Cellular senescence mediates fibrotic pulmonary disease

Marissa J. Schafer, Thomas A. White, Koji Iijima, 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, Tamara Tchkonia, Paul D. Robbins, Marie Christine Aubry, Joaõ F. Passos, James L. KirklandDaniel J. Tschumperlin, Hirohito Kita, Nathan K. LeBrasseur

Research output: Contribution to journalArticle

225 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article number14532
JournalNature communications
Volume8
DOIs
StatePublished - Feb 23 2017
Externally publishedYes

Fingerprint

fibrosis
Pulmonary diseases
Cell Aging
Idiopathic Pulmonary Fibrosis
Lung Diseases
lungs
Quercetin
Health
Lung
health
Bleomycin
Biomarkers
Fibroblasts
Ablation
cells
Genes
pulmonary functions
Tissue
deletion
biomarkers

Cite this

Schafer, M. J., White, T. A., Iijima, K., Haak, A. J., Ligresti, G., Atkinson, E. J., ... LeBrasseur, N. K. (2017). Cellular senescence mediates fibrotic pulmonary disease. Nature communications, 8, [14532]. https://doi.org/10.1038/ncomms14532

Cellular senescence mediates fibrotic pulmonary disease. / Schafer, Marissa J.; White, Thomas A.; Iijima, Koji; Haak, Andrew J.; Ligresti, Giovanni; Atkinson, Elizabeth J.; Oberg, Ann L.; Birch, Jodie; Salmonowicz, Hanna; Zhu, Yi; Mazula, Daniel L.; Brooks, Robert W.; Fuhrmann-Stroissnigg, Heike; Pirtskhalava, Tamar; Prakash, Y. S.; Tchkonia, Tamara; Robbins, Paul D.; Aubry, Marie Christine; Passos, Joaõ F.; Kirkland, James L.; Tschumperlin, Daniel J.; Kita, Hirohito; LeBrasseur, Nathan K.

In: Nature communications, Vol. 8, 14532, 23.02.2017.

Research output: Contribution to journalArticle

Schafer, MJ, White, TA, Iijima, K, Haak, AJ, Ligresti, G, Atkinson, EJ, Oberg, AL, Birch, J, Salmonowicz, H, Zhu, Y, Mazula, DL, Brooks, RW, Fuhrmann-Stroissnigg, H, Pirtskhalava, T, Prakash, YS, Tchkonia, T, Robbins, PD, Aubry, MC, Passos, JF, Kirkland, JL, Tschumperlin, DJ, Kita, H & LeBrasseur, NK 2017, 'Cellular senescence mediates fibrotic pulmonary disease', Nature communications, vol. 8, 14532. https://doi.org/10.1038/ncomms14532
Schafer MJ, White TA, Iijima K, Haak AJ, Ligresti G, Atkinson EJ et al. Cellular senescence mediates fibrotic pulmonary disease. Nature communications. 2017 Feb 23;8. 14532. https://doi.org/10.1038/ncomms14532
Schafer, Marissa J. ; White, Thomas A. ; Iijima, Koji ; Haak, Andrew J. ; Ligresti, Giovanni ; Atkinson, Elizabeth J. ; Oberg, Ann L. ; Birch, Jodie ; Salmonowicz, Hanna ; Zhu, Yi ; Mazula, Daniel L. ; Brooks, Robert W. ; Fuhrmann-Stroissnigg, Heike ; Pirtskhalava, Tamar ; Prakash, Y. S. ; Tchkonia, Tamara ; Robbins, Paul D. ; Aubry, Marie Christine ; Passos, Joaõ F. ; Kirkland, James L. ; Tschumperlin, Daniel J. ; Kita, Hirohito ; LeBrasseur, Nathan K. / Cellular senescence mediates fibrotic pulmonary disease. In: Nature communications. 2017 ; Vol. 8.
@article{523573cc932c470299e3185ad43afe68,
title = "Cellular senescence mediates fibrotic pulmonary disease",
abstract = "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.",
author = "Schafer, {Marissa J.} and White, {Thomas A.} and Koji Iijima and Haak, {Andrew J.} and Giovanni Ligresti and Atkinson, {Elizabeth J.} and Oberg, {Ann L.} and Jodie Birch and Hanna Salmonowicz and Yi Zhu and Mazula, {Daniel L.} and Brooks, {Robert W.} and Heike Fuhrmann-Stroissnigg and Tamar Pirtskhalava and Prakash, {Y. S.} and Tamara Tchkonia and Robbins, {Paul D.} and Aubry, {Marie Christine} and Passos, {Joa{\~o} F.} and Kirkland, {James L.} and Tschumperlin, {Daniel J.} and Hirohito Kita and LeBrasseur, {Nathan K.}",
year = "2017",
month = "2",
day = "23",
doi = "10.1038/ncomms14532",
language = "English (US)",
volume = "8",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",

}

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.

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.

UR - http://www.scopus.com/inward/record.url?scp=85013807598&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85013807598&partnerID=8YFLogxK

U2 - 10.1038/ncomms14532

DO - 10.1038/ncomms14532

M3 - Article

C2 - 28230051

AN - SCOPUS:85013807598

VL - 8

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 14532

ER -