Hedgehog通路在原发性胆汁性胆管炎肝纤维化的作用机制研究

Primary biliary cholangitis (PBC) is an autoimmune disease characterized by chronic inflammation of intrahepatic bile ducts. Patients with PBC may progress to hepatic fibrosis, hepatic decompensation and even death. Hedgehog(Hh) pathway has been identified to be involved in hepatic fibrosis in alcoholic hepatitis and animal model of biliary obstruction. However, it is unclear about the role of Hh in hepatic fibrosis of PBC. We aimed in this study to explore the expression of Hh ligands in the liver of both PBC patients and health controls, and to analyze the relationship of Hh ligands and pathological stage of the liver. Identification of hepatic cells secreting Hh ligands by multiple immunofluorescence and co-culture of biliary epithelial cells and activated CD8+ T cells will explain the reason why Hh ligands increased. We will further intervene the activation of Hh pathway in hepatic stellate cells and mouse model of PBC to see the role of Hh pathway in hepatic fibrosis. This study will clarify the mechanism of Hh pathway in hepatic fibrosis of PBC, and may probably provide new targets for therapy of hepatic fibrosis in PBC.

原发性胆汁性胆管炎（Primary biliary cholangitis，PBC）是肝内小胆管慢性炎症特征的自身免疫性疾病，逐渐进展为肝纤维化、肝功能失代偿甚至死亡。在酒精性肝炎及胆管阻塞动物模型中发现Hedgehog（Hh）通路参与肝纤维化，但在PBC肝纤维化中的作用未明。本课题拟研究PBC患者与健康对照者肝脏组织Hh通路关键分子和Hh配体的表达，分析与肝脏病理分期、临床生化指标的相关性；运用多重免疫荧光定位分泌Hh配体的肝细胞和体外胆管上皮细胞与活化CD8+T细胞共培养，明确PBC的Hh配体增多机制；进而在肝星形细胞系和PBC模型小鼠体内通过多种方式干预Hh通路活化，明确Hh通路对PBC肝纤维化的作用。本研究可阐明Hh通路在PBC肝纤维化中的作用机制，为PBC肝纤维化提供潜在新治疗靶点。

背景：原发性胆汁性胆管炎（Primary biliary cholangitis，PBC）是肝内小胆管慢性炎症、逐渐进展为肝纤维化的自身免疫性疾病，造成肝功能失代偿甚至死亡。Hedgehog通路在PBC肝纤维化中的作用未明。.主要研究内容：本课题拟研究PBC患者与健康对照者肝脏组织Hh通路分子和Hh配体表达；并在小鼠模型体内干预Hh通路活化，明确Hh通路对PBC肝纤维化的作用。.重要结果及关键数据：PBC患者肝脏组织与健康对照相比，Hh通路相关分子Shh、Ptc表达上调，与肝纤维化指标α-SMA正相关，提示Hedgehog通路在PBC中激活并参与发病。CCL4诱导肝纤维化小鼠模型中，Hedgehog通路相关分子Shh、核转录因子Gli1、Gli2的RNA及蛋白水平均显著高于对照小鼠，且与α-SMA正相关，提示Hedgehog通路激活参与肝纤维化。此外，抑制Hedgehog通路预防性治疗肝纤维化小鼠模型，并减弱Shh，Gli1，Gli2过表达，提示抑制Hedgehog通路激活可减轻肝纤维化发病。.科学意义：Hedgehog通路在PBC中激活，并参与肝纤维化发病，抑制Hedgehog通路可减轻肝纤维化。Hedgehog通路可望作为PBC的潜在治疗靶点。