背景:先兆子痫(PE)是由于胎盘功能障碍引起的严重妊娠并发症。血栓调节蛋白(TM),一种在滋养层细胞膜上表达的糖蛋白,通过调节凝血和炎症在胎盘中发挥器官保护作用。TM介导的高迁移率组Box1(HMGB1)的调节是促进胎盘稳态并预防小鼠妊娠并发症的重要机制。这里,我们旨在阐明胎盘TM和HMGB1在人类PE病理生理中的作用。
结果:在这项研究中,从72例PE患者和110例正常对照中获得母体血清和胎盘组织。评估母体血清中的可溶性TM(sTM)和HMGB1水平。使用免疫组织化学和qPCR评估胎盘TM和HMGB1表达水平。正常妊娠血清sTM和HMGB1水平随孕龄逐渐升高;然而,PE组循环sTM和HMGB1水平均显著升高.与正常对照组相比,PE患者血清HMGB1/sTM比值升高,与PE的临床严重程度呈正相关。免疫组织化学分析显示TM的丢失和核外HMGB1的增加。PE胎盘中TMmRNA表达减少,与可溶性fms样酪氨酸激酶-1(sFlt-1)表达呈负相关。
结论:循环sTM和HMGB1的增加可能归因于PE患者胎盘TM脱落的增强。由胎盘TM和HMGB1水平失衡介导的分子事件可能是PE的基本特征;母体血清HMGB1/sTM比率可以反映这种状态。
Preeclampsia (PE) is a severe pregnancy complication due to placental dysfunction. Thrombomodulin (TM), a glycoprotein expressed on the trophoblast cell membrane, plays an organ-protective role in the placenta by regulating coagulation and inflammation. TM-mediated regulation of High Mobility Group Box1(HMGB1) is an essential mechanism that contributes to placental homeostasis and prevents pregnancy complications in mice. Here, we aimed to clarify the role of placental TM and HMGB1 in the pathophysiology of human PE.
In this study, maternal blood serum and placental tissue were obtained from 72 PE patients and 110 normal controls. Soluble TM(sTM) and HMGB1 levels in the maternal serum were assessed. The placental TM and HMGB1 expression levels were evaluated using immunohistochemistry and qPCR. Serum sTM and HMGB1 levels gradually increased with gestational age in normal pregnancies; however, both circulating sTM and HMGB1 levels were significantly higher in the PE group. Serum HMGB1/sTM ratio was elevated in PE patients compared to that in normal controls, which correlated positively with the clinical severity of PE. The immunohistochemistry analysis revealed the loss of TM and the increase in extranuclear HMGB1. TM mRNA expression was diminished in PE placentas, which negatively correlated with soluble fms-like tyrosine kinase-1 (sFlt-1) expression.
The increase in circulating sTM and HMGB1 could be attributed to the enhanced placental TM shedding in PE patients. The molecular events mediated by the imbalance in the placental TM and HMGB1 levels could be an underlying feature of PE; maternal serum HMGB1/sTM ratio could reflect this status.