妊娠期肝内胆汁淤积症高浓度血胆汁酸诱发胎盘炎性反应的机制研究

Intrahepatic cholestasis of pregnancy (ICP) is the most frequent liver disease arising in the second or third trimester of pregnancy. Clinically, ICP is characterized by skin itching, maternal pruritus and elevated level of serum bile acids. In contrast to the benign effects on the mother, ICP has severe consequences for the fetus: it is associated with an increased risk of fetal preterm delivery, fetal distress and fetal loss. The etiology of ICP is multiplex and not fully understood. Although a clear correlation between the elevated maternal serum bile acids and deficient fetal outcome has been established in clinical practice, the underlying mechanisms remain elusive. Our previous microarray study has suggested the inflammatory response in ICP placentas. In this study, we aimed to reveal the regulation mechanisms of placental immune responses by high level of bile acids in ICP patients. First, we plan to reveal the expression pattern of inflammatory genes in placental tissues from healthy and ICP pregnant women and then reveal the underlying mechanisms by using syncytiotrophoblasts treated with different concentration of bile acids. Then we will address the role of bile acids in the immune cell infiltration and immune responses in ICP placentas. Based on the indentified mechanisms, we will also evaluate the effect of inhibiting bile acid triggered signaling in the treatment of ICP by using rat ICP model. Taken together, our study will not only elucidate the function and mechanisms of bile acids in ICP pathology, but also contribute to the development of new therapeutics for this disease.

妊娠期肝内胆汁淤积症（ICP）是一种以高血胆汁酸为主要特征的孕妇妊娠期并发症,可引起胎儿早产甚至死亡。临床发现胎儿并发症发病率与ICP孕妇血液胆汁酸浓度呈正相关，而胆汁酸的作用及其机制未知。利用基因芯片技术，我们前期的研究提示ICP患者胎盘可能存在炎症反应。本课题以此为出发点，旨在系统地研究胎盘微环境中高浓度胆汁酸对胎盘中免疫细胞迁移和炎症反应的调控机制。通过在胎盘组织以及体外培养的胎盘合体滋养层细胞水平研究胆汁酸对炎症相关因子的表达调控及其分子机制；揭示高浓度胆汁酸对免疫细胞在胎盘中的黏附、迁移以及胎盘炎症反应的影响及其机制。进而利用ICP动物模型探讨抑制胆汁酸相关信号通路缓解ICP病症的可能性。本课题的研究不仅将阐明胞外微环境中的胆汁酸分子对免疫细胞异常黏附、迁移和炎症反应的调控机制；还将明确ICP孕妇高血胆汁酸对母体和胎儿的影响及其机理，对于ICP的治疗具有重要的理论意义和应用价值。

妊娠期肝内胆汁淤积症（Intrahepatic cholestasis of pregnancy，以下简称ICP）是一种在妊娠期孕妇中出现的以皮肤瘙痒、黄疸、血液胆汁酸浓度升高和肝酶异常为主要特征的妊娠期并发症，发病率根据人种、季节等的不同分布在0.5-2%之间。虽然ICP对孕妇的影响在产后可以迅速消失，但本病的主要危害在于对围产儿的不良影响，可导致早产（19-60%）、胎儿宫内窘迫（22-33%）、胎死宫内（1-2%）等。血清胆汁酸浓度升高是ICP最为重要的检测指标，尽管高浓度的母体血清胆汁酸和胎儿预后不良之间的关系已经被建立，但高浓度的母体胆汁酸影响胎儿预后的相关机制仍不清楚。在本研究中，我们通过在ICP病人胎盘组织水平、细胞水平和动物胆淤模型上的研究，阐明了ICP病人胎盘微环境胆汁酸对淋巴细胞黏附与迁移的调控机制及其在疾病中的作用机理，即高浓度胆汁酸通过激活胎盘滋养层细胞中的Gpbar1/PI3K./NF-κB信号通路引起胎盘过度炎症反应，胎盘组织、功能发生损伤，从而对胎儿预后造成不良影响。此外，我们探讨了两种临床药物熊去氧胆汁酸和穿心莲内酯对ICP的治疗作用及机制，揭示相比于通过竞争其他胆汁酸结合Gpbar1发挥功能的熊去氧胆汁酸，通过直接抑制NF-κB信号通路发挥功能的穿心莲内酯对缓解胎盘炎症和提高胎儿预后更加有效，这对ICP的机理研究和临床治疗具有重要价值。