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Figure legend (A) Lung tissue isolated from the left lung was stained with Masson’s Trichrome at indicative time after 90Gy exposure (right panel). (B) Heatmap of the gene expression from the IR damaged lung (left) compared to the control (right), Level of miR-21 in the left side of lung compared to the control (right) at indicative time after IR (C) In situ hybridization for miR-21 with either scramble probes (miRScr, top panels) or miR-21 (miR-21, middle and bottom panels) in right side of lung (Cont) or left side of lung (IR) (D) The protein level of collagen 3 type α1 (Col3A1) at indicative time after miR-21 transfection (E) The mRNA level of Col3A1 after miR21 mimic treatment. (F) The levels of indicated proteins after ectopic expression of miR-21 mimic.

Abstract

Radiation-induced lung fibrosis, the most serious effect of lung cancer radiotherapy on normal tissue, remains a major technical obstacle to the broader application of radiotherapy to patients with lung cancer. This study describes the use of an image-guided irradiation system in mice mimicking stereotactic body radiotherapy (SBRT) to examine the molecular features of chronic fibrotic response after radiation injury. MicroRNA (miR) array analysis of injured pulmonary tissue identified a set of miRs whose expression was significantly increased in damaged lung tissue. In particular, miR-21 expression was increased at the radiation injury site, concurrent with collagen deposition. Although the inhibition of miR-21 by its specific inhibitor anti-miR-21 only marginally affected endothelial-mesenchymal transition (EndMT) in lung endothelial cells, this inhibition significantly reduced collagen synthesis in lung fibroblasts. Furthermore, ectopic expression of miR-21 was sufficient to promote a fibrotic response in lung fibroblasts, enhancing Smad2 phosphorylation concurrent with Smad7 downregulation. These findings indicate that the induction of miR-21 expression is responsible for fibrotic responses observed in mesenchymal cells at the injury site through the potentiation of TGF-β signaling. Local targeting of miR-21 at the injured area could have potential therapeutic utility in mitigating radiation-induced lung fibrosis. 

Author information

Kwon OS1, Kim KT1, Lee E2, Kim M2, Choi SH3, Li H4, Fornace AJ Jr4, Cho JH5, Lee YS6, Lee JS7, Lee YJ3, Cha HJ1.​

1Department of Life Sciences, Sogang University, Seoul, Korea.

2College of Pharmacy and Wonkwang Oriental Medicines Research Institute, Wonkwang University, Jeonbuk, Korea.

3Laboratory of Radiation Effect, Division of Radiation effect, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.

4Department of Biochemistry and Molecular and Cellular Biology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, D.C., United States of America.

5Department of Radiation Oncology, Severance Hospital, Yonsei University, Seoul, Korea.

6School of Pharmacy, Ewha University Seoul, Korea.

7Burn Institute, Hangang Sacred Heart Hospital, College of Medicine, Hallym University, Seoul, Korea.