American Association for Cancer Research
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10780432ccr143193-sup-142194_1_supp_2907619_nlhpls.pdf (931.13 kB)

Supplementary Figures 1-6 from A Hypoxia-Induced Vascular Endothelial-to-Mesenchymal Transition in Development of Radiation-Induced Pulmonary Fibrosis

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posted on 2023-03-31, 18:24 authored by Seo-Hyun Choi, Zhen-Yu Hong, Jae-Kyung Nam, Hae-June Lee, Junho Jang, Ran Ji Yoo, Yong Jin Lee, Chang Young Lee, Kyung Hwan Kim, Seungwoo Park, Young Hoon Ji, Yun-Sil Lee, Jaeho Cho, Yoon-Jin Lee

Supplementary Figures 1-6. Supplementary Figure 1. Mouse models of RIPF. Supplementary Figure 2. The ocurrence of EndMT and an EMT in the development of RIPF. Supplementary Figure 3. 2-ME inhibits EMT in the development of RIPF. Supplementary Figure 4. 2-ME inhibits RIPF. Supplementary Figure 5. H&E staining in human RIPF tissues Supplementary Figure 6. Whole-body or thoracic irradiation of mice induces apoptosis and detachment of lung endothelial cells.

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ARTICLE ABSTRACT

Purpose: Radiation-induced pulmonary fibrosis (RIPF) is a late side effect of thoracic radiotherapy. The purpose of our study was to gain further insight into the development of RIPF.Experimental Design/Results: Here, we observed that irradiation of mouse lungs induced collagen deposition, particularly around blood vessels, in the early phase of RIPF. Such deposition subsequently became evident throughout the irradiated tissues. Accompanied by the collagen deposition, vascular EndMT (endothelial-to-mesenchymal transition) began to develop in the early phase of RIPF, before the appearance of EMT (epithelial-to-mesenchymal transition) of alveolar epithelial (AE) II cells in the substantive fibrotic phase. Concomitant with the EndMT, we detected vascular endothelial cell (EC)–specific hypoxic damage in the irradiated lung tissues. In human pulmonary artery endothelial cells (HPAEC), the radiation-induced EndMT via activation of TGFβ-R1/Smad signaling was dependent on HIF1α expression. A novel HIF1α inhibitor, 2-methoxyestradiol (2-ME), inhibited the irradiation-induced EndMT via downregulation of HIF1α-dependent Smad signaling. In vivo, 2-ME inhibited the vascular EndMT, and decreased the collagen deposition associated with RIPF. Furthermore, HIF1α-related EndMT was observed also in human RIPF tissues.Conclusions: We provide the first evidence that an EndMT occurs in RIPF development and that the EndMT may be effectively inhibited by modulating vascular EC-specific hypoxic damage. Clin Cancer Res; 21(16); 3716–26. ©2015 AACR.

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