Pan Jin, Li Deguan, Xu Yanfeng, Zhang Junling, Wang Yueying, Chen Mengyi, Lin Shuai, Huang Lan, Chung Eun Joo, Citrin Deborah E, Wang Yingying, Hauer-Jensen Martin, Zhou Daohong, Meng Aimin
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.
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.
Int J Radiat Oncol Biol Phys. 2017 Oct 1;99(2):353-361. doi: 10.1016/j.ijrobp.2017.02.216. Epub 2017 Mar 4.
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.
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.
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.
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.
电离辐射（IR）诱导的肺纤维化（PF）是胸部放射治疗不可逆的严重晚期效应。本研究的目的是确定使用ABT-263（一种可选择性杀死衰老细胞的衰老细胞溶解药物）清除衰老细胞是否能逆转PF。
C57BL/6J小鼠右侧胸部接受单次17 Gy剂量照射。照射后16周，通过灌胃给予2个周期的溶剂或ABT-263（每周期5天，每天50 mg/kg）。与治疗前或溶剂治疗后照射肺中观察到的变化相比，在最后一次治疗后3周评估ABT-263对IR诱导的衰老细胞增加、选择性炎性细胞因子、基质金属蛋白酶和基质金属蛋白酶组织抑制剂表达升高以及照射肺组织损伤和纤维化严重程度的影响。
C57BL/6小鼠单次接受17 Gy剂量照射后16周，胸部照射导致持续性PF，伴有衰老细胞显著增加。在持续性PF形成后用ABT-263治疗受照射小鼠可减少衰老细胞并逆转疾病。
据我们所知，这是第一项证明PF在成为进展性疾病后可被ABT-263等衰老细胞溶解药物逆转的研究。因此，ABT-263有潜力被开发为PF的新治疗方法。
