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通讯作者:

区景松(1968-),男,广东番禹人,博士生导师,主要从事各种先天性心脏病、后天性心脏病如瓣膜病、冠心病大血管病变等的诊断和治疗方面的研究。E-mail:oujs@mail.sysu.edu.cn

中图分类号:R654,R363

文献标识码:A

文章编号:2096-8965(2021)01-0013-08

DOI:10.12287/j.issn.2096-8965.20210102

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目录contents

    摘要

    循环微粒(细胞外囊泡)在血管调节、炎症、凝血、细胞增殖与凋亡等生物过程中具有细胞间传递信息的功能。 所含成分复杂多样,与心血管疾病的发生发展过程联系紧密。循环微粒(细胞外囊泡)未来可以作为反映凝血功能、炎症反应、组织器官损伤的临床标志物,或者是调控血管稳态、纠正凝血、改善内环境、保护组织器官功能的临床治疗靶点,具有重要的研究意义。本文总结循环微粒(细胞外囊泡)在心血管外科领域的相关研究进展,讨论循环微粒(细胞外囊泡) 在相关疾病过程中所起的作用,及其在相关疾病诊断与治疗当中的研究及应用前景。

    Abstract

    Microparticles (Extracellular Vesicles) which involved widely in multiple biological processes have properties of diverse functions and complex components. Intercellular messages could be transmitted by microparticles (Extracellular Vesicles) in the biological processes such as vascular regulation, inflammation, coagulation, proliferation and apoptosis. Microparticles (extracellular vesicles) have important roles for the development of injury and impair that happened perioperatively and long-term prognosis in cardiovascular surgery. This review summarizes the research progress of microparticles (extracellular vesicles) in the field of cardiovascular surgery and their prospect for diagnostic and therapeutic clinical application.

  • 前言

  • 循环微粒(Circulating Microparticles,MPs)/细胞外囊泡(Extracellular Vesicles,EVs),是机体细胞受到刺激或凋亡时释放的一类双层脂质膜结构的微小囊泡。早在1967年,循环微粒作为血小板的产物被学者Wolf发现,当时认为它是无作用的细胞碎片,其作用被人们忽视。MPs/EVs具有细胞间信息传递的生物活性,在血管调节、炎症、凝血、细胞增殖与凋亡等过程中有着十分重要的作用。MPs/EVs遍布整个机体且作用多样,根据其不同的母系细胞来源分为不同的亚群。除了双层脂质膜,MPs/EVs含有各种内容物如细胞因子、核酸物质、信号蛋白等,随着血液循环到达各个不同的靶点器官及组织。

  • 炎症、组织损伤、肿瘤、缺血等可以刺激不同的机体细胞产生MPs/EVs,如肿瘤坏死因子 α(Tumor Necrosis Factor-α, TNF-α)、白细胞介素、纤溶酶原激活抑制因子1(Plasminogen Activator Inhibitor-1, PAI-1)等刺激内皮细胞产生内皮衍生循环微粒(Endothelium-derived Microparticles, EMP),组织因子刺激血小板产生血小板衍生循环微粒(Platelet-derived Microparticles,PMP)等 [1, 2]。在心血管疾病当中,如高血压、急性冠脉综合症、二尖瓣疾病、主动脉瓣狭窄、先天性心脏病、心脏移植物血管病等,MPs/EVs有所增加,并在心血管疾病发生发展中起到调节内皮功能、促进炎症、调控凋亡等作用 [3-6]。早期的一些研究结果表明,MPs/EVs在机体生理病理过程中所发挥的作用是有害的,特别是在动脉粥样硬化、促进炎症方面 [7]。然而近来有研究指出,MPs/EVs也有抑制炎症反应、促进血管新生等作用 [8, 9],在病理发展过程中起到保护作用。此外,我们之前的研究表明,在不同的生理病理状态下,同一种类细胞所产生的MPs/EVs会呈现出不一样的组分表型 [2]。本文就MPs/EVs在心血管外科领域对凝血功能、内皮功能、重要器官功能损伤等病理过程中起到的作用进行综述。

  • 1 体外循环

  • 体外循环技术是利用特殊装置暂时替代心脏供应血液循环以及肺气体交换功能的生命支持技术,也是心血管外科的常用技术。

  • 手术创伤本身可以刺激MPs/EVs的产生,然而,体外循环作为一个独立的因素,也可以刺激机体细胞如血管内皮细胞、血小板等生成MPs/EVs,并参与血小板活化聚集、氧化应激、炎症反应、内皮功能调节等生物过程,从而对机体产生不良作用,影响患者预后,而且风险会随着体外循环时间延长而增加 [10-14]。相关文献中,对于MPs/EVs升高出现峰值、回到基线水平的时间各有不同。此外,体外循环过程中肝素化、低温等因素,可能也会对血小板功能造成一定的影响 [15-17]。有学者尝试使用小型体外循环管道进行手术,但对MPs/EVs的生成并没有显著影响 [18]。术中使用血液回收装置可有效洗脱MPs/EVs,理论上可减轻体外循环给机体所带来促凝促炎的不良影响,但是否会影响整体预后有待进一步研究。

  • 2 术后凝血

  • 心血管外科手术后出血是常见的并发症。经过开胸、体外循环等过程,不可避免地会出现失血、血液稀释、血液成分丢失、凝血物质消耗等情况,MPs/EVs不仅自身脂质膜表面外露促凝的磷脂酰丝氨酸、组织因子、血管性血友病因子(von Willebrand Factor, vWF),发挥促凝血作用,而且还能反馈激活内皮、血小板等靶细胞,生成更多的循环微粒及细胞因子,促进凝血反应的进一步发展 [19],对术后止血有着十分重要的作用。有研究发现,如果冠脉搭桥术前PMP、红细胞衍生微粒(Red Blood Cell-derived Microparticles,RMP) 水平显著下降,术后存在输血的可能性越大,说明这部分MPs/EVs间接反应了患者术前凝血功能储备[20]

  • 心脏手术会引起MPs/EVs释放明显增加,并参与机体一系列反应,这些MPs/EVs具有促凝活性,激活凝血通路、血小板活化聚集、白细胞血小板聚集等 [21-23]。凝血物质过度消耗、血小板功能损害会造成术后凝血功能障碍。此外,我们在瓣膜疾病患者MPs/EVs的蛋白组分研究中发现,相比于健康人群,在心脏瓣膜手术前,患者血浆MPs/EVs组分中,含有更多凝血相关的蛋白,如vWF、 β2糖蛋白1,而此类蛋白成分在手术后明显减少,提示体外循环手术会使凝血功能受到损害 [24]。 Chung等在体外循环过程中应用一氧化氮及伊洛前列素,起到了减少体外循环过程中MPs/EVs的生成、保护血小板功能的作用,明显减少术后引流量 [25]。这些研究验证了我们的假设,缩短体外循环时间,减少相关MPs/EVs的生成,避免凝血物质的消耗,保存机体凝血功能,可以减少手术后出血并发症。同时我们希望MPs/EVs维持在正常的生理水平,而尽可能避免过度释放,引起血栓栓塞等不良后果。

  • 3 内皮功能与血流稳态

  • 保护内皮功能、维持血流稳态,对手术安全及患者预后有着非常重要的意义。一氧化氮(Nitric Oxide,NO)是目前公认的内皮功能调控关键因子,在维持血管张力及内皮活性方面发挥着重要的作用。

  • 早期研究已证明,MPs/EVs可以抑制内皮调节功能 [26-28]。随着我们研究的深入,发现MPs/EVs可以通过抑制Akt/eNOS(Endothelial Nitric Oxide Synthase)-HSP90(Heat Shock Protein 90)信号通路,使eNOS解偶联,减少NO的生成,产生氧自由基,从而影响内皮依赖的血管舒张功能。我们在最近一项针对瓣膜手术患者的研究中发现,瓣膜疾病本身或者体外循环手术,都可以促使机体细胞产生MPs/EVs,作用于血管内皮细胞。除了抑制Akt/ eNOS-HSP90通路, MPs/EVs还通过影响Akt、 PKCβⅡ(Protein Kinase CβⅡ)、 Caveolin-1,下调eNOS的磷酸化,导致NO生成的减少,引起内皮依赖的血管舒张功能障碍 [12]。此外,我们还发现,在先天性心脏病,特别是合并肺动脉高压的患者, EMP水平明显升高。其通过P38/MAPK通路,促进炎症发生,影响NO的产生,损害内皮功能,并可能由此参与肺动脉高压的发展 [6]。这些内皮功能障碍,会直接影响心脏手术后的血流稳态,增加术后并发症发生,改变病人的预后结局。

  • 机械牵拉可以刺激血管平滑肌细胞,使MPs/EVs的释放明显增加,并通过内质网应激,诱导内皮细胞凋亡,并促进胸主动脉瘤与夹层的形成。内质网应激抑制剂可以减少机械牵拉引起的MPs/EVs释放,减轻内皮细胞凋亡,从而抑制胸主动脉瘤与夹层的形成 [29]。可见MPs/EVs在大血管疾病发生发展过程中也发挥着重要作用。

  • 4 瓣膜疾病

  • 二尖瓣狭窄或关闭不全患者,血浆中EMP的含量显著增加,而且与病变程度呈正相关。这些EMP反过来又会对瓣膜内皮细胞的功能造成影响,并加速瓣膜的损害 [12]。Diehl等学者也发现,在严重主动脉瓣狭窄病人的血浆中EMP数量明显增加 [30]。然而也有文献报道,对于严重主动脉瓣狭窄病人,瓣膜钙化程度与MPs/EVs及其诱导的凝血酶生成没有显著联系 [31]。提示可能在瓣膜狭窄致病机制当中存在其他的作用途径,可能与成骨细胞表型的循环内皮祖细胞、白三烯B4作用及羟基胆固醇激活内质网应激等有密切关系 [32-34]。在我们的蛋白组分研究中,也逐一验证了在凝血功能、内皮功能、系统性炎症反应等方面,心脏瓣膜手术前后的MPs/EVs富含相应的功能蛋白 [24]。在瓣膜手术过程中,因为体外循环以及心肌停搏,引起血流动力学及重要器官氧供需平衡的改变,会导致一系列的病理反应。如前文所提及,MPs/EVs参与其中的氧化应激、炎症反应、内皮功能障碍、凝血功能障碍等过程,在手术过程中循环微粒的过度释放可能是不利的。

  • 经导管主动脉瓣置入术(Transcatheter Aortic Valve Implantation,TAVI)是针对主动脉瓣手术高危人群的一种有效的替代治疗方案。有研究发现, TAVI手术后EMP显著下降,而PMP则长时间维持在较高水平。EMP的减少,可能与TAVI能有效地改善主动脉瓣功能、改善整体血流动力学、减少跨瓣压差及应切力等有关。而新置入瓣膜本身会引起血栓形成,特别是置入体的尖端位置,这可以用来解释为何PMP会维持在较高水平 [35]

  • 5 冠状动脉粥样硬化性心脏病

  • MPs/EVs参与内皮炎症反应、炎症细胞迁移、血管损伤与修复、内皮及血管平滑肌细胞增殖迁移等,在冠状动脉粥样硬化性心脏病的发生发展过程中发挥着重要的作用 [36-40]

  • 冠状动脉旁路移植术(Coronary Artery Bypass Graft Surgery,CABG),即冠脉搭桥术,是冠心病最有效的治疗方法。手术方式可分为非体外循环(Off-pump)和体外循环(On-pump)冠脉搭桥术。

  • 无论是Off-pump还是On-pump,CABG都会引起MPs/EVs水平的升高,术后呈现下降趋势,但仍高于术前水平。然而,有研究表明,Off-pump CABG不会引起氧化应激,但On-pump CABG患者血浆中含有的MPs/EVs,可以诱导氧化应激,促进超氧化物的产生 [10]

  • 移植血管的通畅性直接关系着患者的整体预后。Camera等发现MPs/EVs与冠脉搭桥手术患者的桥血管通畅性有着密切联系。在随访过程中发生桥血管堵塞的患者,血浆中某些亚群的MPs/EVs含量显著升高。例如PMP在血小板激活过程中,传递生物信息至靶细胞,参与细胞增殖、血管新生、炎症反应。该研究根据研究结果,筛选出CD40L+/CD41+、CD62P+/CD41+、TF+/CD41+、 TF+、AnnexinV+/TF+、AnnexinV+/TF+/CD41+ 这6种表型,计算出“微粒积分”,并用作预测冠脉搭桥术后发生桥血管堵塞的风险,指导后续治疗方案 [41]

  • 6 心脏移植物血管病

  • 同种异体心脏移植是终末期心脏病最有效的治疗手段。心脏移植物血管病(Cardiac Allograft Vasculopathy,CAV)是影响心脏移植患者远期预后的主要原因,是免疫与非免疫因素介导的内皮细胞损伤与修复的结果。天然免疫及特异性免疫细胞可以影响炎症反应、血管纤维化、血管平滑肌增殖等,促进CAV的发生 [42-46]

  • 内皮损伤与修复的过程中,内皮细胞持续活化,并释放出MPs/EVs。有研究指出,相比于冠心病和心衰患者,心脏移植患者MPs/EVs带有更多的促凋亡活性 [47, 48]。然而,Singh等发现,并发CAV的患者,MPs/EVs更倾向于内皮的激活,而非凋亡 [49]。该研究提出,可以利用这种表型的EMP作为标志物,来预测术后患者是否罹患CAV。然而MPs/EVs的表型变化在CAV发展过程中所起的作用及机制尚不完全清楚,有待进一步研究。

  • 7 重要器官功能损伤

  • 重要器官功能损伤是心脏外科术后严重的并发症,直接关系到手术成败。MPs/EVs通过促进炎症反应、氧化应激等,促进这些并发症的发生发展。

  • 我们近期的研究发现,患者接受心脏体外循环手术后,血浆内MPs/EVs含量升高,而在术后12小时MPs/EVs的升高程度,与急性心力衰竭的发生有着密切联系,MPs/EVs可有望作为预测术后心衰的新一代标志物 [14]

  • 此外,MPs/EVs可以通过抑制eNOS活性、趋化粒细胞聚集,影响内皮功能、促进炎症反应,导致肺水肿、内皮-肺泡屏障受损,进而引起急性肺损伤 [50]。而且,MPs/EVs在肺损伤发展过程中,也有促炎症的作用 [51]

  • 瓣膜置换手术后患者血浆中提取的MPs/EVs,可以抑制Akt的磷酸化过程,引起FOXO3a(Forkhead Box Protein 3a)的过表达以及FOXO3a的去磷酸化,致使更多的FOXO3a进入细胞核,激活下游信号通路,导致内皮细胞大量释放趋化因子CXCL4和CCL5,刺激中性粒细胞趋化聚集,从而引起肾脏损伤。研究中还发现,在瓣膜手术过程中使用右美托咪定,可以减弱MPs/EVs对FOXO3a产生的作用,有效减缓中性粒细胞趋化反应,减少术后肾功能不全的风险 [52]。有学者发现,在小儿心脏外科手术当中,MPs/EVs的变化可能与年龄相关。研究指出,并发肾损伤的儿童血浆内有更高的MPs/EVs浓度,而罹患肾损伤的婴儿,MPs/EVs却是下降的 [53]。这提示在不同年龄段的病患,机体对损伤刺激的反应调控机制可能有所不同。

  • 心脏外科围手术期脑梗死或脑出血的发生率较低,但后果往往很严重。其中,动脉粥样硬化斑块破裂是术后脑梗的一个重要原因,特别是高龄或合并代谢疾病的高危患者。有研究表明内皮衍生微粒、白细胞衍生微粒可作为标志物,预测颈动脉粥样斑块是否稳定,有助于术前评估病情及临床干预 [54, 55]

  • 由于MPs/EVs涉及的生物过程可在各重要器官组织中演变发展,我们希望未来可以找到各器官组织相应发挥作用的分类分型,更好的解释其在疾病发展演变过程中所起到的作用。

  • 8 左室辅助

  • 左心室辅助装置(Left Ventricular Assist Devices, LVAD)是在左心室不能满足系统灌注需要时,给循环提供支持的心脏机械性辅助装置,使衰竭的心脏得以恢复功能,或等待心脏移植时暂时代替心脏功能。

  • 相比于健康人群或稳定型心绞痛患者,终末期心力衰竭患者MPs/EVs水平更高。然而,不同学者研究心衰患者接受LVAD后MPs/EVs含量的变化,有着不一样的报道结果。Ivak等发现,即使MPs/EVs在术后3个月呈现出下降,至术后6个月回升的趋势,但在整个研究当中没有显著差异 [56]。而Sansone等则观察到,接受LVAD治疗后,无论是血小板表型、白细胞表型、内皮细胞还是红细胞表型的MPs/EVs,均有明显升高。这些MPs/EVs表现出促内皮细胞活化及促凋亡特性 [57]。还有研究发现,外露磷脂酰丝氨酸(Phosphatidylserine,PS)的MPs/EVs水平升高,与LVAD术后不良事件的发生可能存在联系,或许可以成为一个新的标志物 [58]

  • 9 组分与粒径研究

  • MPs/EVs有着它的多样性、复杂性,分析验证其组分对于研究MPs/EVs在不同的生理病理过程中所发挥的功能具有重要的意义。

  • 早期对MPs/EVs的蛋白组学研究是从离体的人脐静脉内皮细胞开始的 [59],后来有学者从健康志愿者的血液中提取MPs/EVs进行更全面的蛋白组学分析,更进一步地验证MPs/EVs在生理过程中发挥的功能 [60]。我们最近的一项研究,除了健康群体,更是对瓣膜病人体外循环手术前后提取的MPs/EVs,通过蛋白组分测定,从细胞组分、分子功能、生物过程多个方面分析,验证了MPs/EVs在补体激活、免疫应答、内皮反应、凝血止血等过程中起到的功能 [24]。有研究发现,心脏外科手术患者不同病理状态下MPs/EVs的DNA成分含量及分布也有明显变化,且与机体炎症反应有着重要的联系 [61]。MPs/EVs中含有长链非编码RNA(Long Non-coding RNA,Inc RNA)、微小RNA(micro RNA,miRNA),在调控血管内皮功能、血管新生、衰老等过程中起着重要作用 [62-68],具有新型标志物或治疗靶点的应用前景。此外,在某些药物作用下, MPs/EVs的产生、功能及组分也会受到影响 [69-72]

  • 我们最近对体外循环手术前后的MPs/EVs粒径大小也作了相关研究,发现术后不同粒径的MPs/EVs含量变化是不同的,并与术后正性肌力药物剂量存在相关性,提示MPs/EVs不同粒径分型,可能成为预测术后心功能的参考指标 [73]

  • 10 总结

  • 随着对MPs/EVs研究的深入,其更多的功能特点不断被挖掘,MPs/EVs涉及血管调节、炎症、凝血、细胞增殖与凋亡等多个生物过程,所含成分复杂多样,其在参与相关疾病发生发展过程中的作用机制仍不完全清楚。在未来的探索中,单纯研究MPs/EVs的浓度含量是远远不够的,在研究分析各个亚群在不同生物过程的作用机制时,需要结合表型、蛋白组分、核酸组分、粒径等多方面验证,会更具有说服力。目前看来,MPs/EVs有望成为有助于决策手术治疗方案、评估疾病状态、验证治疗效果的一种新方法。而MPs/EVs也可以在调控血管稳态、纠正凝血、改善内环境、保护组织器官功能等方面作为新的治疗靶点。

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