Inhibition of Bcl-2/xl With ABT-263 Selectively Kills Senescent Type II Pneumocytes and Reverses Persistent Pulmonary Fibrosis Induced by Ionizing Radiation in Mice

Journal Article · Sun Oct 01 04:00:00 EDT 2017 · International Journal of Radiation Oncology, Biology and Physics

DOI:https://doi.org/10.1016/J.IJROBP.2017.02.216· OSTI ID:22723020

Pan, Jin ^[1]; Li, Deguan ^[2]; Xu, Yanfeng ^[1]; Zhang, Junling; Wang, Yueying ^[2]; Chen, Mengyi; Lin, Shuai; Huang, Lan ^[1]; Chung, Eun Joo; Citrin, Deborah E. ^[3]; Wang, Yingying; Hauer-Jensen, Martin ^[4]; Zhou, Daohong ^[4]; Meng, Aimin ^[1]

---

1. Key Laboratory of Human Disease Comparative Medicine, Ministry of Health, Institute of Laboratory Animal Science, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing (China)
2. Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Tianjin (China)
3. Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (United States)
4. Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas (United States)

Purpose: Ionizing radiation (IR)–induced pulmonary fibrosis (PF) is an irreversible and severe late effect of thoracic radiation therapy. The goal of this study was to determine whether clearance of senescent cells with ABT-263, a senolytic drug that can selectively kill senescent cells, can reverse PF. Methods and Materials: C57BL/6J mice were exposed to a single dose of 17 Gy on the right side of the thorax. Sixteen weeks after IR, they were treated with 2 cycles of vehicle or ABT-263 (50 mg/kg per day for 5 days per cycle) by gavage. The effects of ABT-263 on IR-induced increases in senescent cells; elevation in the expression of selective inflammatory cytokines, matrix metalloproteinases, and tissue inhibitors of matrix metalloproteinases; and the severity of the tissue injury and fibrosis in the irradiated lungs were evaluated 3 weeks after the last treatment, in comparison with the changes observed in the irradiated lungs before treatment or after vehicle treatment. Results: At 16 weeks after exposure of C57BL/6 mice to a single dose of 17 Gy, thoracic irradiation resulted in persistent PF associated with a significant increase in senescent cells. Treatment of the irradiated mice with ABT-263 after persistent PF had developed reduced senescent cells and reversed the disease. Conclusions: To our knowledge, this is the first study to demonstrate that PF can be reversed by a senolytic drug such as ABT-263 after it becomes a progressive disease. Therefore, ABT-263 has the potential to be developed as a new treatment for PF.

• OSTI ID: 22723020
• Journal Information: International Journal of Radiation Oncology, Biology and Physics, Journal Name: International Journal of Radiation Oncology, Biology and Physics Journal Issue: 2 Vol. 99; ISSN IOBPD3; ISSN 0360-3016
• Country of Publication: United States
• Language: English

Related Subjects

62 RADIOLOGY AND NUCLEAR MEDICINE
FIBROSIS
GY RANGE
INHIBITION
IONIZING RADIATIONS
IRRADIATION
MICE
RADIATION DOSES