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

IL-33信号在先兆子痫病理生理学中的作用

• 批准号: 10537658
• 负责人: Xi Wang
• 金额: $ 3.88万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2024-08-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10537658
• 关键词: Address; Affect; Arteries; Attenuated; Biological Availability; Blood Pressure; Blood Vessels; Cells; Characteristics; Child; Clinical Data; Clinical Research; Complex; Data; Development; Disease; Etiology; Exhibits; Fetal Growth Retardation; Fetal Mortality Statistics; Fetal Weight; Fetal health; Functional disorder; Human Characteristics; Hypertension; Immune; Immune response; Impairment; In Vitro; Inflammasome; Inflammation; Inflammatory; Infusion procedures; Ischemia; Link; Maternal Health; Maternal Mortality; Mediating; Modeling; NK Cell Activation; Natural Killer Cells; Organ; Oxidative Stress; Perfusion; Placenta; Plasma; Play; Population; Pre-Eclampsia; Pregnancy; Prevalence; Process; Publishing; Rattus; Recombinants; Research; Risk; Role; Signal Pathway; Signal Transduction; Spiral Artery of the Endometrium; Supplementation; Techniques; Testing; United States; Uterus; Vascular Diseases; Vascular resistance; Woman; Women' s Health; base; cell type; effective therapy; fetal; improved; in vivo; kidney vascular structure; maternal hypertension; maternal morbidity; neutralizing antibody; new therapeutic target; novel; pathophysiology of preeclampsia; pregnant; pressure; receptor; response; theories; therapeutic target

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.

项目摘要/摘要 子痫前期(PE)是一种妊娠特有的疾病，其特征是在 妊娠20周后合并终末器官功能障碍。这种疾病的流行已经 在过去20年中持续增加，是胎儿和产妇发病率的主要原因。尽管 PE对母儿健康造成的负担，除分娩外，尚无有效的治疗方法 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 治疗靶点。众所周知，免疫反应的改变有助于PE的病理生理学。然而， 虽然临床上对这些改变的反应的潜在和促进机制还不是很清楚 研究发现，NLRP3炎症体的激活升高是导致改变的潜在因素 免疫反应。胎盘缺血的降低子宫灌流压力(RUPP)模型 Lab Use是一个被广泛认可的模型，它概括了人类体育的许多特征。使用这个模型， 我们的初步数据显示，NLRP3调节母亲血压的升高，胎儿宫内发育 限制，以及TH17和细胞溶解NK(CNK)细胞在RUPP大鼠的激活。这与NLRP3的研究是一致的 在其他炎症性疾病过程中的激活，这也显示NLRP3激活增加导致 增加TH17和CNK细胞的活性。以往研究表明，NLRP3激活可实现TH17和CNK细胞 通过抑制IL-33信号而激活，IL-33信号通路已知能抑制TH17和CNK细胞的激活。 我们的初步数据将异常的IL-33信号与NLRP3激活联系起来，并显示IL-33在 Rupp大鼠降低了母亲的血压，改善了胎儿生长受限，并降低了 激活TH17和杀伤细胞的NK细胞。这些数据支持这项提案中详细阐述的想法。中环 这一建议背后的假设是胎盘缺血诱导的NLRP3激活损害了IL-33信号诱导 Th17和CNK细胞激活导致炎症和氧化应激导致血管功能障碍 母体高血压和宫内生长受限的发生。这一假设将通过 以下是使用体内和体外技术的具体目的。具体目标1：检验以下假设 IL-33信号降低介导TH17和细胞溶解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。特定目标2：验证阻断怀孕大鼠的IL-33信号将 诱导TH17和细胞溶解的NK细胞活化，炎症和氧化应激导致血管功能障碍， 高血压和胎儿宫内发育迟缓的发生。