The role of IL-33 signaling in the pathophysiology of preeclampsia

项目总结/摘要 先兆子痫（PE）是一种妊娠特异性疾病，其特征是在妊娠期发生高血压， 妊娠20周后合并终末器官功能障碍。这种疾病的流行 在过去20年中，这一比例持续上升，是胎儿和产妇发病的主要原因。尽管 PE对母亲和胎儿健康造成的负担，除了分娩外，没有有效的PE治疗方法。 胎儿-胎盘单位，迫切需要了解PE的病理生理学，以确定潜在的 治疗目标已知改变的免疫应答有助于PE病理生理学。但 尽管临床上对这些改变的应答的潜在和促成机制还没有很好地理解， 研究已经鉴定了NLRP 3炎性体的升高的活化作为改变炎症的潜在贡献者。 免疫反应。胎盘缺血的子宫灌注压降低（RUPP）模型，我们 实验室使用，是一个广泛认可的模型，并概括了人类PE的许多特征。利用这个模型， 我们的初步数据显示，NLRP 3介导母体血压升高，子宫内生长， 限制，以及TH 17和细胞溶解NK（cNK）细胞活化。这与NLRP 3的研究一致 在其他炎性疾病过程中也显示NLRP 3活化增加， 增加TH 17和cNK细胞活化。先前的研究表明NLRP 3激活实现TH 17和cNK细胞 通过抑制IL-33信号传导（已知抑制TH 17和cNK细胞活化的信号传导途径）来激活。 我们的初步数据将异常的IL-33信号传导与NLRP 3激活联系起来，并显示在正常人中补充IL-33， RUPP大鼠导致母体血压降低，宫内生长受限改善， TH 17和溶细胞NK细胞的活化。这些数据支持了本提案中详细阐述的想法。中央 该提议背后的假设是胎盘缺血诱导的NLRP 3活化损害IL-33信号传导以诱导 TH 17和cNK细胞活化导致炎症和氧化应激，从而引起血管功能障碍， 母体高血压和宫内生长受限的发展。这一假设将通过 使用体内和体外技术的以下具体目的。具体目标1：检验以下假设： IL-33信号传导减少介导TH 17和细胞溶解性NK细胞活化、炎症和氧化应激 导致血管功能障碍，以及母体高血压和IUGR的发展， 胎盘缺血具体目的2：检验阻断妊娠大鼠中的IL-33信号传导将 诱导TH 17和溶细胞NK细胞活化、炎症和氧化应激，导致血管功能障碍， 以及高血压和IUGR的发展。

Project Summary/Abstract Preeclampsia (PE) is a pregnancy specific disorder characterized by the development of hypertension in combination with end-organ dysfunction after 20 weeks of gestation. The prevalence of this disorder has continuously increased over the past 20 years and it is a leading cause of fetal and maternal morbidity. Despite the burden PE causes on maternal and fetal health, no effective treatment for PE exists other than delivery of the fetal-placental unit and there is an urgent need to understand PE pathophysiology in order to identify potential therapeutic targets. It is known that altered immune responses contribute to PE pathophysiology. However, the mechanisms underlying and contributing to those altered responses are not well understood though clinical studies have identified elevated activation of the NLRP3 inflammasome as a potential contributor to altered immune responses. The Reduced Uterine Perfusion Pressure (RUPP) model of placental ischemia, which our lab uses, is a widely acknowledged model and recapitulates many characteristics of human PE. Using this model, our preliminary data shows NLRP3 mediates increases in maternal blood pressure, intrauterine growth restriction, and TH17 and cytolytic NK (cNK) cell activation in RUPP rats. This is consistent with studies on NLRP3 activation in other inflammatory disease processes, which also show increased NLRP3 activation causing increased TH17 and cNK cell activation. Previous studies propose NLRP3 activation achieves TH17 and cNK cell activation through inhibition of IL-33 signaling, a signaling pathway known to inhibit TH17 and cNK cell activation. Our preliminary data links aberrant IL-33 signaling to NLRP3 activation and shows supplementation of IL-33 in RUPP rats results in lower maternal blood pressure, improved intrauterine growth restriction, and decreased activation of TH17 and cytolytic NK cells. This data supports the ideas detailed in this proposal. The central hypothesis behind this proposal is placental ischemia induced NLRP3 activation impairs IL-33 signaling to induce TH17 and cNK cell activation leading to inflammation and oxidative stress to cause vascular dysfunction and the development of maternal hypertension and intrauterine growth restriction. This hypothesis will be tested through the following specific aims using both in vivo and in vitro techniques. Specific aim 1: Test the hypothesis that decreased IL-33 signaling mediates TH17 and cytolytic NK cell activation, inflammation, and oxidative stress leading to vascular dysfunction, and the development of maternal hypertension and IUGR in response to placenta ischemia. Specific aim 2: Test the hypothesis that blockade of IL-33 signaling in pregnant rats will induce TH17 and cytolytic NK cell activation, inflammation, and oxidative stress leading to vascular dysfunction, and the development of hypertension and IUGR.