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Stereotactic lung irradiation in mice promotes long-term senescence and lung injury
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International audience. Purpose: Lung cancer will be treated more frequently using stereotactic body radiation therapy, and preclinical research tomodel long-term toxicity of ablative doses of radiation is crucial. Stereotactic lung irradiation of a small volume can induceradiation 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 ofablative doses of ionizing radiation on senescence-associated processes. The left lung of p16$^{INK4a}$ -LUC knock-in mice wasexposed 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 lungtarget 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 senescentcell types may contribute to radiation injury.Conclusions: This work provides important information on the long-term effects of ablative radiation doses in the normal lungand strongly suggests that stress-induced senescence is involved in stereotactic body radiation therapyeinduced late fibrosis.
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