妊娠期糖尿病母胎界面先天性免疫诱导的炎症反应

Gestational diabetes mellitus (GDM) as one of common pregnancy complications, has great influences on series of long-term issues, including women in GDM developing type 2 diabetes, high risk of metabolism syndrome in their offspring' adult period. With new criteria for the diagnosis of GDM gradually promoted, greater number of pregnancies are in need of careful glucose control. Meanwhile, maternal-fetal interface connects the abnormal maternal metabolism and fetal physical responses, which provide a window to investigate the mechanism of maternal-fetal complications in GDM. As chronic inflammatory responses is a common feature in metabolism syndrome and GDM, innate immunity (such as toll-like receptor, TLR4 signaling pathway) induced inflammatory response in maternal-fetal interface of preeclampsia and obesity was also found to be involved and play a key role in the pathogenesis. Given the above evidence, the aim of the present study is as follows: 1.to investigate the TLR4 expression and distribution at protein level in placenta of gestational diabetes mellitus and analysis the association between the TLR4,inflammatory response and placenta function. 2. As experimental diabetes has been shown maternal and fetal lipid metabolism impaired， to investigate the effect of TLR4 agonists, lipopolysaccharide and saturated fatty acid (SFA), on inflammatory response and function of cultured placental trophoblast cells, which is TLR4 pathway dependent. 3. To explore the regulator of TLR4 signaling pathway of maternal-fetal interface in GDM, as the magnitude of inflammatory cytokine production need to be controlled to protect placenta locally, or even the fetus from inflammatory damage.

妊娠期糖尿病（Gestational Diabetes Mellitus, GDM）是常见的妊娠合并症，随着新诊断标准的推行，临床上需要干预的对象逐年增加。母胎界面将母体异常代谢状态和胎儿相应生理反应联系起来。由于在代谢综合征和GDM中均存在慢性低度炎症反应，而母胎界面先天性免疫Toll-like receptor，TLR4所诱导的炎症反应是包括肥胖、先兆子痫等在内的重要的致病机制。因此，本课题结合GDM胎盘炎症反应及功能改变,研究TLR4的蛋白水平的表达和分布，明确TLR4细胞来源；使用TLR4配体LPS及饱和脂肪酸刺激体外培养的胎盘细胞，证实母体异常代谢状态能够通过激活胎盘局部滋养层细胞的先天性免疫TLR4通路依赖性炎症反应，影响胎盘细胞功能；进一步针对特定TLR4通路调控因子，了解胎盘局部相应的TLR4通路调控机制如何避免炎症持续存在所导致的母胎界面局部乃至对胎儿的过度损伤。

妊娠期糖尿病（gestational diabetes mellitus, GDM）作为妊娠期特有的常见合并症，表现为随着孕周增加而逐渐加重的胰岛素抵抗，由于疾病可能带来的不良母儿深远影响而日益受到重视。本研究初步探讨GDM母胎界面的先天性免疫反应中重要的病原模式识别受体TLR4（Toll.-like Receptor, TLR4）通路在GDM发病中作用。比较了年龄、孕周、体重、血脂代谢情况匹配的GDM病例组和对照组胎盘样本，大体病理变化，炎症反应，TLR4通路表达分布及激活，胰岛素抵抗通路分布及激活情况；体外培养胎盘滋养细胞，比较TLR4通路特有配体LPS及不良代谢产物（高糖）刺激，观察TLR4通路激活情况；采用TLR4阻断剂验证不良代谢产物通过并依赖于TLR4通路激活，进而造成胎盘局部胰岛素抵抗，参与GDM发病。研究充分考虑到可能造成胰岛素抵抗及炎症反应的多种因素，进行样本入组剔除及匹配，发现GDM时母胎界面TLR4通路激活，较之正常妊娠存在表达及功能差异，且具有空间特定分布模式，同时，相应部位胰岛素受体通路关键分子活化存在差异，表现为胰岛素抵抗，体外细胞TLR4阻断实验证实上述因果关系。提示GDM胎盘的近母体面滋养层细胞对于GDM发病具有重要作用，充分肯定了后续探讨GDM母胎界面参与GDM发病研究的必要性，为分析表达定位取材、体外模型选择提供科学依据。