Absence of mitochondrial superoxide dismutase results in a murine hemolytic anemia responsive to therapy with a catalytic antioxidant.
Absence of mitochondrial superoxide dismutase results in a murine hemolytic anemia responsive to therapy with a catalytic antioxidant.
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DOI：
10.1084/jem.193.8.925
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发表时间：
2001-04-16
影响因子：
15.3
通讯作者：
Burakoff, S J
中科院分区：
文献类型：
--
作者：
Friedman, J S;Rebel, V I;Derby, R;Bell, K;Huang, T T;Kuypers, F A;Epstein, C J;Burakoff, S J
锰超氧化物歧化酶2 （SOD2）是线粒体O2−解毒途径的关键组成部分，对该位点的靶向破坏可导致小鼠胚胎或新生儿死亡。为了在更长的时间内跟踪细胞中SOD2缺乏的影响，我们创造了造血嵌合体，其中所有血细胞都来自SOD2敲除、杂合或野生型胎鼠的胎儿肝干细胞。每种基因型的干细胞有效地挽救了造血功能，并允许致命辐射的宿主动物长期存活。外周血白细胞群分析显示，当比较Sod2 +/+、Sod2−/−和Sod2 +/−胎儿肝受体时，T细胞、B细胞或髓细胞的重构动力学没有差异。然而，接受Sod2 - / -细胞的动物持续贫血，结果提示溶血过程。红细胞祖细胞中SOD2的缺失导致蛋白质氧化损伤增强，膜变形改变，红细胞存活率降低。用具有SOD和过氧化氢酶活性的催化抗氧化剂Euk-8治疗贫血动物，可显著纠正这种氧化应激诱导的状况。这种疗法可能被证明对治疗人类疾病有用，如铁母细胞性贫血，这与SOD2缺乏症最相似。
Manganese superoxide dismutase 2 (SOD2) is a critical component of the mitochondrial pathway for detoxification of O2 −, and targeted disruption of this locus leads to embryonic or neonatal lethality in mice. To follow the effects of SOD2 deficiency in cells over a longer time course, we created hematopoietic chimeras in which all blood cells are derived from fetal liver stem cells of Sod2 knockout, heterozygous, or wild-type littermates. Stem cells of each genotype efficiently rescued hematopoiesis and allowed long-term survival of lethally irradiated host animals. Peripheral blood analysis of leukocyte populations revealed no differences in reconstitution kinetics of T cells, B cells, or myeloid cells when comparing Sod2 +/+, Sod2 −/−, and Sod2 +/− fetal liver recipients. However, animals receiving Sod2 −/− cells were persistently anemic, with findings suggestive of a hemolytic process. Loss of SOD2 in erythroid progenitor cells results in enhanced protein oxidative damage, altered membrane deformation, and reduced survival of red cells. Treatment of anemic animals with Euk-8, a catalytic antioxidant with both SOD and catalase activities, significantly corrected this oxidative stress–induced condition. Such therapy may prove useful in treatment of human disorders such as sideroblastic anemia, which SOD2 deficiency most closely resembles.