Stereotactic Lung Irradiation in Mice Promotes Long-Term Senescence and Lung Injury

Purpose: Lung cancer will be treated more frequently using stereotactic body radiation therapy, and preclinical research to model long-term toxicity of ablative doses of radiation is crucial. Stereotactic lung irradiation of a small volume can induce radiation pneumonitis and fibrosis in normal tissues. Methods and Materials: Senescence has been reported to contribute to lung fibrosis, and we investigated in vivo the effects of ablative doses of ionizing radiation on senescence-associated processes. The left lung of p16^INK4a-LUC knock-in mice was exposed to a single dose or fractionated radiation doses in a millimetric volume using a small animal radiation research platform. Results: Single or fractionated ablative radiation induces acute and very long-term p16^INK4a activation in the irradiated lung target volume associated with lung injury. We observed a panel of heterogeneous senescent cells including pneumocytes, macrophages, and endothelial cells that accumulated around the radiation-induced lung focal lesion, suggesting that different senescent cell types may contribute to radiation injury. Conclusions: This work provides important information on the long-term effects of ablative radiation doses in the normal lung and strongly suggests that stress-induced senescence is involved in stereotactic body radiation therapy–induced late fibrosis.