布加综合征（BCS）可导致肝纤维化，但其与慢性肝炎所致肝纤维化的分子机制可能有所不同。研究表明，肝星状细胞（HSC）及其特异性标记分子内皮唾液酸蛋白在肝纤维化的发生过程中起着重要的调节作用，而缺氧微环境和缺氧诱导因子（HIF）可能调节内皮唾液酸蛋白表达。我们推测，BCS造成缺氧微环境后，HIF信号途径调节内皮唾液酸蛋白表达，进而影响HSC功能和肝纤维化的发生。本研究包括两大部分。1）在BCS动物模型及临床患者中，检测肝脏组织中HIF表达水平、HSC激活水平及内皮唾液酸蛋白表达水平，并分析它们与肝纤维化之间的相互关系。2）在体外细胞系中，探讨缺氧微环境是否通过上游的HIF诱导HSC中内皮唾液酸蛋白表达，并分析内皮唾液酸蛋白是否通过影响下游的MAP激酶ERK-1/2磷酸化以及早期转录因子c-Fos表达以影响细胞增殖和迁移。本研究将阐明HIF通过调节内皮唾液酸蛋白的表达以影响BCS发生肝纤维化。

Budd-Chiari syndrome (BCS), which is characterized by hepatic venous outflow obstruction, can frequently induce the development of liver fibrosis. However, the mechanisms of BCS-related and chronic viral hepatitis-related liver fibrosis may be largely different. Hepatic stellate cell (HSC) and its specific marker endosialin play an important regulatory role in the development of liver fibrosis. Additionally, hypoxia microenvironment and hypoxia inducible factor (HIF) are involved in the regulation of endosialin. Therefore, we hypothesize that hypoxia microenvironment caused by BCS can regulate the expression of endosialin in HSC via HIF signaling pathway, and then affect the function of HSC and development of liver fibrosis. The present work will be divided into two major parts: 1) in the BCS animal model and clinical studies, the relationship between the severity of liver fibrosis and the expression of HIF and endosialin in HSC will be explored; and 2) in the in vitro cell system, the effect of hypoxic microenvironment, HIF-1α or HIF-2α on the expression of endosialin in HSC will be explored, and the effect of endosialin on the MAP kinase ERK-1/2 phosphorylation and the expression of early transcription factor c-Fos will be detected. This work will elucidate whether HIF signaling pathway regulates endosialin expression, thereby inducing the development of BCS-related liver fibrosis.