Bleomycin promotes cellular senescence and activation of the cGAS-STING pathway without direct effect on fibrosis in an idiopathic pulmonary fibrosis model

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, <i>Col1a1</i> and <i>Acta2</i> 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.