Identification of molecular signatures involved in radiation-induced lung fibrosis

Abstract

In radiotherapy, radiation (IR)-inducedlungfibrosishas severe and dose-limiting side effects. To elucidate themoleculareffects of IRfibrosis, we examined thefibrosisprocess in irradiated mouselungtissues. High focal IR (90Gy) was exposed to a 3-mm volume of the leftlungin C57BL6 mice. In the diffused irradiation, 20Gy dose delivered with a 7-mm collimator almost covered the entire leftlung. Histological examination forlungtissues of both irradiated and neighboring regions was done for 4weeks after irradiation. Long-term effects (12months) of 20Gy IR were compared on a diffuse region of the leftlungand non-irradiated rightlung.Fibrosiswas initiated as early as 2weeks after IR in the irradiatedlungregion and neighboring region. Upregulation of gtse1 in both 90Gy-irradiated and neighboring regions was observed. Upregulation of fgl1 in both 20Gy diffused irradiated and non-irradiated lungs was identified. When gtse1 or flg1 was knock-downed, TGFβ or IR-induced epithelial-mesenchymal transition was inhibited, accompanied with the inhibition of cellular migration, suggestingfibrosisresponsible genes. Immunofluorescence analysis using mouse fibroticlungtissues suggested that fibrotic regions showed increased expressions of Gtse1 and Fgl1, indicating novelmolecularsignaturesof gtse1and fgl1 for IR-inducedlungfibrosis. Even though theirmolecularmechanisms and IR doses or irradiated volumes forlungfibrosismay be different, these genes may be novel targets for understanding IR-inducedlungfibrosisand in treatment strategies. KEY MESSAGES: Upregulation of gtse1 by 90Gy focal irradiation and upregulation of fgl1 by 20Gy diffused irradiation are identified in mouselungfibrosismodel. Gtse1 and Fgl1 areinvolvedin radiation or TGFβ-induced epithelial-mesenchymal transition.Radiation-inducedfibrotic regions of mouse lungs showed increased expressions of Gtse1 and Fgl1. Gtse1 and Fgl1 are suggested to be novel targets forradiation-inducedlungfibrosis.