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

Publication date: Available online 4 March 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): 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, Aimin Meng
PurposeIonizing radiation (IR)-induced pulmonary fibrosis (PF) is an irreversible and severe late effect of thoracic radiotherapy. 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/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 (Mmps) and tissue inhibitors of Mmps (Timps), 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 the treatment or after vehicle treatment.ResultsThe results show that 16 weeks after exposure of C57BL/6 mice to a single dose of 17 Gy thoracic irradiation resulted in persistent pulmonary fibrosis associated with a significant increase in senescent cells. Treatment of the irradiated mice with ABT-263 after they had developed persistent pulmonary fibrosis reduced senescent cells and reversed the disease.ConclusionsTo our knowledge, this is the first study to demonstrate that PF can be reserved 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.

Teaser

Ionizing radiation (IR)-induced pulmonary fibrosis (PF) is an irreversible and severe late effect of thoracic radiotherapy. Our studies show that ABT-263, a specific Bcl-2/xl inhibitor and a newly identified senolytic drug that can selectively kill senescent cells, could reverse PF even when the pulmonary fibrosis had already became persistent in mice after thoracic irradiation. This finding suggests that ABT-263 has the potential to be used as an effective treatment for PF.


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