• Int. J. Radiat. Oncol. Biol. Phys. · Oct 2017

    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.

    • Jin Pan, Deguan Li, Yanfeng Xu, Junling Zhang, Yueying Wang, Mengyi Chen, Shuai Lin, Lan Huang, Eun Joo Chung, Deborah E Citrin, Yingying Wang, Martin Hauer-Jensen, Daohong Zhou, and Aimin Meng.
    • 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.
    • Int. J. Radiat. Oncol. Biol. Phys. 2017 Oct 1; 99 (2): 353-361.

    PurposeIonizing 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 MaterialsC57BL/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.ResultsAt 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.ConclusionsTo 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.Copyright © 2017 Elsevier Inc. All rights reserved.

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