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Radiation-induced pulmonary fibrosis (RIPF) is a long-term side effect of thoracic radiation therapy. 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. 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 pharmacologic HIF-1α inhibitor on RIPF after image guided radiation therapy (IGRT) for spontaneous lung adenocarcinoma, we generated conditional tdTomato; K-RasG12D; and p53 flox/flox mice to facilitate tracking of tumor cells expressing tdTomato. We found that vascular endothelial-specific HIF-1α deletion shortly before radiation therapy inhibited the progression of RIPF along with reduced EndMT, whereas prolonged deletion of endothelial HIF-1α before irradiation did not. Moreover, we revealed that postirradiation 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. 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. Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.

Citation

Jae-Kyung Nam, A-Ram Kim, Seo-Hyun Choi, Ji-Hee Kim, Su Chul Han, Seungwoo Park, Yong Jin Lee, Joon Kim, Jaeho Cho, Hae-June Lee, Yoon-Jin Lee. Pharmacologic Inhibition of HIF-1α Attenuates Radiation-Induced Pulmonary Fibrosis in a Preclinical Image Guided Radiation Therapy. International journal of radiation oncology, biology, physics. 2021 Feb 01;109(2):553-566


PMID: 32942004

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