摘要：缺血处理是指对组织、器官或血管床进行可逆的、短暂且重复的缺血再灌注干预，以增强靶器官对缺血再灌注损伤的抵抗力[1-3]。根据干预部位的不同，缺血可分为原位缺血处理（situ ischemic conditioning，SIC）和远端缺血处理（remote is
撰文：朱亚军，李晓果，雷兴伟，唐流洋，文道琛，曾博，张晓枫，黄自超，郭宗铎
缺血处理是指对组织、器官或血管床进行可逆的、短暂且重复的缺血再灌注干预，以增强靶器官对缺血再灌注损伤的抵抗力[1-3]。根据干预部位的不同，缺血可分为原位缺血处理（situ ischemic conditioning，SIC）和远端缺血处理（remote ischemic conditioning，RIC）。原位缺血处理是直接在关键靶器官进行原位缺血再灌注干预，而远端缺血处理则是在远离靶器官的部位进行干预，两者均能对靶器官产生保护作用。然而，由于原位缺血处理存在加重靶器官的缺血再灌注损伤的风险，而远端缺血处理因其具备安全无创、操作简便、患者耐受性好等优势受到越来越多的关注。近年来，针对远端缺血处理激发的保护作用开展了大量动物和临床研究，主要涉及心脏、大脑和肺等多种器官[4-8]，已证实远端缺血处理对靶器官具有保护作用。此外，脑卒中后远端缺血处理可以发挥神经保护作用。研究表明，远端缺血处理不仅能降低脑梗死的风险[9]，还能减轻脑梗死的范围[10]，从而改善脑卒中后的神经功能。目前研究认为远端缺血处理发挥神经保护的潜在机制可能与抑制神经炎症、调节免疫应答、调节细胞自噬、抑制细胞凋亡以及减轻细胞水肿有关[11-15]。然而，相关的信号通路尚未得到彻底澄清。
来自中国重庆医科大学附属第一医院郭宗铎团队在《中国神经再生研究（英文）》（Neural Regeneration Research）上发表了题为“ The potential mechanism and clinical application value of remote ischemic conditioning in stroke”的综述。文章分析了不同类型的远端缺血处理方法在动物和临床研究中的现状，对它们的神经保护作用机制以及信号通路进行了共性和差异性的总结。提出Notch1/PI3K/Akt信号通路在各类远端缺血处理的神经保护机制中参与许多细胞过程，可作为未来卒中治疗中的潜在靶点。
远端缺血处理是指在人体重要器官的远端肢体实施重复的、间歇的和短暂的缺血再灌注治疗，从而激发人体的内源性保护机制，达到保护重要器官的目的。如前所述[16]，远端缺血处理可分为远端缺血预处理（remote ischemic pre-conditioning，RIPC）、远端缺血后处理（remote ischemic post-conditioning，RIPostC）和慢性远端缺血处理（chronic remote ischemic conditioning，CRIC）。在卒中发生前实施的干预称为远端缺血预处理；相反，卒中后实施的干预则称为远端缺血后处理。而进行长期重复的远端缺血处理以发挥持续保护作用的治疗策略被称为慢性远端缺血处理[16, 17]（图1）。
图1 不同类型远端缺血处理的简化示意图（图源：Zhu et al., Neural Regen Res, 2025）
目前，远端缺血处理的干预位置主要在股动脉和肱动脉[18-21]，且干预双侧肢体较单侧更为常见[8, 18, 22-25]。在动物研究中，典型的干预方法是以阻断10min和再灌注10 min为一个循环，共3个循环[26, 27]。然而，临床研究中更多地以阻断5 min和再灌注5 min为一个循环，共5个循环[28, 29]。动物实验中包括有创和无创的远端缺血处理两种。实施有创的远端缺血处理，首先切开动物腹股沟区域的内侧皮肤，随后钝性分离股动脉前方的肌肉，使股动脉充分暴露。最后通过夹闭/松开动脉夹实现股动脉的缺血再灌注[30, 31]（图2A）。此外，无创的远端缺血处理主要是使用止血带在动物后肢的大腿根部施压，使下肢足趾颜色由红变淡，皮肤温度下降，达到阻断血流的目的，然后松解止血带实现再灌注[12, 32]（图 2B）。在临床研究中，远端缺血处理实施则通过在上臂或大腿上缠绕血压计，施加超过正常血压 20mmHg 的压力来阻断肱/股动脉血流[7, 33, 34]（图 2C）。
图2 动物和人类实施的远端缺血处理简化示意图（图源：Zhu et al., Neural Regen Res, 2025）
脑缺血动物模型是远端缺血处理治疗脑卒中的最主要的研究对象。目前研究报道远端缺血预处理、远端缺血后处理和慢性远端缺血处理均在脑缺血疾病发生发展过程中发挥了神经保护作用，其中以远端缺血后处理的研究最为广泛[35-38]。首先，远端缺血预处理能有效减轻脑缺血动物模型脑梗死的严重程度并改善神经功能。Nizari等[18]和Zhang等[39]均发现远端缺血预处理可以缩小脑缺血模型的脑梗死范围。此外，在有关远端缺血后处理的研究中，发现远端缺血后处理除了可减少梗死面积外[40-42]，还可减轻脑水肿[43]，并且认为这可能与远端缺血后处理保护血脑屏障有关。同时，远端缺血后处理还可调节外周免疫反应减轻炎症性脑损伤[37, 44]，也可缓解脑血管痉挛[45, 46]。在这些研究中，最常见的干预方式是以10min为缺血再灌注的间隔时间并实施双侧肢体的干预。最后，目前有关慢性远端缺血处理在脑缺血中的研究相对较少。目前研究认为慢性远端缺血处理，不仅能有效减轻脑梗死的严重程度，还能减少神经元的死亡[47]。此外，慢性远端缺血处理的神经保护作用可能与调节脂质代谢、抗凝功能和免疫炎症反应有关[25]。
目前研究仅涉及远端缺血后处理[48, 49]和慢性远端缺血处理[50, 51]改善脑血管狭窄认知功能障碍的报道。一方面，远端缺血后处理可通过防止细胞死亡和脱髓鞘、促进脑血管重塑来改善认知功能[48]，也可通过增强脑灌注和减少突触损伤来改善认知功能障碍[49]。另一方面，慢性远端缺血处理则通过促进微血管再生和扩张改善认知功能[50, 51]。目前干预时间范围从1周[49]、2周[48]、1个月到4个月[50]不等，但是寻找最佳治疗效果的最优干预时间还有待进一步研究。
与脑缺血相似，远端缺血后处理在出血性卒中后可减轻脑水肿，促进神经功能恢复[8]。此外，远端缺血后处理还能缓解蛛网膜下腔出血后脑血管痉挛[52]；还加快了颅内血肿的消退[53]。
很多研究发现不同类型远端缺血处理均可改善脑缺血后脑灌注水平并减轻脑损伤。首先，脑血管扩张参与改善脑灌注。Nizari等[18]发现，远端缺血预处理可通过刺激脑血管内皮细胞扩张皮质动脉和毛细血管来减轻缺血再灌注损伤。此外，Hoda等[54]发现远端缺血后处理也能扩张脑血管，并认为这与激活内皮一氧化氮合酶，提高脑内一氧化氮水平相关。远端缺血处理还能通过促进脑血管重塑改善脑灌注水平，这主要见于远端缺血后处理和慢性远端缺血处理 的报道[47]。目前，许多研究观察到远端缺血处理干预后脑血管平滑肌细胞显著增殖和微血管形成增加[50, 51, 55]。虽然远端缺血处理增加脑灌注的具体机制尚未阐明，但可以明确的是不论是内皮细胞还是平滑肌细胞在远端缺血处理改善脑灌注方面均发挥着重要作用。
不同类型的远端缺血处理对脑卒中后的免疫系统应答具有不同的调节机制。简单来说，远端缺血后处理似乎主要调节先天性免疫，远端缺血预处理 则主要调节适应性免疫，而慢性远端缺血处理通过激活补体系统，调节体液免疫。首先，远端缺血预处理 在调节机体免疫应答方面可以通过改变T淋巴细胞和B淋巴细胞的增殖和分化发挥重要作用。一方面，远端缺血预处理可在脑卒中后通过体液免疫增加B淋巴细胞从外周向大脑的浸润，从而减轻神经炎症反应[44]。另一方面，远端缺血预处理 还可以调节T淋巴细胞分化，尤其是CD4+ T淋巴细胞和CD8+ T淋巴细胞[44, 56, 57]。但关于远端缺血预处理是否促进T淋巴细胞浸润脑组织并不明确。其次，虽然仅有一项研究证明了远端缺血后处理对T淋巴细胞和B淋巴细胞的调节作用[44]，但更多的研究表明远端缺血后处理对免疫应答的调节更依赖于巨噬细胞[37, 53, 58, 59]。此外，远端缺血后处理不仅能增加血液和大脑中巨噬细胞的数量，还能促进抗炎性巨噬细胞的分化[53, 58]。最后，有关慢性远端缺血处理对脑卒中免疫应答调控的研究很少。目前只有Song等[60]发现慢性远端缺血处理可激活补体系统的经典通路，包括C3、C4b和C1等成分的上调。然而，关于慢性远端缺血处理激活补体以缓解神经炎症的详细机制还缺乏报道。
远端缺血后处理还可调节自噬[61-63]和抑制神经细胞凋亡[27, 64]。首先，远端缺血后处理可抑制细胞凋亡[65-70]，其一是通过激活下游抗凋亡基因Bcl-2阻碍细胞的程序性死亡[27]；其二是通过减轻内质网应激抑制凋亡[15]。另一方面，尽管远端缺血后处理可调节自噬状态，但具体作用仍不明确[71, 72]。有研究发现远端缺血后处理 通过促进Bcl-2 的磷酸化激活自噬，减少线粒体损伤并维持神经细胞的正常功能[71, 73, 74]。然而，有研究认为远端缺血后处理能抑制自噬的发生，而不会激活自噬，且过度的自噬会加重脑组织神经细胞的损伤[75]。
远端缺血后处理可促进神经和突触再生改善认知功能[49, 76, 77]。首先，远端缺血后处理通过增加神经干细胞的增殖及其向病变部位的迁移来促进神经发生[25]。其次，远端缺血后处理可抑制谷氨酸分泌并促进氨基丁酸释放以降低神经元兴奋毒性，维持突触信号传导[78]。此外，Wang等[76]还发现，远端缺血后处理能增加突触生成相关蛋白的表达以促进突触生成。
远端缺血处理的内源性保护信号通路是一个复杂多样的网络，由相互影响的各种信号通路组成。目前有研究表明，远端缺血处理可以通过Notch1将外部信号传入细胞，诱导PI3K磷酸化，并促进Akt磷酸化，激活各种下游信号元件[79-81]，调控细胞生理病理过程（图3）。
图3 远端缺血处理调节Notch1/PI3K/Akt信号通路的机制示意图
首先，远端缺血处理可增加一氧化氮水平，通过上调一氧化氮合酶的表达促进血管扩张，最终改善脑灌注。Ren等[55]发现远端缺血处理诱导梗死灶周围Notch1上调，并且还有研究证明了Akt磷酸化对一氧化氮合酶调控的影响[54, 82]。其次，远端缺血处理在促进一氧化氮合酶的表达同时，增强抗凋亡基因Bcl-2的表达，并抑制促凋亡基因Bax，从而激活PI3K和Akt磷酸化抑制神经元凋亡[27]。
糖原合酶激酶3β作为PI3K/Akt信号通路的下游成分，在调节自噬、炎症和神经再生等细胞过程中发挥着关键作用[83-85]。在自噬方面远端缺血后处理通过促进Akt和糖原合酶激酶3β磷酸化激活自噬，减少白质损伤[8]。同时糖原合酶激酶3β磷酸化诱导的Bcl-2/Beclin1复合物解离是激活自噬的关键。对于促进神经再生，研究表明糖原合酶激酶3β的磷酸化还能导致环磷酸腺苷反应结合蛋白的磷酸化，而磷酸化是激活脑源性神经营养因子等基因产物的关键步骤[77, 86]；这反过来又促进了神经可塑性和突触形成过程。对于抑制炎症，尽管Ramagiri等[77]发现远端缺血处理增加糖原合酶激酶3β的表达，并降低了促炎症因子水平，但其调控途径仍不清楚。在神经系统疾病中，研究发现糖原合酶激酶3β表达的增加可能会通过抑制NF-κB蛋白水平来阻碍炎症反应，同时远端缺血处理 可以阻碍NF-κB表达[87, 88]。因此，根据目前研究推测远端缺血处理可上调糖原合酶激酶3β的表达并抑制NF-κB，抑制神经炎症[26, 59, 89-91]。
临床研究针对脑缺血设计了有关远端缺血预处理、远端缺血后处理和慢性远端缺血处理的试验[92-94]。虽然一些试点研究尚未取得研究成果，但有研究都报告了远端缺血处理对脑缺血的益处[95-98]。有研究表明，远端缺血预处理可能有助于减少脑缺血的复发，这与患者内皮功能密切相关[99]。远端缺血预处理可通过扩张皮质血管改善脑灌注，并通过促进内皮细胞和平滑肌细胞的形成促进血管重塑[18, 55]。此外，目前已证实远端缺血后处理对脑缺血患者存在治疗效果。有研究表明远端缺血后处理 可提高脑缺血患者的长期神经功能评分，包括MRS、Barthel和NIHSS评分[100] [101]。此外，还有研究发现，远端缺血后处理的治疗作用与减少患者炎症水平有关[22, 102]。此外，虽然一些研究没有发现远端缺血后处理有明显的治疗效果，但它们证实了治疗过程的安全性[19, 93, 103]。慢性远端缺血处理是最近提出一种治疗方法，通过延长干预周期，可能会对脑缺血患者的长期康复带来更持续的改善。虽然目前进行的研究数量有限，但一些研究已经注意到了它的治疗效果，即增强肢体功能和认知能力的长期恢复[94, 104]。
对于明确诊断为脑血管狭窄患者，是慢性远端缺血处理的重要研究对象。长期认知功能障碍是脑血管狭窄患者面临的最大临床挑战，有研究推测，慢性远端缺血处理通过减少白质损伤来改善认知功能[105]。此外， 慢性远端缺血处理 还能显著降低脑血管狭窄患者发生缺血性脑血管事件的概率[24, 105, 106]。值得注意的是，近年来还开展了一些对烟雾病患者实施慢性远端缺血处理的研究，一方面，有研究[107]报道慢性远端缺血处理可增强烟雾病患者的脑血流量，改善缺血症状。另一方面，慢性远端缺血处理还可减缓狭窄闭塞病变的进展速度[23]。
由于出血性脑卒中（如脑出血和蛛网膜下腔出血）发病时的不可预测性，这类患者主要接受远端缺血后处理治疗[108-112]。有2项研究发现远端缺血后处理可加速脑出血患者血肿吸收，减轻脑水肿，并最终改善长期预后水平[113, 114]。对于蛛网膜下腔出血患者，少数研究报道远端缺血后处理对蛛网膜下腔出血患者具有安全性[115, 116]，但其治疗效果尚未见报道，其治疗作用有待进一步探讨和明确。
综上所述，远端缺血处理在脑卒中的病理过程中确实起到了神经保护作用。不同的远端缺血处理干预方法具有不同的优缺点、应用范围和研究对象。目前研究表明远端缺血后处理具有简便、无创、安全等特点，有可能成为脑卒中治疗的主要干预方法。此外，慢性远端缺血处理是一种新的治疗方案，其在脑卒中中的潜在应用价值有待进一步探索。在远端缺血处理的神经保护机制中，Notch1/PI3K/Akt 信号通路参与了许多细胞过程，但仍有许多未知领域需要进一步研究，以寻找有效治疗靶点改善卒中患者的预后。这篇综述也存在不足：首先，文章总结了各种类型远端缺血处理的研究进展及临床应用现状，但对远端缺血处理作用机制的阐述相对浅显。其次，文章介绍了远端缺血预处理、远端缺血后处理和慢性远端缺血处理对脑卒中的神经保护作用，但没有比较和总结它们在治疗效果上的差异。第三，在远端缺血处理的信号通路方面，文章只关注了Notch1/PI3K/Akt信号通路，对该通路与其他信号通路之间的联系讨论较少。
此外，未来远端缺血处理在各类脑血管疾病中的研究可以关注以下几个方面：1）短期远端缺血处理（远端缺血后处理和远端缺血预处理）和 慢性远端缺血处理 哪种干预方法对于卒中患者更有益？2）目前研究很难解释远端缺血处理完整的机制链，而激活 Notch1/PI3K/Akt信号通路促进神经再生的内源性机制值得进一步研究。3）远端缺血处理治疗出血性脑卒中的临床研究极少，目前仅报道了对脑出血治疗效果，对 蛛网膜下腔出血并不明确。4）烟雾病患者可能出现出血或缺血并发症，关注远端缺血处理对烟雾病的神经保护作用具有很大的研究价值。
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文章来源：Zhu Y, Li X, Lei X, Tang L, Wen D, Zeng B, Zhang X, Huang Z, Guo Z (2025) The potential mechanism and clinical application value of remote ischemic conditioning in stroke. Neural Regen Res 20(6):1613-1627.
来源：中国神经再生研究杂志