海军军医大学学报  2025, Vol. 46 Issue (1): 111-117   PDF    
自噬在创伤性脑损伤中的研究进展
史汉童, 王承清, 郭彦谷, 叶益超, 张丹枫, 侯立军     
海军军医大学(第二军医大学)第二附属医院神经外科, 上海 200003
摘要: 创伤性脑损伤(TBI)致死致残率高,多发生于机动车车祸伤或竞技体育运动中。TBI主要包括原发性损伤和继发性损伤。原发性损伤多为外力直接作用所致,继发性损伤包括脑水肿、神经细胞兴奋性毒性损伤、氧化应激损伤、神经炎症等。对TBI继发性损伤的有效干预不仅有助于改善患者预后,还可能降低患者因TBI所致帕金森病等神经退行性疾病的风险。自噬是维持细胞稳态的一种重要调节方式,研究发现神经退行性疾病和TBI中存在自噬功能障碍,推测自噬可能是TBI病理发展过程中的重要环节之一,也是TBI患者晚年罹患阿尔茨海默病等认知障碍性疾病风险增高的可能原因之一。深入研究自噬在TBI病理机制中的作用,有助于为TBI的临床治疗提供新的靶点,同时也为TBI患者认知障碍的防治开发新的思路。
关键词: 创伤性脑损伤    自噬    自噬通量    线粒体自噬    铁蛋白自噬    
Autophagy in traumatic brain injury: research progress
SHI Hantong, WANG Chengqing, GUO Yangu, YE Yichao, ZHANG Danfeng, HOU Lijun     
Department of Neurosurgery, The Second Affiliated Hospital of Naval Medical University (Second Military Medical University), Shanghai 200003, China
Abstract: Traumatic brain injury (TBI) is mostly caused by motor vehicle traffic accidents or competitive sports, with high mortality and disability. TBI mainly includes primary injury and secondary injury. Primary injuries were caused directly by external forces. Secondary injuries include brain edema, excitotoxic effect of neuron cells, oxidative stress and neuroinflammation, etc. Effective intervention of secondary injury not only helps to improve the prognosis of patients with TBI, but also reduces the risk of Parkinson's disease and other neurodegenerative diseases related to TBI. Autophagy is one of approaches to regulate homeostasis in cells, and autophagy dysfunction has been found in several neurodegenerative diseases and TBI. It is speculated that autophagy dysfunction may play an important role in TBI and explain why patients with TBI have higher risk of neurodegenerative disease. Discovering the role of autophagy in the pathological mechanism of TBI may provide new targets for TBI clinical treatment and cognitive impairment prevention in patients with TBI.
Key words: traumatic brain injury    autophagy    autophagic flux    mitophagy    ferritinophagy    

创伤性脑损伤(traumatic brain injury,TBI)是指由于外力作用于头部引起的脑组织结构和功能改变或其他脑部改变的病理状态[1]。在中低收入国家中,TBI是造成青壮年人群死亡及致残的主要原因。据统计,全球每年因TBI造成的经济损失约有4 000亿美元,给患者家庭和社会带来了巨大负担[2]。TBI包含原发性损伤和继发性损伤,原发性损伤多为外部暴力直接作用所致,治疗多以手术治疗为主,部分轻型损伤者采取保守治疗;继发性损伤则为脑组织缺血缺氧、氧化应激损伤、能量代谢障碍和神经炎症激活等过程所致,防止继发性脑损伤是TBI早期治疗目标之一[3]。TBI继发性损伤机制极为复杂,例如,TBI后神经元释放兴奋性毒性氨基酸,使细胞内钙离子水平增高,诱发细胞凋亡;TBI后的神经炎症反应引起脑组织损伤和神经元死亡,进一步破坏血脑屏障,加重脑组织缺血缺氧损伤等[4]

自噬作为机体维持稳态的重要调节方式,参与多种神经系统退行性疾病的发生、发展[5]。TBI后的神经元及小胶质细胞中存在自噬体堆积、自噬分子标志物含量增高等自噬功能障碍的表现,提示自噬在TBI病理损伤机制中发挥重要作用[6]。应用雷帕霉素上调自噬水平后,脑组织的氧化应激损伤明显减轻、脑损伤与脑水肿程度减弱、神经系统功能显著改善[7]。尽管上调自噬可以改善TBI预后,但自噬对于神经细胞的作用不仅只有保护,更像是一把“双刃剑”,有实验研究表明过度自噬可以导致神经元死亡[8]。本文重点介绍自噬在TBI后的变化、自噬对TBI的影响及近年来以自噬为靶点的TBI治疗方式。

1 自噬的过程

自噬是维持细胞及细胞器稳态的重要途径,也是机体应对损伤的重要反应之一[9]。在功能层面上,自噬是一种分解循环再利用的过程,其底物包括长寿命蛋白、异常蛋白、蛋白多聚体、受损的细胞器及入侵的细菌,具有一定程度的防御功能[10-11]。自噬在进化上高度保守,执行多种重要生理功能,在多种神经系统退行性疾病中均发现有自噬功能异常[12],例如,在阿尔茨海默病(Alzheimer disease,AD)中,自噬功能障碍干扰了淀粉样前体蛋白(amyloid precursor protein,APP)剪切和β-淀粉样蛋白(β-amyloid,Aβ)降解,导致神经元死亡、淀粉样斑块沉积等AD特征性病理变化[13]

根据细胞内底物运送到溶酶体腔的方式不同,哺乳动物的自噬分为巨自噬、微自噬和伴侣分子介导的自噬,本文中的自噬主要是指巨自噬。自噬过程主要包括自噬体形成和自噬体清除。在自噬的起始阶段,由Unc-51样激酶(Unc-51-like kinase,ULK)1或ULK2、RB1可诱导卷曲蛋白1(RB1-inducible coiled-coil 1,RB1CC1)、自噬相关蛋白(autophagy-related protein,ATG)13、ATG101组成ULK复合体[14],并在内质网膜附近聚集形成点状突起样结构(ω小体),逐渐延伸包裹待降解底物,形成自噬体[15-16]。其后自噬体与溶酶体结合,由溶酶体内的酶降解自噬底物,并释放分解产物供其他生理过程使用,即自噬体清除[17]。根据自噬降解目标的不同,巨自噬又细分为本体自噬和选择性自噬。本体自噬一般是降解目标的整体,而选择性自噬则有特异的降解目标,如线粒体自噬、内质网自噬、核糖体自噬、过氧化物酶体自噬、脂噬、铁蛋白自噬等。

从自噬体开始形成、自噬体-溶酶体融合至底物酶解的完整过程称为自噬通量(autophagic flux)[18-19]。微管相关蛋白轻链3(microtubule-associated protein light chain 3,LC3)-Ⅱ、选择性自噬接头蛋白p62/(又称sequestosome 1,SQSTM1)、苄氯素1(beclin 1,BECN1)等分子在自噬过程中起到重要作用,被视为衡量自噬水平的重要指标[20-23]。自噬是动态的过程,为准确判定自噬水平变化,在科学研究中需要使用相应的工具药干预自噬的不同阶段后对自噬相关指标进行判读,常用的自噬抑制剂有3-甲基腺嘌呤(3-methyladenine,3-MA)、巴弗洛霉素A1和氯喹,自噬激动剂如雷帕霉素[24]

2 TBI与自噬的关系 2.1 自噬通量与TBI

TBI中自噬的变化情况仍有争议,自噬过度与自噬功能受损的现象在相关研究中均有报道,本文主要侧重于讨论自噬功能受损对TBI的影响。

研究发现,TBI后的神经元中自噬相关分子标志物如LC3Ⅱ/Ⅰ、SQSTM1/p62在蛋白水平上显著升高,而在mRNA水平上则无明显的变化,提示TBI后LC3Ⅱ/Ⅰ、SQSTM1/p62的增加与自噬起始增加无关,而与自噬体清除障碍有关,即自噬通量受损[25]。神经元自噬通量受损常为暂时性的,多在伤后立刻发生,1~3 d达到峰值,伤后7 d逐步消退[26]。溶酶体作为参与人体分解代谢的细胞器,在自噬过程中发挥不可或缺的作用。TBI后溶酶体膜的通透性发生改变,溶酶体膜表面磷脂酶A2(phospholipase A2 group ⅣA,PLA2G4A)异常活化,将溶酶体膜中的甘油磷脂分解并释放花生四烯酸,而溶血磷脂则留在溶酶体膜表面,改变溶酶体膜的流动性及通透性,影响自噬体与溶酶体的融合过程,从而造成自噬功能缺陷和神经元死亡[27],提示TBI后神经元早期自噬通量受损可能与溶酶体功能障碍有关[28-29]

与神经元一致,TBI后活化的小胶质细胞与单核细胞中也同样存在自噬通量受损的现象,并在伤后3 d达到峰值[26, 29]。有趣的是,对比TBI后脑内单核细胞和外周血单核细胞发现,仅脑内单核细胞存在自噬通量受损的现象,提示局部细胞微环境的改变可能影响自噬水平[29]。TBI后,受损细胞释放损伤相关的分子模式(damage-associated molecular pattern,DAMP),自噬通量受损会严重影响小胶质细胞的吞噬功能,导致DAMP积聚。而DAMP作为一种内源性危险信号,可诱导细胞死亡并激活免疫反应,加重TBI后的炎症反应[25, 29],提示TBI后神经炎症反应可能是由于小胶质细胞自噬异常影响吞噬功能所致。

2.2 线粒体自噬与TBI

线粒体自噬是自噬的一种特殊形式,是以线粒体为底物的自噬。在正常生理状态下,线粒体可以均等分裂成2个膜电位相似的子代线粒体。在线粒体功能障碍的情况下,线粒体会不均等分裂为2个子代线粒体,其中膜电位较低、视神经萎缩蛋白1(optic atrophy 1,OPA1)水平较低的子代线粒体氧化呼吸作用减弱,更有可能通过自噬途径降解,即线粒体自噬[30]。一般情况下,神经元可以通过线粒体自噬的方式消除受损的线粒体,更好地保存线粒体DNA以维持神经元的能量供应和正常功能。线粒体在受损后,释放大量活性氧(reactive oxygen species,ROS)和炎症因子,导致细胞内的氧化应激损伤。受损的线粒体可激活线粒体自噬,从而维持能量供应和氧化应激损伤之间的动态平衡[31]。但是TBI后线粒体自噬功能受到抑制,不足以清除受损的线粒体,导致神经元内受损线粒体堆积、能量代谢障碍、氧化应激水平增高,进一步加重线粒体功能障碍,并引起神经元死亡[32]。动物实验发现,增强线粒体自噬可以降低氧化应激水平并改善TBI预后[33]

2.3 铁蛋白自噬与TBI

铁蛋白自噬可简述为有核受体共激活因子4(nuclear receptor coactivator 4,NCOA4)参与的、以铁蛋白为底物的特异性自噬,其过程与本体自噬基本一致,含有铁蛋白的自噬体与溶酶体融合,释放自由铁,而细胞内的铁浓度也可以负反馈调节铁蛋白自噬通量,以维持细胞内铁稳态[34-35]。在细胞内铁浓度过高时,E3泛素连接酶HECW2(HECT, C2 and WW domain containing E3 ubiquitin protein ligase 2)激活,通过泛素依赖的方式降解NCOA4从而下调铁蛋白自噬水平,提示NCOA4是调节铁蛋白自噬的关键因子[36]

TBI后会产生大量的游离铁,超过了细胞自我调节能力,游离铁可通过芬顿反应产生ROS,引起脂质过氧化,消耗谷胱甘肽,诱发铁死亡[37]。但铁死亡所需要的过量游离铁是否主要来自铁蛋白自噬,尚有待进一步研究证实。

3 以自噬为靶点的TBI治疗策略

自噬在TBI中的作用似乎取决于细胞对功能失调或有害分子的负荷能力,即在自噬水平不足时增强自噬有助于改善TBI预后,在自噬过度时则抑制自噬才有治疗效果[6]

3.1 通过下调自噬实现对TBI的脑保护作用

白藜芦醇是一种天然多酚类化合物,可激活PI3K/Akt/哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR)通路,也可下调Toll样受体4(Toll-like receptor 4,TLR4)/NF-κB和上调去乙酰化酶sirtuin 1(SIRT1),从而抑制自噬,减轻神经损伤,改善认知功能[38-41]

近期研究发现,在TBI模型中,鼻内应用胰岛素可以抑制小胶质细胞并下调IL-1β和TNF-α的表达水平,降低TBI后神经炎症水平,减小病灶并改善记忆功能。进一步的机制研究发现,鼻内应用胰岛素可以抑制TBI后自噬,同时也可激活PI3K/Akt/mTOR信号通路,抑制内质网应激介导的细胞凋亡,提示鼻内应用胰岛素可能是TBI的一种较有前景的治疗策略[42]

右美托咪定通过ROS/核因子E2相关因子2(nuclear factor erythroid 2-related factor 2,Nrf2)信号通路抑制自噬和神经炎症,下调LC3、BECN1、NF-κB蛋白以及炎症因子IL-1β、IL-6和TNF-α的表达,改善TBI后早期脑损伤,提高神经元存活率,并提高大鼠TBI后的存活率和神经学评分[43]。右美托咪定还可通过使环状RNA circLrp1b/miRNA-27a-3p/DNA损伤调节自噬调控因子2(DNA damage regulated autophagy modulator 2,DRAM2)信号通路失活,在体内抑制TBI中的神经炎症和自噬[44]。因此,右美托咪定也有可能成为TBI的治疗药物之一。

在TBI中,血脑屏障破坏是极为重要的病理生理过程。在脑缺血模型中,消旋-3-正丁基苯酞(DL-3-n-butylphthalide,DL-NBP)可以减少脑水肿、抑制氧化应激、减少神经元死亡、抑制神经炎症发生并促进神经炎症消退,从而发挥神经保护作用[45]。在TBI模型中,DL-NBP可以通过抑制自噬的激活,上调紧密连接蛋白的表达,并通过抑制线粒体凋亡改善神经元存活情况,阻断紧密连接蛋白丢失和神经元凋亡,并促进TBI后运动功能恢复,从而发挥其在TBI中的神经保护作用[46]

血小板源性生长因子(platelet derived growth factor,PDGF)也是一种极有前景的TBI治疗药物,研究发现PDGF可以通过抑制内质网应激和自噬介导的焦亡发挥神经保护作用并促进TBI后的脑功能恢复[47]

3.2 通过上调自噬实现对TBI的脑保护作用

随着对自噬研究机制的逐步深入,增强自噬也有可能改善TBI预后。有研究发现艾氯胺酮可以有效降低TBI诱导的氧化应激。TBI损伤后应用艾氯胺酮,可上调受损皮质中BECN1、LC3-Ⅱ表达水平并增加LC3阳性细胞数量;艾氯胺酮也可促进转录因子EB(transcription factor EB,TFEB)的核易位,升高磷酸化腺苷酸活化蛋白激酶(adenosine 5'-monophosphate-activated protein kinase,AMPK)α水平,降低磷酸化mTOR水平。该研究提示艾氯胺酮可能通过增强自噬、减轻氧化应激等途径在TBI小鼠模型中发挥神经保护作用,其机制涉及AMPK/mTOR依赖的TFEB核易位诱导的自噬和TFEB/Nrf2诱导的抗氧化系统[48]

体外研究发现,miRNA-124-3p可通过促进自噬减轻TBI导致的脑部小血管内皮细胞损伤,miRNA-124-3p的神经保护作用可能与其抑制mTOR信号转导和诱导脑内小血管内皮细胞内自噬活性有关[49]

囊泡运输蛋白SEC22同系物B(SEC22 vesicle trafficking protein homolog B,SEC22B)是一种促进凋亡的激酶,也是凋亡信号转导的关键分子之一,在损伤皮质区神经元中表达,且在脑外伤后表达水平显著降低;过表达SEC22B可显著改善脑外伤诱导的细胞凋亡、神经功能缺损和血脑屏障通透性,并伴有自噬激活,表明SEC22B可能通过促进自噬在TBI后发挥神经保护作用[50]

在脊髓损伤模型中,Kruppel样因子2(Kruppel-like factor 2,KLF2)可通过增加自噬通量改善血脊髓屏障完整性并促进脊髓损伤后的功能恢复[51]。但KLF2在TBI中能否通过相似机制发挥神经保护作用、改善TBI预后仍有待验证。

4 传统医学疗法通过对自噬的干预治疗TBI

中国传统医学在治疗TBI方面具有突出的贡献。针灸作为传统医学的重要组成部分之一,为TBI的治疗提供了一个新颖的途径。针灸电刺激疗法治疗可以通过上调IL-10水平并影响AMPK/mTOR信号通路,抑制过度自噬,促进TBI大鼠神经功能恢复,减轻病理损伤和神经元凋亡[52-53]

以自噬为靶点治疗TBI的传统中药提取物研究也取得了一定进展。粉防己碱可以降低TBI后神经系统氧化应激损伤,促进自噬并抑制铁死亡,同时这种神经保护作用在应用雷帕霉素(自噬激动剂)后进一步加强,提示粉防己碱可以通过促进自噬、减少铁死亡改善TBI预后[54]。人参皂苷通过上调自噬减轻脑外伤所致的神经损伤[55]。羟基红花黄色素A通过调节神经元自噬抑制核苷酸结合寡聚化结构域样受体蛋白3(nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3,NLRP3)炎性小体,对急性TBI具有神经保护作用[56]

血府逐瘀汤是中国传统的著名方剂,由11味中药材组成,具有理气活血的作用,常用于治疗心脑血管疾病,对TBI模型大鼠也有治疗作用[57]。有研究通过转移RNA来源的小RNA(transfer RNA-derived small RNA,tsRNA)测序技术发现,血府逐瘀汤可能通过上调tsRNA的表达抑制自噬以发挥神经保护作用,改善TBI预后[58]

5 小结

自噬参与TBI的病理过程并影响TBI预后及远期认知功能。近年来,以自噬为靶点的TBI治疗药物研究取得了较为重大的进展。除上述内容外,还有研究发现热激蛋白B2(heat shock protein family B member 2,HSPB2)可以通过调节自噬促进神经再生,加快TBI后感觉运动恢复[59];亚急性TBI脑提取物通过调节自噬通量促进人神经干细胞的神经元分化,提示自噬通量在调节神经元分化中起着重要作用,可以作为提高早期移植疗效的潜在靶点[60]。鉴于自噬在TBI治疗中的双向作用,即促进或抑制自噬均可能改善TBI动物模型的神经系统功能、认知功能和行为能力,有两个问题需要进一步探索:(1)自噬在TBI病理发展过程中起到的作用是否一成不变,是否存在自噬角色转换的“扳机点”?(2)应用促进或抑制自噬药物的时机应如何选择,才能最大化发挥其神经保护作用?尽管目前自噬在TBI病理机制中的作用尚不完全明确,但不能否认自噬是一种很有前景的TBI治疗靶点,对自噬的进一步研究有助于为TBI的治疗提供新的策略。

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