A feasible study of human amniotic mesenchymal stem cells for prevention and treatment of amniotic fluid embolism

doi:10.3969/j.issn.2095-4344.0451

Abstract

Abstract:

BACKGROUND: Currently, there are two difficult problems concerning amniotic fluid embolism. One is to find out the specific indicators for diagnosis of amniotic fluid embolism and the other is to prevent and treat amniotic fluid embolism. However, there are yet no effective treatments, and symptomatic treatment for clinical manifestations is the only treatment for amniotic fluid embolism, which has poor outcomes and leads to a high mortality rate.
OBJECTIVE: To explore the feasibility of human amniotic mesenchymal stem cells to prevent and treat amniotic fluid embolism.
METHODS: CNKI and PubMed data bases were searched for relevant articles with the key words of “amniotic fluid embolism, human amniotic mesenchymal stem cells” in Chinese and English, respectively. And finally 43 articles were included and summarized.
RESULTS AND CONCLUSION: From the point of view of the pathogenesis of immune inflammatory reaction of amniotic fluid embolism, the immunology of pregnancy is related to transplantation biology. It is theoretically suggested that human amniotic mesenchymal stem cells can prevent and treat amniotic fluid embolism, regulate the immune system of the puerpera with amniotic fluid embolism, and reduce acute lung injury caused by amniotic fluid embolism. This method provides a new perspective for research on the prevention and treatment of amniotic fluid embolism.

中国组织工程研究杂志出版内容重点：干细胞；骨髓干细胞；造血干细胞；脂肪干细胞；肿瘤干细胞；胚胎干细胞；脐带脐血干细胞；干细胞诱导；干细胞分化；组织工程

Key words: Amnion, Mesenchymal Stem Cells, Embolism, Amniotic Fluid, Lung Injury, Tissue Engineering

CLC Number:

R394.2

Zhang Li, Wang Yu-dan, Xie Cheng-ming, Yu Jian. A feasible study of human amniotic mesenchymal stem cells for prevention and treatment of amniotic fluid embolism[J]. Chinese Journal of Tissue Engineering Research, 2018, 22(5): 781-786.

Figures/Tables 1

2.1 羊水栓塞 2.1.1 发病机制及研究进展羊水栓塞的发病机制并不清楚，但研究证明已不再是单纯性的机械栓塞。1995年Clark发现正常产妇的血液中有鳞状上皮等羊水成分，但并未发生羊水栓塞；1997年余艳红等用羊水灌注离体肺，并未发生机械性栓塞、肺水肿及肺动脉高压，但在镜下肺组织血管内发现有胎儿的毳毛等。羊水栓塞发生时免疫反应比栓塞现象更多，其临床表现与过敏性休克和全身炎症反应综合征类似，目前研究者更倾向于“妊娠过敏反应”及“炎症爆发”学说。因此许多学者的研究方向已转向研究羊水栓塞发生时炎症因子水平的变化。在羊水栓塞动物模型中，可以检测到核转录调控因子κB、白细胞介素6、白细胞介素8[4]、肿瘤坏死因子α以及基质金属蛋白酶9等促炎因子水平升高[5-6]，基质金属蛋白酶抑制剂1抗炎因子水平下降。有学者认为，羊水栓塞是一种无抗体参与的类过敏反应。发病机制可能为羊水、胎粪导致肥大细胞脱颗粒，使血栓素、前列腺素、白三烯等进入母体的血液循环，进而导致一系列病理生理变化。另有学者称，补体激活途径比过敏反应更可能是羊水栓塞的发病机制。在羊水栓塞患者血清中可检测到C3和C4水平降低，且比正常人降低两三倍，说明羊水栓塞发生时补体被大量激活与消耗。卢颖州等[7]在孕鼠羊水栓塞动物模型中检测到补体C3a、C4a水平升高。龙艳丽等[8]在孕兔羊水栓塞模型中发现补体C3a水平升高。另外，羊水栓塞发生时，母体凝血途径被激活。妊娠晚期母体呈现高凝状态，羊水进入母体血液循环，激活凝血系统，大量血小板与凝血因子被消耗，导致纤溶系统被激活，从而使母体高凝状态迅速转变为低凝状态，出现弥漫性血管内凝血，出血不止是羊水栓塞弥漫性血管内凝血最显著的表现，发生率达85%。 2.1.2 目前的治疗方法目前对羊水栓塞的治疗没有常规且有效的治疗方法，大多针对其临床表现对症、支持治疗。心肺功能支持治疗：经胸或食管超声心动图可评估左心室功能，并有助于心脏复苏的抢救[9]。有报道指出，全血细胞计数、电解质、动脉血气和凝血四项(凝血酶原时间、活化部分凝血活酶时间、凝血酶时间、纤维蛋白原)等指标应在羊水栓塞发生的初步阶段间断反复检测，为迅速发展的弥漫性血管内凝血提供帮助，在短时间内及时调整治疗方案。由于羊水栓塞能够引起肺部的严重损伤，因此，呼吸系统的支持必不可少[10]，可经面罩给氧，要保持血氧饱和度在90%以上[11]，严重者则需要进行气管插管[12]。除静脉补液容量复苏，还需肾上腺素、去甲肾上腺素、多巴胺、多巴酚丁胺等升压支持治疗，并维持收缩压> 90 mm Hg(1 mm Hg=0.133 kPa)，尿量> 25 mL/h。纠正凝血功能：羊水栓塞可引起凝血系统障碍，导致非常严重的产科大出血[13]，以子宫收缩乏力最为常见。临床上有行子宫切除术[14]，继而大规模输血抢救成功的案例。有报道称，羊水栓塞输血时红细胞与新鲜冷冻血浆的理想比例是1︰1-1︰1.5[15]。回收式自体输血在产科患者大出血中也得到广泛应用，羊水栓塞患者可加用白细胞滤器过滤血液中的羊水成分[16]。血浆置换能对羊水栓塞弥漫性血管内凝血起到作用，不仅仅是因为补充了大量被消耗的凝血因子[17]，还可能与通过血浆置换清除了母体血液中的炎性过敏介质和细胞因子有关。地塞米松治疗：有临床报道，地塞米松对羊水栓塞起到了治疗作用[18-19]，其机制可能为地塞米松抑制羊水栓塞发生时白三烯、5-羟色胺、血栓素或者前列腺素的形成和释放，防止炎性物质进入母体，减轻羊水栓塞时的过敏性反应[20]。但临床上对于高剂量的使用皮质类固醇激素治疗存在争议。 C1酯酶抑制剂治疗：据报道，羊水栓塞发生时，C1酯酶抑制因子显著降低。C1酯酶抑制剂在凝血、纤溶系统中起着重要作用，可抑制C1酯酶、凝血因子Ⅻa，还可抑制补体激活[21]。临床上1例羊水栓塞患者子宫收缩乏力导致大出血，静脉注射1 000 U的C1酯酶抑制剂后，子宫迅速收缩，并于30 min后停止出血[22]。中医疗法：有学者提出，用过敏性休克和弥漫性血管内凝血两者相互作用分析羊水栓塞的临床表现，两者的拮抗作用可解释羊水栓塞临床症状不典型，也可解释羊水栓塞表现出的多种临床症状。由此结合中医辨证，尝试性的提出了中医治疗淤血性出血的处方：大黄15 g，茜草15 g，川楝子10 g，郁金12 g，用法：用水煎服[23]。 2.2 人羊膜间充质干细胞 hAMSCs来源于废弃胎盘组织，不受伦理学限制，可无创性、大量获得，增殖能力强。hAMSCs与其他干细胞一样都具有低免疫原性[24]，可抑制淋巴细胞增殖反应，同种异体和异种间移植不会引起排斥反应[25-26]。hAMSCs具有免疫调节作用，其作用机制可能为抑制活化T细胞的增殖[27]、抑制体内B细胞转化为成熟的浆细胞，减少抗体产生，降低NK细胞的毒性作用，使树突状细胞的抗原提呈作用减弱，对免疫系统进行调节。在炎症方面可表现为减少促炎因子的释放，增加抗炎因子的产生。hAMSCs具有多向分化潜能，不仅可以诱导分化为成骨细胞[28]、成脂细胞、神经细胞，还能分化为气管上皮细胞，血管内皮细胞[29]、心肌细胞、肝细胞[30]、肾小管上皮细胞。hAMSCs归巢至受损伤的器官与组织，多向分化为机体所需要的细胞从而替代凋亡和坏死的细胞，达到修复损伤的作用。"

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