Hypoxia-reoxygenation - A potent inducer of apoptotic changes in the human placenta and possible etiological factor in preeclampsia
Hypoxia-reoxygenation - A potent inducer of apoptotic changes in the human placenta and possible etiological factor in preeclampsia
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DOI：
10.1161/01.res.0000024411.22110.aa
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发表时间：
2002-06-28
影响因子：
20.1
通讯作者：
Burton, GJ
中科院分区：
文献类型：
--
作者：
Hung, TH;Skepper, JN;Burton, GJ
先兆子痫是一种严重的人类妊娠疾病，其特征在于母体内皮细胞的广泛活化。胎盘的氧化应激被认为是一个关键的中间步骤，促使凋亡片段进入母体循环，但原因仍然未知。我们推测，间歇性胎盘灌注，继发于子宫内膜动脉滋养层浸润不足，导致缺血-再灌注型损伤。因此，我们测试是否缺氧-复氧（H/R）在体外刺激人胎盘组织的细胞凋亡相比，控制保持缺氧或常氧的整个。H/R后，线粒体细胞色素c的释放显着增加，并与强烈的免疫标记活性caspase 3在合体滋养层细胞和胎儿内皮细胞。也有增加标记的合胞体滋养层细胞核裂解的聚（ADP-核糖）聚乙烯酶（PARP），和较高的胞质浓度裂解的PARP片段检测Western印迹。合体滋养层细胞核染色质浓缩增加，TUNEL阳性率显著增高。这些变化伴随着增加乳酸脱氢酶释放到培养基中。预管理的自由基清除剂，去铁胺，减少细胞色素c的释放和TUNEL阳性指数，表明羟基自由基的产生介导这些过程。相比之下，缺氧单独引起的TUNEL阳性指数增加较小，大多数合体滋养细胞核显示核溶解，而常氧对照组仍常染色质。我们的结论是，H/R刺激细胞凋亡的变化，而缺氧主要诱导坏死的合胞体滋养层。因此，胎盘灌注的质量可能是先兆子痫病理生理学中比绝对量更重要的因素。
Preeclampsia is a severe disorder of human pregnancy characterized by generalized activation of maternal endothelial cells. Oxidative stress of the placenta is considered a key intermediary step, precipitating deportation of apoptotic fragments into the maternal circulation, but the cause remains unknown. We hypothesize that intermittent placental perfusion, secondary to deficient trophoblast invasion of the endometrial arteries, leads to an ischemia-reperfusion-type insult. We therefore tested whether hypoxia-reoxygenation (H/R) in vitro stimulates apoptosis in human placental tissues compared with controls kept hypoxic or normoxic throughout. After H/R, release of cytochrome c from mitochondria was significantly increased and was associated with intense immunolabeling for active caspase 3 in the syncytiotrophoblast and fetal endothelial cells. There was also increased labeling of syncytiotrophoblastic nuclei for cleaved poly (ADP-ribose) polyinerase (PARP), and higher cytosolic concentrations of cleaved PARP fragment were detected by Western blot. Syncytiotrophoblastic nuclei displayed increased chromatin condensation, and a significantly greater percentage was TUNEL positive. These changes were accompanied by increased lactate dehydrogenase release into the medium. Preadministration of the free radical scavenger, desferrioxamine, reduced cytochrome c release and the TUNEL-positive index, suggesting generation of hydroxyl radicals mediates these processes. By contrast, hypoxia alone caused a smaller increase in the TUNEL-positive index, and the majority of syncytiotrophoblastic nuclei displayed karyolysis, whereas normoxic controls remained euchromatic. We conclude that H/R stimulates apoptotic changes within the syncytiotrophoblast, whereas hypoxia principally induces necrosis. The quality of placental perfusion may therefore be a more important factor in the pathophysiology of preeclampsia than the absolute quantity.