特发性肺纤维化
衰老
博莱霉素
肺
医学
肺纤维化
纤维化
肺功能测试
间质性肺病
癌症研究
生物
病理
疾病
免疫学
内科学
化疗
作者
Marissa J. Schafer,Thomas A. White,Koji Izutsu,Andrew J. Haak,Giovanni Ligresti,Elizabeth J. Atkinson,Ann L. Oberg,Jodie Birch,Hanna Salmonowicz,Yi Zhu,Daniel L. Mazula,Robert W. Brooks,Heike Fuhrmann-Stroissnigg,Tamar Pirtskhalava,Y. S. Prakash,Tamar Tchkonia,Paul D. Robbins,Marie Christine Aubry,João F. Passos,James L. Kirkland,Daniel J. Tschumperlin,Hirohito Kita,Nathan K. LeBrasseur
摘要
Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by interstitial remodelling, leading to compromised lung function. Cellular senescence markers are detectable within IPF lung tissue and senescent cell deletion rejuvenates pulmonary health in aged mice. Whether and how senescent cells regulate IPF or if their removal may be an efficacious intervention strategy is unknown. Here we demonstrate elevated abundance of senescence biomarkers in IPF lung, with p16 expression increasing with disease severity. We show that the secretome of senescent fibroblasts, which are selectively killed by a senolytic cocktail, dasatinib plus quercetin (DQ), is fibrogenic. Leveraging the bleomycin-injury IPF model, we demonstrate that early-intervention suicide-gene-mediated senescent cell ablation improves pulmonary function and physical health, although lung fibrosis is visibly unaltered. DQ treatment replicates benefits of transgenic clearance. Thus, our findings establish that fibrotic lung disease is mediated, in part, by senescent cells, which can be targeted to improve health and function.
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