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A Hypoxia-Induced Vascular Endothelial-to-Mesenchymal Transition in Development of Radiation-Induced Pulmonary Fibrosis

Authors
 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 
Citation
 Clinical Cancer Research, Vol.21(16) : 3716-3726, 2015 
Journal Title
 Clinical Cancer Research 
ISSN
 1078-0432 
Issue Date
2015
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.
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/140916
DOI
10.1158/1078-0432.CCR-14-3193
Appears in Collections:
1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원)
1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > Dept. of Thoracic and Cardiovascular Surgery (흉부외과학교실)
1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > Dept. of Radiation Oncology (방사선종양학교실)
Yonsei Authors
이창영(Lee, Chang Young)
조재호(Cho, Jae Ho)
홍진우(Hong, Zhen-Yu)
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Full Text
http://clincancerres.aacrjournals.org/content/21/16/3716.long
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