Hyperoxia causes maturation-dependent cell death in the developing white matter
Hyperoxia causes maturation-dependent cell death in the developing white matter
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DOI：
10.1523/jneurosci.3213-07.2008
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发表时间：
2008-01-30
影响因子：
5.3
通讯作者：
Rosenberg, Paul A.
中科院分区：
文献类型：
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作者：
Gerstner, Bettina;DeSilva, Tara M.;Rosenberg, Paul A.
脑室周围白质软化是早产儿脑性瘫痪的主要原因。氧气暴露可能是这些婴儿脑损伤的另一个原因。在这项研究中，我们研究了在体外和体内高氧诱导的成熟依赖性少突胶质细胞（OL）死亡的途径。使发育和成熟的OL经受80%氧气（0-24小时）。乳酸脱氢酶（LDH）测定用于评估细胞活力。此外，3-，6-，和10-d-大的幼鼠进行80%的氧气（24小时），和他们的大脑进行处理的髓鞘碱性蛋白染色。在前OL（O 4+，O 1-）中在80%氧气中孵育6 - 24小时后检测到显著的细胞死亡，但在成熟OL（MBP +）中未检测到。细胞死亡是通过半胱天冬酶依赖性凋亡途径进行的，并且可以被泛半胱天冬酶抑制剂zVAD-favor阻断。BCL 2（智人B细胞慢性淋巴细胞白血病/淋巴瘤2）的过表达显着减少细胞凋亡。氧暴露2 h后检测超氧阴离子的积累和活性氧（ROS）的产生。脂氧合酶抑制剂2，3，5-三甲基-6-（12-羟基-5-10-十二碳二炔基）-1，4-苯醌和N-苄基-N-羟基-5-苯基戊酰胺可完全保护细胞免受氧化损伤。超氧化物歧化酶（SOD 1）的过度表达显着增加前OL的损伤，但不成熟OL。我们通过测试高氧对新生儿白色物质的影响来扩展这些研究。出生后第3天（P3）和P6大鼠（但不是P10幼崽）在暴露于80%氧气24小时后显示双侧MBP（髓鞘碱性蛋白）表达减少。高氧引起氧化应激并触发前OLs的成熟依赖性凋亡，这涉及ROS的产生和caspase激活，并导致新生大鼠脑中的白色损伤。这些观察结果可能与早产儿中观察到的白色损伤相关。
Periventricular leukomalacia is the predominant injury in the preterm infant leading to cerebral palsy. Oxygen exposure may be an additional cause of brain injury in these infants. In this study, we investigated pathways of maturation-dependent oligodendrocyte (OL) death induced by hyperoxia in vitro and in vivo. Developing and mature OLs were subjected to 80% oxygen (0-24 h). Lactate dehydrogenase (LDH) assay was used to assess cell viability. Furthermore, 3-, 6-, and 10-d-old rat pups were subjected to 80% oxygen (24 h), and their brains were processed for myelin basic protein staining. Significant cell death was detected after 6 - 24 h incubation in 80% oxygen in pre-OLs (O4 +, O1-), but not in mature OLs (MBP +). Cell death was executed by a caspase-dependent apoptotic pathway and could be blocked by the pan-caspase inhibitor zVAD-fmk. Overexpression of BCL2 (Homo sapiens B-cell chronic lymphocytic leukemia/lymphoma 2) significantly reduced apoptosis. Accumulation of superoxide and generation of reactive oxygen species (ROS) were detected after 2 h of oxygen exposure. Lipoxygenase inhibitors 2,3,5-trimethyl-6-(12-hydroxy-5-10-dodecadiynyl-1,4-benzoquinone and N-benzyl-N-hydroxy-5-phenylpentamide fully protected the cells from oxidative injury. Overexpression of superoxide dismutase (SOD1) dramatically increased injury to pre-OLs but not to mature OLs. We extended these studies by testing the effects of hyperoxia on neonatal white matter. Postnatal day 3 (P3) and P6 rats, but not P10 pups, showed bilateral reduction in MBP (myelin basic protein) expression with 24 h exposure to 80% oxygen. Hyperoxia causes oxidative stress and triggers maturation-dependent apoptosis in pre-OLs, which involves the generation of ROS and caspase activation, and leads to white matter injury in the neonatal rat brain. These observations may be relevant to white matter injury observed in premature infants.