PI3K/Akt信号通路抑制免疫炎症反应对子痫前期的保护作用及机制研究

Immuno-inflammatory response plays an immportant role in the pathogenesis and organ damage of preeclampisa. Our preliminary study found that an ultra-low-dose LPS injection protocol in early pregnant rats can induce an animal model of preeclampsia, when inhibit the PI3K/Akt signaling pathway, preeclampsia aggravated as immuno-inflammatory response exploded. This study will use pathologic, immunologic, and molecular biologic technologies, using in vivo and in vitro models, in order to explore: 1) PI3K/Akt signaling pathway can inhibit the immuno-inflammatory response of preeclampsia. 2) The mechanisms study: PI3K/Akt inhibits trophoblasts secret chemotactic factors, decreasing the immunocytes accumulated at the maternal-fetal interface; PI3K/Akt directly suppresss the MAPKK inflammatory pathway by activating MKP-1; PI3K/Akt inhibits the expression of NF-κB by inactivating GSK3β. 3) The protective effect for preeclampsia by activation of PI3K/Akt signaling pathway. This study will investigate the immuno-inflammation mechanism of preeclampsia, and can provide new insight into therapeutics target point of preeclampsia.

免疫炎症反应在子痫前期发病及脏器损害中起着重要作用。我们前期研究发现：应用早孕期超低剂量脂多糖（LPS）注射激活免疫炎症反应能够诱导出大鼠子痫前期样表型，当阻断PI3K/Akt信号通路后免疫炎症反应加剧，同时子痫前期病情加重。本研究将采用病理、免疫及分子生物学技术，从整体到细胞水平，探讨：1）PI3K/Akt信号通路抑制子痫前期免疫炎症反应；2）PI3K/Akt信号通路抑制子痫前期免疫炎症反应的机制: PI3K/Akt信号通路抑制滋养细胞分泌趋化因子，减少免疫炎症细胞向母胎界面聚集；PI3K/Akt通路激活MKP-1直接抑制MAPKK炎症通路；PI3K/Akt通路同时灭活GSK3β抑制促炎因子NF-κB分泌。3）激活PI3K/Akt信号通路对子痫前期的保护作用。本研究将探索子痫前期免疫炎症机制，从而为临床子痫前期新治疗靶点的研究提供新思路。

子痫前期（Preeclampsia）是最常见的妊娠期并发症之一，发病率约占孕产妇总数的2-8%，也是孕产妇及围产儿死亡的主要原因。由于子痫前期的发病机制至今未明，所以目前尚无有效的防治方法。虽然有多种因素参与子痫前期的病理生理过程，但是大量研究表明免疫炎症反应过度激活在子痫前期的发病及脏器功能损害中起着关键作用，阻断这一过程明显改善子痫前期预后。然而既往的报道主要侧重于研究促进子痫前期免疫炎症反应的机制，对于抑制子痫前期免疫炎症反应的研究甚少。本研究结果显示：1、LPS刺激孕鼠后出现子痫前期表现；2、LPS刺激孕鼠后免疫炎症激活；3、体外研究证实LPS调控Akt通路变化；4、LPS刺激孕鼠建立子痫前期模型后Akt通路表达量下降；5、Curcumin激活Akt通路后子痫前期鼠症状改善同时免疫炎症反应减轻。本研究提示Akt通路可能是子痫前期治疗新的靶点。