曹 燕,张瓅文,孙 宁,石广霞,王雪蕊,刘存志
·前沿进展·
慢性脑缺血炎性反应机制的研究进展
曹 燕,张瓅文,孙 宁,石广霞,王雪蕊,刘存志
慢性脑缺血是血管性痴呆(VD)、阿尔茨海默病(AD)和Binswanger病等多种神经系统疾病的病理基础,具有较长的可干预时间窗,深入研究慢性脑缺血炎性反应机制对缺血性脑血管疾病的防治具有重要临床意义。本文就慢性脑缺血炎性反应机制的研究进展进行综述。
脑缺血;炎症;细胞因子类;综述
曹燕,张瓅文,孙宁,等.慢性脑缺血炎性反应机制的研究进展[J].实用心脑肺血管病杂志,2016,24(8):1-4.[www.syxnf.net]
CAO Y,ZHANG L W,SUN N,et al.Progress on inflammatory reaction mechanism of chronic cerebral ischemia[J].Practical Journal of Cardiac Cerebral Pneumal and Vascular Disease,2016,24(8):1-4.
慢性脑缺血是一种由长期脑血流灌注不足导致的病理状态,是血管性痴呆(VD)、阿尔茨海默病(AD)和 Binswanger病等多种神经系统疾病的病理基础[1-2]。慢性脑缺血常伴有脑白质脱髓鞘、脑梗死和血管性认知功能障碍等,其与急性缺血性脑卒中相比,具有较长的可干预时间窗。故深入研究慢性脑缺血的发病机制对缺血性脑血管疾病的防治具有重要的临床意义。慢性脑缺血的主要病理学改变为神经元凋亡、炎性反应、氧化应激反应、能量代谢障碍、胆碱能功能紊乱等[3]。其中,炎性反应在慢性脑缺血损伤的发病机制中发挥着重要作用。临床研究表明,慢性脑缺血可导致VD患者血浆和脑脊液中炎性因子水平明显升高[4]。本文通过分析和总结国内外慢性脑缺血损伤的炎性反应机制研究进展,为临床防治慢性脑缺血损伤提供参考,现报道如下。
胶质细胞可通过直接调控神经元间突触联系来维持神经元微循环稳态,其与神经元共同参与学习和记忆过程。胶质细胞活化是中枢神经系统炎性反应的关键,其通过产生自由基、改变血管舒缩性、释放细胞因子和趋化因子等而引起或加重颅脑损伤。
1.1小胶质细胞小胶质细胞作为中枢神经系统的免疫细胞,可由静息态进入活化态,其是神经炎症发生的标志。慢性脑缺血发生2周后,小胶质细胞自噬途径启动,会诱导白质病变,引发炎性反应,进一步加重认知功能损伤[5]。有研究表明,慢性脑缺血发生第6周和第8周,大鼠海马和皮质区域出现小胶质细胞活化,表现为细胞染色加深,胞体增大,突起增多、变短,呈“阿米巴样”改变[6]。有研究表明,小鼠脑组织慢性脑缺血发生约13周后,小胶质细胞仍处于激活状态[7];而严重慢性脑缺血发生17周后,小胶质细胞功能受损,其清除β淀粉样蛋白功能下降,可能与AD的发病机制有关[8]。
1.2星形胶质细胞星形胶质细胞是中枢神经系统数量最多的免疫细胞。在正常生理条件下,星形胶质细胞为神经元提供代谢和营养支持,维持神经元的正常功能。有研究表明,慢性脑缺血发生8周后,星形胶质细胞数量明显增多,染色光密度增大,表达量增高,这种变化持续至24周后达高峰,第16周时出现胶质瘢痕,可抑制轴突再生,造成不可逆损伤[9]。另外,星形胶质细胞与脑内谷氨酸代谢有关[10],可清除突触间隙的谷氨酸。慢性脑缺血发生10周后,星形胶质细胞数量进一步增多,海马组织对谷氨酸的摄取减少,可能造成认知功能损伤[11]。
炎性递质的产生可诱导白细胞浸润、影响神经胶质细胞表达,其参与脑缺血后炎性损伤过程。另外,炎性递质可作为内皮细胞活化的信号,刺激细胞黏附分子的产生。有研究表明,血清炎性递质水平与缺血性脑血管疾病患者脑动脉狭窄的发生发展及其狭窄程度密切相关[12]。
2.1肿瘤坏死因子α(TNF-α)TNF-α属于前炎性因子,其具有神经毒性作用,是炎性反应的起始因子。VD患者血清TNF-α和白介素1β(IL-1β)水平高于正常人,低于AD患者[13]。慢性脑缺血大鼠脑组织TNF-α和IL-1β水平高于正常脑组织[14],其大量表达可以加剧血管炎性反应,增加兴奋性神经递质的释放,进一步诱导细胞坏死并加重早期脑梗死[15]。有研究发现,TNF-α和IL-1β水平与脑缺血后的线粒体凋亡导致的细胞凋亡有关[16]。慢性脑缺血会引起脑组织和血清TNF-α水平升高[17-18];脑组织中TNF-α的表达滞后于血清,但表达量远高于血清[19-20]。
2.2IL-1β活化的星形胶质细胞、少突胶质细胞等均可分泌IL-1β,其可促进黏附分子的表达,从而加重局部炎性反应。慢性脑缺血发生后,缺血侧脑组织中IL-1β水平升高,于1 d后达最大值,后逐渐减少,1周后恢复至参考范围[19]。有研究表明,慢性脑缺血大鼠造模1周后,皮质及海马等部位IL-1β水平较高,而造模2周后脑室周围白质、胼胝体等区域IL-1β水平较高[17]。有研究表明,慢性脑缺血发生第12周和第17周,海马和皮质区域IL-1β蛋白及mRNA表达水平均高于假手术组[18-21]。IL-1β在慢性脑缺血发生后不同时间点的表达量不同,提示慢性脑缺血发生后不同时期炎性反应程度存在差异。
2.3白介素6(IL-6)慢性脑缺血发生后大量释放IL-6,可造成脑组织损伤;VD患者脑脊液中IL-6水平升高[4]。慢性脑缺血发生2 h后IL-6释放增加,24 h达峰值,3 d后恢复至参考范围,而7 d后IL-6水平再次呈上升趋势[19]。有研究表明,慢性脑缺血发生后第4周胼胝体、第9周海马IL-6水平均高于假手术组[22-23],提示IL-6的延迟增多可能与脑缺血早期释放IL-1β、TNF-α等炎性因子有关[24]。
2.4黏附分子黏附分子介导的黏附过程参与缺血性脑损伤,脑缺血时产生的炎性因子可诱导血管内皮细胞黏附分子的表达,也可诱导中性粒细胞和单核细胞趋化因子的产生。黏附分子表达上调是炎性反应中白细胞黏附并透过血管屏障的起始因素。有研究表明,在慢性脑缺血大鼠脑血管内皮中,细胞间黏附分子1(ICAM-1)和血管细胞黏附分子1(VCAM-1)含量均明显增高,当ICAM-1和VCAM-1受到抑制时可改善大鼠的认知功能[25-26]。提示认知功能障碍可能是由于微血管炎性反应参与慢性脑缺血引起。
慢性脑缺血发生后,细胞内核转录因子-κB(NF-κB)、Janus激酶-信号转导和转录激活因子(JAK/STAT)、Toll样受体/髓样分化因子88(TLRs/MyD88)信号通路以及丝裂原活化蛋白激酶(MAPK)等相关信号通路激活均会介导炎性反应。
3.1NF-κB信号通路NF-κB是炎性反应中重要的转录因子,可与多种炎性反应基因的启动子结合。慢性脑缺血发生时NF-κB因TNF-α等炎性因子作用而活化,并快速易位进入细胞核内,促进细胞因子及黏附分子等炎性酶类靶基因的表达,导致脑内微血管和海马区的炎性反应,造成神经元损伤[27-28]。慢性脑缺血发生后7 d,海马NF-κB P65蛋白和mRNA均达到峰值[20]。NF-κB活化后进入细胞核内与炎性反应关键酶——环氧合酶2(COX-2)启动子区域的NF-κB结合位点结合,可促进COX-2基因的转录表达,增加炎性因子的释放;有临床数据表明,慢性脑缺血患者的大脑小胶质细胞COX-2表达上调,可能与缺血后脑组织损伤和认知功能障碍有关[29-30]。
3.2JAK/STAT信号通路JAK/STAT信号通路是一条由细胞因子刺激激活的信号转导通路,可参与细胞的增殖分化、凋亡及免疫调节等生理过程。JAK/STAT信号通路的传递由3个成分组成,即酪氨酸激酶相关受体、酪氨酸激酶JAK和转录因子STAT。在慢性脑缺血引发的炎性反应中,JAK/STAT家族的调控对神经元凋亡具有重要作用。有研究表明,慢性脑缺血的大鼠皮质和海马中广泛分布着信号转导和转录激活因子1(STAT1)蛋白阳性细胞[31]。慢性脑缺血发生后,胶质细胞内JAK活化,诱导信号转导和转录激活因子3(STAT3)核转位,同时诱导胶质细胞释放炎性因子,导致轴突-胶质细胞连接完整性中断,影响神经元功能,造成认知功能障碍[32]。
3.3TLRs/MyD88信号通路TLRs/MyD88信号通路作为调节胶质细胞炎性反应的主要信号通路,海马TLR4和MyD88在慢性脑缺血状态下激活,促进IL-1β和IL-6等炎性因子的释放,引起炎性损伤[33]。慢性脑缺血发生后可导致Toll样受体4(TLR4)增多,激活其下游信号转导通路元件MyD88的表达,同时不改变Toll样受体2(TLR2)和TLRs的干扰素活化因子(TRIF)的表达[34]。有研究表明,TLR4受体敲除可减轻脑缺血造成的炎性反应[35],提示慢性脑缺血可激活具有MyD88依赖性的TLR4信号通路。
3.4MAPK信号通路MAPK信号通路由上游激活蛋白、MAPK激酶的激酶和MAPK激酶组成,且依次激活,共同调节细胞生长、分化和炎性反应等多种生理病理过程。慢性脑缺血发生后会出现MAPK家族的高度磷酸化[36-38],这种MAPK信号通路的激活可上调IL-1β、IL-6和TNF-α等炎性因子水平[22,33]。故临床采用抑制剂阻断MAPK信号通路时,促炎因子明显减少[39-40]。
慢性脑缺血损伤的病理过程十分复杂,主要由长期脑低灌注造成细胞内氧和葡萄糖的缺失引起氧化应激、炎性反应、线粒体功能障碍和白质损伤等[41],其中,炎性反应扮演了重要角色。小胶质细胞和星形胶质细胞的免疫细胞活化伴随着IL-1β、TNF-α等炎性因子及黏附分子的合成及分泌,NF-κB、JAK/STAT等信号通路的激活会触发炎症级联反应[42],导致胼胝体和海马白质损伤和神经元-突触丢失,最终导致认知功能下降[43]。故抑制慢性脑缺血后炎症级联反应可能是改善脑缺血损伤后认知障碍的潜在治疗靶点,这为防治慢性脑缺血损伤提供了新思路。故如何抑制炎性反应以及炎性反应时间点是今后研究的一个新方向。
文献检索策略
英文文献通过PubMed进行检索,检索公式:(chronic cerebral ischemia OR chronic cerebral hypoperfusion)AND inflammation;中文文献通过中国知网(CNKI)、万方数据知识服务平台、维普网进行检索,先以“慢性脑缺血”为检索词获得相关文献后再以“炎症”为关键词进行二次检索。中英文检索均辅以人工检索,文献检索时间截止至2016年5月。文献纳入标准:(1)国内外公开发表的与慢性脑缺血炎性反应机制相关的研究报道;(2)临床研究类文献和动物实验类文献。文献排除标准:(1)资料来源不清,综述及会议论文、学位论文;(2)重复发表文献(选择最先发表的文献)。检索完成后逐一阅读纳入文献并汇总实验设计、研究方向及最新进展。
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(本文编辑:李洁晨)
Progress on Inflammatory Reaction Mechanism of Chronic Cerebral Ischemia
CAOYan,ZHANGLi-wen,SUNNing,SHIGuang-xia,WANGXue-rui,LIUCun-zhi.
AcupunctureCenterofBeijingChineseMedicineHospitalAffiliatedtoCapitalMedicalUniversity,Beijing100010,China
LIUCun-zhi,AcupunctureCenterofBeijingChineseMedicineHospitalAffiliatedtoCapitalMedicalUniversity,Beijing100010,China;E-mail:lcz623780@126.com
Chronic cerebral ischemia is the pathologic basis of multiple nervous system disease,including vascular dementia,Alzheimer disease,Binswanger disease and so on,but it has relatively long intervention time-window,so in-depth study for inflammatory reaction mechanism of chronic cerebral ischemia has important clinical significance for prevention and treatment of ischemic cerebrovascular disease.This paper reviewed related research progress on inflammatory reaction mechanism of chronic cerebral ischemia.
Brain ischemia;Inflammation;Cytokines;Review
国家自然科学基金面上项目(81473501);国家自然科学基金青年科学基金项目(81303122)
100010北京市,首都医科大学附属北京中医医院针灸中心(曹燕,石广霞,王雪蕊,刘存志);山东中医药大学针灸推拿学院(曹燕,张瓅文,孙宁)
刘存志,100010北京市,首都医科大学附属北京中医医院针灸中心;E-mail:lcz623780@126.com
R 743.31
A
10.3969/j.issn.1008-5971.2016.08.001
2016-06-07;
2016-08-19)