Mdr2 (Abcb4)-/- mice spontaneously develop severe biliary fibrosis via massive dysregulation of pro- and antifibrogenic genes
Mdr2 (Abcb4)-/- mice spontaneously develop severe biliary fibrosis via massive dysregulation of pro- and antifibrogenic genes
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DOI：
10.1016/j.jhep.2005.06.025
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发表时间：
2005-12-01
影响因子：
25.7
通讯作者：
Schuppan, D
中科院分区：
文献类型：
--
作者：
Popov, Y;Patsenker, E;Schuppan, D
背景/目的：Mdr 2（Abcb 4）-/-小鼠出现类似原发性硬化性胆管炎的肝脏病变。我们的目的是描述Mdr 2-/-小鼠纤维化的演变。方法：Mdr 2-/-小鼠及其野生型同窝出生后2，4和8周处死。用生化法测定肝胶原。通过实时RT-PCR从肝脏定量纤维化相关转录物水平，并通过底物测定确定NIMP活性。肝组织学进行了评估，结缔组织染色和免疫组织化学α-平滑肌肌动蛋白（α-SMA）。结果：Mdr 2-/-小鼠表现出时间依赖性增加的相对和总的肝胶原蛋白（5倍，在8周，相比野生型对照），和最大α-SMA免疫反应在4周。与野生型对照相比，前胶原α 1（I）、TGF β 1、TGF β 2、MMP-2和MMP-13、TIMP-1、PDGF β受体和派-1的促纤维化mRNA水平上调高达27倍。大多数转录物在4周达到峰值，但前胶原α 1（1）mRNA稳步增加，TIMP-1 mRNA持续升高（20倍），MMP-13 mRNA被抑制，间质胶原酶和明胶酶活性下调。这是由于上调的促纤维化和下调的纤维溶解基因和活性的特征性时间模式。这些小鼠是测试用于治疗（胆汁）肝纤维化的潜在抗纤维化药物的有吸引力的模型。(c)2005年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
Background/Aims: Mdr2 (Abcb4)-/- mice develop hepatic lesions resembling primary sclerosing cholangitis. Our aim was to characterize the evolution of fibrosis in Mdr2-/- mice.Methods: Mdr2-/-mice and their wild-type littermates were sacrificed at 2,4 and 8 weeks after birth. Hepatic collagen was determined biochemically. Fibrosis related transcript levels were quantified from livers by real-time RT-PCR, and NIMP activities determined by substrate assays. Liver histology was assessed by connective tissue staining and immunohistochemistry for alpha-smooth muscle actin (alpha-SMA).Results: Mdr2-/- mice demonstrated a time-dependent increase of relative and total hepatic collagen (fivefold at 8 weeks, compared to wildtype controls), and maximal alpha-SMA immunoreactivity at 4 weeks. Compared to wildtype controls profibrogenic mRNA levels for procollagen alpha 1(I), TGF beta 1, TGF beta 2, MMP-2 and -13, TIMP-1, PDGF beta receptor, and PAI-1 were upregulated up to 27-fold. Most transcripts peaked at 4 weeks, but procollagen alpha 1(l) mRNA increased steadily, TIMP-1 mRNA was constantly elevated (20-fold), MMP-13 mRNA was suppressed and interstitial collagenase and gelatinase activities were downregulated.Conclusions: Mdr2-/- mice spontaneously progress to severe biliary fibrosis. This is due to a characteristic temporal pattern of upregulated profibrogenic and downregulated fibrolytic genes and activities. These mice are an attractive model to test potential antifibrotics for the treatment of (biliary) liver fibrosis. (c) 2005 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.