Long-term acetaminophen treatment induced liver fibrosis in mice and the involvement of Egr-1
Long-term acetaminophen treatment induced liver fibrosis in mice and the involvement of Egr-1
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长期对乙酰氨基酚治疗诱导小鼠肝纤维化及Egr-1的参与
DOI：
10.1016/j.tox.2017.03.008
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发表时间：
2017-05-01
期刊：
影响因子：
4.5
通讯作者：
Wang, Zhengtao
中科院分区：
文献类型：
--
作者：
Bai, Qingyun;Yan, Hongyu;Wang, Zhengtao
对乙酰氨基酚(APAP)所致的急性肝损伤已有较好的研究。然而，长期服用APAP是否会导致肝纤维化仍不是很清楚。本研究旨在探讨APAP长期治疗所致小鼠肝纤维化及其与早期生长反应1(Egr-1)的关系。C57BL/6小鼠分别灌胃给予APAP(200、300 mg/kg)2、6、10周。APAP(200,300 mg/kg)染毒6周或10周后，小鼠肝脏羟脯氨酸含量增加，胶原沉积增多，炎性细胞浸润增多。APAP组小鼠肝脏胶原(COL)1a1、COL3a1、转化生长因子-β(TGF-β)的mRNA表达及血清COL1、COL3、TGF-β含量均升高。APAP处理组小鼠肝脏α-平滑肌肌动蛋白(α-SMA)、磷酸化ERK1/2和Smad2/3的表达均增加。此外，在APAP处理的小鼠中发现肝脏Egr-1的mRNA表达增加及其随后的核转位。进一步应用EGR-1基因敲除小鼠。APAP诱导的肝纤维化在Egr-1基因敲除小鼠中被发现更为严重。APAP肝毒代谢产物N-乙酰-对苯二酚亚胺(NAPQI)可诱导肝星状Lx2细胞α-SMA、COL1a1、COL3a1、TGF-β的mRNA表达增加，诱导ERK1/2和Smad2/3磷酸化及Egr-1核转位。综上所述，长期服用APAP可导致小鼠肝纤维化，Egr-1在这一过程中起关键作用。本研究为临床长期摄入APAP的患者提供了警示和参考。(C)2017爱思唯尔B.V.保留所有权利。
Acetaminophen (APAP)-induced acute liver injury has already been well studied. However, whether long-term administration of APAP will cause liver fibrosis is still not very clear. This study aims to investigate the liver fibrosis in mice induced by long-term APAP treatment and the involvement of early growth response 1 (Egr-1). C57BL/6 mice were orally given with APAP (200, 300 mg/kg) for 2, 6 or 10 weeks, respectively. Liver hydroxyproline content, collagen deposition and inflammatory cells infiltration were increased in mice treated with APAP (200, 300 mg/kg) for 6 or 10 weeks. Liver mRNA expression of collagen (COL)1a1, Col3a1, transforming growth factor-beta (TGF-beta) and serum contents of COL1, COL3, TGF-beta were all increased in APAP-treated mice. Liver expression of alpha-smooth muscle actin (alpha-SMA) and phosphorylated ERK1/2 and Smad2/3 were all increased in APAP-treated mice. Furthermore, increased liver mRNA expression of Egr-1 and its subsequent nuclear translocation were found in APAP-treated mice. Egr-1 knock-out mice were further applied. APAP-induced liver fibrosis was found to be more serious in Egr-1 knock-out mice. N-acetyl-p-benzoquinoneimine (NAPQI), the APAP hepatotoxic metabolite, increased cellular mRNA expression of alpha-SMA, Col1a1, Col3a1, TGF-beta, induced ERK1/2 and Smad2/3 phosphorylation and Egr-1 nuclear translocation in hepatic stellate LX2 cells. In conclusion, long-term administration of APAP induced liver fibrosis in mice, and Egr-1 was critically involved in this process. This study points out a warning and reference for patients with long-term APAP ingestion in clinic. (C) 2017 Elsevier B.V. All rights reserved.