Article(id=1194613945353871529, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1194613942065533315, articleNumber=null, orderNo=null, doi=10.11855/j.issn.0577-7402.1295.2024.0307, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1695571200000, receivedDateStr=2023-09-25, revisedDate=null, revisedDateStr=null, acceptedDate=1701360000000, acceptedDateStr=2023-12-01, onlineDate=1762747759426, onlineDateStr=2025-11-10, pubDate=1743091200000, pubDateStr=2025-03-28, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1762747759426, onlineIssueDateStr=2025-11-10, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1762747759426, creator=13701087609, updateTime=1762747759426, updator=13701087609, issue=Issue{id=1194613942065533315, tenantId=1146029695717560320, journalId=1189873630562394117, year='2025', volume='50', issue='3', pageStart='245', pageEnd='365', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=0, createTime=1762747758641, creator=13701087609, updateTime=1762749141462, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1194619742100103439, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1194613942065533315, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1194619742100103440, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1194613942065533315, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=358, endPage=365, ext={EN=ArticleExt(id=1194613945647472810, articleId=1194613945353871529, tenantId=1146029695717560320, journalId=1189873630562394117, language=EN, title=Regulatory mechanisms and therapeutic strategies of microcirculation after spinal cord injury, columnId=1190243275882729994, journalTitle=Medical Journal of Chinese People’s Liberation Army, columnName=Review, runingTitle=null, highlight=null, articleAbstract=

Spinal cord injury (SCI) is a structural and functional disruption of the spinal cord caused by various factors, leading to neurological dysfunction. As a common central nervous system disorder in clinical practice, SCI poses significant risks to human life and health. Its pathological mechanism is exceedingly complex, involving multiple pathological processes. Given the irreversibility of primary injury, targeting secondary injury has gradually become the main direction for the clinical treatment of SCI in recent years. Recent studies have highlighted the crucial role of blood-spinal cord barrier damage and microvascular dysfunction in the progression of secondary injury following SCI. Therefore, investigating the pathological mechanisms of microcirculation and exploring targeted therapies could provide valuable insights for clinical SCI treatment. This paper aims to provide an objective review of the role of microcirculation in SCI, identify the critical regulators of microvascular function, and summarize strategies for treating SCI by targeting microcirculation. The findings of this study may offer novel references for the clinical management of SCI.

, correspAuthors=Ya-Feng Ren, authorNote=null, correspAuthorsNote=
E-mail:
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脊髓损伤(SCI)是由各种因素导致的脊髓结构和功能破坏,进而引起的脊髓神经功能障碍。作为临床常见的中枢神经系统疾病,SCI的发生严重危害人们的生命健康,其病理机制十分复杂,涉及多种病理过程,其中考虑到原发性损伤的不可逆性,近些年靶向继发性损伤已逐渐成为临床治疗SCI的主要方向。研究表明,SCI后微循环中血脊髓屏障及微血管的破坏是导致继发性损伤的关键,而了解SCI后微循环的病理机制及相关靶向治疗策略可为SCI的临床治疗提供新思路。本文主要梳理了微循环在SCI中的作用,总结了微循环的主要调控因子,并归纳出针对微循环来治疗SCI的策略,以期为临床治疗SCI提供参考。

, correspAuthors=任亚锋, authorNote=null, correspAuthorsNote=
任亚锋,E-mail:
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黄靖,硕士研究生,主要从事脊髓损伤康复治疗方面的研究

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黄靖,硕士研究生,主要从事脊髓损伤康复治疗方面的研究

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黄靖,硕士研究生,主要从事脊髓损伤康复治疗方面的研究

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脊髓损伤后微循环的调控机制及治疗策略
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黄靖 1 , 任亚锋 2, * , 尚文雅 1 , 张芝兰 1 , 黄晓萌 1 , 李冰 2
解放军医学杂志 | 综述 2025,50(3): 358-365
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解放军医学杂志 | 综述 2025, 50(3): 358-365
脊髓损伤后微循环的调控机制及治疗策略
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黄靖1, 任亚锋2, * , 尚文雅1, 张芝兰1, 黄晓萌1, 李冰2
作者信息
  • 1河南中医药大学康复医学院,河南郑州 450046
  • 2河南中医药大学第一附属医院康复中心,河南郑州 450000
  • 黄靖,硕士研究生,主要从事脊髓损伤康复治疗方面的研究

通讯作者:

任亚锋,E-mail:
Regulatory mechanisms and therapeutic strategies of microcirculation after spinal cord injury
Jing Huang1, Ya-Feng Ren2, * , Wen-Ya Shang1, Zhi-Lan Zhang1, Xiao-Meng Huang1, Bing Li2
Affiliations
  • 1Rehabilitation School of Henan University of Chinese Medicine, Zhengzhou, Henan 450046, China
  • 2Rehabilitation Center of the First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan 450000, China
出版时间: 2025-03-28 doi: 10.11855/j.issn.0577-7402.1295.2024.0307
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脊髓损伤(SCI)是由各种因素导致的脊髓结构和功能破坏,进而引起的脊髓神经功能障碍。作为临床常见的中枢神经系统疾病,SCI的发生严重危害人们的生命健康,其病理机制十分复杂,涉及多种病理过程,其中考虑到原发性损伤的不可逆性,近些年靶向继发性损伤已逐渐成为临床治疗SCI的主要方向。研究表明,SCI后微循环中血脊髓屏障及微血管的破坏是导致继发性损伤的关键,而了解SCI后微循环的病理机制及相关靶向治疗策略可为SCI的临床治疗提供新思路。本文主要梳理了微循环在SCI中的作用,总结了微循环的主要调控因子,并归纳出针对微循环来治疗SCI的策略,以期为临床治疗SCI提供参考。

脊髓损伤  /  微循环  /  血脊髓屏障  /  调节因子  /  靶向治疗

Spinal cord injury (SCI) is a structural and functional disruption of the spinal cord caused by various factors, leading to neurological dysfunction. As a common central nervous system disorder in clinical practice, SCI poses significant risks to human life and health. Its pathological mechanism is exceedingly complex, involving multiple pathological processes. Given the irreversibility of primary injury, targeting secondary injury has gradually become the main direction for the clinical treatment of SCI in recent years. Recent studies have highlighted the crucial role of blood-spinal cord barrier damage and microvascular dysfunction in the progression of secondary injury following SCI. Therefore, investigating the pathological mechanisms of microcirculation and exploring targeted therapies could provide valuable insights for clinical SCI treatment. This paper aims to provide an objective review of the role of microcirculation in SCI, identify the critical regulators of microvascular function, and summarize strategies for treating SCI by targeting microcirculation. The findings of this study may offer novel references for the clinical management of SCI.

spinal cord injury  /  microcirculation  /  blood-spinal cord barrier  /  regulators  /  targeted therapy
黄靖, 任亚锋, 尚文雅, 张芝兰, 黄晓萌, 李冰. 脊髓损伤后微循环的调控机制及治疗策略. 解放军医学杂志, 2025 , 50 (3) : 358 -365 . DOI: 10.11855/j.issn.0577-7402.1295.2024.0307
Jing Huang, Ya-Feng Ren, Wen-Ya Shang, Zhi-Lan Zhang, Xiao-Meng Huang, Bing Li. Regulatory mechanisms and therapeutic strategies of microcirculation after spinal cord injury[J]. Medical Journal of Chinese People’s Liberation Army, 2025 , 50 (3) : 358 -365 . DOI: 10.11855/j.issn.0577-7402.1295.2024.0307
脊髓损伤(spinal cord injury,SCI)是一种伴有严重感觉、运动和自主神经功能障碍的中枢神经系统(central nervous system,CNS)疾病[1-2]。据统计,全球每年约有93万人遭受SCI,可能因此留下无法挽回的后遗症,其高发病率和高致残率会降低患者的日常生活能力,甚至危及其生命,给患者及家属带来严重的心理负担和经济压力[3-4]。因此,深入研究SCI的病理机制和治疗方法具有重要的现实意义和社会价值[5]。SCI的病理过程主要包括原发性和继发性两个阶段,前者是指脊髓受外力冲击而引起的局部血管破裂出血、神经元死亡、轴突破坏及突触丢失等,由此发展而来的缺血缺氧以及神经细胞损伤可导致大量炎性细胞浸润、细胞因子分泌增加,进而触发炎症级联反应,加重对血脊髓屏障(blood spinal cord barrier,BSCB)和周围血管完整性的破坏,从而造成继发性脊髓神经功能障碍[6]。研究发现,血管破裂出血、BSCB破坏、血液供应减少、内源性血管生成等与SCI后微循环紊乱密切相关,由此可见微循环破坏贯穿于SCI整个病理过程,是SCI发生的重要病理机制[7]。与此同时,有研究发现,保护血管内皮细胞及BSCB结构和功能的完整性,可有效抑制脊髓继发性损伤,表明靶向微循环治疗SCI可能是恢复脊髓神经功能的关键[8-9]。为此,本文梳理微循环在SCI中的具体作用机制,归纳SCI后微循环的正负向调节因子,并总结修复SCI后微循环的最新策略和关键机制,以期为SCI的临床治疗提供新的理论依据和借鉴。
脊髓微循环是指由毛细血管及其连接的微动脉和微静脉而构成的血管系统。BSCB作为脊髓微循环的主要结构和功能基础,主要由血管内皮细胞及其紧密连接(tight junction,TJ)、周细胞、基底膜、星形胶质细胞等构成[10]。其中内皮细胞之间主要依靠TJ中的闭锁蛋白(occludin,OCLN)、Claudin蛋白、紧密连接蛋白ZO-1(zona occludens 1,ZO-1)以及黏着连接(adherent junction,AJ)形成封闭的管腔内壁,同时它们与贴附在管腔外侧的周细胞共同包埋在基膜中。而在基膜外侧,星形胶质细胞会通过特化的底足结构进一步包裹血管,使脊髓血管外形成由三层细胞组成的致密结构,从而保证脊髓微循环功能的正常运行。
生理状态下,微循环作为气体和物质交换的关键场所,为脊髓神经细胞的存活和发育提供了可靠的物质保障;同时,微循环中的BSCB拥有的致密结构能有效隔绝大分子物质及有害因子的进入,从而维持脊髓内环境的相对稳定。这些功能得以实现的基础离不开微循环中各结构和功能的完整性。作为直接接触血液的细胞,血管内皮细胞可借助细胞间TJ严格控制分子的跨细胞交换,还可通过膜受体感知血流动力学和血源性信号的变化以合成并分泌多种生物活性物质,这有利于调节微循环的血管通透性和血管生成[11]。位于基底膜中的周细胞可通过物理接触和旁分泌信号与内皮细胞进行通讯以实现对内皮细胞生长发育及成熟的稳定监控;此外,周细胞凭借其特有的收缩功能可灵活调控血管舒缩,被认为是微循环血流改变的重要贡献者[12]。具有高度分支特点的星形胶质细胞一方面可广泛接触神经元突起,另一方面其延伸出的细足可包裹血管表面,这帮助构建了神经活动与血管之间的功能桥梁[13]。而基底膜是指由胶原蛋白、纤连蛋白、层粘连蛋白和其他糖蛋白组成的细胞外基质,其可为微循环中各种细胞的生长发育提供营养和支持,还可限制免疫细胞的扩散,为微循环中各细胞的物质交换和信号通信提供特定的血管周围微环境[14]
脊髓微循环障碍贯穿于SCI整个病理过程,损伤后初始阶段的血管破裂出血,随之发展的脊髓血供减少、继发性BSCB破坏,以及脊髓自我修复阶段的内源性血管生成等,均是SCI后脊髓微循环障碍的主要表现,同时这些表现也以不同方式影响脊髓的功能恢复。
微血管作为稳定供应营养和氧气的重要结构,在神经发生和维持生理功能中起着至关重要的作用。研究发现,在SCI急性期,机械性因素可引起SCI后血管破裂和神经元脱髓鞘,继而导致血管内皮细胞急剧坏死,使得内皮细胞对髓鞘碎片的吞噬作用减弱并引发神经炎症,最终加剧神经细胞死亡[15]。同时,血管破裂后大量血源性分子、红细胞的泄漏以及凝血酶的激活,增加了细胞外铁超载、红细胞溶解以及谷氨酰胺水平,其共同作用于轴突损伤,从而加剧脊髓的继发性神经功能障碍[16-17]
在SCI早期,凝血系统激活和血管内皮损伤可促使微血栓形成进而引起血管痉挛甚至闭塞,破坏局部组织的血液供应,并加重脊髓组织缺血,最终诱导病变部位的神经细胞凋亡[18]。由此可见,恢复脊髓组织的局部血供、缓解脊髓缺血可能是减轻继发性损伤的关键。在CNS中血管平滑肌细胞和周细胞在调控血管收缩及血流变化方面作用显著。Zhu等[19]报道,上调SCI后周细胞的活性,可促进其与内皮细胞的黏附并增加微血管的血液流速进而修复SCI。由此可见,调节SCI后影响血流变化的细胞或因子的表达可能是恢复脊髓血供的新途径。
BSCB是位于血液与脊髓实质之间的物理屏障,可有效防止毒素、血细胞和病原体进入脊髓,对维持脊髓稳态至关重要。SCI早期的机械外力、组织压迫、血管扩张的剪切力可造成神经血管单元破坏,随之病变周围血管密度的持续降低也是加速BSCB破坏的主要原因。研究发现,BSCB的破坏可增加对多种有害因子和物质的通透性,进一步破坏血管完整性,同时增加病变部位免疫细胞的浸润而引发神经炎症[20]。更为重要的是,SCI后的神经炎症与BSCB破坏形成了一种正反馈,由此引发炎症级联反应,加剧对邻近正常组织的损害[21]。与此同时,崩解的屏障对大分子物质的过度通透也会促进病变区域的组织水肿,最终致使脊髓空洞面积增大而造成脊髓神经功能的不可逆损伤[22]
血管生成是指从预先存在的血管中形成新的血管,也是病理条件下机体产生新血管的主要机制[23]。SCI后3~7 d会出现内源性血管生成,这是脊髓组织自我修复能力的体现,其不仅可短暂增加血管密度以缓解组织的缺血缺氧,还可作为引导损伤轴突再生的支架来促进脊髓的神经功能恢复[24]。然而这种短暂的血管密度的提高并不能满足周围组织的代谢需求,同时新生的血管缺少周围其他细胞的支持而对于BSCB的修复作用甚微[25]
VEGF是一种促血管生成活性的生长因子,可通过调控血管内皮细胞的迁移和增殖来参与血管形成过程,这对缓解组织细胞的缺血缺氧至关重要[26]。研究发现,向SCI后病变部位持续释放VEGF可促进血管重塑,从而有利于SCI大鼠的轴突再生和运动功能恢复[27]。另有研究显示,恢复脊髓微循环的氧气供应以减轻SCI后神经元的损伤和凋亡与VEGF信号通路激活密切相关[28]。综上,上调SCI后VEGF的表达,可通过促进血管再生、提高血管密度、改善脊髓微循环而缓解神经细胞的缺血缺氧状况,进而减轻脊髓继发性损伤。
IGF-1是一种存在于CNS中的小分子肽类,在血循环中其与高亲和力结合蛋白的结合可保护细胞存活及组织完整,这对协调组织器官的生长平衡至关重要[29]。研究发现,SCI后IGF-1的表达减少可加剧神经元死亡,而外源性注入IGF-1可增加神经细胞存活进而改善SCI大鼠的功能恢复,表明IGF-1对脊髓的神经功能恢复具有积极调控作用[30]。Li等[31]采用慢病毒转染技术实现SCI小鼠体内IGF-1过表达,结果发现,IGF-1过表达可激活磷脂酰肌醇3-激酶(phosphoinositide 3-kinase,PI3K)/蛋白激酶B(protein kinase B,Akt)通路而抑制内皮细胞凋亡并缓解内皮损伤,进而保护BSCB的完整性,提示IGF-1可能是SCI后修复微循环的关键因子。
SIRT1是一种组蛋白脱乙酰酶,其能感受细胞中的能量变化,具有延缓细胞衰老、帮助细胞抵御外界应激并改善细胞代谢的作用[32]。研究发现,SIRT1广泛分布于血管内皮细胞中,可抵抗SCI后的氧化应激而对维持血管周围稳态具有重要意义[33]。然而,SIRT1往往在SCI后下调而不利于脊髓微环境的调节。Jiang等[34]发现,内皮细胞中SIRT1的特异性敲除可加重BSCB的破坏,导致广泛炎症,进而造成神经细胞死亡;相反SIRT1激动剂的使用可降低衔接蛋白p66Shc的乙酰化和磷酸化水平,以减弱氧化应激产物活性氧(ROS)在内皮中的累积,最终得以保护内皮细胞并阻止脊髓功能的恶化。因此,正向调节SIRT1可为SCI微循环提供适宜的微环境。
MMPs是一类含锌肽酶,可降解和重塑细胞外基质和其他细胞外蛋白,在屏障功能中起关键作用[35]。研究表明,MMP超家族的两个重要成员MMP-2和MMP-9参与了SCI后BSCB的破坏,主要表现为对AJ和TJ结构的损伤及降解[36]。Ying等[37]发现,水上跑步机训练改善SCI大鼠运动功能恢复的主要机制是通过抑制MMP-2/MMP-9的表达从而减轻微循环的组织结构损伤来实现的。由此可见,抑制MMP-2/MMP-9的活性可能是保护微循环中BSCB结构和功能完整的基础。
EGFR属于人表皮生长因子受体酪氨酸激酶家族,是细胞生长、增殖、分化过程中的关键调节因子,对维持细胞生理稳定具有重要作用[38]。研究发现,SCI后星形胶质细胞和血管内皮细胞中促炎因子的分泌增加及ZO-1和Occludin的降解破坏与EGFR/p38丝裂原活化蛋白激酶(p38 mitogen-activated protein kinase,p38MAPK)/核因子κB(nuclear factor kappa-B,NF-κB)信号通路激活有关,且阻断EGFR通路可保护BSCB的功能从而抑制继发性损伤的进展,表明SCI后EGFR可能对微循环起着负向调控作用[39]
UTX是重要的表观遗传调控分子,广泛参与细胞增殖、组织分化、炎症反应、代谢调控等过程,对调控细胞的生长发育以及疾病的病理发展至关重要[40]。研究表明,SCI后内皮细胞中UTX表达明显上调不利于脊髓神经功能的恢复,相反,特异性敲除内皮细胞中UTX可增强SCI后血管生成从而改善SCI[41]。进一步研究发现,下调SCI后UTX的表达可通过抑制MLCK/p-MLC通路活性来降低BSCB的通透性,最终得以恢复SCI小鼠的神经功能[42]。以上结果提示靶向抑制UTX可能是改善SCI的新靶点。
AQP4是一种水通道蛋白,能够促进所有细胞和组织的双向水流动。研究显示,在CNS中,AQP4高度表达于星形胶质细胞,可介导脊髓与大脑屏障的水交换,对维持大脑和脊髓的稳态意义重大[43]。作为脊髓中的跨膜蛋白,AQP4在SCI后过度表达,由此引起脊髓组织水肿加重,促进BSCB渗透性增加,导致BSCB功能破坏而加剧继发性神经功能障碍[44]。由此可见,调节AQP4的活性可能是保护脊髓微循环而改善SCI的关键。
TRPM4是细胞中的主要阳离子通道,广泛分布于血管平滑肌,并依赖于细胞中钙离子浓度而激活;活化的TRPM4能介导血管的收缩活动,对稳定循环系统起重要作用[45]。研究发现,SCI后TRPM4可参与促进毛细血管碎裂相关的继发性出血;而敲除小鼠体内的TRPM4基因,可保护毛细血管结构的完整,减少继发性出血,降低SCI的病变面积并显著改善脊髓神经功能[46]。随后研究发现,SUR1和TRPM4共表达而形成的具有分子伙伴关系的SUR1-TRPM4通道在控制SCI后继发性出血方面具有优势,因此针对此通道开发相应的抑制剂和基因敲除疗法对保护CNS意义深远[47]
近几年,为探寻治疗SCI的有效方法,研究者针对SCI微循环障碍的药物治疗进行研究,发现一些西药和中药可通过多途径修复微循环进而治疗SCI。因此,总结这些药物及其作用机制将为临床治疗SCI提供新的参考和理论依据。
抑制SCI后的神经炎症是保护神经血管单元的重要途径,人免疫球蛋白G(hIgG)已被批准用于临床调节某些疾病的神经炎症;研究显示,将hIgG以2 g/kg的剂量对SCI大鼠进行静脉推注,能显著增加TJ蛋白的表达并抑制炎症酶MMP-9的活性,从而抑制免疫细胞浸润而保护神经血管单元,减轻脊髓继发性病变[48]。因此推测hIgG可能是一种对SCI很有前途的治疗药物。SCI后凝血酶相关的蛋白酶激活受体1(protease-activated receptor-1,PAR1)的激活是导致TJ丢失和BSCB分解的关键因素,而甲磺酸萘莫司他(nafamostat,NM)是一种经美国食品药品管理局(FDA)批准的丝氨酸蛋白酶抑制药,研究发现,在SCI后2~12 h给予NM治疗,能有效抑制凝血酶及PAR1/MMP-9轴,从而保护BSCB免于分解并减少外周免疫细胞浸润以发挥对脊髓的神经保护作用,这为NM的临床转化提供了客观依据[49]。托珠单抗作为获批临床的人源化IL-6受体(IL-6R)单克隆抗体,近年来已广泛用于神经系统疾病的治疗。Luo等[50]对SCI小鼠采用托珠单抗治疗,可显著降低损伤核心巨噬细胞中IL-6的表达,从而促进SCI小鼠血管内皮细胞间TJ的恢复和轴突再生,提示托珠单抗可能是重建BSCB改善脊髓功能的潜在药物。艾拉莫德(IGU)是一种抗风湿药,已被批准用于临床。研究发现,IGU也可能是治疗SCI的潜在药物,主要表现为对SCI小鼠给予IGU治疗,可经NF-κB途径抑制缺氧诱导因子-1α(hypoxia-inducible factor-1α,HIF-1α)的活性进而调节内皮细胞的糖酵解水平,并帮助修复内皮之间TJ的结构,保证了BSCB的完整[51]。氟芬那酸作为一种传统抗炎镇痛药应用于临床已经超过50年,朱䒟教授课题组发现,在损伤后1 h对SCI小鼠腹腔注射氟芬那酸治疗,可阻断TRPM4离子通道、抑制损伤后上调的MMP-2和MMP-9活性进而减少继发性出血、保护BSCB并促进血管新生,拓展了氟芬那酸在临床上的应用[9]。格列本脲是经FDA批准的SUR1-TRPM4通道阻滞药,既往研究发现,其能通过抑制SUR1-TRPM4通道而发挥作用,并被证实在SCI的临床前动物模型中有益,可降低SCI后SUR1-TRPM4通道的活性,保护微血管以减少水肿形成和继发性出血,抑制细胞坏死并发挥较强的抗炎作用[52]。而后一项临床研究也证实,SCI患者口服格列本脲治疗,可减少损伤后的毛细血管破裂现象进而使得继发性微血栓形成减少,提示格列本脲具有一定的临床应用价值,未来可对其进行大样本、多中心的临床研究,以丰富SCI的临床治疗[53]
SCI在中医学中属“体堕”“瘫痪”范畴,以气虚血瘀型较为常见,其主要病机为气机阻滞、瘀血凝滞、督脉不通,因此治则当以化瘀通络、协调气血为主[54-55]。补阳还五汤是由黄芪120 g、归尾6 g、赤芍4.5 g、地龙3 g、川芎3 g、桃仁3 g、红花3 g组成的中医药方,具有补气活血、祛瘀通络的功效;研究发现,此药方用于治疗SCI效果显著,主要表现为可提高SCI大鼠的HIF-1α和VEGF含量,改善缺血缺氧微环境并促进血管形成,进而缓解脊髓继发性功能障碍[56]。类似药方还有补肾活血方,其能够激活SCI后Notch-1蛋白,进而调控VEGF的表达以促进SCI血管新生,并减少局部氧化应激发生,这均促进了神经元细胞的存活,从而有效恢复SCI后的神经功能[57]。动物实验显示,川芎嗪可通过抑制血管内皮细胞凋亡、促进血液流动等途径来改善SCI后微循环障碍进而修复受损的脊髓组织[58-59]。一项临床研究发现,SCI患者采用川芎嗪注射液治疗,可显著提高感觉和运动功能评分从而改善预后[60]。但目前关于川芎嗪的临床研究相对较少,其对SCI的临床疗效仍待进一步探究。近年研究发现,含有中草药成分的药物可在SCI后修复BSCB而恢复脊髓功能。例如,丹参酮ⅡA磺酸钠是唇形科植物丹参中的主要活性成分,在治疗心血管疾病尤其是改善微循环方面效果显著[61]。Li等[62]的体内外实验表明,丹参酮ⅡA磺酸钠可通过激活Notch通路抑制炎性介质的释放,这有助于增加ZO-1的表达并保护血管的结构,实现对SCI微循环的保护。同样,存在于唇形科刺蕊草属植物广藿香挥发油中的广霍香醇,能明显减少SCI后内质网应激和细胞凋亡的发生以抑制TJ和内皮细胞丢失,从而使BSCB的完整性得到改善进而恢复神经功能[63]。陆皂苷A是一种具有良好抗炎活性和细胞保护作用的三萜皂苷,能逆转SCI后由血管内皮MMP-9诱导的BSCB损伤而有效改善SCI[64]。研究发现,积雪草苷可激活MAPK信号通路以及抑制SCI后内质网应激和周细胞凋亡而发挥神经保护作用,还能降低周细胞中MMP-9水平进而上调内皮细胞中连接蛋白活性以阻止BSCB破坏[65]。由此可见,依赖于这些中药活性成分而研制出新药方,将为SCI后微循环的修复提供新可能。
近几年,组织工程技术在修复SCI方面取得进展,其中以干细胞来源的外泌体移植、生物材料组合疗法的工程技术均可促进SCI后微循环结构及功能完整进而发挥有益的神经保护功能。外泌体是干细胞中的重要活性物质,其可避免干细胞移植后的低存活率及免疫抑制并模拟细胞旁分泌物质来发挥作用。其中以骨髓间充质干细胞来源的外泌体在SCI中的研究较多,一方面其可激活TIMP2/MMP信号通路以减少细胞间连接蛋白丢失进而减轻BSCB损伤;另一方面SCI后植入可有效降低Caspase-1、IL-1β的表达以抑制周细胞的焦亡,这提高了血管壁上周细胞的覆盖从而保证了微循环的结构正常[66-67]。Xie等[68]发现,人脐带间充质干细胞来源的外泌体能经miR-501-5p/MLCK轴增进TJ结构的完整,从而有效降低内皮细胞的渗透作用来改善脊髓的神经功能恢复。
考虑到SCI后微环境的改变会降低药物及细胞因子的保护作用,研究者设计了多种具有良好生物相容性和可降解性的水凝胶,为SCI微循环修复提供了可靠的药物递送系统。Xin等[69]将负载巴多昔芬的复合水凝胶植入SCI大鼠,发现其可经NF-κB/MMP途径减弱氧化应激,上调TJ蛋白的活性,显著抑制炎症扩散,从而减轻BSCB的破坏。一种基于热敏水凝胶的G蛋白偶联受体124(G protein-coupled receptor 124,GPR124)的递送系统不仅可持续向受损组织输送GPR124,还可保持GPR124良好的生物活性,更重要的是,GPR124与生物活性多功能水凝胶的联合干预,可高效促进磷酸烯醇丙酮酸羧激酶2(phosphoenolpyruvate carboxykinase 2,PCK2)的活化以提高内皮细胞的能量代谢,最终恢复内皮细胞的不良状态而重建BSCB[70]。研究发现,将自组装肽支架RADA-16I移植到SCI后的微血管细胞中,可显著促进轴突的定向再生并支持血管形成,由此重塑BSCB结构而改善SCI后脉管系统,表明血管化支架在修复SCI方面极具潜力[71]
除了常规的药物治疗及手术干预外,在SCI后展开相关的康复治疗是维持患者现有神经功能、预防并发症出现的重要手段。以运动康复训练和物理治疗为主的康复干预方式在修复脊髓微循环并改善SCI方面优势显著,而了解其具体的作用机制可为SCI的临床康复治疗提供参考和指导。其中运动康复是一种通过运动和体育活动来恢复、改善和维护SCI患者身体健康和功能的过程,研究发现,SCI患者坚持6个月的有氧运动训练可增加脊髓组织中的神经血管偶联,这有利于提高局部代谢能力而减少SCI后并发症的发生[72]。Ying等[73]发现,通过使SCI大鼠进行水上跑步机训练,可明显恢复其运动功能,并证实水上跑步机训练可通过激活脑源性神经营养因子(brain-derived neurotrophic factor,BDNF)/酪氨酸激酶受体B(tyrosine kinase receptor B,TrkB)-环磷腺苷效应元件结合蛋白(cAMP-response element binding protein,CREB)信号通路,进而保护BSCB的完整而改善脊髓神经功能。此外,物理治疗手段如高压氧疗法、肌肉及神经电刺激疗法均可改善SCI后血管结构和功能,在治疗SCI方面疗效显著。一项临床研究表明,高压氧治疗较常规康复更能促进患者神经功能恢复并提升日常生活活动能力,其能通过增加SCI患者的血氧含量、促进毛细血管再生、保护血管正常结构、恢复脊髓血供等途径发挥神经保护作用[74]。Chen等[75]发现,对SCI大鼠采用高压氧治疗可上调微循环的正向调节因子SIRT1的表达,进而有效抑制炎症级联反应、细胞凋亡和自噬等病理过程,显著改善SCI大鼠的功能恢复。研究发现,对SCI患者展开为期12周的臀肌和腘绳肌低强度电刺激治疗可明显改变股总动脉的血管直径和血流量,这对于改善SCI患者的血管功能及预防压疮等并发症的出现具有显著的临床意义[76]。此外,迷走神经刺激也是一种很有前途的神经调控技术,电生理学评估和运动试验均表明其对治疗SCI有效。研究发现,这种有益作用是通过下调TNF-α的表达并抑制受体相互作用蛋白(receptor-interacting protein,RIP)1/RIP3/混合谱系激酶结构域样假激酶(mixed lineage kinase domain-like protein,MLKL)通路介导的内皮细胞坏死性凋亡,从而减轻SCI后BSCB破坏,进而减少神经炎症和神经损伤来实现的[77]。综上,配合相关康复干预措施可保护并重塑血管系统,这对SCI后功能恢复意义重大。
生理状态下,脊髓微循环中各结构和功能的完整是脊髓神经功能得以正常发挥的基本保障,而SCI造成的血管破裂出血、脊髓血供减少、继发性BSCB破坏等均可引起脊髓微循环障碍而加速继发性SCI发展。近几年随着对微循环的研究增多,研究人员愈发重视微循环在SCI后的调控作用。本文梳理了微循环在SCI后的主要表现、作用及相关治疗策略,发现SCI后血管破裂出血、脊髓血供减少、继发性BSCB破坏等是引发神经元死亡、轴突损伤、神经炎症的重要原因;而维持血管内皮结构完整、促进血管再生并恢复血流、保护BSCB正常功能等是靶向改善脊髓微循环进而修复SCI的关键途径。虽然有许多药物已被证实对修复脊髓微循环有效,但单独使用这些药物往往达不到有效的药物利用率,使得其临床应用受限。组织工程技术作为近几年的研究热点,其中干细胞移植和生物材料在SCI后神经元再生、药物及小分子物质的递送及控制释放方面具有显著优势。研究发现,SCI后纳米材料或水凝胶结合药物的组合疗法可促进药物疗效的高效发挥进而最大限度保护微循环结构完整,促进脊髓神经功能恢复[78-79]。因此,组织工程技术是未来修复SCI微循环极具潜力的疗法。同时,在SCI早期展开相关的康复治疗,对维持现有神经功能及预防并发症至关重要,虽然有许多物理治疗在修复脊髓微循环方面优势显著,但大多研究往往只探讨了一种干预方式的有益作用,对于多种物理治疗方式的联合干预效果仍有待进一步探讨。另外,现有的研究大多聚焦于影响脊髓微循环的蛋白组学的探讨,对于基因层面的研究相对较少,近期研究显示,非编码RNA可通过影响血管再生来调节SCI后微循环,这为基因靶向微循环而治疗SCI提供了新证据[80]
目前关于SCI后微循环破坏的具体分子机制尚未完全明确,这为靶向微循环来修复SCI带来了一定的困难。近年来,温度敏感TRP通道的发现,对调控血管结构和功能意义重大。多项研究表明,SCI后TRP通道的激活是导致血管内皮损伤并引发脊髓微循环障碍的关键,这增加了对脊髓微循环破坏的分子机制的认识,为调控脊髓微循环提供了新的作用靶点[81-82]。同时,微循环的正向调节因子VEGF、IGF-1、SIRT1及负向调节因子MMPs、EGFR、UTX、AQP4、TRPM4等在调控SCI后微循环的完整性方面也发挥着重要作用,针对这些因子开发相应的激动剂及抑制剂将为SCI的功能恢复带来更多可能。此外,目前针对SCI后微循环的探讨仍存在一些不足,特别是以改善微循环而修复SCI的研究多局限于细胞、动物实验,缺少大量的临床验证,因此未来研究重点应为努力实现这些基础实验成果的临床转化,进而为临床从微循环入手治疗SCI提供新思路。
  • 河南省中医药科学研究专项(2022JDZX015)
  • 河南省中医药科学研究专项(2021JDZY022)
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doi: 10.11855/j.issn.0577-7402.1295.2024.0307
  • 接收时间:2023-09-25
  • 首发时间:2025-11-10
  • 出版时间:2025-03-28
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  • 收稿日期:2023-09-25
  • 录用日期:2023-12-01
基金
Henan Provincial Scientific Research Program on Traditional Chinese Medicine(2022JDZX015)
河南省中医药科学研究专项(2022JDZX015)
Henan Provincial Scientific Research Program on Traditional Chinese Medicine(2021JDZY022)
河南省中医药科学研究专项(2021JDZY022)
作者信息
    1河南中医药大学康复医学院,河南郑州 450046
    2河南中医药大学第一附属医院康复中心,河南郑州 450000

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2种不同金属材料的力学参数

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genus
种数
Number of
species
占总种数比例
Percentage of
total species (%)

Genus
种数
Number of
species
占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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