Shackel N A, McGuinness P H, Abbott C A, Gorrell M D, McCaughan G W
AW Morrow Gastroenterology and Liver Centre, Centenary Institute of Cancer Medicine and Cell Biology, Royal Prince Alfred Hospital and the University of Sydney, Sydney, Australia.
Gut. 2001 Oct;49(4):565-76. doi: 10.1136/gut.49.4.565.
Primary biliary cirrhosis (PBC) is an autoimmune disease in which the pathogenesis of progressive liver injury is poorly understood.
To provide novel insights into the pathogenesis of PBC related liver injury using cDNA array analysis, which simultaneously examines expression of many genes.
Utilising cDNA arrays of 874 genes, PBC was compared with primary sclerosing cholangitis (PSC) associated cirrhosis and non-diseased liver. Differential expression of 10 genes was confirmed by real time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR).
Array analysis identified many differentially expressed genes that are important in inflammation, fibrosis, proliferation, signalling, apoptosis, and oxidative stress. PBC was associated with increased expression of both Th1 and Th2 type molecules of the immune response. Fibrosis related gene expression featured upregulation of connective tissue growth factor and transforming growth factor beta3. Many more apoptosis associated molecules exhibited increased expression, consistent with apoptosis being a more active and regulated process, in PSC associated cirrhosis than in PBC. Increased expression of many genes of the Wnt and notch pathways implicated these highly conserved and linked pathways in PBC pathogenesis. The observed increases in expression of c-jun, c-myc, and c-fos related antigen 1 are consistent with increased Wnt pathway activity in PBC. Differential expression of four components of the Wnt pathway, Wnt-5a, Wnt-13, FRITZ, and beta-catenin, was confirmed by quantitative RT-PCR.
Many genes implicated in intrahepatic inflammation, fibrosis, and regeneration were upregulated in PBC cirrhosis. In particular, increased expression of a number of Drosophila homologues was seen in PBC.
原发性胆汁性肝硬化（PBC）是一种自身免疫性疾病，其进行性肝损伤的发病机制尚不清楚。
利用cDNA阵列分析同时检测多个基因的表达，为PBC相关肝损伤的发病机制提供新的见解。
使用包含874个基因的cDNA阵列，将PBC与原发性硬化性胆管炎（PSC）相关肝硬化及非病变肝脏进行比较。通过实时定量逆转录聚合酶链反应（RT-PCR）确认了10个基因的差异表达。
阵列分析鉴定出许多在炎症、纤维化、增殖、信号传导、细胞凋亡和氧化应激中起重要作用的差异表达基因。PBC与免疫反应中Th1和Th2型分子的表达增加有关。纤维化相关基因表达的特征是结缔组织生长因子和转化生长因子β3上调。与PSC相关肝硬化相比，PBC中有更多的细胞凋亡相关分子表达增加，这与细胞凋亡是一个更活跃且受调控的过程相一致。Wnt和Notch通路的许多基因表达增加，提示这些高度保守且相互关联的通路参与了PBC的发病机制。观察到的c-jun、c-myc和c-fos相关抗原1表达增加与PBC中Wnt通路活性增加一致。通过定量RT-PCR确认了Wnt通路的四个成分Wnt-5a、Wnt-13、FRITZ和β-连环蛋白的差异表达。
在PBC肝硬化中，许多与肝内炎症、纤维化和再生相关的基因上调。特别是，在PBC中发现了一些果蝇同源物的表达增加。
