Research Paper Advance Articles
Bleomycin promotes cellular senescence and activation of the cGAS-STING pathway without direct effect on fibrosis in an idiopathic pulmonary fibrosis model
- 1 Department of Neurodevelopmental Disorder Genetics, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
- 2 Department of Medicine, McMaster University, Hamilton, Canada
- 3 Department of Medicine, Division of Respirology, Firestone Institute for Respiratory Health, McMaster University, Hamilton, Canada
Received: October 17, 2024 Accepted: July 30, 2025 Published: August 28, 2025
https://doi.org/10.18632/aging.206312How to Cite
Copyright: © 2025 Miura et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Bleomycin is an effective anticancer agent that causes drug-induced interstitial pneumonia (IP). Medical history is a risk factor for adverse effects, particularly a history of IP and age-related fibrosis. Anti-cancer drugs for lung cancer with idiopathic pulmonary fibrosis (IPF) often aggravate pulmonary fibrosis. Thus, we examined the pathological effects of bleomycin, an anticancer drug, in precision-cut lung slices (PCLS) of lungs with usual interstitial pneumonia (UIP). We found that the lungs of mice with induced UIP (iUIP), which exhibit a pathology similar to that of IPF, underwent accelerated senescence. Treatment of iUIP PCLS with bleomycin reduced the nuclear membrane component lamin B1 and nuclear DNA with γH2AX leaked into the cytoplasm. This perinuclear DNA may activate NF-κB through the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. As a result, the unresolved DNA damage associated with the failure of DNA repair and senescence progression is more advanced in these cells. However, Col1a1 and Acta2 expression was not induced in either bleomycin-treated normal or iUIP PCLS, suggesting that there was no direct fibrotic effect on the lungs. We concluded that lungs with iUIP exhibited accelerated senescence following bleomycin treatment, leading to cell death.
Abbreviations
AEC: alveolar epithelial cell; BMS: bleomycin mixed with microbubbles followed by sonoporation; cGAS-STING: cyclic GMP-AMP synthase-stimulator of interferon genes; Col1/Col1a1: collagen type I alpha 1 chain; DAMPs: damage-associated molecular patterns; DMEM: Dulbecco’s modified Eagle medium; DSBs: double-stranded DNA breaks; DDR: DNA damage response; FBS: fetal bovine serum; γH2AX: histone H2AX; HBSS: Hank’s balanced salt solution; IHC: immunohistochemical; IF: immunofluorescence; IP: interstitial pneumonia; IL: interleukin; IPF: idiopathic pulmonary fibrosis; iUIP: induced-usual interstitial pneumonia; i.t.: intratracheal; IRF3: interferon regulatory factor-3; MMP: matrix metalloproteinase; NSIP: nonspecific interstitial pneumonia; PBS: phosphate-buffered saline; PCLS: precision-cut lung slices; qRT-PCR: quantitative reverse transcription-polymerase chain reaction; ROS: reactive oxygen species; SASP: senescence-associated secretory phenotype; SP-D: surfactant protein-D; TAF: telomere-associated foci; Tgfβ1: Transforming growth factor-β1; TUNEL: transferase dUTP nick end labeling; UIP: usual interstitial pneumonia.