Identification of molecular signatures involved in radiation-induced lung fibrosis

Abstract

In radiotherapy, radiation (IR)-induced lung fibrosis has severe and dose-limiting side effects. To elucidate the molecular effects of IR fibrosis, we examined the fibrosis process in irradiated mouse lung tissues. High focal IR (90 Gy) was exposed to a 3-mm volume of the left lung in C57BL6 mice. In the diffused irradiation, 20 Gy dose delivered with a 7-mm collimator almost covered the entire left lung. Histological examination for lung tissues of both irradiated and neighboring regions was done for 4 weeks after irradiation. Long-term effects (12 months) of 20Gy IR were compared on a diffuse region of the left lung and non-irradiated right lung. Fibrosis was initiated as early as 2 weeks after IR in the irradiated lung region 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, suggesting fibrosis responsible genes. Immunofluorescence analysis using mouse fibrotic lung tissues suggested that fibrotic regions showed increased expressions of Gtse1 and Fgl1, indicating novel molecular signatures of gtse1and fgl1 for IR-induced lung fibrosis. Even though their molecular mechanisms and IR doses or irradiated volumes for lung fibrosis may be different, these genes may be novel targets for understanding IR-induced lung fibrosis and in treatment strategies.Key messages Upregulation of gtse1 by 90Gy focal irradiation and upregulation of fgl1 by 20Gy diffused irradiation are identified in mouse lung fibrosis model.Gtse1 and Fgl1 are involved in radiation or TGFβ-induced epithelial-mesenchymal transition.Radiation-induced fibrotic regions of mouse lungs showed increased expressions of Gtse1 and Fgl1.Gtse1 and Fgl1 are suggested to be novel targets for radiation-induced lung fibrosis. Electronic supplementary materialThe online version of this article (10.1007/s00109-018-1715-9) contains supplementary material, which is available to authorized users.

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“…A recent study reported that FGL1 as a molecular candidate for radiation-induced lung fibrosis suggesting the involvement of radiation epithelial to mesenchymal transition using L132 human pulmonary epithelial cells [28]. Consistent with this previous report, irradiated HH showed upregulation of fibrotic/mesenchymal markers such as α-SMA and FSP-1 when FGL1 is elevated in Figure 3.…”

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