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

Abstract

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. Senescence has been reported to contribute to lung fibrosis, and we investigated invivo the effects of ablative doses of ionizing radiation on senescence-associated processes. The left lung of p16INK4a-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. Single or fractionated ablative radiation induces acute and very long-term p16INK4a 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. 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.