Cellular senescence mediates fibrotic pulmonary disease

TLDR

Idiopathic pulmonary fibrosis is a fatal disease marked by interstitial remodeling and lung function decline, and although senescence markers are present in affected tissue, the contribution of senescent cells to disease progression remains unclear. The study demonstrates that senescent fibroblasts secrete fibrogenic factors, and that selective removal of these cells using the senolytic cocktail dasatinib plus quercetin or a suicide‑gene strategy improves pulmonary function and physical health in a bleomycin‑induced IPF model. Elevated senescence biomarkers, including p16, correlate with disease severity, and targeted ablation of senescent cells—by senolytics or genetic clearance—reduces functional impairment, establishing senescent cells as a therapeutic target in fibrotic lung disease.

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.