Placental dysfunction and maternal endothelial cell dysfunction in the pathogenesis of preeclampsia

本研究旨在从中性粒细胞-内皮细胞相互作用的角度阐明胎盘异常与子痫前期母体内皮细胞功能障碍的潜在细胞机制之间的关系。首先，我们研究了子痫前期妇女血清对中性粒细胞的影响。结果表明，与正常孕妇相比，子痫前期妇女血清中n -甲氧基-蛋氨酸-leucyl-苯丙氨酸诱导的超氧化物产生显著增加，中性粒细胞超氧化物产生的增加诱导内皮细胞损伤。此外，子痫前期妇女血清抑制3h -胸腺嘧啶结合，降低培养滋养细胞的细胞活力。凝胶渗透表明，最大的生长抑制活性对应于分子量为50 kDa。血清对中性粒细胞的增强活性与胎盘细胞毒活性相同。接下来，我们用一氧化氮合酶抑制剂（L-NAME）治疗妊娠大鼠，研究胎盘缺血/缺氧是否刺激母体血清细胞毒因子(s)的产生。L-NAME处理的妊娠大鼠光镜观察显示，与对照妊娠大鼠相比，巨细胞数量减少，海绵滋养层退化。L-NAME处理的妊娠大鼠血清对胎盘滋养细胞有细胞毒活性。经L-NAME处理的妊娠大鼠血清TNF-α水平升高，胎盘滋养细胞TNF-α表达升高。这些发现表明，胎盘缺血/缺氧刺激因子，如炎性细胞因子，促进子痫前期几种形式的内皮功能障碍，并导致妊娠期间发生这种疾病的重大风险

The aim of this study was to clarify the relationship between placental abnormalities and the potential cellular mechanisms contributing to the maternal endothelial cell dysfunction in preeclampsia from the viewpoint of neutrophill-endothelial cell interaction.Firstly, we investigated the effect of sera from women with preeclampsia on neutrophils. It was demonstrated that the sera from women with preeclampsia significantly enhance N-formyl-methionyl-leucyl-phenylalanine-induced superoxide production as compared to the sera of normal pregnant women, and that enhanced superoxide production of neutrophils induces the endothelial cell injury. In addition, sera from women with preeclampsia inhibited 3H-thymidine incorporation and reduced cellular viability of cultured trophoblasts. Gel permeation showed that the greatest growth-inhibitory activity corresponded to a molecular weight of 50 kDa. The serum enhanced activity to neutrophils was found in the same fraction of the placental cytotoxic activity.Next, we investigated whether placental ischemia/hypoxia stimulates the production of maternal serum cytotoxic factor(s) using pregnant rats treated with the nitric oxide synthase inhibitor(L-NAME). In L-NAME treated pregnant rats, light microscopy showed that giant cells were decreased in number and spongiotrophoblast layers were degenerated compared to control pregnant rats. Maternal serum cytotoxic activity to placental trophoblasts was present in L-NAME treated pregnant rats. Elevated serum TNF-α levels and increased expression of TNF-α in placental trophoblasts were observed in L-NAME treated pregnant rats.These findings suggest that placental ischemia/hypoxia stimulate the factor(s), such as inflammatory cytokines, that promote several forms of endothelial dysfunction in preeclampsia, and contribute to the substantial risks for developing this disorder during pregnancy