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. 2018 May 20;38(5):572-577.
doi: 10.3969/j.issn.1673-4254.2018.05.11.

[Role of endoplasmic reticulum stress-induced apoptosis of trophoblasts in intrahepatic cholestasis during pregnancy]

[Article in Chinese]
Hai-Zhen Wang  1 , Dan-Chun Cai, Dan-Dan Liao, Mei Zhong, Yun-Fei Gao, Chao Sheng
Affiliations

[Role of endoplasmic reticulum stress-induced apoptosis of trophoblasts in intrahepatic cholestasis during pregnancy]

[Article in Chinese]
Hai-Zhen Wang et al. Nan Fang Yi Ke Da Xue Xue Bao. .

Abstract
in English, Chinese

Objective: To investigate the role of endoplasmic reticulum stress (ERS)-induced trophoblast apoptosis in the development of intrahepatic cholestasis during pregnancy (ICP).

Methods: Twenty pregnant women with ICP and 20 normal pregnant women undergoing cesarean section were enrolled in this study. The number of placenta syncytial knots in these women was determined using HE staining. The mRNA expressions of GRP78, CHOP, caspase-3, and caspase-7 were detected using RT-PCR in the placental tissues of the women and also in HTR-8/SVneo cells treated with different doses of deoxycholic acid (DCA). Caspase-3 and caspase-7 activities were also detected in DCA-treated HTR-8/SVneo cells using commercial assay kits, and the presence of apoptotic bodies in the cells were detected with electron microscopy.

Results: Compared with normal placental tissues, the placenta from women with ICP showed significantly increased syncytial knots (P<0.01) and obviously enhanced mRNA expressions of GRP78, CHOP, caspase-3, and caspase-7 (P<0.05). In HTR-8/SVneo cells treated with different doses of DCA (0, 10, 50, and 100 µmol/L), the mRNA expressions of GRP78, CHOP, caspase-3 and caspase-7 were significantly increased in a dose-dependent manner (P<0.05) and the protein levels of GRP78 and CHOP were also increased dose-dependently. Treatment with DCA at 50 µmol/L for 24 h significantly upregulated caspase-3 and caspase-7 activity in the cells (P<0.05), and the cells treated with 50 µmol/L DCA for 12 h showed the presence of apoptotic bodies.

Conclusion: The activation of ERS and enhanced apoptosis of the trophoblasts occur in the placenta of women with ICP. DCA can significantly increase the expressions of ERS markers and thus lead to trophoblast apoptosis, suggesting that ERS-induced trophoblasts apoptosis may play a key role in the development of ICP.

目的: 探讨内质网应激介导滋养细胞凋亡在妊娠期肝内胆汁淤积症(ICP)中的作用及机制。

方法: 收集2015年12月~ 2016年12月在南方医科大学南方医院住院分娩的ICP孕妇20例为病例组, 另以同期因社会因素行择期剖宫产术的20例无合并症的正常孕妇为正常对照组。利用HE染色计量观察正常对照孕妇及ICP孕妇胎盘合体细胞结节数量; RT-PCR法检测正常孕妇及ICP孕妇胎盘组织中GRP78、CHOP、caspase-3及caspase-7的mRNA表达; 建立不同浓度胆酸(0、10、50、100 μmol/L)体外刺激HTR-8/SVneo人早孕滋养细胞株模型, 利用RT-PCR法检测HTR-8/SVneo细胞GRP78、CHOP、caspase-3及caspase-7的mRNA表达及利用蛋白印迹法检测GRP78、CHOP蛋白的表达; caspase-3、caspase-7活性检测试剂盒分别检测其活化程度; 电镜观察细胞凋亡形态。

结果: ICP组较对照组孕妇胎盘组织中合体细胞结节数明显增多(P < 0.01); GRP78、CHOP、caspase-3及caspase-7的mRNA表达明显上调(P < 0.05);不同浓度(0、10、50、100 μmol/L)去氧胆酸作用细胞24 h后, GRP78、CHOP、caspase-3及caspase-7 mRNA的表达水平较对照组显著增高(P < 0.05), GRP78、CHOP蛋白的表达水平较对照组也显著增高, 且均存在浓度依赖效应; 50 μmol/L去氧胆酸作用细胞24 h后检测caspase-3及caspase-7活性增高(P < 0.05); 50 μmol/L去氧胆酸作用细胞12 h后电镜观察HTR-8/SVneo细胞呈现凋亡小体。

结论: ICP孕妇胎盘组织中存在滋养细胞过度凋亡及内质网应激激活的现象。去氧胆酸可以呈浓度依赖性地促进滋养细胞内质网应激相关基因mRNA和蛋白的表达, 引起细胞凋亡, 提示内质网应激介导的滋养细胞凋亡在ICP的发病机制中可能起着重要的作用。

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Figures

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1
ICP孕妇胎盘组织形态学异常 Histological abnormalities of the trophoblasts in ICP placenta. A: Histological observation of the trophoblasts in normal and ICP placentas. Arrows indicate the syncytial knots (SKs)(Original magnification: ×200); B: Number (Mean±SD) of SKs in the placenta (averaged from at least 4 fields per section; n=20). **P < 0.01.
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ICP孕妇胎盘组织GRP78及CHOP mRNA表达增高 mRNA expression of GRP78 and CHOP were significantly higher in ICP placenta. GRP78 and CHOP mRNA levels were detected by RT-PCR (n= 20). The data are shown as Mean±SD. *P < 0.05.
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ICP孕妇胎盘组织caspase-3 and caspase-7 mRNA表达增高 mRNA expression of caspase-3 and caspase-7 were significantly higher in ICP placenta as detected by RT-PCR (n=20). The data are shown as Mean±SD. *P < 0.05.
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去氧胆酸上调HTR- 8/SVneo细胞中GRP78、CHOP、caspase-3及caspase-7 mRNA的表达 Upregulated mRNA expressions of GRP78, CHOP, caspase-3, and caspase-7 detected by RT-PCR in HTR-8/ SVneo cells treated with DCA at 10, 50, and 100 µmol/L for 24 h. Data are shown as Mean±SD.
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去氧胆酸上调HTR- 8/SVneo细胞中GRP78、CHOP蛋白的表达 Upregulated protein expressions of GRP78 and CHOP detected by Western blotting in HTR- 8/SVneo cells treated with DCA at 10, 50, and 100 µmol/L for 24 h.
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去氧胆酸增高HTR- 8/SVneo细胞中caspase-3及caspase-7的活性 DCA treatment at 50 μmol/L for 24 h upregulated the levels of caspase-3 (A) and caspase-7 (B) activity in HTR-8/SVneo cells. Data are shown as Mean±SD. *P < 0.05.
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去氧胆酸促进HTR-8/SVneo细胞凋亡小体形成 DCA treatment at 50 μmol/L for 12 h promoted the formation of apoptotic bodies in HTR-8/ SVneo cells (electron microscopy, ×10 000).
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References

    1. Geenes V, Chappell LC, Seed PT, et al. Association of severe intrahepatic cholestasis of pregnancy with adverse pregnancy outcomes: a prospective population-based case-control study. Hepatology. 2014;59(4):1482–1491. doi: 10.1002/hep.26617. [Geenes V, Chappell LC, Seed PT, et al. Association of severe intrahepatic cholestasis of pregnancy with adverse pregnancy outcomes: a prospective population-based case-control study[J]. Hepatology, 2014, 59(4): 1482-1491.] - DOI - PMC - PubMed
    1. Ozkan S, Ceylan Y, Ozkan OV, et al. Review of a challenging clinical issue: Intrahepatic cholestasis of pregnancy. World J Gastroenterol. 2015;21(23):7134–41. doi: 10.3748/wjg.v21.i23.7134. [Ozkan S, Ceylan Y, Ozkan OV, et al. Review of a challenging clinical issue: Intrahepatic cholestasis of pregnancy[J]. World J Gastroenterol, 2015, 21(23): 7134-41.] - DOI - PMC - PubMed
    1. Henderson CE, Rezai S, Mercado R. The risk of infant and fetal death by each additional week of expectant management in intrahepatic cholestasis of pregnancy by gestational age. Am J Obst Gynecol. 2015;212(1):S52–3. [Henderson CE, Rezai S, Mercado R. The risk of infant and fetal death by each additional week of expectant management in intrahepatic cholestasis of pregnancy by gestational age[J]. Am J Obst Gynecol, 2015, 212(1): S52-3.] - PubMed
    1. Pilliod RA, Page J, Snowden J, et al. 110: The small for gestational age fetus: risk of stillbirth and infant death by each additional week of expectant management. Am J Obst Gynecol. 2016;214(1):S77. [Pilliod RA, Page J, Snowden J, et al. 110: The small for gestational age fetus: risk of stillbirth and infant death by each additional week of expectant management[J]. Am J Obst Gynecol, 2016, 214(1): S77.] - PubMed
    1. 王 冬梅, 朱 启英, 丁 丽, et al. 妊娠肝内胆汁淤积症患者胎盘细胞凋亡及调控基因的研究. http://med.wanfangdata.com.cn/Paper/Detail/PeriodicalPaper_zhfck200301002. 中华妇产科杂志. 2003;(1):8–10. [王冬梅, 朱启英, 丁丽, 等.妊娠肝内胆汁淤积症患者胎盘细胞凋亡及调控基因的研究[J].中华妇产科杂志, 2003, (1): 8-10.]

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