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

Abstract

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 17Gy on the right side of the thorax. Sixteen weeks after IR, they were treated with 2 cycles of vehicle or ABT-263 (50mg/kg per day for 5days 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 3weeks after the last treatment, in comparison with the changes observed in the irradiated lungs before treatment or after vehicle treatment. At 16weeks after exposure of C57BL/6 mice to a single dose of 17Gy, 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.