Journal Article

Cellular senescence mediates fibrotic pulmonary disease

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

2017

Overview

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. Removal of senescent cells rejuvenates lungs of aged mice. Here the authors show that elimination of senescent cells using either genetic or pharmacological means improves lung function and physical health in a mouse model of idiopathic pulmonary fibrosis (IPF), suggesting potential therapy for treatment of human IPF.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/106 / 13/31 / 14/19 / 38/61 / 38/91 / 631/443/1784 / 631/80/509 / 64/60 / 692/1807/1809 / 692/308/2778 / Aging / Animals / Biomarkers / Biomarkers - metabolism / Bleomycin / Cell cycle / Cellular Senescence / Cyclin-Dependent Kinase Inhibitor p16 - metabolism / Cyclin-dependent kinases / Fibroblasts - metabolism / Fibroblasts - pathology / Humanities and Social Sciences / Humans / Idiopathic Pulmonary Fibrosis - pathology / Internal medicine / Kinases / Lung - pathology / Lung diseases / Male / Medical schools / Medicine / Mice / multidisciplinary / Pathology / Proteome - metabolism / Respiratory function / Science / Science (multidisciplinary) / Senescence / Suicide