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, João F. Passos, James L. Kirkland, Daniel J. Tschumperlin, Hirohito Kita and Nathan K. LeBrasseur ()
Additional contact information
Marissa J. Schafer: Robert and Arlene Kogod Center on Aging, Mayo Clinic College of Medicine
Thomas A. White: Robert and Arlene Kogod Center on Aging, Mayo Clinic College of Medicine
Koji Iijima: Mayo Clinic College of Medicine
Andrew J. Haak: Mayo Clinic College of Medicine
Giovanni Ligresti: Mayo Clinic College of Medicine
Elizabeth J. Atkinson: Mayo Clinic College of Medicine
Ann L. Oberg: Mayo Clinic College of Medicine
Jodie Birch: Institute for Cell and Molecular Biosciences, Newcastle University Institute for Ageing
Hanna Salmonowicz: Institute for Cell and Molecular Biosciences, Newcastle University Institute for Ageing
Yi Zhu: Robert and Arlene Kogod Center on Aging, Mayo Clinic College of Medicine
Daniel L. Mazula: Robert and Arlene Kogod Center on Aging, Mayo Clinic College of Medicine
Robert W. Brooks: The Scripps Research Institute
Heike Fuhrmann-Stroissnigg: The Scripps Research Institute
Tamar Pirtskhalava: Robert and Arlene Kogod Center on Aging, Mayo Clinic College of Medicine
Y. S. Prakash: Mayo Clinic College of Medicine
Tamara Tchkonia: Robert and Arlene Kogod Center on Aging, Mayo Clinic College of Medicine
Paul D. Robbins: The Scripps Research Institute
Marie Christine Aubry: Mayo Clinic College of Medicine
João F. Passos: Institute for Cell and Molecular Biosciences, Newcastle University Institute for Ageing
James L. Kirkland: Robert and Arlene Kogod Center on Aging, Mayo Clinic College of Medicine
Daniel J. Tschumperlin: Mayo Clinic College of Medicine
Hirohito Kita: Mayo Clinic College of Medicine
Nathan K. LeBrasseur: Robert and Arlene Kogod Center on Aging, Mayo Clinic College of Medicine

Nature Communications, 2017, vol. 8, issue 1, 1-11

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms14532

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