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

Journal Reference

Clin Cancer Res. 2015, 21(16):3716-26.

Choi SH¹, Hong ZY², Nam JK¹, Lee HJ¹, Jang J¹, Yoo RJ³, Lee YJ³, Lee CY⁴, Kim KH², Park S⁵, Ji YH⁵, Lee YS⁶, Cho J⁷, Lee YJ⁸.

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Division of Radiation Effects, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
Department of Radiation Oncology, Yonsei University College of Medicine, Seoul, Korea.
Molecular Imaging Research Center, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
Thoracic and Cardiovascular Surgery, Yonsei University College of Medicine, Seoul, Korea.
Research Center for Radiotherapy, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
College of Pharmacy and Division of Life and Pharmaceutical Sciences, Ewha Womans University, Seoul, Korea.
Department of Radiation Oncology, Yonsei University College of Medicine, Seoul, Korea. [email protected] [email protected].
Division of Radiation Effects, Korea Institute of Radiological and Medical Sciences, Seoul, Korea. [email protected] [email protected].

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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 Radiation-induced pulmonary fibrosis. 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 radiation-induced pulmonary fibrosis, 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), theradiation-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 radiation-induced pulmonary fibrosis. Furthermore, HIF1α-related EndMT was observed also in human radiation-induced pulmonary fibrosis tissues.

CONCLUSIONS:

We provide the first evidence that an EndMT occurs in radiation-induced pulmonary fibrosis development and that the EndMT may be effectively inhibited by modulating vascular EC-specific hypoxic damage.

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