ATX-LPA轴在PBC发病机制中的作用及其相关机制的研究

Primary biliary cholangitis is an autoimmune disease characterized by progressive destruction of intrahepatic biliary epithelial cells,and can lead to fibrosis, eventually cirrhosis.The pathogenesis for PBC is still unclear. Innate immune response may be involved in the pathogenesis of PBC. Kupffer cells as specialized macrophages located in the liver are an integral part of liver's inherent immunity, and play an important role in inflammatory injury. Hepatic stellate cells can produce the extracellular matrix, the activation and apoptosis of stellate cells are the core links of liver fibrosis. During the liver injury, activated HSCs is critically important for the KCs activation. Autotaxin can convert lysophosphatidylcholine into LPA. When the level of ATX is high, the concentration of LPA and the expression of its receptor are increased. ATX-LPA axis can activate the stellate cells, inhibit the apoptosis of stellate cells, and induce liver fibrosis，it can also promote the differentiation of monocytes into macrophages.This research will focus on the PBC patients, making and exploring the role of ATX-LPA axis during various clinical phases, including the PBC occurrence, development, and efficacy, meanwhile，investigating the processes of interaction among ATX-LPA axis, BECs, HSCs, and KCs in the pathogenesis of PBC. This will be a big step in the direction of prediction of disease severity and developing target therapies for PBC.

PBC是肝内胆管上皮细胞（BECs）进行性炎症破坏，逐渐出现肝纤维化、肝硬化的自身免疫性疾病，固有免疫应答可能参与其发生发展。枯否细胞（KCs）是寄居在肝脏的巨噬细胞，参与肝脏的炎症损伤。肝星状细胞（HSCs）激活和凋亡是肝纤维化的核心环节。在肝损伤过程中HSCs的激活能够促进KCs的活化。Autotaxin(ATX) 能水解溶血磷脂酰胆碱(LPC)产生溶血磷脂酸(LPA)。当ATX增加，LPA及其受体表达亦增加，ATX-LPA轴具有活化HSCs和抑制其凋亡的作用，同时能够促进血液单核细胞向组织迁移分化为巨噬细胞细胞。本项目以PBC病人为研究对象，从疾病的发生发展、疗效方面展开研究，最终阐明ATX-LPA轴在PBC疾病进程中的作用，揭示ATX-LPA轴及其和KCs、HSC和BECs的相互调控与疾病进展、疗效之间的关系，为寻求预测疾病严重程度及设计新的PBC治疗靶点提供理论依据。

原发性胆汁性胆管炎（primary biliary cholangitis, PBC）是一种慢性自身免疫性肝病，以肝内进行性胆汁淤积为特征，近年来PBC的检出率逐年升高，但其免疫发病机制仍不完全清楚，临床上仍未改变熊去氧胆酸单一治疗的用药格局。 Autotaxin(ATX) 是一种分泌型糖蛋白，具有溶血磷脂酶D活性，是血液中溶血磷脂酸 (LPA)的主要催化酶。ATX-LPA轴与炎症、纤维化及肿瘤密切相关，也是胆汁淤积的潜在致病因素。 为了阐明ATX-LPA与PBC疾病进程及UDCA疗效的相关性及其在PBC的免疫发病机制中的作用,该项目以PBC病人为研究对象，研究结果显示PBC患者外周血ATX水平显著高于酒精性肝硬化和健康对照组，但与非PBC相关肝癌患者相比，ATX水平无显著性差异；PBC患者肝组织中ATX的表达显著高于健康人及酒精性肝硬化患者，而进展期ATX表达显著高于早期PBC患者。未发生HCC的PBC患者与发生HCC的PBC患者相比，后者基线ATX水平显著升高；多因素Logistic回归分析显示,ATX是PBC进展为HCC的独立预测因素；基线外周血ATX水平在预测PBC相关肝癌具有较高的灵敏度和特异度。ATX可通过调节单核细胞，巨噬细胞和B细胞参与PBC的免疫发病机制。综上所述，本研究的研究结果将对预测PBC疾病结局和开发治疗药物奠定重要的理论基础。在该项目的资助下至今共发表论文8篇，2篇论文正在撰写中。共培养硕士生2名，1名已毕业，另一名将于今年毕业。 该项目共投入53万元，支出473033.14元，剩余56966.86元，剩余经费将用于本项目后续研究。