denver, Colorado, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9587-3335","authenticated-orcid":true,"given":"David W.H.","family":"Riches","sequence":"additional","affiliation":[{"name":"Program in Cell Biology, Department of Pediatrics, National Jewish Health, Denver, Colorado, USA."},{"name":"Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA."},{"name":"Department of Research, Veterans Affairs Eastern Colorado Health Care System, Denver, Colorado, USA."},{"name":"Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2020,12,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(11)60052-4"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2014.02.003"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200005043421806"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.03.00298303"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.00196412"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1378\/chest.125.1.197"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1011802"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm.150.1.8025779"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2016.01.018"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/labinvest.2016.145"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2012-0224OC"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2005-0155OC"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1002\/path.1531"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0061017"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.02.00252602"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1513\/pats.200601-001TK"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1100447"},{"key":"B18","doi-asserted-by":"crossref","DOI":"10.1038\/cddis.2013.146","article-title":"Histone modifications are responsible for decreased Fas expression and apoptosis resistance in fibrotic lung fibroblasts","volume":"4","author":"Huang","year":"2013","journal-title":"Cell Death Dis"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201707-1497OC"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2010-0284RC"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1172\/JCI66700"},{"key":"B22","doi-asserted-by":"crossref","DOI":"10.1017\/S1462399411001967","article-title":"Myofibroblast differentiation and survival in fibrotic disease","volume":"13","author":"Kis","year":"2011","journal-title":"Expert Rev Mol Med"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2807"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2013-0386OC"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00010.2008"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1242\/dev.00491"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)63240-3"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2015-0095OC"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.03.010"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.07.034"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1002\/dvdy.10092"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1002\/eji.1830200815"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2011-0316OC"},{"issue":"5","key":"B34","first-page":"367","article-title":"Explant outgrowth, propagation and characterization of human pericytes","volume":"17","author":"Maier","year":"2010","journal-title":"Microcirculation"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaa2151"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1186\/1755-1536-6-15"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1117988108"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2012-0030OC"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1053\/jhep.2003.50067"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1002\/hep.20427"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1400062111"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1201840109"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2008.080433"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-15647-5"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.05.019"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2016.07.004"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2013.03.010"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0001516"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2013.11.018"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1172\/JCI89919"},{"key":"B51","doi-asserted-by":"crossref","DOI":"10.3389\/fcell.2019.00026","article-title":"Thy-1 as an integrator of diverse extracellular signals","volume":"7","author":"Hagood","year":"2019","journal-title":"Front Cell Dev Biol"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00254.2018"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)62982-3"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1038\/356314a0"},{"issue":"2 Pt 1","key":"B55","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1164\/ajrccm.162.2.9907012","article-title":"The Fas\/Fas-ligand system is not required for bleomycin-induced pulmonary fibrosis in mice","volume":"162","author":"Aoshiba","year":"2000","journal-title":"Am J Respir Crit Care Med"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1172\/JCI5628"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1053\/gast.2002.35953"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-8570-8_5"},{"key":"B59","doi-asserted-by":"crossref","DOI":"10.1186\/1471-2105-14-128","article-title":"Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool","volume":"14","author":"Chen","year":"2013","journal-title":"BMC Bioinformatics"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw377"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/141618\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T00:49:19Z","timestamp":1779151759000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/141618"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,8]]},"references-count":60,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,1,11]]},"published-print":{"date-parts":[[2021,1,11]]}},"alternative-id":["10.1172\/jci.insight.141618"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.141618","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2020.08.18.255869","asserted-by":"object"}]},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,12,8]]},"article-number":"e141618"}}