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

Research output: Contribution to journalArticle

53 Citations (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.

Original languageEnglish
Pages (from-to)3716-3726
Number of pages11
JournalClinical Cancer Research
Volume21
Issue number16
DOIs
Publication statusPublished - 2015 Aug 15

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Pulmonary Fibrosis
Blood Vessels
Radiation
Collagen
Endothelial Cells
Alveolar Epithelial Cells
Lung
Hypoxia
Pulmonary Artery
Research Design
Radiotherapy
Thorax
Down-Regulation

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Choi, Seo Hyun ; Hong, Zhen Yu ; Nam, Jae Kyung ; Lee, Hae June ; Jang, Junho ; Yoo, Ran Ji ; Lee, Yong Jin ; Lee, Chang Young ; Kim, Kyung Hwan ; Park, Seungwoo ; Ji, Young Hoon ; Lee, Yun Sil ; Cho, Jaeho ; Lee, Yoon Jin. / A hypoxia-induced vascular endothelial-to-mesenchymal transition in development of radiation-induced pulmonary fibrosis. In: Clinical Cancer Research. 2015 ; Vol. 21, No. 16. pp. 3716-3726.
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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.",
author = "Choi, {Seo Hyun} and Hong, {Zhen Yu} and Nam, {Jae Kyung} and Lee, {Hae June} and Junho Jang and Yoo, {Ran Ji} and Lee, {Yong Jin} and Lee, {Chang Young} and Kim, {Kyung Hwan} and Seungwoo Park and Ji, {Young Hoon} and Lee, {Yun Sil} and Jaeho Cho and Lee, {Yoon Jin}",
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Choi, SH, Hong, ZY, Nam, JK, Lee, HJ, Jang, J, Yoo, RJ, Lee, YJ, Lee, CY, Kim, KH, Park, S, Ji, YH, Lee, YS, Cho, J & Lee, YJ 2015, 'A hypoxia-induced vascular endothelial-to-mesenchymal transition in development of radiation-induced pulmonary fibrosis', Clinical Cancer Research, vol. 21, no. 16, pp. 3716-3726. https://doi.org/10.1158/1078-0432.CCR-14-3193

A hypoxia-induced vascular endothelial-to-mesenchymal transition in development of radiation-induced pulmonary fibrosis. / Choi, Seo Hyun; Hong, Zhen Yu; Nam, Jae Kyung; Lee, Hae June; Jang, Junho; Yoo, Ran Ji; Lee, Yong Jin; Lee, Chang Young; Kim, Kyung Hwan; Park, Seungwoo; Ji, Young Hoon; Lee, Yun Sil; Cho, Jaeho; Lee, Yoon Jin.

In: Clinical Cancer Research, Vol. 21, No. 16, 15.08.2015, p. 3716-3726.

Research output: Contribution to journalArticle

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T1 - A hypoxia-induced vascular endothelial-to-mesenchymal transition in development of radiation-induced pulmonary fibrosis

AU - Choi, Seo Hyun

AU - Hong, Zhen Yu

AU - Nam, Jae Kyung

AU - Lee, Hae June

AU - Jang, Junho

AU - Yoo, Ran Ji

AU - Lee, Yong Jin

AU - Lee, Chang Young

AU - Kim, Kyung Hwan

AU - Park, Seungwoo

AU - Ji, Young Hoon

AU - Lee, Yun Sil

AU - Cho, Jaeho

AU - Lee, Yoon Jin

PY - 2015/8/15

Y1 - 2015/8/15

N2 - 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.

AB - 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.

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