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李盼盼,符 健,陈 伟,陈 丽.前列地尔对暴发性肝衰竭大鼠 eIF2α / ATF4 / CHOP 通路及肝功能的影响[J].中国比较医学杂志,2021,31(8):55~62.
前列地尔对暴发性肝衰竭大鼠 eIF2α / ATF4 / CHOP 通路及肝功能的影响
Effects of alprostadil on the eIF2α/ ATF4 / CHOP pathway and liver function in rats with fulminant hepatic failure
投稿时间:2020-09-25  
DOI:10. 3969 / j.issn.1671-7856. 2021. 08. 008
中文关键词:  前列地尔  暴发性肝功能衰竭  大鼠  真核翻译起始因子 2α  激活转录因子 4  C/ EBP 同源蛋白
英文关键词:alprostadil  fulminant hepatic failure  rat  eukaryotic translation-initiation factor 2α  activating transcription factor 4  C/ EBP homologous protein
基金项目:
作者单位E-mail
李盼盼 海南省人民医院(海南医学院附属海南医院)感染科,海口 570100 yangyaowu19621@ 163.com 
符 健 海南省人民医院(海南医学院附属海南医院)感染科,海口 570100  
陈 伟 海南医学院第二附属医院药学部,海口 570100  
陈 丽 海南省人民医院(海南医学院附属海南医院)感染科,海口 570100  
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中文摘要:
       目的 探究前列地尔(PGE1)对暴发性肝衰竭(FHF)大鼠对肝功能的影响,并探讨其对真核翻译起始因子 2α(eIF2α) / 激活转录因子 4(ATF4) / C/ EBP 同源蛋白(CHOP)通路的调控作用。 方法 SPF 级 SD 雄性大鼠 90 只按随机数表法分为对照组、模型组、阳性对照组、低、中、高剂量 PGE1 组,除对照组外,其它组大鼠均采用腹腔注射 D-氨基半乳糖(D-GalN)-大肠杆菌内毒素脂多糖(LPS)的方法建立 FHF 大鼠模型,对照组腹腔注射等量的生理盐水。 造模 6 h 后,阳性对照组及低、中、高剂量 PGE1 组分别尾静脉注射促肝细胞生长素 1. 36 mg / kg,PGE1 12. 5、25、37. 5 μg / kg,每天 1 次,连续给药 3 d,对照组和模型组尾静脉注射等量的生理盐水。在造模 72 h 后处死大鼠,腹主动脉采血,检测血清丙氨酸氨基转氨酶(ALT)、天门冬氨酸氨基转移酶(AST)、总胆红素(TBIL)水平;解剖取肝组织用苏木精-伊红(HE)染色法观察各组大鼠肝组织病理学变化;采用实时荧光定量 PCR(qRT-PCR)和蛋白免疫印迹(Western blot)法检测肝组织中 eIF2α/ ATF4 / CHOP / 半胱氨酸天冬氨酸蛋白酶-3(Caspase-3)mRNA 和蛋 白、磷酸化-eIF2α(p-eIF2α)蛋白水平。 结果 与对照组相比,模型组肝细胞广泛变性并有局灶性坏死,中央静脉受损,血清 ALT、AST、TBIL,肝组织中 eIF2α、ATF4、CHOP、Caspase-3 mRNA 及 p-eIF2α/ eIF2α、ATF4、CHOP、Caspase- 3 蛋白水平均升高(P<0. 05);与模型组相比,阳性对照组、低、中、高剂量 PGE1 组肝细胞损害有所降低,坏死细胞数量减少,血清 ALT、AST、TBIL 水平,肝组织中 eIF2α、ATF4、CHOP、Caspase-3 mRNA 及 p-eIF2α/ eIF2α、ATF4、 CHOP、Caspase-3 蛋白水平降低(P<0. 05);且随着 PGE1 给药剂量的增加,低、中、高剂量 PGE1 组血清 ALT、AST、 TBIL 水平,肝组织中 eIF2α、ATF4、CHOP、Caspase-3 mRNA 及 p-eIF2α/ eIF2α、ATF4、CHOP、Caspase-3 蛋白水平依次 降低(P<0. 05),呈剂量依赖性;与阳性对照组相比,低、中剂量 PGE1 组血清 ALT、AST、TBIL 水平,肝组织中 eIF2α、 ATF4、CHOP、Caspase-3 mRNA 及 p-eIF2α/ eIF2α、ATF4、CHOP、Caspase-3 蛋白水平均升高(P<0. 05),高剂量 PGE1 组血清 ALT、AST、 TBIL 水平,肝组织中 eIF2α、ATF4、CHOP、Caspase-3 mRNA 及 p-eIF2α/ eIF2α、ATF4、 CHOP、 Caspase-3 蛋白水平差异无统计学意义(P>0. 05)。 结论 PGE1 可能通过抑制 eIF2α/ ATF4 / CHOP 通路表达,减轻大鼠肝细胞凋亡,达到保护肝的作用,可能作为 FHF 潜在的治疗药物。
英文摘要:
       Objective To investigate the effects of prostaglandin E1 ( PGE1) on liver function in rats with fulminant hepatic failure ( FHF), and to explore its regulatory effects on the eukaryotic translation-initiation factor 2α (eIF2α) / activating transcription factor 4 (ATF4) / C/ EBP homologous protein (CHOP) pathway. Methods Overall, 90 specific pathogen-free Sprague-Dawley rats were divided into control, model, positive control, low-, medium-, and high- dose PGE1 groups according to the random number table method . Except for the control group, all rats were intraperitoneally injected with D-galactosamine (D-GalN)-lipopolysaccharide (LPS) to establish the FHF rat model, and the control group received an intraperitoneal injection of the same volume of normal saline. At 6 hours after modeling, the positive control group and low-, medium-, and high-dose PGE1 groups were administered a tail vein injection of 1. 36 mg / kg hepatocyte growth promoting factor and 12. 5, 25, or 37. 5 μg / kg PGE1, respectively, once a day for 3 consecutive days. The control group and the model group were administered a tail vein injection of the same volume of normal saline. The rats were euthanized at 72 hours after modeling and abdominal aorta blood was collected. The serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBIL) were measured. Liver tissues were dissected and stained with hematoxylin and eosin ( HE) to observe pathological changes. mRNA and protein levels of eIF2α/ ATF4 / CHOP / caspase-3 were detected by real-time fluorescence quantitative PCR (qRT-PCR) and Western blot was used to measure phosphorylated-eIF2α ( p-eIF2α) protein levels. Results Compared with the control group, hepatocytes in the model group showed extensive degeneration and focal necrosis, and the central venous was damaged. The levels of ALT, AST, and TBIL in serum, mRNA levels of eIF2α, ATF4, CHOP, and caspase-3, and protein levels of p-eIF2α/ eIF2α, ATF4, CHOP, and caspase-3 in liver tissues were higher (P< 0. 05). Compared with the model group, the damage to hepatocytes and the number of necrotic cells were decreased in the positive control, low-, medium-, and high-dose PGE1 groups. The levels of ALT, AST, and TBIL in serum, mRNA levels of eIF2α, ATF4, CHOP, and caspase-3 and protein levels of p-eIF2α/ eIF2α, ATF4, CHOP, and caspase-3 in liver tissues were lower (P< 0. 05). With an increase in PGE1 dosage, the levels of ALT, AST, and TBIL in serum, mRNA levels of eIF2α, ATF4, CHOP, and caspase-3 and protein levels of p-eIF2α/ eIF2α, ATF4, CHOP, and caspase-3 in the liver tissues of low-, medium-, and high-dose PGE1 groups were decreased (P< 0. 05) dose-dependently. Compared with the positive control group, the levels of ALT, AST, and TBIL in serum, mRNA levels of eIF2α, ATF4, CHOP, and caspase-3 and protein levels of p-eIF2α/ eIF2α, ATF4, CHOP, and caspase-3 in the liver tissues of the low- and medium-dose PGE1 groups were higher (P< 0. 05). However, there was no significant difference in the levels of ALT, AST, and TBIL in serum, mRNA levels of eIF2α, ATF4, CHOP, and caspase-3 and protein levels of p-eIF2α/ eIF2α, ATF4, CHOP, and caspase-3 in liver tissues between the positive control group and the high-dose PGE1 group ( P> 0. 05). Conclusions PGE1 may reduce the apoptosis of rat hepatocytes and protect the liver by inhibiting the expression of the eIF2α/ ATF4 / CHOP pathway, which may be a potential therapeutic target for FHF.
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