TY - JOUR
T1 - Cellular senescence mediates fibrotic pulmonary disease
AU - Schafer, Marissa J.
AU - White, Thomas A.
AU - Iijima, Koji
AU - Haak, Andrew J.
AU - Ligresti, Giovanni
AU - Atkinson, Elizabeth J.
AU - Oberg, Ann L.
AU - Birch, Jodie
AU - Salmonowicz, Hanna
AU - Zhu, Yi
AU - Mazula, Daniel L.
AU - Brooks, Robert W.
AU - Fuhrmann-Stroissnigg, Heike
AU - Pirtskhalava, Tamar
AU - Prakash, Y. S.
AU - Tchkonia, Tamara
AU - Robbins, Paul D.
AU - Aubry, Marie Christine
AU - Passos, Joaõ F.
AU - Kirkland, James L.
AU - Tschumperlin, Daniel J.
AU - Kita, Hirohito
AU - LeBrasseur, Nathan K.
N1 - Publisher Copyright:
© 2017 The Author(s).
PY - 2017/2/23
Y1 - 2017/2/23
N2 - 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.
AB - 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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U2 - 10.1038/ncomms14532
DO - 10.1038/ncomms14532
M3 - Article
C2 - 28230051
AN - SCOPUS:85013807598
SN - 2041-1723
VL - 8
JO - Nature communications
JF - Nature communications
M1 - 14532
ER -