FTY720对实验性肝纤维化小鼠肝损伤的保护作用

doi:10.13481/j.1671-587x.20150611

摘要/Abstract

摘要：

目的:观察FTY720对刀豆蛋白A(Con A)所致肝纤维化小鼠的保护作用,探讨其可能的作用机制。方法:采用刀豆蛋白A(Con A)建立小鼠肝纤维化动物模型,取40只BALB/C小鼠随机分为空白对照组、模型组、FTY720低剂量(1 mg·kg^-1)组和FTY720高剂量(4 mg·kg^-1)组,每组10只。测定各组小鼠血清丙氨酸氨基转移酶(ALT)、天冬氨酸氨基转移酶(AST)活性和肝脏指数,观察肝脏组织学病理变化。结果:FTY720低剂量组和高剂量组ALT、AST 活性明显低于模型组(P<0.05 或P<0.01)。光学显微镜观察,模型组有炎性细胞浸润,肝细胞坏死。Masson 染色,模型组血管周围有明显纤维条束,肝小叶发生融合;与模型组比较,FTY720低剂量组和高剂量组损伤程度较轻,且随FTY720剂量增加肝组织损伤程度逐渐减轻。结论:FTY720对实验性肝纤维化小鼠的保护作用可能是通过降低ALT 和AST活性,进而减轻肝脏损伤程度而延缓纤维化进程。

关键词: FTY720, 刀豆蛋白A, 肝纤维化, 肝损伤, 动物模型

Abstract:

Objective To observe the protective effects of FTY720 on the Con A-induced mouse hepatic fibrosis injury, and to find the possible mechanisms of protective effects. Methods The pathologic models of hepatic fibrosis injury in the mice caused by Con A were set up.Forty mice were randomly divided into control group, model group, high dose of FTY720(4 mg·kg^-1) group and low dose of FTY720 (1 mg·kg^-1) dose group (n=10). The serum alanine aminotransferase(ALT) and asparate aminotransferase (AST) activities, hepatic index and pathological changes of hepatic tissue were detected. Results Compared with model group, the serum ALT and AST activities in low and high doses of FTY720 groups were decreased significantly (P< 0.05 or P< 0.01). The optical microscope results showed that there were inflammatory cells and hepatocellular necrosis in model group. The masson staining results showed that there were surrounding fiber bundle and hepatic lobule fusion in model group; compared with model group, the damage degree in low and high doses of FTY720 groups was reduced. The protective effects of FTY720 on hepatic injury showed linear relation to the drug dose. Conclusion FTY720 could decrease the levels of ALT/AST, thus FTY720 alleviate hepatic damage degree and delay the process of hepatic fibrosis.The protective effects of FTY720 on hepatic injury in experimental hepatic fibrosis mice may be related to the mechanisms mentioned above.

Key words: FTY720, concanavalin A, hepatic fibrosis, hepatic injury, animal model

中图分类号:

R392.12

张宸豪, 李瑶, 陈为, 赵良中, 李妍. FTY720对实验性肝纤维化小鼠肝损伤的保护作用[J]. 吉林大学学报(医学版), 2015, 41(06): 1154-1157.

ZHANG Chenhao, LI Yao, CHEN Wei, ZHAO Liangzhong, LI Yan. Protective effect of FTY720 on hepatic injury in experimental hepatic fibrosis mice[J]. Journal of Jilin University Medicine Edition, 2015, 41(06): 1154-1157.

参考文献

[1] 孙颖,滕光菊,常彬霞,等.自身免疫性肝炎采用免疫抑制剂治疗的疗效预测[J].肝脏,2012,17(11):803-807.

[2] Di Nuzzo L,Orlando R,Nasca C,et al. Molecular pharmacodynamics of new oral drugs used in the treatment of multiple sclerosis [J]. Drug Des Devel Ther,2014,8:555-568.

[3] 周琬琦,张海婧,金晶,等. S1P1受体激动剂FTY720的免疫抑制作用[J].药学学报,2012,47(4) :546-550.

[4] 张雷,朱彤,孙尔维,等.FTY720作用机制及诱导移植免疫耐受的研究[J].中华外科杂志,2003,41(10):773-777.

[5] Boldison J,Chu CJ,Copland DA,et al.Tissue-resident exhausted effector memory CD8⁺ T cells accumulate in the retina during chronic experimental autoimmune uveoretinitis[J]. J Immunol,2014,192(10):4541-4550.

[6] 姜慧卿,张晓岚.肝纤维化的发生机制[J]. 世界华人消化杂志,2000,8(6):687-689.

[7] 纪辉,迟宝荣,张一宁.肝纤维化与肝星状细胞[J]. 吉林大学学报:医学版,2008,34(3):539-541.

[8] 高润平,齐晓艳.肝纤维化的发生机制与治疗进展[J]. 世界华人消化杂志,2006,14(23):2263-2269.

[9] Matsuda S,Minowa A,Suzuki S,et al. Differential activation of c-Jun NH2-terminal kinase and p38 pathways during FTY720-induced apoptosis of T lymphocytes that is suppressed by the extracellular signal-regulated kinase pathway[J].J Immunol,1999,162(6):3321-3326.

[10] Guo R,Ma H, Gao F,et al. Metallothionein alleviates oxidative stress-induced endoplasmic reticulum stress and myocardial dysfunction [J].J Mol Cell Cardiol,2009,47(2) :228-237.

[11] Ishitsuka A,Fujine E,Mizutani,et al.YFTY720 and cisplatin synergistically induce the death of cisplatin-resistant melanoma cells through the downregulation of the PI3K pathway and the decrease in epidermal growth factor receptor expression[J].Int J Mol Med,2014,34(4) :1169-1174.

[12] Jiang J, Huang X, Wang Y,et al. FTY720 induces cell cycle arrest and apoptosis of rat glomerular mesangial cells [J]. Mol Biol Rep, 2012,39(8) :8243-8250.

[13] Essis SA,Laurier-Laurin ME,Pépin ,et al. GluN2B-containing NMDA receptors are upregulated in plasma membranes by the sphingosine-1-phosphate analog FTY720P[J].Brain Res,2015,doi: 10.1016/j.brainres.2015.07.055. [Epub ahead of print].

[14] Endo H,Chihara N,Sekiguchi MDK. A case of multiple sclerosis who relapsed early after fingolimod therapy introduced [J]. Rinsho Shinkeigaku, 2015,55(6) :417-420.

[15] 郭若涵,白彬.大型动物实验性肝纤维化及肝纤维化模型的研究进展[J]. 世界华人消化杂志,2013,21(5):421-426.

[16] 李政通,李俊,黄成,等. CCI4诱导的大鼠肝纤维化模型肝纤维化逆转与MAPK信号通路的研究[J].中国药理学通报,2011,27(6):809-814.

[17] 王晓艳,万晓龙,郭晓燕,等.阿罗洛尔、普奈洛尔和卡维地洛对肝硬化大鼠门脉高压症的疗效比较[J].西安交通大学学报:医学版,2015,36(16):730-734.

[18] 王林,李波,耿智敏,等.索拉菲尼对肝星状细胞活性及活化的影响[J].郑州大学学报:医学版,2014,49(4):501-504.

[19] 李彬彬,明健,陈大贵,等.microRNA在肝纤维化进程中的作用[J].临床肝胆病杂志,2013,29(5):385-388.

[20] 陆伦根,李郑红.肝纤维化及肝硬化研究近况[J].临床肝胆病杂志,2013,29(5):321-323.