title: A Hypoxia-Induced Vascular Endothelial-to-Mesenchymal Transition in Development of Radiation-Induced Pulmonary Fibrosis.
abstract: OBJECTIVE
  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.
  
  
  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.
authors.affiliation: Division of Radiation Effects, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
authors.forename: Seo-Hyun
authors.initials: SH
authors.lastname: Choi
authors.affiliation: Department of Radiation Oncology, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Zhen-Yu
authors.initials: ZY
authors.lastname: Hong
authors.affiliation: Division of Radiation Effects, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
authors.forename: Jae-Kyung
authors.initials: JK
authors.lastname: Nam
authors.affiliation: Division of Radiation Effects, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
authors.forename: Hae-June
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Division of Radiation Effects, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
authors.forename: Junho
authors.initials: J
authors.lastname: Jang
authors.affiliation: Molecular Imaging Research Center, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
authors.forename: Ran Ji
authors.initials: RJ
authors.lastname: Yoo
authors.affiliation: Molecular Imaging Research Center, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
authors.forename: Yong Jin
authors.initials: YJ
authors.lastname: Lee
authors.affiliation: Thoracic and Cardiovascular Surgery, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Chang Young
authors.initials: CY
authors.lastname: Lee
authors.affiliation: Department of Radiation Oncology, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Kyung Hwan
authors.initials: KH
authors.lastname: Kim
authors.affiliation: Research Center for Radiotherapy, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
authors.forename: Seungwoo
authors.initials: S
authors.lastname: Park
authors.affiliation: Research Center for Radiotherapy, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
authors.forename: Young Hoon
authors.initials: YH
authors.lastname: Ji
authors.affiliation: College of Pharmacy and Division of Life and Pharmaceutical Sciences, Ewha Womans University, Seoul, Korea.
authors.forename: Yun-Sil
authors.initials: YS
authors.lastname: Lee
authors.affiliation: Department of Radiation Oncology, Yonsei University College of Medicine, Seoul, Korea. yjlee8@kcch.re.kr jjhmd@yuhs.ac.
authors.forename: Jaeho
authors.initials: J
authors.lastname: Cho
authors.affiliation: Division of Radiation Effects, Korea Institute of Radiological and Medical Sciences, Seoul, Korea. yjlee8@kcch.re.kr jjhmd@yuhs.ac.
authors.forename: Yoon-Jin
authors.initials: YJ
authors.lastname: Lee
mesh_terms: D000077584:2-Methoxyestradiol; D000818:Animals; D001808:Blood Vessels / Q000473:pathology / Q000528:radiation effects; D015687:Cell Hypoxia / Q000528:radiation effects; D003094:Collagen / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000528:radiation effects; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics; D008168:Lung / Q000187:drug effects* / Q000473:pathology / Q000528:radiation effects; D051379:Mice; D011658:Pulmonary Fibrosis / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D017564:Radiation Pneumonitis / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D011878:Radiotherapy / Q000009:adverse effects
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D004958:Estradiol; D000077584:2-Methoxyestradiol; D003094:Collagen