Cyclooxygenase-2 prevents fas-induced liver injury through up-regulation of epidermal growth factor receptor.
Cyclooxygenase-2 prevents fas-induced liver injury through up-regulation of epidermal growth factor receptor.
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DOI：
10.1002/hep.23052
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发表时间：
2009-09
期刊：
影响因子：
13.5
通讯作者：
Wu, Tong
中科院分区：
文献类型：
--
作者：
Li, Guiying;Han, Chang;Xu, Lihong;Lim, Kyu;Isse, Kumiko;Wu, Tong
COX-2来源的前列腺素参与多种病理生理反应，如炎症、癌变、调节细胞生长和存活等。本研究利用COX-2转基因和基因敲除小鼠模型互补的方法，在体内评价COX-2在Fas诱导的肝细胞凋亡和肝功能衰竭中的作用机制。我们利用白蛋白启动子增强子驱动的载体构建了COX-2在肝脏靶向表达的转基因小鼠。COX-2转基因(TG)、COX-2基因敲除(KO)小鼠和野生型小鼠用抗Fas抗体Jo2(0.5µg/g体重)处理4~6小时，通过组织病理学、血清转氨酶、TUNEL染色和半胱氨酸天冬氨酸氨基转移酶(Caspase)活性评价肝损伤程度。与野生型小鼠相比，COX-2转基因小鼠表现出对Fas诱导的肝损伤的抵抗，表现为ALT和AST水平较低，肝损伤较轻，肝细胞凋亡较少(p<；0.01)。与野生型小鼠相比，COX-2KO小鼠血清ALT、AST水平显著升高，肝细胞凋亡率显著升高，caspase-8、9、3活性显著升高(p<；0.01)。与野生型对照相比，COX-2TG肝脏表达高水平的表皮生长因子受体(EGFR)；COX-2KO肝脏表达最低水平的EGFR。预先给予COX-2抑制剂(NS-398)或EGFR抑制剂(AG1478)可加重Jo2介导的肝损伤和肝细胞凋亡。这些发现表明，COX-2至少部分地通过上调EGFR来预防Fas诱导的肝细胞凋亡和肝功能衰竭。
COX-2-derived PGs participate in a number of pathophysiological responses such as inflammation, carcinogenesis, and modulation of cell growth and survival. This study utilized complementary approaches of COX-2 transgenic and knockout mice models to evaluate the mechanism of COX-2 in Fas-induced hepatocyte apoptosis and liver failure, in vivo. We generated transgenic mice with targeted expression of COX-2 in the liver by using the albumin promoter-enhancer driven vector. The COX-2 transgenic (Tg), COX-2 knockout (KO), and wild type mice were treated with the anti-Fas antibody Jo2 (0.5 µg/g body weight) for 4–6 hours and the extent of liver injury was assessed by histopathology, serum transaminases, TUNEL staining and caspase activation. The COX-2 Tg mice showed resistance to Fas-induced liver injury when compared to the wild type mice, as reflected by the lower ALT and AST levels, less liver damage and less hepatocyte apoptosis (p<0.01). In contrast, the COX-2 KO mice showed significantly higher serum ALT and AST levels, more prominent hepatocyte apoptosis, and higher levels of caspase-8, 9, 3 activities than the wild type mice (p<0.01). The COX-2 Tg livers express higher levels of epidermal growth factor receptor (EGFR) than the wild type controls; the COX-2 KO livers express lowest levels of EGFR. Pretreatment with the COX-2 inhibitor (NS-398) or the EGFR inhibitor (AG1478) exacerbated Jo2-mediated liver injury and hepatocyte apoptosis. These findings demonstrate that COX-2 prevents Fas-induced hepatocyte apoptosis and liver failure at least in part through upregulation of EGFR.
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影响因子：
--
作者：
Michalopoulos GK;Bowen WC;Mulè K;Luo J
通讯作者：
Luo J
影响因子：
4.8
作者：
Buchanan, FG;Wang, DZ;DuBois, RN
通讯作者：
DuBois, RN
影响因子：
2.9
作者：
MACMANUS, JP;BRACELAND, BM
通讯作者：
BRACELAND, BM
DOI：
10.1073/pnas.0704126104
发表时间：
2007-10-23
影响因子：
11.1
作者：
Natarajan, Anuradha;Wagner, Bettina;Sibilia, Maria
通讯作者：
Sibilia, Maria
影响因子：
25.7
作者：
Huether, A;Höpfner, M;Scherübl, H
通讯作者：
Scherübl, H