Cellular senescence mediates fibrotic pulmonary disease

By M. Schafer, T. White, K. Iijima, A. Haak, G. Ligresti, Elizabeth J. Atkinson, A. Oberg, Jodie Birch, Hanna Salmonowicz, Yi Zhu and 13 more. Nature Communications, 2017

1,412 citations recorded by the source corpus.

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.

Subfields: Physiology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/c5c5558d7a1277ed980c20a0d376463320360555

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Citations in the corpus

Cellular Senescence: Aging, Cancer, and Injury. (2019, background): “Eliminating senescent cells or inhibiting ROS alleviates IPF in bleomycin-treated mice (152, 277).”
Cellular Senescence: A Translational Perspective (2017, methodology): “Using several different approaches in preclinical studies, the combination of D+ Q as well as N were shown to clear senescent cells in vivo (Zhu et al., 2015a; Zhu et al., 2015b; Roos et al., 2016; Schafer et al., 2017; Chang et al., 2016).”
Fisetin is a senotherapeutic that extends health and lifespan (2018, background): “Intermittent oral D + Q treatment improves pulmonary function and reduces pulmonary fibrosis in a bleomycin-induced murine model of idiopathic pulmonary fibrosis [35], reduces high fat diet-induced liver steatosis [36], alleviates gait impairment caused by leg irradiation [30] and reduces osteoporos”
Unmasking Transcriptional Heterogeneity in Senescent Cells (2017, methodology): “To understand whether genes present in the core signature were differentially regulated in diseased and senescence-enriched tissues, we used an RNA sequencing (RNA-seq) dataset from lung tissues of patients with idiopathic pulmonary fibrosis, in which known senescence markers were detected [32].”
Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study (2019, methodology): “Our previous work demonstrated increased senescent cell abundance in lungs of subjects with IPF, including upregulation of p16 (CDKN2A), which correlatedwith disease severity [5].”
Senescence and aging: Causes, consequences, and therapeutic avenues (2018, background): “Elimination of senescent fibroblasts in a mouse model of lung fibrosis reduced expression of profibrotic SASP components and improved pulmonary function (Schafer et al., 2017).”