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

 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 
 Clinical Cancer Research, Vol.21(16) : 3716-3726, 2015 
Journal Title
 Clinical Cancer Research 
Issue Date
Animals ; Blood Vessels/pathology ; Blood Vessels/radiation effects ; Cell Hypoxia/radiation effects ; Collagen/metabolism ; Endothelial Cells/drug effects ; Endothelial Cells/radiation effects ; Epithelial-Mesenchymal Transition/genetics* ; Estradiol/administration & dosage ; Estradiol/analogs & derivatives ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/antagonists & inhibitors ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics ; Lung/drug effects* ; Lung/pathology ; Lung/radiation effects ; Mice ; Pulmonary Fibrosis/drug therapy ; Pulmonary Fibrosis/genetics* ; Pulmonary Fibrosis/pathology ; Radiation Pneumonitis/drug therapy ; Radiation Pneumonitis/genetics* ; Radiation Pneumonitis/pathology ; Radiotherapy/adverse effects
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.
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1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Thoracic and Cardiovascular Surgery (흉부외과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Radiation Oncology (방사선종양학교실) > 1. Journal Papers
Yonsei Authors
Lee, Chang Young(이창영)
Cho, Jae Ho(조재호) ORCID logo https://orcid.org/0000-0001-9966-5157
Hong, Zhen-Yu(홍진우)
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