A novel mouse model of depletion of stellate cells clarifies their role in ischemia/reperfusion- and endotoxin-induced acute liver injury.
A novel mouse model of depletion of stellate cells clarifies their role in ischemia/reperfusion- and endotoxin-induced acute liver injury.
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DOI：
10.1016/j.jhep.2013.09.013
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发表时间：
2014-02
影响因子：
25.7
通讯作者：
Gandhi, Chandrashekhar R.
中科院分区：
文献类型：
--
作者：
Stewart, Rachel K.;Dangi, Anil;Huang, Chao;Murase, Noriko;Kimura, Shoko;Stolz, Donna B.;Wilson, Gregory C.;Lentsch, Alex B.;Gandhi, Chandrashekhar R.
关键词：
肝星状细胞(HSC)位于肝窦内皮细胞和肝细胞之间，表达胶质纤维酸性蛋白(GFAP)。HSCs在肝损伤过程中被激活，通过产生过多的细胞外基质而导致肝纤维化。HSC还产生多种生长因子、趋化因子和细胞因子，可能在急性肝损伤中发挥重要作用。然而，由于HSCs从正常肝脏中被耗尽的模型不存在，这一功能还没有被阐明。我们用连续3天(相隔3天)注射CCl_4(0.16μL/g；ip)处理GFAP启动子下表达HSV-胸苷激酶的小鼠，以刺激HSC进入细胞周期并增殖。随后是10天的更昔洛韦(40μg/g/day；ip)治疗，预计将消除活跃增殖的造血干细胞。小鼠随后接受肝脏缺血/再灌注(I/R)或内毒素治疗。CCl_4/更昔洛韦治疗导致大部分HSC耗竭(约为-72%)，而肝脏从最初的CCl_4诱导的损伤中恢复(组织学、血清ALT和中性粒细胞浸润证实)。在HSC耗竭的小鼠中，I/R或内毒素血症(由组织病理学和血清ALT确定)造成的肝损伤程度较低。肝组织肿瘤坏死因子-α、中性粒细胞趋化因子CXCL1和内皮素-A受体的表达也明显低于对照组。HSC在I/R和内毒素诱导的急性肝细胞损伤中均起重要作用，其中肿瘤坏死因子-α和内皮素-1是这些作用的重要介导物。
Hepatic stellate cells (HSCs) that express glial fibrillary acidic protein (GFAP) are located between the sinusoidal endothelial cells and hepatocytes. HSCs are activated during liver injury and cause hepatic fibrosis by producing excessive extracellular matrix. HSCs also produce many growth factors, chemokines and cytokines, and thus may play an important role in acute liver injury. However, this function has not been clarified due to unavailability of a model in which HSCs are depleted from the normal liver. We treated mice expressing HSV-thymidine kinase under the GFAP promoter (GFAP-Tg) with 3 consecutive (3 days apart) CCl4 (0.16 μl/g; ip) injections to stimulate HSCs to enter the cell cycle and proliferate. This was followed by 10-day ganciclovir (40 μg/g/day; ip) treatment, which is expected to eliminate actively proliferating HSCs. Mice were then subjected to hepatic ischemia/reperfusion (I/R) or endotoxin treatment. CCl4/ganciclovir treatment caused depletion of the majority of HSCs (about 64-72%), while the liver recovered from the initial CCl4-induced injury (confirmed by histology, serum ALT and neutrophil infiltration). The magnitude of hepatic injury due to I/R or endotoxemia (determined by histopathology and serum ALT) was lower in HSC-depleted mice. Their hepatic expression of TNF-α, neutrophil chemoattractant CXCL1 and endothelin-A receptor also was significantly lower than the control mice. HSCs play an important role both in I/R- and endotoxin-induced acute hepatocyte injury, with TNF-α and endothelin-1 as important mediators of these effects.
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影响因子：
82.9
作者：
通讯作者：
--
影响因子：
6.7
作者：
Hagens, WI;Olinga, P;Poelstra, K
通讯作者：
Poelstra, K
DOI：
10.1073/pnas.86.8.2698
发表时间：
1989-04-01
影响因子：
11.1
作者：
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通讯作者：
EVANS, RM
影响因子：
13.5
作者：
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通讯作者：
KAMADA, T
影响因子：
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作者：
Jaruga, B;Hong, F;Gao, B
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