{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T11:54:15Z","timestamp":1793534055799,"version":"4.5.0"},"reference-count":47,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2019,1,1]],"date-time":"2019-01-01T00:00:00Z","timestamp":1546300800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Although cellular senescence may be a protective mechanism in modulating proliferative capacity, fibroblast senescence is now recognized as a key pathogenic mechanism in idiopathic pulmonary fibrosis (IPF). In aged mice, abundance and persistence of apoptosis-resistant senescent fibroblasts play a central role in nonresolving lung fibrosis after bleomycin challenge. Therefore, we investigated whether quercetin can restore the susceptibility of senescent IPF fibroblasts to proapoptotic stimuli and mitigate bleomycin-induced pulmonary fibrosis in aged mice. Unlike senescent normal lung fibroblasts, IPF lung fibroblasts from patients with stable and rapidly progressing disease were highly resistant to Fas ligand (FasL)-induced and TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. Senescent IPF fibroblasts exhibited decreased expression of FasL and TRAIL receptors and caveolin-1, as well as increased AKT activation, compared with senescent normal lung fibroblasts. Although quercetin alone was not proapoptotic, it abolished the resistance to FasL- or TRAIL-induced apoptosis in IPF fibroblasts. Mechanistically, quercetin upregulated FasL receptor and caveolin-1 expression and modulated AKT activation. In vivo quercetin reversed bleomycin-induced pulmonary fibrosis and attenuated lethality, weight loss, and the expression of pulmonary senescence markers p21 and p19-ARF and senescence-associated secretory phenotype in aged mice. Collectively, these data indicate that quercetin reverses the resistance to death ligand\u2013induced apoptosis by promoting FasL receptor and caveolin-1 expression and inhibiting AKT activation, thus mitigating the progression of established pulmonary fibrosis in aged mice. Therefore, quercetin may be a viable therapeutic option for IPF and other age-related diseases that progress with the accumulation of senescent fibroblasts.<\/jats:p>","DOI":"10.1165\/rcmb.2017-0289oc","type":"journal-article","created":{"date-parts":[[2018,8,15]],"date-time":"2018-08-15T11:39:26Z","timestamp":1534333166000},"page":"28-40","source":"Crossref","is-referenced-by-count":197,"title":["Quercetin Enhances Ligand-induced Apoptosis in Senescent Idiopathic Pulmonary Fibrosis Fibroblasts and Reduces Lung Fibrosis\n                    <i>In Vivo<\/i>"],"prefix":"10.1093","volume":"60","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2667-3919","authenticated-orcid":false,"given":"Miriam S.","family":"Hohmann","sequence":"first","affiliation":[{"name":"Departmento de Ci\u00eancias Patol\u00f3gicas, Universidade Estadual de Londrina, Londrina, Paran\u00e1, Brasil; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David M.","family":"Habiel","sequence":"additional","affiliation":[{"name":"Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana L.","family":"Coelho","sequence":"additional","affiliation":[{"name":"Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"Waldiceu A.","family":"Verri","sequence":"additional","affiliation":[{"name":"Departmento de Ci\u00eancias Patol\u00f3gicas, Universidade Estadual de Londrina, Londrina, Paran\u00e1, Brasil; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cory M.","family":"Hogaboam","sequence":"additional","affiliation":[{"name":"Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, 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