A dynamically resolved single-cell architecture of radiation pneumonitis provides insights into acute lung injury

Abstract Background Radiation pneumonitis (RP) is a deleterious complication of thoracic radiotherapy, yet the cellular mechanisms driving its onset and progression remain unclear. Here we constructed a single-cell dynamic architecture of RP rats with acute lung injury at multiple time points after radiation from 84,865 high-quality cells through single-cell RNA sequencing. Results Endothelial and epithelial cells are damaged within 24 hours after radiation, while epithelial-mesenchymal transitions (EMT) occur in RP lesions at 1–2 weeks. Identification of radiation-induced EMT signature highly correlated with and superior to known EMT signature. Radiation induces oxidative stress and promotes apoptosis in monocytes one week after radiation exposure, and the induced inflammation persists. Macrophage components enhance the pro-inflammatory response following radiation via MIF signaling and exhibit four distinct intercellular communication patterns. The ligand Mif was associated with radiation-induced expression enhancement, and its blockade alleviated pneumonia symptoms. The dynamics and differentiation of lymphocytes reveal that effector and helper T cells activate within 2–4 weeks post-radiation, while tissue-resident memory T cells proliferate at 6 weeks. Conclusions This RP architecture provides a comprehensive view of the cellular architecture and dynamics following radiation exposure, enhancing our understanding of RP’s pathogenesis and offering biomarkers and potential therapeutic targets for early diagnosis and intervention.