Amifostine ameliorates bleomycin-induced murine pulmonary fibrosis via NAD+/SIRT1/AMPK pathway-mediated effects on mitochondrial function and cellular metabolism

作者：Feng Guo, Feng Xu, Shujuan Li, Yun Zhang, Dan Lv, Lin Zheng, Yongxiong Gan, Miao Zhou, Keyu Zhao, Shuling Xu, Bin Wu, Zaichun Deng, Panfeng Fu · 发表于：European journal of medical research · 年份：2024 · DOI：10.1186/s40001-023-01623-4 · 被引用次数：19 · 研究领域：Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis、Effects of Radiation Exposure、Lung Cancer Treatments and Mutations

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a devastating chronic lung disease characterized by irreversible scarring of the lung parenchyma. Despite various interventions aimed at mitigating several different molecular aspects of the disease, only two drugs with limited clinical efficacy have so far been approved for IPF therapy. OBJECTIVE: We investigated the therapeutic efficacy of amifostine, a detoxifying drug clinically used for radiation-caused cytotoxicity, in bleomycin-induced murine pulmonary fibrosis. METHODS: C57BL6/J mice were intratracheally instilled with 3 U/kg of bleomycin. Three doses of amifostine (WR-2721, 200 mg/kg) were administered intraperitoneally on days 1, 3, and 5 after the bleomycin challenge. Bronchoalveolar lavage fluid (BALF) was collected on day 7 and day 21 for the assessment of lung inflammation, metabolites, and fibrotic injury. Human fibroblasts were treated in vitro with transforming growth factor beta 1 (TGF-β1), followed by amifostine (WR-1065, 1-4 µg/mL) treatment. The effects of TGF-β1 and amifostine on the mitochondrial production of reactive oxygen species (ROS) were assessed by live cell imaging of MitoSOX. Cellular metabolism was assessed by the extracellular acidification rate (ECAR), the oxygen consumption rate (OCR), and the concentrations of various energy-related metabolites as measured by mass spectrum (MS). Western blot analysis was performed to investigate the effect of amifostine on sirtuin 1 (SIRT1) and adenosine ...