补体介导的巨噬细胞-滋养细胞母胎对话参与子痫前期的发病机制研究

Preeclampsia is a serious hypertensive disorder of pregnancy and is one of the leading causes of maternal and neonatal mortality. In recent years, several studies have suggested that the complement system is involved in the development of preeclampsia. Our previous study found that level of complement C5a is significantly elevated in peripheral blood and placental tissue in women with preeclampsia and animal models, accompanying infiltration of macrophages. Besides, we detected expression of C5a receptor (C5aR) in placental macrophages. Based on the above findings, we proposed the hypothesis that complement C5a mediated macrophage activation is involved in the regulation of placental trophoblast function in preeclampsia. And we continue to explore: 1) mononuclear/macrophage typing in peripheral blood and placental tissues, and the effect of C5a on macrophage polarization; 2) clear C5a-mediated Macrophage activation is involved in the regulation of trophoblast function; 3) elucidation of the specific molecular mechanism of C5a regulation of macrophage activation; 4) exploring the correlation between C5a levels and preeclampsia clinical indicators and peripheral blood mononuclear cell subtypes. This project will help us to understand the relationship between the complement system, immune cells and preeclampsia, and provide a theoretical basis for the future synthesis of drugs or compounds targeting C5a, and open up new horizons for the treatment of preeclampsia.

子痫前期是严重的妊娠期高血压疾病，是导致孕产妇及围产儿死亡的主要原因之一。近年来研究认为补体系统参与了子痫前期的发生发展。我们的前期研究发现补体C5a在子痫前期患者外周血、胎盘组织及动物模型中表达显著升高，且伴有巨噬细胞浸润，我们的预实验也证实胎盘巨噬细胞膜上表达C5a特异性受体C5aR。本项目在此基础上，提出研究假设补体C5a介导的巨噬细胞活化参与子痫前期胎盘滋养细胞功能的调控。并进一步探索：1）外周血及胎盘组织中单核/巨噬细胞的极化分型，及C5a对巨噬细胞极化的影响；2）明确C5a介导的巨噬细胞活化参与滋养细胞功能的调控；3）阐明C5a调控巨噬细胞活化的具体分子机制；4）探索C5a水平与子痫前期临床指标及外周血单个核细胞亚型的相关性。本项目将有助于我们深入理解补体系统、免疫细胞与子痫前期之间的联系，为将来以C5a为靶点的药物或化合物的合成提供理论依据，为子痫前期治疗开拓新的视野。

子痫前期（PE）是危及生命的多系统疾病，是导致孕产妇及围产儿死亡的主要原因之一。研究显示补体系统的激活与PE的病理过程密切相关。我们的研究报道了补体C5a在母体外周血及胎盘组织中高表达，并且进一步证实C5a通过介导巨噬细胞的活化调控胎盘细胞的功能以及母体的外周血管功能。C5a促进巨噬细胞向M1型巨噬细胞转化，产生大量促炎因子表达，如IL-6、IL1β、MCP-1等；C5a与其受体C5aR结合，通过AKT/Hif-1α/sFlt1通路使得巨噬细胞活化，进一步影响滋养细胞的功能，整体敲除或细胞水平干预C5aR，则抑制了巨噬细胞的活化，保护了滋养细胞功能，进一步降低血压。另外，外周血C5a水平与PE临床指标存在密切关系，C5a与母体血压及动脉硬化程度呈正相关。因此，干预C5a将为PE治疗带来获益，也提供理论依据。

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