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A hypoxia-induced vascular endothelial-to-mesenchymal transition in development of radiation-induced pulmonary fibrosis

Title
A hypoxia-induced vascular endothelial-to-mesenchymal transition in development of radiation-induced pulmonary fibrosis
Authors
ChoiS.-H.HongZ.-Y.NamJ.-K.LeeH.-J.JangJ.YooR.J.Y.J.C.Y.KimK.H.ParkS.JiY.H.Y.-S.ChoY.-J.
Ewha Authors
이윤실
SCOPUS Author ID
이윤실scopus
Issue Date
2015
Journal Title
Clinical Cancer Research
ISSN
1078-0432JCR Link
Citation
vol. 21, no. 16, pp. 3716 - 3726
Publisher
American Association for Cancer Research Inc.
Indexed
SCI; SCIE; SCOPUS WOS scopus
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 (endothelialto-mesenchymal transition) began to develop in the early phase of RIPF, before the appearance of EMT (epithelial-tomesenchymal 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. © 2015 American Association for Cancer Research.
DOI
10.1158/1078-0432.CCR-14-3193
Appears in Collections:
약학대학 > 약학과 > Journal papers
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