Sparing and enhancing dose protraction effects for radiation damage to the aorta of wild-type mice

Abstract

Purpose

Our previous work indicated the greater magnitude of damage to the thoracic aorta at 6 months after starting 5 Gy irradiation in descending order of exposure to X-rays in 25 fractions > acute X-rays > acute γ-rays > X-rays in 100 fractions ≫ chronic γ-rays, in which the limitations of the study included a lack of data for fractionated γ-ray exposure. To better understand effects of dose protraction and radiation quality, the present study examined changes after exposure to γ-rays in 25 fractions, and compared its biological effectiveness with five other irradiation regimens.

Materials and Methods

Male C57BL/6J mice received 5 Gy of ¹³⁷Cs γ-rays delivered in 25 fractions spread over six weeks. At 6 months after starting irradiation, mice were subjected to echocardiography, followed by tissue sampling. The descending thoracic aorta underwent scanning electron microscopy, immunofluorescence staining and histochemical staining. The integrative analysis of multiple aortic endpoints was conducted for inter-regimen comparisons.

Results

Exposure to γ-rays in 25 fractions induced vascular damage (evidenced by increases in endothelial detachment and vascular endothelial cell death, decreases in endothelial waviness, CD31, endothelial nitric oxide synthase and vascular endothelial cadherin), inflammation (evidenced by increases in tumor necrosis factor α, CD68 and F4/80) and fibrosis (evidenced by increases in transforming growth factor β1, alanine blue stain and intima-media thickness). The integrative analysis revealed biological effectiveness in descending order of exposure to X-rays in 25 fractions > acute X-rays > γ-rays in 25 fractions > acute γ-rays > X-rays in 100 fractions ≫ chronic γ-rays.

Conclusions

The results suggest that dose protraction effects on aortic damage depend on radiation quality, and are not a simple function of dose rate and the number of fractions.

Keywords:

• Aorta
• vascular damage
• inflammation
• fibrosis
• dose protraction effects

Acknowledgements

The authors are grateful to Dr. Kyoji Furukawa (Kurume University, Japan) for his early involvement, and to the three reviewers for their constructive and helpful comments.

Disclosure statement

The authors report no conflict of interest. The authors alone are responsible for the content and writing of the paper. The views expressed in this paper represent collective opinions of the authors, and are not necessarily those of their professional affiliations.

Additional information

Funding

This work was supported in part by the Program of the Network-type Joint Usage/Research Center for Radiation Disaster Medical Science of Hiroshima University, Nagasaki University, and Fukushima Medical University.

Notes on contributors

Nobuyuki Hamada

Nobuyuki Hamada, RT, Ph.D., is a Senior Research Scientist at CRIEPI and a Visiting Professor at Hiroshima University Research Institute for Radiation Biology and Medicine. He serves on ICRP Task Groups 111, 119 and 123, NCRP PAC 1, OECD/NEA/CRPPH/HLG-LDR/Rad-Chem AOP Topical Group, and IRPA Task Group on Tissue Reactions. He has published >150 papers in peer reviewed international journals.

Ki-ichiro Kawano

Ki-ichiro Kawano, Ph.D., is a post-doctoral fellow at Hiroshima University Research Institute for Radiation Biology and Medicine. He is a molecular biologist, and has published 18 papers in peer-reviewed international journals.

Seiko Hirota

Seiko Hirota, Ph.D., is an Assistant Professor at Hiroshima University Research Institute for Radiation Biology and Medicine. She has a physics background and experience in retrospective dosimetry. Now she works in radiation epidemiology, especially for health effects in atomic bomb survivors.

Yusuke Saito

Yusuke Saito is a fifth grader at Hiroshima University School of Medicine.

Farina Mohamad Yusoff

Farina Mohamad Yusoff, MBBS, Ph.D., is an Assistant Professor at Hiroshima University Research Institute for Radiation Biology and Medicine. She serves on the RQP Committee and a Fellow of the Society for Vascular Medicine. She has significant basic, translational, clinical research experience in vascular regeneration and medicine, and has authored and coauthored >60 papers in the scientific literature.

Tatsuya Maruhashi

Tatsuya Maruhashi, MD, Ph.D., is an Associate Professor at Hiroshima University Research Institute for Radiation Biology and Medicine. His specialty is clinical vascular function testing. He has published >100 papers in peer reviewed international journals.

Makoto Maeda

Makoto Maeda, Ph.D., is a Technical Staff in the Electron Microscope Unit at Hiroshima University Natural Science Center for Basic Research and Development. His work contributes to chemical engineering, earth science, material science and biology research.

Takaharu Nomura

Takaharu Nomura, Ph.D., is a Senior Research Scientist at CRIEPI and a part-time instructor at Okayama University.

Ayumu Nakashima

Ayumu Nakashima, MD, Ph.D., is a Professor at Hiroshima University Graduate School of Biomedical and Health Sciences. He is a councilor of the Japanese Society of Nephrology. He has published >150 papers in peer reviewed international journals.

Shinji Yoshinaga

Shinji Yoshinaga, Ph.D., is a Professor at Hiroshima University Research Institute for Radiation Biology and Medicine.

Yukihito Higashi

Yukihito Higashi, MD, Ph.D., is a Professor at Hiroshima University Research Institute for Radiation Biology and Medicine. He has served as the primary investigator in numerous basic and clinical studies, working to translate his findings from the laboratory to patient care. He has made significant contributions to medical literature, publishing more than 400 original articles in journals.