细胞凋亡与不良妊娠结局关系的研究进展

doi:10.12280/gjfckx.20241001

摘要/Abstract

摘要：

细胞凋亡是一种程序性细胞死亡方式，在妊娠生理和病理过程中扮演着关键角色。细胞异常凋亡，尤其是胎盘滋养细胞的过度凋亡，可能导致滋养细胞功能障碍、血管重塑异常、氧化应激增加和免疫失衡，进而引发复发性流产（recurrent spontaneous abortion，RSA）、子痫前期（preeclampsia，PE）、妊娠期糖尿病（gestational diabetes mellitus，GDM）和早产等不良妊娠结局。研究表明，细胞凋亡的调控对妊娠至关重要。在RSA中，p53介导的凋亡和微小RNA-184（miR-184）、miR-27a的异常表达破坏滋养细胞的增殖与凋亡平衡。在PE中，miR-4531/CX3CL1信号通路通过调控血管内皮损伤参与PE发病机制。在GDM中，胃饥饿素通过下调内质网应激信号通路显示出潜在治疗价值。在早产中，内质网应激通过肌醇需求酶1α（inositol-requiring enzyme 1α，IRE1α）/c-Jun氨基端蛋白激酶（c-Jun N-terminal protein kinase，JNK）通路诱导早产儿肺上皮细胞凋亡。未来需深入研究细胞凋亡的机制及治疗靶点，为预防和治疗不良妊娠结局提供新思路。

关键词: 细胞凋亡, 妊娠结局, 流产，习惯性, 先兆子痫, 糖尿病，妊娠, 早产

Abstract:

Apoptosis is a programmed cell death that plays a crucial role in the physiological and pathological processes of pregnancy. Abnormal apoptosis, especially excessive apoptosis of trophoblast cells in the placenta, may lead to trophoblast dysfunction, abnormal vascular remodeling, increased oxidative stress, and immune imbalance, thereby cause adverse pregnancy outcomes such as recurrent spontaneous abortion (RSA), pre-eclampsia (PE), gestational diabetes mellitus (GDM), and preterm birth. The regulation of apoptosis is vital for pregnancy. In the RSA, p53-mediated apoptosis and abnormal expression of miR-184 and miR-27a disrupt the balance between trophoblast proliferation and apoptosis. In PE, the miR-4531/CX3CL1 signaling pathway is involved in the pathogenesis of PE by regulating vascular endothelial injury. In GDM, ghrelin shows potential therapeutic value by downregulating the endoplasmic reticulum stress signaling pathway. In preterm birth, endoplasmic reticulum stress induces apoptosis of alveolar epithelial cells via the inositol-requiring enzyme 1α(IRE1α)/c-Jun N-terminal protein kinase(JNK) pathway. Future research needs to further explore its mechanisms and therapeutic targets to provide new ideas for the prevention and treatment of adverse pregnancy outcomes.

Key words: Apoptosis, Pregnancy outcome, Abortion, habitual, Pre-eclampsia, Diabetes, gestational, Premature birth

马玲, 李亚西, 赵敏, 王静, 李红丽. 细胞凋亡与不良妊娠结局关系的研究进展[J]. 国际妇产科学杂志, 2025, 52(2): 121-126.

MA Ling, LI Ya-xi, ZHAO Min, WANG Jing, LI Hong-li. Progress on the Relationship between Apoptosis and Adverse Pregnancy Outcomes[J]. Journal of International Obstetrics and Gynecology, 2025, 52(2): 121-126.

参考文献 35

[1]	Xie X, Liu J, Gao J, et al. The crosstalk between cell death and pregnancy related diseases: A narrative review[J]. Biomed Pharmacother, 2024, 176:116815. doi: 10.1016/j.biopha.2024.116815.
[2]	de Dios N, Riedel R, Schanton M, et al. Placental apoptosis increased by hypoxia inducible factor-1 stabilization is counteracted by leptin[J]. Biol Reprod, 2024, 111(3):708-722. doi: 10.1093/biolre/ioae095.
[3]	Zhao X, Yang Y, Xie Q, et al. Identification of Biomarkers and Mechanisms Associated with Apoptosis in Recurrent Pregnancy Loss[J]. Biochem Genet, 2024 Oct 14. doi: 10.1007/s10528-024-10932-0.
[4]	Vinik Y, Maimon A, Dubey V, et al. Programming a Ferroptosis-to-Apoptosis Transition Landscape Revealed Ferroptosis Biomarkers and Repressors for Cancer Therapy[J]. Adv Sci(Weinh), 2024, 11(17):e2307263. doi: 10.1002/advs.202307263.
[5]	Yuan J, Ofengeim D. A guide to cell death pathways[J]. Nat Rev Mol Cell Biol, 2024, 25(5):379-395. doi: 10.1038/s41580-023-00689-6.
[6]	Saddam M, Paul SK, Habib MA, et al. Emerging biomarkers and potential therapeutics of the BCL-2 protein family: the apoptotic and anti-apoptotic context[J]. Egypt J Med Hum Genet, 2024, 25:12. doi:10.1186/s43042-024-00485-7.
[7]	Pandey SK, Shteinfer-Kuzmine A, Chalifa-Caspi V, et al. Non-apoptotic activity of the mitochondrial protein SMAC/Diablo in lung cancer: Novel target to disrupt survival, inflammation, and immunosuppression[J]. Front Oncol, 2022, 12:992260. doi: 10.3389/fonc.2022.992260.
[8]	Flores-Romero H, Hohorst L, John M, et al. BCL-2-family protein tBID can act as a BAX-like effector of apoptosis[J]. EMBO J, 2022, 41(2):e108690. doi: 10.15252/embj.2021108690.
[9]	Czabotar PE, Garcia-Saez AJ. Mechanisms of BCL-2 family proteins in mitochondrial apoptosis[J]. Nat Rev Mol Cell Biol, 2023, 24(10):732-748. doi: 10.1038/s41580-023-00629-4.
[10]	Sahoo G, Samal D, Khandayataray P, et al. A Review on Caspases: Key Regulators of Biological Activities and Apoptosis[J]. Mol Neurobiol, 2023, 60(10):5805-5837. doi: 10.1007/s12035-023-03433-5. pmid: 37349620
[11]	Carneiro BA, El-Deiry WS. Targeting apoptosis in cancer therapy[J]. Nat Rev Clin Oncol, 2020, 17(7):395-417. doi: 10.1038/s41571-020-0341-y. pmid: 32203277
[12]	Seyrek K, Ivanisenko NV, König C, et al. Modulation of extrinsic apoptotic pathway by intracellular glycosylation[J]. Trends Cell Biol, 2024, 34(9):728-741. doi: 10.1016/j.tcb.2024.01.003.
[13]	Qian J, Zhao L, Xu L, et al. Cell Death: Mechanisms and Potential Targets in Breast Cancer Therapy[J]. Int J Mol Sci, 2024, 25(17):9703. doi: 10.3390/ijms25179703.
[14]	马丹丹, 郭明明, 宋凯, 等. 内质网应激——凋亡途径与创伤后应激障碍[J]. 成都中医药大学学报, 2024, 47(5):76-80. doi: 10.13593/j.cnki.51-1501/r.2024.05.014.
[15]	Chen X, Shi C, He M, et al. Endoplasmic reticulum stress: molecular mechanism and therapeutic targets[J]. Signal Transduct Target Ther, 2023, 8(1):352. doi: 10.1038/s41392-023-01570-w.
[16]	Chipurupalli S, Samavedam U, Robinson N. Crosstalk Between ER Stress, Autophagy and Inflammation[J]. Front Med(Lausanne), 2021, 8:758311. doi: 10.3389/fmed.2021.758311.
[17]	Shi T, van Soest D, Polderman PE, et al. DNA damage and oxidant stress activate p53 through differential upstream signaling pathways[J]. Free Radic Biol Med, 2021, 172:298-311. doi: 10.1016/j.freeradbiomed.2021.06.013.
[18]	Fusée L, Salomao N, Ponnuswamy A, et al. The p53 endoplasmic reticulum stress-response pathway evolved in humans but not in mice via PERK-regulated p53 mRNA structures[J]. Cell Death Differ, 2023, 30(4):1072-1081. doi: 10.1038/s41418-023-01127-y.
[19]	秦朗, 高睿. 《自然流产诊治中国专家共识(2020年版)》评述[J]. 西部医学, 2021, 33(5):625-631. doi:10.3969/j.issn.1672-3511.2021.05.001.
[20]	梁婷婷, 赵靖嵩, 马成龙, 等. 微小RNA-184促进滋养层细胞凋亡而引起复发性流产的研究[J]. 现代预防医学, 2021, 48(6):1123-1127.
[21]	周立花, 胡英, 邹晖. 复发性流产患者绒毛组织中miR-27a表达对滋养细胞增殖和凋亡的影响及其作用机制[J]. 吉林大学学报(医学版), 2022, 48(4):1018-1027. doi: 10.13481/j.1671-587X.20220423.
[22]	Wang J, Ding J, Zhang S, et al. Decreased USP2a Expression Inhibits Trophoblast Invasion and Associates With Recurrent Miscarriage[J]. Front Immunol, 2021, 12:717370. doi: 10.3389/fimmu.2021.717370.
[23]	Kokori E, Aderinto N, Olatunji G, et al. Maternal and fetal neurocognitive outcomes in preeclampsia and eclampsia; a narrative review of current evidence[J]. Eur J Med Res, 2024, 29(1):470. doi: 10.1186/s40001-024-02070-5. pmid: 39342384
[24]	Wu D, Zhou B, Hong L, et al. Trophoblast cell-derived extracellular vesicles regulate the polarization of decidual macrophages by carrying miR-141-3p in the pathogenesis of preeclampsia[J]. Sci Rep, 2024, 14(1):24529. doi: 10.1038/s41598-024-76563-y. pmid: 39424901
[25]	Guzik TJ, Nosalski R, Maffia P, et al. Immune and inflammatory mechanisms in hypertension[J]. Nat Rev Cardiol, 2024, 21(6):396-416. doi: 10.1038/s41569-023-00964-1. pmid: 38172242
[26]	张雅, 刘晓红. GRHL2在子痫前期患者胎盘中的表达及对滋养层细胞增殖、侵袭的影响[J]. 中国妇幼健康研究, 2024, 35(9):7-13. doi: 10.3969/j.issn.1673-5293.2024.09.002.
[27]	Huang SJ, Chen CP, Buchwalder L, et al. Regulation of CX3CL1 Expression in Human First-Trimester Decidual Cells: Implications for Preeclampsia[J]. Reprod Sci, 2019, 26(9):1256-1265. doi: 10.1177/1933719118815592. pmid: 30606080
[28]	Wu H, Guo H, Liu H, et al. Copper sulfate-induced endoplasmic reticulum stress promotes hepatic apoptosis by activating CHOP, JNK and caspase-12 signaling pathways[J]. Ecotoxicol Environ Saf, 2020, 191:110236. doi:10.1016/j.ecoenv.2020.110236.
[29]	Verlohren S, Brennecke SP, Galindo A, et al. Clinical interpretation and implementation of the sFlt-1/PlGF ratio in the prediction, diagnosis and management of preeclampsia[J]. Pregnancy Hypertens, 2022, 27:42-50. doi: 10.1016/j.preghy.2021.12.003.
[30]	Wang H, Li N, Chivese T, et al. IDF Diabetes Atlas: Estimation of Global and Regional Gestational Diabetes Mellitus Prevalence for 2021 by International Association of Diabetes in Pregnancy Study Group′s Criteria[J]. Diabetes Res Clin Pract, 2022, 183:109050. doi: 10.1016/j.diabres.2021.109050.
[31]	He M, Guo X, Jia J, et al. Regulatory mechanisms underlying endoplasmic reticulum stress involvement in the development of gestational diabetes mellitus entail the CHOP-PPARα-NF-κB pathway[J]. Placenta, 2023, 142:46-55. doi: 10.1016/j.placenta.2023.08.070. pmid: 37639950
[32]	Li X, Ji Q, Zhong C, et al. Ghrelin regulates the endoplasmic reticulum stress signalling pathway in gestational diabetes mellitus[J]. Biochem Biophys Res Commun, 2024, 709:149844. doi: 10.1016/j.bbrc.2024.149844.
[33]	Liu ZN, Jiang Y, Liu XQ, et al. MiRNAs in Gestational Diabetes Mellitus: Potential Mechanisms and Clinical Applications[J]. J Diabetes Res, 2021,, 2021:4632745. doi: 10.1155/2021/4632745.
[34]	蒋昊天, 陈超. 不同胎龄早产儿的生存状况及其变化趋势[J]. 中华围产医学杂志, 2024, 27(10):865-870. doi: 10.3760/cma.j.cn113903-20240709-00508.
[35]	Tong X, Li M, Liu N, et al. Hyperoxia induces endoplasmic reticulum stress-associated apoptosis via the IRE1 α pathway in rats with bronchopulmonary dysplasia[J]. Mol Med Rep, 2021, 23(1):33. doi: 10.3892/mmr.2020.11671.