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Abstract
Purpose: Radiation-induced pulmonary fibrosis (RIPF) is a long-term side effect of thoracic radiotherapy. Hypoxia-induced vascular endothelial mesenchymal transition (EndMT) can occur during the development of RIPF. Here, we examined the direct contribution of endothelial HIF-1α (EC-HIF1α) on RIPF.

Methods and materials: An inducible Cre-lox-mediated endothelial Hif1a deletion mouse line was used to evaluate the potential of HIF-1α inhibition to suppress RIPF. To evaluate the effects of a pharmacological HIF-1α inhibitor on RIPF following image-guided radiotherapy (IGRT) for spontaneous lung adenocarcinoma, we generated conditional tdTomato; K-RasG12D; p53 flox/flox mice to facilitate tracking of tumor cells expressing tdTomato.

Results: We found that vascular endothelial-specific HIF-1α deletion shortly prior to radiation therapy inhibited the progression of RIPF along with reduced EndMT, whereas prolonged deletion of endothelial HIF-1α prior to irradiation did not. Moreover, we revealed that post-irradiation treatment with the novel HIF-1α inhibitor, 2-methoxyestradiol (2-ME), could efficiently inhibit RIPF and EndMT. In addition, IGRT using primary mouse models of non-small cell lung cancer showed that combined treatment of 2-ME with ablative high-dose radiation therapy efficiently inhibited RIPF and the growth of both multifocal and single tumors, concomitantly reducing radiation-induced EndMT of normal as well as tumor regions.

Conclusion: These results suggest that a negative regulator of HIF-1α-mediated EndMT, such as 2-ME, may serve as a promising inhibitor of RIPF in radiation therapy.

Affiliations

Jae-Kyung Nam  1 , A-Ram Kim  2 , Seo-Hyun Choi  2 , Ji-Hee Kim  2 , Su Chul Han  3 , Seungwoo Park  3 , Yong Jin Lee  4 , Joon Kim  5 , Jaeho Cho  6 , Hae-June Lee  2 , Yoon-Jin Lee  7
1 Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul 01812, Korea; Division of Applied RI, Korea Institute of Radiological & Medical Sciences, Seoul, 139-706, Korea.
2 Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul 01812, Korea.
3 Comprehensive Radiation Irradiation Center, Korea Institute of Radiological & Medical Sciences, Seoul 01812, Korea.
4 Division of Applied RI, Korea Institute of Radiological & Medical Sciences, Seoul, 139-706, Korea.
5 Laboratory of Biochemistry, Division of Life Sciences, Korea University, Seoul 02841, Korea.
6 Department of Radiation Oncology, Yonsei University College of Medicine, Seoul 03722, Korea.
7 Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul 01812, Korea. Electronic address: yjlee8@kirams.re.kr.