PDF(Pubmed)
Abstract：
We show that redox active iron can induce a regulated form of non-apoptotic cell death and tissue damage called ferroptosis that can contribute to secondary damage and functional loss in the acute and chronic periods after spinal cord injury (SCI) in young, adult, female mice. Phagocytosis of red blood cells at sites of hemorrhage is the main source of iron derived from hemoglobin after SCI. Expression of hemeoxygenase-1 that induces release of iron from heme, is increased in spinal cord macrophages 7 days after injury. While iron is stored safely in ferritin in the injured spinal cord, it can, however, be released by NCOA4-mediated shuttling of ferritin to autophagosomes for degradation (ferritinophagy). This leads to the release of redox active iron that can cause free radical damage. Expression of NCOA4 is increased after SCI, mainly in macrophages. Increase in the ratio of redox active ferrous (Fe2+) to ferric iron (Fe3+) is also detected after SCI by capillary electrophoresis inductively coupled mass spectrometry. These changes are accompanied by other hallmarks of ferroptosis, i.e., deficiency in various elements of the antioxidant glutathione (GSH) pathway. We also detect increases in enzymes that repair membrane lipids (ACSL4 and LPCAT3) and thus promote on-going ferroptosis. These changes are associated with increased levels of 4-hydroxynonenal (4-HNE), a toxic lipid peroxidation product. Mice with mild SCI (30 kdyne force) treated with the ferroptosis inhibitor (UAMC-3203-HCL) either early or delayed times after injury showed improvement in locomotor recovery and secondary damage. Cerebrospinal fluid and serum samples from human SCI cases show evidence of increased iron storage (ferritin), and other iron related molecules, and reduction in GSH. Collectively, these data suggest that ferroptosis contributes to secondary damage after SCI and highlights the possible use of ferroptosis inhibitors to treat SCI.
摘要：
我们表明，氧化还原活性铁可以诱导一种非凋亡性细胞死亡和组织损伤的调节形式，称为铁性凋亡，这可能导致年轻脊髓损伤（SCI）后急性和慢性阶段的继发性损伤和功能丧失。成人,雌性老鼠出血部位红细胞的吞噬作用是SCI后血红蛋白铁的主要来源。血红素加氧酶-1的表达诱导血红素释放铁,脊髓巨噬细胞在损伤后7天增加。虽然铁安全地储存在受损脊髓的铁蛋白中，它可以，然而,通过NCOA4介导的铁蛋白穿梭至自噬体以进行降解（铁蛋白吞噬）而释放。这导致可引起自由基损伤的氧化还原活性铁的释放。SCI后NCOA4的表达增加，主要在巨噬细胞中。在SCI之后,通过毛细管电泳电感耦合质谱法也检测到氧化还原活性亚铁(Fe2+)与三价铁(Fe3+)的比率的增加。这些变化伴随着铁死亡的其他标志，即，抗氧化剂谷胱甘肽（GSH）途径的各种元素缺乏。我们还检测到修复膜脂质（ACSL4和LPCAT3）的酶的增加，从而促进持续的铁死亡。这些变化与4-羟基壬烯醛（4-HNE）水平升高有关，一种有毒的脂质过氧化产物。在损伤后早期或延迟时间用铁凋亡抑制剂（UAMC-3203-HCL）处理的轻度SCI（30kdyne力）小鼠显示运动恢复和继发性损伤的改善。来自人类SCI病例的脑脊液和血清样本显示铁储存（铁蛋白）增加的证据，和其他铁相关分子，减少GSH。总的来说，这些数据表明铁性凋亡有助于SCI后的继发性损伤,并强调了铁性凋亡抑制剂治疗SCI的可能性.
