Kupffer cells abrogate cholestatic liver injury in mice
Kupffer cells abrogate cholestatic liver injury in mice
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DOI：
10.1053/j.gastro.2005.11.015
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发表时间：
2006-03-01
期刊：
影响因子：
29.4
通讯作者：
Gregory, SH
中科院分区：
文献类型：
--
作者：
Gehring, S;Dickson, EM;Gregory, SH
背景与目的：胆道梗阻和胆汁淤积可引起肝细胞凋亡和坏死。结扎小鼠胆总管为研究其潜在机制提供了一个很好的模型。在大多数肝损伤动物模型中，Kupffer细胞在调节炎症反应中起关键作用。本研究旨在确定库普弗细胞在胆汁淤积引起的损伤中的作用。方法：小鼠不经处理或静脉注射多层脂质体包封二磷酸二氯乙烯致库普弗细胞衰竭，结扎并切开胆总管；假手术的动物作为对照。同样，白细胞介素-6 （IL-6）缺乏和肿瘤坏死因子受体缺乏的小鼠接受胆管结扎（BDL）或假手术。结果：所有BDL小鼠术后3天血清丙氨酸转氨酶水平均升高，但il -6缺陷小鼠或结扎前库普弗细胞缺失小鼠血清丙氨酸转氨酶水平明显升高。BDL肝脏的组织学检查显示门静脉炎症、中性粒细胞浸润、胆管增生和肝细胞坏死。图像分析证实，Kupffer细胞耗尽和il -6缺乏的动物肝脏中有更多的坏死。来自BDL动物的纯化Kupffer细胞在培养中产生更多的IL-6。同样，通过激光捕获显微解剖从BDL小鼠肝脏获得的Kupffer细胞表达IL-6信使RNA水平升高。重组小鼠IL-6在BDL前1小时给予，完全逆转了Kupffer细胞耗尽小鼠肝损伤的增加。结论：这些发现表明Kupffer细胞通过细胞因子依赖机制（包括产生IL-6）消除胆汁淤积性肝损伤。
Background & Aims: Biliary obstruction and cholestasis can cause hepatocellular apoptosis and necrosis. Ligation of the common bile duct in mice provides an excellent model in which to study the underlying mechanisms. Kupffer cells play a key role in modulating the inflammatory response observed in most animal models of liver injury. This study was performed to determine the role of Kupffer cells in the injury attending cholestasis. Methods: Mice were not treated or were rendered Kupffer cell-depleted by intravenous inoculation of multilamellar liposome-encapsulated dichloromethylene diphosphonate, the common bile duct was ligated and divided; sham-operated animals served as controls. Similarly, interleukin-6 (IL-6)-deficient and tumor necrosis factor-receptor-deficient mice underwent bile duct ligation (BDL) or sham operations. Results: Serum alanine transaminase levels were increased in all BDL mice at 3 days after surgery, but were significantly higher in IL-6-deficient mice or mice rendered Kupffer cell-depleted before ligation. Histologic examination of BDL livers showed portal inflammation, neutrophil infiltration, bile duct proliferation, and hepatocellular necrosis. Photoimage analyses confirmed more necrosis in the livers of Kupffer cell-depleted and IL-6-deficient animals. Purified Kupffer cells derived from BDL animals produced more IL-6 in culture. Similarly, Kupffer cells obtained by laser capture microdissection from the livers of BDL mice expressed increased levels of IL-6 messenger RNA. Recombinant mouse IL-6 administered I hour before BDL completely reversed the increased liver damage assessed otherwise in Kupffer cell-depleted mice. Conclusions: These findings indicate that Kupffer cells abrogate cholestatic liver injury by cytokine-dependent mechanisms that include the production of IL-6.