子痫前期母胎界面TLR4作用的研究进展

doi:10.12280/gjfckx.20230679

摘要/Abstract

摘要：

子痫前期是一种多脏器和系统损害的妊娠并发症，严重危害母儿健康，但子痫前期的病因和发病机制尚未完全阐明。正常妊娠过程中，母胎界面Toll样受体4（Toll-like receptor 4，TLR4）调控炎症免疫微环境稳态；子痫前期过程中，母胎界面TLR4信号异常，不仅介导母胎界面炎症免疫紊乱，还与铁死亡、焦亡、代谢重编程和细胞衰老等新型病理现象密切相关，并可能介导子代神经系统发育异常。此外，靶向母胎界面TLR4可能是子痫前期新药研究的潜在药理机制之一。结合近年相关文献，综述子痫前期母胎界面TLR4的多种可能作用，为子痫前期发病机制和治疗手段的研究提供参考。

关键词: 先兆子痫, Toll样受体4, 母体胎儿间交换, 炎症, 炎症趋化因子类, 母胎界面

Abstract:

Pre-eclampsia is a pregnancy complication with multiple organs and system injuries, seriously impairing maternal and fetal health. Nevertheless, the etiopathogenesis of pre-eclampsia has not been fully elucidated yet. In normal pregnancy, Toll-like receptor 4(TLR4) at the maternal-fetal interface regulates the homeostasis of the inflammatory-immune microenvironment. In pre-eclampsia, abnormal TLR4 signaling at the maternal-fetal interface not only mediates deviated inflammatory-immune reaction, but also interacts with other novel pathological phenomena, including ferroptosis, pyroptosis, metabolism reprogramming, and cellular senescence. Furthermore, TLR4 at the maternal-fetal interface may mediate the abnormal development of the nervous system in the offspring. In addition, targeting TLR4 at the maternal-fetal interface may be one of the potential pharmacological mechanisms for new therapeutic research in pre-eclampsia. Based on recent relevant literature, this article explores the multiple possible roles of TLR4 at the maternal-fetal interface in pre-eclampsia and provides reference for the study of the pathogenesis and therapies of pre-eclampsia.

Key words: Pre-eclampsia, Toll-like receptor 4, Maternal-fetal exchange, Inflammation, Chemokines, Maternal-fetal interface

黄晓彤, 程湘玮, 张阳. 子痫前期母胎界面TLR4作用的研究进展[J]. 国际妇产科学杂志, 2023, 50(6): 689-694.

HUANG Xiao-tong, CHENG Xiang-wei, ZHANG Yang. Research Progress into the Role of TLR4 at the Maternal-Fetal Interface in Pre-Eclampsia[J]. Journal of International Obstetrics and Gynecology, 2023, 50(6): 689-694.

图/表 1

参考文献 38

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药物	子痫前期细胞/动物模型	潜在作用机制	参考文献
阿司匹林	大鼠，怀孕第14天尾静脉注射LPS（1 μg/kg）	抑制胎盘TLR4/MyD88/NF-κB信号通路活化和IL-6、IL-1β、单核细胞趋化蛋白1（MCP-1）等炎症细胞因子的表达	Sun等^[25]
二甲双胍	HTR-8/SVneo滋养细胞系，LPS（200 ng/mL，24 h）	抑制滋养细胞TLR4/NF-κB/PFKFB3途径，改善糖代谢稳态失衡，促进ATP生成，抑制滋养细胞焦亡	Zhang等^[5]
	大鼠，怀孕第13~18天腹腔注射LPS（20~70 μg/kg）	抑制胎盘NF-κB信号通路活化和炎症细胞因子TNF-α、IL-6的生成；增加超氧化物歧化酶（SOD）活性、降低诱导型一氧化氮合酶（iNOS）活性、降低MDA和一氧化氮（NO）水平以减少氧化/硝化应激	Hu等^[26]
普伐他汀	大鼠，怀孕第5天尾静脉注射LPS（0.5 μg/kg）	抑制胎盘TLR4/NF-κB信号通路活化和炎症细胞因子IL-6、MCP-1的表达，改善子宫螺旋动脉重铸	Yang等^[27]
姜黄素	大鼠，怀孕第5天尾静脉注射LPS（0.5 μg/kg）	抑制胎盘TLR4/NF-κB信号通路活化和炎症细胞因子IL-6、MCP-1的表达，改善子宫螺旋动脉重铸	Gong等^[28]
维生素D	大鼠，怀孕第5天尾静脉注射LPS（0.5 μg/kg）	抑制胎盘TLR4/NF-κB信号通路活化和炎症细胞因子TNF-α、γ干扰素（IFN-γ）、IL-6的表达，改善胎盘血管内皮功能，减轻胎盘病理损伤，提高子代的学习和认知能力	Ma等^[29]
孕酮+维生素D	子痫前期患者单核细胞	下调子痫前期孕妇单核细胞中 NLRP1/NLRP3炎症小体；抑制TLR4/MyD88/NF-κB 通路活化	Matias等^[30]
雌二醇	大鼠，怀孕第7~11天腹腔注射L-NAME（50 mg/kg）	抑制胎盘TLR4/MyD88/IRAK4/TRAF6 信号通路活化；抑制NO生成和iNOS 活性；抑制炎症细胞因子IL-1β、IL-6、IFN-γ和MCP-1 表达；抑制细胞因子CD49d、细胞间黏附分子1（ICAM1）、血管间黏附分子1（VCAM1）、淋巴细胞功能相关抗原-1（LFA-1）、MMP-2、MMP-9 和sFlt-1的表达以保护血管内皮功能	Lin等^[31]
催乳素	胎盘外植体，LPS（500 ng/mL，24 h）	抑制胎盘外植体TLR4/NF-κB信号通路活化和IL-6、IL-1β、TNF-α等炎症细胞因子的表达	Olmos-Ortiz等^[32]
L-瓜氨酸	怀孕的达尔盐敏感性大鼠（DSSR）	抑制胎盘TLR4/MyD88/NF-κB信号通路活化；促进NO、内皮型一氧化氮合酶（eNOS）、内皮源性超极化因子（EDHF）生成以改善内皮功能；抑制sFlt-1的表达以促进胎盘血管生成；延缓胎盘衰老	Man等^[33]
非瑟酮	大鼠，怀孕第14天尾静脉注射LPS（1 μg/kg）	抑制胎盘中的 TLR4/NF-κB通路活化；促进核转录因子红系2相关因子2（Nrf2）/HO-1通路；减少TNF-α、IL-6、IL-1β和MDA的生成；提高SOD和谷胱甘肽含量；降低sFlt-1/胎盘生长因子（PlGF）比值	Li等^[18]
丙泊酚	HTR-8/SVneo滋养细胞系，LPS（100 ng/mL）	抑制滋养细胞miR-216a-5p/TLR4/MyD88/NF-κB信号通路，改善滋养细胞功能障碍	Wang等^[34]
甘草甜素	大鼠，怀孕第7~11天腹腔注射L-NAME（50 mg/kg）	抑制胎盘TLR4和高迁移率族蛋白B1表达，抑制炎症细胞因子TNF-α、iNOS、IL-1和IL-6的表达	Liu等^[17]
夹竹桃素	大鼠，怀孕第13~19天腹腔注射L-NAME（200 mg/kg）	抑制胎盘TLR4/NF-κB信号通路活化；降低血清和胎盘炎症细胞因子IL-6水平；改善血清和胎盘中sFlt-1和PlGF的失衡	Sha等^[35]
黄芪甲苷	大鼠，怀孕第14天尾静脉注射LPS（1 μg/kg）	抑制胎盘TLR4/NF-κB信号通路活化和炎症细胞因子IL-6、IL-1β的表达；改善胎盘中sFlt-1和PlGF/血管内皮生长因子（VEGF）的失衡	Tuerxun等^[36]
人参皂苷Rg2	大鼠，怀孕第8~19天口服管饲L-NAME（50 mg/kg）	抑制大脑TLR4/MyD88/NF-κB信号通路活化和炎症细胞因子 IL-1β、TNF-α表达	Cai等^[37]
天麻素	大鼠，怀孕第13~21天腹腔注射L-NAME（100 mg/kg）；HTR-8/SVneo滋养细胞系，缺氧处理	抑制胎盘和滋养细胞的TLR4/MyD88/NF-κB信号通路活化；改善胎盘细胞和滋养细胞的凋亡	Mei等^[38]

药物	子痫前期细胞/动物模型	潜在作用机制	参考文献
阿司匹林	大鼠，怀孕第14天尾静脉注射LPS（1 μg/kg）	抑制胎盘TLR4/MyD88/NF-κB信号通路活化和IL-6、IL-1β、单核细胞趋化蛋白1（MCP-1）等炎症细胞因子的表达	Sun等^[25]
二甲双胍	HTR-8/SVneo滋养细胞系，LPS（200 ng/mL，24 h）	抑制滋养细胞TLR4/NF-κB/PFKFB3途径，改善糖代谢稳态失衡，促进ATP生成，抑制滋养细胞焦亡	Zhang等^[5]
	大鼠，怀孕第13~18天腹腔注射LPS（20~70 μg/kg）	抑制胎盘NF-κB信号通路活化和炎症细胞因子TNF-α、IL-6的生成；增加超氧化物歧化酶（SOD）活性、降低诱导型一氧化氮合酶（iNOS）活性、降低MDA和一氧化氮（NO）水平以减少氧化/硝化应激	Hu等^[26]
普伐他汀	大鼠，怀孕第5天尾静脉注射LPS（0.5 μg/kg）	抑制胎盘TLR4/NF-κB信号通路活化和炎症细胞因子IL-6、MCP-1的表达，改善子宫螺旋动脉重铸	Yang等^[27]
姜黄素	大鼠，怀孕第5天尾静脉注射LPS（0.5 μg/kg）	抑制胎盘TLR4/NF-κB信号通路活化和炎症细胞因子IL-6、MCP-1的表达，改善子宫螺旋动脉重铸	Gong等^[28]
维生素D	大鼠，怀孕第5天尾静脉注射LPS（0.5 μg/kg）	抑制胎盘TLR4/NF-κB信号通路活化和炎症细胞因子TNF-α、γ干扰素（IFN-γ）、IL-6的表达，改善胎盘血管内皮功能，减轻胎盘病理损伤，提高子代的学习和认知能力	Ma等^[29]
孕酮+维生素D	子痫前期患者单核细胞	下调子痫前期孕妇单核细胞中 NLRP1/NLRP3炎症小体；抑制TLR4/MyD88/NF-κB 通路活化	Matias等^[30]
雌二醇	大鼠，怀孕第7~11天腹腔注射L-NAME（50 mg/kg）	抑制胎盘TLR4/MyD88/IRAK4/TRAF6 信号通路活化；抑制NO生成和iNOS 活性；抑制炎症细胞因子IL-1β、IL-6、IFN-γ和MCP-1 表达；抑制细胞因子CD49d、细胞间黏附分子1（ICAM1）、血管间黏附分子1（VCAM1）、淋巴细胞功能相关抗原-1（LFA-1）、MMP-2、MMP-9 和sFlt-1的表达以保护血管内皮功能	Lin等^[31]
催乳素	胎盘外植体，LPS（500 ng/mL，24 h）	抑制胎盘外植体TLR4/NF-κB信号通路活化和IL-6、IL-1β、TNF-α等炎症细胞因子的表达	Olmos-Ortiz等^[32]
L-瓜氨酸	怀孕的达尔盐敏感性大鼠（DSSR）	抑制胎盘TLR4/MyD88/NF-κB信号通路活化；促进NO、内皮型一氧化氮合酶（eNOS）、内皮源性超极化因子（EDHF）生成以改善内皮功能；抑制sFlt-1的表达以促进胎盘血管生成；延缓胎盘衰老	Man等^[33]
非瑟酮	大鼠，怀孕第14天尾静脉注射LPS（1 μg/kg）	抑制胎盘中的 TLR4/NF-κB通路活化；促进核转录因子红系2相关因子2（Nrf2）/HO-1通路；减少TNF-α、IL-6、IL-1β和MDA的生成；提高SOD和谷胱甘肽含量；降低sFlt-1/胎盘生长因子（PlGF）比值	Li等^[18]
丙泊酚	HTR-8/SVneo滋养细胞系，LPS（100 ng/mL）	抑制滋养细胞miR-216a-5p/TLR4/MyD88/NF-κB信号通路，改善滋养细胞功能障碍	Wang等^[34]
甘草甜素	大鼠，怀孕第7~11天腹腔注射L-NAME（50 mg/kg）	抑制胎盘TLR4和高迁移率族蛋白B1表达，抑制炎症细胞因子TNF-α、iNOS、IL-1和IL-6的表达	Liu等^[17]
夹竹桃素	大鼠，怀孕第13~19天腹腔注射L-NAME（200 mg/kg）	抑制胎盘TLR4/NF-κB信号通路活化；降低血清和胎盘炎症细胞因子IL-6水平；改善血清和胎盘中sFlt-1和PlGF的失衡	Sha等^[35]
黄芪甲苷	大鼠，怀孕第14天尾静脉注射LPS（1 μg/kg）	抑制胎盘TLR4/NF-κB信号通路活化和炎症细胞因子IL-6、IL-1β的表达；改善胎盘中sFlt-1和PlGF/血管内皮生长因子（VEGF）的失衡	Tuerxun等^[36]
人参皂苷Rg2	大鼠，怀孕第8~19天口服管饲L-NAME（50 mg/kg）	抑制大脑TLR4/MyD88/NF-κB信号通路活化和炎症细胞因子 IL-1β、TNF-α表达	Cai等^[37]
天麻素	大鼠，怀孕第13~21天腹腔注射L-NAME（100 mg/kg）；HTR-8/SVneo滋养细胞系，缺氧处理	抑制胎盘和滋养细胞的TLR4/MyD88/NF-κB信号通路活化；改善胎盘细胞和滋养细胞的凋亡	Mei等^[38]