Nakken Karl Esten, Nygård Ståle, Haaland Terese, Berge Knut Erik, Arnkvaern Kristin, Ødegaard Annlaug, Labori Knut Jørgen, Raeder Morten G
Institute for Experimental Medical Research, Ullevål University Hospital and University of Oslo, Oslo, Norway.
Scand J Gastroenterol. 2007 Oct;42(10):1245-55. doi: 10.1080/00365520701320521.
Abcb4 (-/-) mice secrete phosphatidylcholine-free, cytotoxic bile and develop chronic cholangitis. The aim of this study was to identify differentially transcribed genes whose products contribute to the liver tissue pathology during this disease.
Hepatic gene transcription was measured in 3-, 6-, 9- and 20-week-old Abcb4 (-/-) mice (FVB.129P2-abcb4(tm1Bor)/J) using cDNA microarrays, with FVB/NJ Abcb4 (+/+) mice serving as controls. Focus was on inflammatory-, remodelling- and fibrosis genes. Marked differential transcription of inflammatory-, tissue remodelling- and fibrosis genes found by cDNA microarrays was verified by real-time polymerase chain reaction (PCR). Liver pathology was quantified by histopathology scoring.
Transcription of clade A3 Serpin genes showed early, marked down-regulation. The chemokine genes Ccl2, Ccl20 and Cxcl10 were markedly up-regulated. Tissue remodelling- and fibrosis genes exhibiting markedly up-regulated transcription included: Ctgf, Elf3, Lgals3, Mmp12, Mmp15, Spp1, Loxl2, Pdgfa, Pdgfrb, Sparc, Tgfb1, Tgfb2, Tgfbi, Tgfbr2 and Col1a1, Col1a2, Col2a1, Col3a1, Col4a1 genes. Microarray-based recordings of differential gene transcription of the majority of these genes harmonized with the liver histopathology score. Thus, cDNA microarray-based analysis showed increasing differential transcription of several inflammatory-, tissue remodelling- and fibrosis genes during the first 9 weeks of disease and a tendency towards differential transcription to stabilize at an elevated level from 9 to 20 weeks of disease.
Multiple genes regulating inflammation, tissue remodelling and fibrosis not previously linked to Abcb4 (-/-) cholangitis are identified as being differentially transcribed in Abcb4 (-/-) livers, where they contribute to the pathogenesis of liver tissue pathology.
Abcb4（-/-）小鼠分泌无磷脂酰胆碱的细胞毒性胆汁，并发展为慢性胆管炎。本研究的目的是鉴定差异转录基因，其产物在该疾病过程中对肝组织病理学有影响。
使用cDNA微阵列测量3周、6周、9周和20周龄的Abcb4（-/-）小鼠（FVB.129P2-abcb4（tm1Bor）/J）的肝脏基因转录，以FVB/NJ Abcb4（+/+）小鼠作为对照。重点关注炎症、重塑和纤维化相关基因。通过实时聚合酶链反应（PCR）验证cDNA微阵列发现的炎症、组织重塑和纤维化基因的明显差异转录。通过组织病理学评分对肝脏病理进行量化。
A3丝氨酸蛋白酶抑制剂家族基因的转录显示早期明显下调。趋化因子基因Ccl2、Ccl20和Cxcl10明显上调。转录明显上调的组织重塑和纤维化基因包括：Ctgf、Elf3、Lgals3、Mmp12、Mmp15、Spp1、Loxl2、Pdgfa、Pdgfrb、Sparc、Tgfb1、Tgfb2、Tgfbi、Tgfbr2以及Col1a1、Col1a2、Col2a1、Col3a1、Col4a1基因。基于微阵列的这些基因大多数差异基因转录记录与肝脏组织病理学评分一致。因此，基于cDNA微阵列的分析显示，在疾病的前9周，几种炎症、组织重塑和纤维化基因的差异转录增加，并且在疾病9至20周期间，差异转录有稳定在升高水平的趋势。
多个调节炎症、组织重塑和纤维化的基因，以前未与Abcb4（-/-）胆管炎相关联，被鉴定为在Abcb4（-/-）肝脏中差异转录，它们在肝组织病理学的发病机制中起作用。
