Pharmacologic Inhibition of HIF-1α Attenuates Radiation-Induced Pulmonary Fibrosis in a Preclinical Image Guided Radiation Therapy

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

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

Abstract

Purpose: 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. 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 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. Results: 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. 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.

Original languageEnglish
Pages (from-to)553-566
Number of pages14
JournalInternational Journal of Radiation Oncology Biology Physics
Volume109
Issue number2
DOIs
Publication statusPublished - 2021 Feb 1
Externally publishedYes

ASJC Scopus subject areas

  • Radiation
  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

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