脑动脉瘤发病机制探讨PPT课件.ppt

脑动脉瘤发病机制探讨,谭华桥MDPhD浙江省人民医院神经介入中心浙江省人民医院卒中中心,上海.2013.12,1,脑动脉瘤定义,Abrainaneurysmisaprotrudingbubbleorsaconabloodvesselcausedbyaweakspotinthevesselwallthatballoonsoutovertime.,2,脑动脉瘤患病率,尸检研究：0.2%-9.9%(平均5%)血管造影研究:3.7%-6.0%回顾性荟萃研究:2%(排除成人多囊肾或动脉瘤性SAH家族史）最新研究(AnnInternMed)：7%（中国),3,动脉瘤性SAH发病率和危害性,动脉瘤性SAH发病率WHO研究发现欧洲和亚洲国家校正年龄年动脉瘤性SAH发病率相差10倍（中国2/100000;芬兰22.5/100000)最新的荟萃研究：动脉瘤性SAH发病率2-16/100000,动脉瘤性SAH危害性10-15%患者在入院接受治疗前死亡致死率高达40%50%,致残率高达10%20%,4,动脉瘤好发部位,5,脑动脉瘤病理,内弹力板缺乏,中膜平滑肌细胞凋亡减少，中膜变薄甚至连续性中断.,a=外膜m=中膜,i=内膜,eel=外弹力板Iel=内弹力板,6,脑动脉瘤病理变化过程,内皮功能紊乱,血管平滑肌细胞（VSMC)表型转化,细胞外基质（ECM)重塑,VSMC凋亡、血管退变,VSMC凋亡、血管退变,局限性扩张,动脉瘤形成,生长、破裂,7,脑动脉瘤发病因素,先天性或遗传性因素脑血管解剖变异先天性中膜缺损遗传基因差异家族性颅内动脉瘤,后天性获得因素血流动力学环境因素，如吸烟、饮酒、高血压、高脂血症、雌激素、感染、创伤等,8,脑动脉瘤发生-先天性或遗传性因素,脑血管解剖变异Willis环及脑动脉系统常见的解剖形态学异常双侧脑动脉直径的显著差异某些脑动脉节段先天性缺如或发育不全某些胚胎发育过程中的原始动脉通道(如残存的三叉动脉、舌下动脉等)残留某些先天性脑血管疾病，如:MOYAMOYA病、AVM等,9,脑动脉瘤发生-先天性或遗传性因素,先天性中膜缺陷理论基础：脑主要动脉的分支部位动脉壁存在中膜缺陷,而动脉分叉是颅内动脉瘤的好发部位.理论缺陷：约80%的脑血管分叉部均存在中膜缺损,而动脉瘤的发病率却远远低于这一水平.动脉瘤瘤壁组织中中膜结构的损伤可能并非动脉瘤形成时的始动因素,而是动脉瘤发生、发展的结果,10,脑动脉瘤发生-先天性或遗传性因素,遗传基因证据常染色体显性遗传多囊肾疾病(ADPKD)神经纤维瘤病I型马凡氏综合症多发性内分泌瘤病I型弹性假黄色瘤遗传性出血性毛细血管扩张症埃当综合征II和IV型,相关候选基因与细胞外基质成分合成相关的基因:ELN（弹性蛋白）、COL（胶原蛋白）3A1、COL1A2、LOX、FBN2与细胞外基质降解相关的多种蛋白酶编码基因:MMPs、TIMPs、A1antitrypsinCOL1A2和ELN是最有可能与颅内动脉瘤等位遗传基因相关的候选基因。,遗传性因素,11,血流动力学因素在脑动脉瘤发生中发挥重要作用,脑动脉瘤发生-后天获得性因素,12,Stroke.2002;33:1911-1915,方法：结扎双侧肾后动脉诱发肾性高血压+结扎单侧颈总动脉增加对侧ACA-OA血流结果：增加的血流动力学应力和诱导高血压能够诱发大鼠实验性脑动脉瘤形成,13,内弹力板破坏和高血压能够诱发大鼠颅内动脉瘤形成，两者在颅内动脉瘤形成中具有协同效应,Hypertension.2009;54:1337-1344,14,Stroke.2008;39:2085-2090,单独增加血流动力学损伤能够诱发新生脑动脉瘤，这种新生动脉瘤破坏性重塑依赖于增加的血流,15,Stroke.2007;38:1924-1931,高的壁切应力和切应力梯度易于导致顶端动脉瘤形成,16,高的壁切应力和正性切应力梯度是诱发动脉瘤样重塑的危险血流动力学,Stroke.2010;41:1774-1782,17,Neurosurgery65:169178,2009,18,.bFGF=basicfibroblastgrowthfactor;COX2=cyclooxygenase-2;ECM=extracellularmatrix;ICAM=intercellularadhesionmolecule;IL=interleukin;MCP=monocytechemoattractantProteinMMP=matrixmetalloproteinase;NK=naturalkiller;NO=nitricoxide;PGD=prostaglandinD;PGE=prostaglandinE;ROS=reactiveoxygenspecies;TGF=transforminggrowthfactor;TLR=toll-likereceptor;TNF=tumornecrosisfactor;VCAM=vascularcelladhesionmoleculeVEGF=vascularendothelialgrowthfactorVSMC=vascularsmoothmusclecell,Cerebralaneurysm(CA)formationandrupture.,Stroke.2013;44:3613-3622.,19,InflammatoryPathwaysandMediatorsImplicatedinCAFormationandRupture,Stroke.2013;44:3613-3622.,20,InflammatoryPathwaysandMediatorsImplicatedinCAFormationandRupture,Stroke.2013;44:3613-3622.,IL-1indicatesinterleukin1;KLF-4,Kruppel-liketranscriptionfactor4;MCP-1,monocytechemoattractantprotein-1;MMP,matrixmetalloproteinase;NF-B,nuclearfactor-B;SMC,smoothmusclecell;andTNF,tumornecrosisfactor-.,21,C,complementsystem;C3aandC5a,anaphylatoxins;CRP,Creactiveprotein;EC,endothelialcell;IFN-g,interferongamma;IgG,immunoglobulinG;IgM,immunoglobulinM;IL-1b,interleukin1-beta;M,macrophage;MCP-1,monocytechemotacticprotein;MHC-IandMHC-II,majorhistocompabilitycomplexesIandI;MMP,matrixmetalloproteinase;NK,naturalkillercell;RNS,reactivenitrogenspecies;ROS,reactiveoxygenspecies;SCR,scavengerreceptor;SMC,smoothmusclecell;T,Tcell;TGF-b,tissuegrowthfactorbeta;TNF-a,tumornecrosisfactor-alpha;VCAM-1,vascularcelladhesionmolecule-1.,Probableactivatorsandmainfunctionsofmacrophagesinintracranialaneurysms.,22,probableactivationmechanismsandfunctionsofadaptiveimmunityinintracranialaneurysms,CytokinesandinflammatorymediatorsInterferongamma,IFN-g;Tumornecrosisfactoralphaandbeta,TNF-aandTNF-b;Interleukins,IL,MHC=majorhistocompabilitycomplexTCR=TcellreceptorM=macrophageTcellrecognizestheTh=CD4(helperTcells,)Tc=CD8(cytotoxicTcells)NK=Naturalkiller,23,JournalofCerebralBloodFlowSM-actin,smoothmuscle-actin;SSAO,semicarbazide-sensitiveamineoxidase;NO,nitricoxide;TNF,tumornecrosisfactor-;MCP1,monocytechemoattractantprotein1;IL1,Interleukin1;ROS,reactiveoxygenspecies;MMPs,matrixmetalloproteinases.,24,Stroke.2009;40:942-951,MCP-1在动脉瘤形成早期阶段表达上调，MCP-1基因敲出的大鼠动脉瘤形成下降、巨噬细胞聚集下降，MMP-2和MMP-9、iNOS表达下降，在MCP-1表达的细胞中显示NF-kappa-激活。阻止MCP-1激活则抑制动脉瘤形成。MCP-1作为单核/巨噬细胞趋化因子在动脉瘤形成中起关键作用，MCP-1在动脉瘤壁表达通过NF-kappa-激活。,25,Circulation.2007;116:2830-2840,NF-通过诱发一些同巨噬细胞聚集和激活的炎症基因在脑动脉瘤形成中发挥重要作用,26,增加的TNF和FAS相关死亡域蛋白通过促进血管和免疫细胞炎症反应和随后的凋亡对脑动脉施加有害影响，消弱血管壁。,Neurosurgery57:558-564,2005,27,SchematicmodelforTNFsignalingincerebralaneurysm,TNFmayparticipateintheinflammatory,apoptotic,andvesseldestructiveprocessesincerebralaneurysmsbypromotingthesynthesisofIL-1,IL-6,FADDprotein,andmetalloproteinases(MMPs),respectively.Activationoftheseproinflammatoryproteinsfromleukocytes,andtissuedegradingenzymesassociatedwithapoptosis,mayweakenthearterialwall,leadingtoaneurysmformationandrupture.However,IL-10expressionmaynegativelymodulateTNFandinhibitTNF-associatedinflammation,28,PLoSONE8(9):e74357.doi:10.1371/journal.pone.0074357,在血流动力学触发的动脉瘤起始阶段，SMC而不是巨噬细胞负责动脉瘤样病变发展的关键炎症介质-MMP生产,29,ROS生成基因p47phox在动脉瘤壁炎性浸润的巨噬细胞和SMC上调，上调的ROS生成基因和抑制的ROS清除基因提示ROS在动脉瘤壁生成过量。自由基吞噬体通过抑制炎症相关基因表达有效抑制动脉瘤形成，而且p47phox敲出的大鼠动脉瘤形成受抑制，动脉瘤壁炎症反应下降。ROS和ROSp47phox积极参与脑动脉瘤的形成,LaboratoryInvestigation(2009)89,730741,30,Circulation.2000;101:2532-2538,31,CurrNeurovascRes.2013;10(3):247255.,Potentialmediatorsofoxidativestressincerebralaneurysmpathogenesis.,32,CSincreaseswallshearstressincerebralvesselsandcausesendothelialdysfunctionwithVSMCproinflammatoryphenotypicmodulation.Theresultantinflammatoryresponseimplicatesseveralinflammatorycellsandmediators(ROSinparticular)andleadstoextracellularmatrixremodelingandsubsequentaneurysmformation.FurtherCSinducedmatrixbreakdown,celldeath,andformationofanorganizingthrombuseventuallyculminateinCArupture.,MediatorsofInflammation2012,doi:10.1155/2012/271582,CigaretteSmokeandInflammat