A Role for Natural Killer Cells in the Development of Intrauterine Growth Restriction and Hypertension During Pregnancy

子痫前期(PE)是一种多系统妊娠障碍，影响5-8%的妊娠，是 世界范围内孕产妇和胎儿发病率的主要原因。尽管进行了数十年的研究，目前唯一的治愈方法 因为PE是胎儿和胎盘的早产，这往往是造成胎儿不良的重要原因 结果。因此，迫切需要更好地了解PE的病理生理学，以确定有效的 治疗靶点。临床研究发现，PE与一种以细胞溶解为主的 自然杀伤(NK)细胞免疫图谱与与正常妊娠相关的调节性NK图谱。 此外，蜕膜NK细胞调节失调已被公认为是复发的原因之一。 流产和胎盘功能不全。然而，细胞溶解NK(CNK)细胞在 在PE病理生理学中的作用尚不清楚。这项提案中概述的实验将提供更好的 了解CNK细胞可能介导PE病理生理的机制。我们的动物模型， 降低子宫灌流压力(RUPP)大鼠胎盘缺血模型 先兆子痫妇女的特征包括高血压、宫内生长受限和 CNK活化和增殖。我们的初步数据显示，RUPP大鼠的NK细胞完全耗尽 结果降低血压，降低氧化应激(ROS)，改善IUGR。我们还发现了 RUPP大鼠体内升高的肿瘤坏死因子-α和干扰素-γ均显著低于NK细胞。 耗尽。这些数据支持NK细胞在PE中参与高血压和IUGR的假说。 然而，由于其中许多实验耗尽了整个NK细胞群，我们仍然不完全了解 CNK细胞在PE中的作用因此，我们计划使用采用转移技术来确定 胎盘缺血诱导CNK细胞引起ROS增加和血管功能障碍 妊娠期高血压与胎儿宫内发育迟缓我们还计划使用药物抑制来阻断肿瘤坏死因子-α和干扰素- γ，并评价RUPP大鼠的ROS生成、血管功能、高血压和宫内发育迟缓的变化。基于 我们之前的数据，我们提出了胎盘缺血激活CNK细胞导致全身性 炎症和氧化应激，导致产妇血管功能障碍、高血压和 妊娠期胎儿宫内生长受限。为了验证这一假设，我们将在体内和体外使用 检查以下特定目标的技巧：特定目标1：检验胎盘 缺血刺激的CNK细胞增加胎盘和肾脏ROS，炎性细胞因子(肿瘤坏死因子-α和干扰素-γ)， 血管功能障碍导致妊娠期高血压和IUGR。具体目标2：测试 阻断胎盘缺血大鼠CNK相关细胞因子减轻氧化应激的假说 炎症导致血管功能改善，血压降低，宫内发育迟缓 怀孕了。

Preeclampsia (PE) is a multisystem pregnancy disorder that affects 5-8% of pregnancies and is one of the leading causes of maternal and fetal morbidity worldwide. Despite decades of research, currently the only cure for PE is premature delivery of the fetus and placenta, which often contributes significantly to poor fetal outcomes. Thus, there is an urgent need to better understand PE pathophysiology to identify effective therapeutic targets. Clinical studies have found that PE is strongly associated with a predominantly cytolytic Natural killer (NK) cell immune profile versus the regulatory NK profile associated with normal pregnancy. Furthermore, dysregulation of decidual NK cells has been well recognized to contribute to recurrent miscarriages and placental insufficiency. However, the precise role that cytolytic NK (cNK) cells play in contributing to PE pathophysiology is unknown. The experiments outlined in this proposal will provide a better understanding of the mechanisms by which cNK cells may mediate PE pathophysiology. Our animal model, the Reduced Uterine Perfusion Pressure (RUPP) rat model of placental ischemia, recapitulates many characteristics of preeclamptic women including hypertension, intrauterine growth restriction, and increased cNK activation and proliferation. Our preliminary data shows that total depletion of NK cells in RUPP rats results in lowered blood pressure, decreased oxidative stress (ROS), and improved IUGR. We have also found that both TNF-α and IFN-γ, which are increased in RUPP rats, are significantly decreased following NK cell depletion. These data support the hypothesis that NK cells contribute to hypertension and IUGR in PE. However as many of these experiments depleted the entire NK cell population, we still do not fully understand the role of cNK cells in PE. Therefore, we plan to use adoptive transfer techniques to determine the role of placental ischemia-induced cNK cells to cause increased ROS and vascular dysfunction leading to hypertension and IUGR in pregnancy. We also plan to use pharmacological inhibition to block TNF-α and IFN- γ and evaluate changes in ROS production, vascular function, hypertension and IUGR in RUPP rats. Based on our previous data, we propose the hypothesis that placental ischemia activates cNK cells leading to systemic inflammation and oxidative stress, which contribute to maternal vascular dysfunction, hypertension and intrauterine growth restriction during pregnancy. To test this hypothesis, we will use in vivo and in vitro techniques to examine the followings specific aims: Specific Aim 1: To test the hypothesis that placental ischemia stimulated cNK cells increase placental and renal ROS, inflammatory cytokines (TNF-α and IFN-γ), and vascular dysfunction leading to hypertension and IUGR in pregnancy. Specific Aim 2: To test the hypothesis that blockade of cNK associated cytokines in placental ischemic rats decreases oxidative stress and inflammation resulting in improved vascular function, lower blood pressure, and decreased IUGR during pregnancy.