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.
Highlights
Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by interstitial remodelling, leading to compromised lung function
To explore the hypothesis that senescent cells and the senescence-associated secretory phenotype (SASP) regulate lung fibrosis, we interrogated microarray and RNA sequencing (RNAseq) data sets corresponding to independent IPF and control human cohorts for differential expression of established senescence genes
Correlation analyses revealed that elevated pulmonary p16 expression assessed via microarray was associated with reduced forced vital capacity (FVC), diffusion capacity and 12-item short form health survey physical component score (Supplementary Fig. 1)
Summary
Aerosolized intratracheal instillation of the chemotherapeutic agent bleomycin induces lung fibrosis in mice and recapitulates critical features of human IPF15 Using this murine model, we fluorescence-activated cell sorted (FACS) whole lungs isolated 14 days post bleomycin or phosphatebuffered saline (PBS) exposure based on cell-surface marker presentation (Fig. 2a–d) and conducted gene expression profiling on populations of fibroblasts (PDGFRa þ , EPCAM À , CD31 À and CD45 À ) (Fig. 2b,e), epithelial cells (EPCAM þ , PDGFRa À , CD31 À and CD45 À ) (Fig. 2c,f) and endothelial cells (CD31 þ , PDGFRa À , EPCAM À and CD45 À ) (Fig. 2d,g). Similar to human IPF, bleomycin-mediated lung injury induces a senescent signature characterized by increased transcriptional activation of p16 and SASP components in fibroblasts and epithelial cells. CM collected from irradiated bronchiolar epithelial cells did not activate a fibrogenic response, as measured by aSMA fibrotic activation of naive IMR90 cells (Supplementary Fig. 2), suggesting that cell-type-specific SASP composition may differentially affect pathological phenotypes within the lung
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