补体C5a调控胎盘血管新生参与子痫前期发病的机制研究

Preeclampsia (PE) is a prevalent life-threatening hypertensive disorder of pregnancy and is a leading cause of maternal and neonatal morbidity and mortality. Recent studies have indicated that the complement system contributes to the pathologic process of PE. Complement C5a is one of the most important active products of complement system, the role of which in regulating the pathogenesis of PE remains unclear. We have previously found that women with PE have elevated serum C5a level compared with healthy pregnant women. Similarly, the placentas of women with PE showed an elevated C5a deposition, which was mainly colocalized with macrophages. Besides, we detected an increased C5a receptor (C5aR) expression in the trophoblasts of women with PE. Based on above findings, we continue to explore: 1) Whether the development of PE will be alleviated or the clinical symptoms will be relieved after inhibition of C5a in the mouse model of PE 2) The molecular mechanism of C5a activation in the remodeling of placenta. 3) The role of C5a/C5aR axis in the angiogenesis and spiral artery remodeling of the placenta. 4) The dynamic changes of C5a in the circulation of women with PE and analyze the relationship between C5a and clinical parameters. Our findings will illuminate the detailed role of complement system in PE, and provide potential therapeutics targeting the C5a/C5aR axis as the new approach for the management of PE.

子痫前期（Preeclampsia, PE）是严重的妊娠期高血压疾病，是导致孕产妇和新生儿死亡的主要原因之一。近年来研究发现，补体系统参与了PE的发生发展过程。补体C5a作为补体系统最重要的活性物质之一，其在PE发病过程的调控机制仍不清楚。 我们前期研究发现，PE患者血清C5a水平较正常孕妇高，C5a在胎盘组织中沉积增加且主要来源于胎盘巨噬细胞，同时在胎盘滋养细胞上发现C5a特异性受体C5aR的表达。本项目将在此基础上进一步探索：1）抑制C5a后是否缓解模型小鼠PE的发生，改善PE的临床症状；2）C5a参与胎盘重构的分子机制；3）C5a/C5aR轴对胎盘血管新生、螺旋动脉重塑的影响；4）C5a在PE患者循环血中的动态变化及其与临床指标的相关性；本项目将有助于我们深入理解补体系统与PE发病之间的联系，为将来以C5a/C5aR轴为靶点的药物或化合物的合成提供理论依据，为PE治疗开拓新的视野。

先兆子痫是以高血压及蛋白尿为主要临床表现，其发病率约为5-8%。免疫失衡及炎症激活在先兆子痫的发病机制中起了主要作用。研究方法：从正常妊娠妇女和先兆子痫者的胎盘及血清中细胞因子、黏附因子水平，进行免疫测定及免疫组化分析。还通过流式细胞仪及免疫组化分析了两组不同人群外周血及胎盘中单核细胞、巨噬细胞的不同表型。结果：1、炎症因子（IL-1β、IL-6、IL-7、IL-8、IL-17a）、单核细胞趋化蛋白（MCP-1）、巨噬细胞炎症蛋白（MIP-1β）在先兆子痫者的血清中明显升高，并且IL-1β、IL-6、MCP-1在先兆子痫者的胎盘中同样升高。2、在先兆子痫者的外周血中，单核细胞呈现炎症前M1样的表型，而在其胎盘中，M1 巨噬细胞侵润显著增加。结论：证实了免疫失衡是先兆子痫患者炎症状态的重要促进因素，它可能有助于改进先兆子痫的治疗策略。