Iron chelator deferasirox rescued mice from Fas-induced fulminant hepatitis
Iron chelator deferasirox rescued mice from Fas-induced fulminant hepatitis
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DOI：
10.1111/j.1872-034x.2011.00821.x
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发表时间：
2011-07-01
影响因子：
4.2
通讯作者：
Kato, Junji
中科院分区：
文献类型：
--
作者：
Sato, Tsutomu;Kobune, Masayoshi;Kato, Junji
目的：暴发性肝炎是一种以肝细胞严重损伤导致肝功能衰竭为特征的疾病。原位肝移植是一种被证明可以提高患者生存率的治疗方法;然而，需要更少的负担和更安全的策略。在以前的研究中，我们表明，铁密切参与肝细胞凋亡，证明自发发展的暴发性肝炎在Long-Evans肉桂大鼠喂养缺铁饮食，防止。最近，一种新的铁螯合剂，地拉罗司，已成为广泛用于治疗输血性含铁血黄素沉着症。地拉罗司由于方便、每日一次口服给药而表现出良好的疗效和改善的依从性。局我们的目的是探讨地拉罗司作为治疗药物对暴发性hepatitis.Methods的疗效：人原代肝细胞进行Fas刺激的凋亡与去铁胺（DFO）在体外的挑战。在进一步的体内实验中，我们测试了DFO在由Fas刺激诱导的小鼠暴发性肝炎模型中的作用。结果：DFO与铁的螯合作用抑制了抗Fas抗体对人原代肝细胞的增殖诱导活性。DFO抑制Fas诱导的活性氧（ROS）的产生和caspase-3的激活，这两个也被抑制抗氧化剂，N-乙酰-L-半胱氨酸。在体内实验中，地拉罗司有效地降低了肝脏铁浓度和拯救Fas诱导的暴发性hepatitis.Conclusion小鼠：这些研究结果表明，铁螯合产生了肝脏保护作用，清除活性氧上游的caspase-3和铁螯合与地拉罗司是一个潜在的治疗暴发性肝炎患者。
Aim: Fulminant hepatitis is a disease characterized by development of hepatic failure due to severe liver cell injury. Orthotopic liver transplantation is the therapy proven to improve patient survival; however, less burdensome and safer strategies are required. In a previous study, we showed that iron was intimately involved in hepatocyte apoptosis by demonstrating that spontaneous development of fulminant hepatitis in Long-Evans cinnamon rats was prevented by feeding an iron-deficient diet. Recently, a new iron chelator, deferasirox, has become widely available for the treatment of transfusional hemosiderosis. Deferasirox demonstrated good efficacy and improved compliance due to convenient, once-daily p.o. administration. Our aim was to investigate the efficacy of deferasirox as a therapeutic drug against fulminant hepatitis.Methods: Human primary hepatocytes undergoing Fas-stimulated apoptosis were challenged with deferoxamine (DFO) in vitro. In further in vivo experiments, we tested DFO in a mice model of fulminant hepatitis induced by Fas-stimulation.Results: The apoptosis-inducing activity of anti-Fas antibody on human primary hepatocytes was inhibited by the chelation of iron with DFO. DFO suppressed the Fas-induced production of reactive oxygen species (ROS) and the activation of caspase-3, both of which were also suppressed by antioxidant, N-acetyl-L-cystein. In the in vivo experiments, deferasirox effectively reduced hepatic iron concentrations and rescued mice from Fas-induced fulminant hepatitis.Conclusion: These findings indicated that the iron chelation exerted a hepatoprotective effect by scavenging ROS upstream of caspase-3 and that iron chelation with deferasirox is a potential treatment for patients with fulminant hepatitis.