摘要
脑卒中是全球范围内导致死亡的主要疾病,目前已经成为仅次于心脏病和癌症的第三大致死原因。而缺血性中风的发病率约占中风的87%,是脑卒中的主要类型,具有发病率高、致残率高、复发率高、死亡率高等特点,给患者及其家庭带来了痛苦,也对社会医疗体系造成了沉重的经济负担。
缺血性中风引起的脑缺血及继发的再灌注会导致严重的脑损伤。尽快恢复脑损伤后的血液供应,挽救濒临死亡的神经元、神经胶质细胞和血管内皮细胞,是减轻脑缺血后脑损伤的关键。如何诱导血管形成来促进缺血周边血管发生或侧支循环的建立,在已阻塞或狭窄的动脉周围组成内生的旁路循环,实现损伤组织缺血区的自我搭桥,是探求减轻缺血组织损伤、促进功能重建的应予关注之点。
我们在前期的一系列实验中发现,电针可以增加脑缺血再灌注损伤后大鼠骨髓和外周血中内皮祖细胞(Endothelial progenitor cells, EPCs)的数量,增强脑损伤区的血管内皮细胞生长因子(Vascular endothelial growth factor, VEGF)、血管内皮细胞生长因子受体2(Vascular endothelial growthFactor receptor2, VEGFR2)的表达。而EPCs与血管形成密切相关,同时能够参与内皮修复;VEGF则是EPCs动员、迁移、归巢过程中最有潜力的因子。这就说明针刺能够刺激机体产生相关的生长因子,并能够上调骨髓与外周血中EPCs的水平,与脑缺血再灌注损伤区的血管形成及内皮修复有关。此外,有研究报道碱性成纤维细胞生长因子(basic fibroblast growth factor, bFGF)与VEGF在血管新生过程中起着协同作用,且能够促进内皮细胞的增殖、迁移,对神经元也有着积极影响;而CD34作为EPCs的一种表面抗原,也可以用来标记血管密度,以观察组织的血管生成情况。为了进一步研究针刺对脑缺血再灌注区域的EPCs表达及对血管修复情况的影响,我们拟观察针刺后不同时间点脑缺血再灌注损伤区的CD34+、bFGF的表达情况。
由于我们前期的实验都属于动物的在体实验,为了更清楚地观察针刺的效果,探索其相关机制,拟通过培养EPCs并采用“针灸血清”对其干预的方式进一步进行研究,以观察针刺对EPCs的增殖、迁移、黏附等能力的影响。
通过这一研究,我们将更进一步地探明针刺对脑缺血再灌注区域血管新生的影响及其对EPCs的作用,有可能使我们阐明针刺通过调理气血、疏通经络的作用促进损伤后血管发生的相关机理,对进一步探索针刺的治疗机理研究起到重要作用。
实验一电针对脑缺血再灌注大鼠bFGF、CD34表达的影响
目的:观察电针及预电针对脑缺血再灌注大鼠缺血大脑皮层bFGF和CD34表达的影响,探讨电针对脑缺血后血管形成的影响。
方法:雄性SD大鼠随机分为正常组、假手术组、模型组、电针组、预电针组,后三组制造大脑中动脉闭塞(Middle cerebral artery occlusion, MACO)模型。预电针组与电针组取“后三里”和“曲池”穴,分别于MACO造模前、后进行电针治疗。采用免疫组化法观察各组在MACO再灌注后12h、24h、48h三个时间点时缺血大脑皮层bFGF和CD34的表达情况。
结果:
(1)正常组及假手术组bFGF、CD34阳性表达较少。
(2)模型组bFGF阳性表达在脑缺血再灌注后12h处于较低水平,随时间延长呈现上升趋势,24h基本达到峰值,此后又逐渐下降;CD34则由脑缺血再灌注后12h的低值开始,随着时间的延长,呈上升趋势,至48h仍在上升;二者各时间点均与正常组及假手术组有明显差异。
(3)电针组bFGF阳性表达在脑缺血再灌注后12h时与模型组无明显差异,此后呈快速上升趋势且在24h、48h时均于模型组有明显差异:CD34阳性表达在12-24h时上升速度明显较模型组为快,而在24-48h时上升速度基本与模型组平行,在12h与模型比较无明显差异,24h、48h则明显较模型组为高,有明显差异;
(4)预电针组bFGF呈快速上升趋势且下降速度较缓,各时间点相较于模型组、电针组也均有明显差异;CD34阳性表达呈持续上升趋势,各时间点均与模型组、电针组有明显差异。
结论:电针及预电针都能明显提高脑缺血再灌注大鼠缺血大脑皮层bFGF和CD34的表达,能够为血管生成创造有利条件。
实验二内皮祖细胞的分离、培养与鉴定
目的:探讨Sprague Dawley (SD)大鼠骨髓源性EPCs分离、培养与鉴定的方法。
方法:通过密度梯度离心法从4周龄SD大鼠骨髓中分离单个核细胞,使用EGM-2MV培养基进行诱导培养,采用形态学特征观察、摄取Dil-Ac-LDL与结合FITC-UEA-1试验、免疫荧光化学鉴定其表面抗原CD133与VEGFR2等方法对其进行鉴定,并通过管腔形成实验观察形成管腔的能力。
结果:
(1)形态学观察:分离的BMNCs经诱导培养后,在生长的早(第8天左右)、晚期(第15天左右)其细胞形态有一定差异,早期以纺锤形、三角形、圆形细胞多见,晚期以圆形、短梭形细胞多见;
(2)摄取Dil-Ac-LDL与结合FITC-UEA-1实验:显示第8天、第21天的细胞均为阳性;
(3)免疫荧光化学染色:第8天的细胞表达CD133、VEGFR2;
(4)管腔形成实验:在Matrigel基质上15h左右能够生成血管样结构。
结论:利用密度梯度离心法分离大鼠BMNCs后以EGM-2MV进行诱导培养,可以获得两种不同形态的细胞;经过鉴定证明获得的细胞符合EPCs的特征;本方法能够简单、快速、可靠、大量地获取EPCS。
实验三针刺血清对内皮祖细胞增殖、迁移、黏附功能的影响
目的:探讨电针血清及预电针血清对体外培养的EPCs增殖、迁移、黏附等功能的影响。
方法:实验一中模型组、电针组、预电针组分别于再灌注48h时获取各组血清,同期获取正常组血清。将不同处理组的血清加至体外分离、培养、鉴定过的SD大鼠骨髓来源的EPCs,并设对照组,采用MTT法确定体外干预时合适的血清浓度,再分别采用MTT法、迁移实验、黏附实验观察各组血清对EPCs (?)曾殖、迁移、黏附能力的影响。
结果:
(1)20%浓度的预电针血清体外培养的EPCs(?)曾殖能力影响最显著;
(2)预电针组血清对体外培养的EPCs增殖、迁移、黏附能力影响最显著,与正常红、模型组、电针组比较有显著差异;
(3)电针血清可以提高体外培养的EPCs增殖、迁移、黏附能力,其迁移、黏附能力与模型组、正常组比较有显著差异;增殖能力与模型组无明显差异,与正常组比较有显著差异。
(4)模型组血清可以提高体外培养的EPCs增殖、迁移、黏附能力,与正常组比较有显著差异;
(5)正常组的EPCs增殖、迁移、黏附能力较对照组为高,与对照组相比有明显差
结论:电针血清及预电针血清均能明显提高EPCs的增殖、迁移、黏附能力,这可能是电针能促进缺血、损伤后组织修复和血管形成的因素之一,是针灸能够“行气血、通经络”原因之一。
Stroke is the major disease which leads to death in the worldwide. At present, it have become the third largest cause of death only less than heart disease and cancer. Among all strokes,87%is ischemic, which is the main type of stroke with high morbidity, disability, mortality, recurrence, and so on. Ischemic stroke harms to patients and their families seriously, also imposes a significant economic burden on our healthcare system.
Ischemic stroke brought about cerebral lack of blood, and the secondary reperfusion also can induce to severe brain damage. To return the blood supply of injuried brain as soon as possible and save the dying neurons, glial cells and vascular endothelial cells, which is the key to reduce injury of ischemic stroke. How to induce angiogenesis to promote the establishment of ischemic peripheral vascular or collateral circulation, is the most important for reducing tissue damage and promoting the functional reconstruction.
In a series of experiment, we found that electroacupuncture can increase endothelial progenitor cells (EPCs) of bone marrow and peripheral blood in rat after cerebral ischemia and reperfusion injury, also can enhance the expression of VEGF, VEGFR2in the brain. While EPCs has close correlation with angiogenesis, also can participate in endothelial repair; VEGF is the most potential factor for EPCs in the process of which mobilization, homing, migration. It showed that acupuncture can stimulate the body to produce growth factors which related to EPCs, and promote the angiogenesis and endothelial repair. In addition, other studies have reported that bFGF and VEGF play a synergistic role in the process of angiogenesis, which can promote endothelial cell proliferation, migration, also had a positive effect on neuron; CD34is a surface antigen of EPCs, also can be used to mark the microvascular density to observe the angiogenesis of tissue. In order to research further the effect of acupuncture on EPCs expression and repairment of blood vessels in the region of cerebral ischemia-reperfusion, we intend to observe the expression of CD34+, bFGF in different time points.
Our previous experiment belonged to the animal experiment. In order to observe the effects of acupuncture more clearly, and explore its mechanism, we intend to clture EPCs and use the "acupuncture serum" to intervene the EPCs for observing the effect of acupuncture on EPCs proliferation, migration, adhesion and so on. The "acupuncture serum" refers to the serum collected from the human or animal body which were treated by acupuncture or moxibustion.
Through this research, we will further study the effects of acupuncture on the angiogenesis and EPCs after the cerebral ischemia-reperfusion, which may enable us to clarify the mechanism of promoting angiogenesis after injury by means of acupuncture promoting the move qi and blood and dredging collateral channels, also can play an important role for further exploring the mechanism of acupuncture treatment.
PART ONE The effect of acupuncture on expression of bFGF, CD34in rats with cerebral ischemia reperfusion
Objective: To observe the effect of electroacupuncture on expression of bFGF and CD34in ischemic cerebral cortex of cerebral ischemia-reperfusion rat, to study the influence of electroacupuncture on promoting angiogenesis after cerebral ischemia.
Methods: male SD rats were randomly divided into normal group, sham-operated group, model group, electroacupuncture group and pre-electroacupuncturc group, later three groups manufactured middle cerebral artery occlusion (MACO) model. The pre-electroacupuncture group and electroacupuncture group cured separately before or after modeling using "Housanli(ST36)" and "Quchi(LT1L)" point. bFGF and CD34expression was observed in ischemic cerebral cortex of MACO rats after reperfusion12hours,24hours,48hours using immunohistochemistry.
Result.
(1) In normal group and sham operation group, the positive of CD34and bFGF was less.
(2) The positive bFGF in model group was at a low level after cerebral ischemia-reperfusion12hours, later it increased with change of Lime, after cerebral ischemia-reperfusion24hours, it reached the peak, then gradually decreased; CD34was at a low value after cerebral ischemia-reperfusion12hours, with the extension of time, the rise began, and it still rose after cerebral ischemia-reperfusion48hours. bFGF and CD34in model group were different obviously from the normal group and sham-operated group at each time point.
(3) The positive bFGF in the electroacupuncture group had no significant difference with the model group after cerebral ischemia-reperfusion12hours, then it rapidly increased and had significant difference with the model group after cerebral ischemia-reperfusion24and48hours; the positive CD34had a rapid rise after cerebral ischemia-reperfusion12~24hours, while after cerebral ischemia-reperfusion24~48hours, it rose in parallel to model group, after cerebral ischemia-reperfusion12hours, the positive CD34had no significant difference with the model group, but after24and48hours, it higher than in model group and had significant difference;
(4) the bFGF in pre-electroacupuncture group rose rapidly and descended slowly, which was different obviously with the model group and electroacupuncture group at each time point; the expression of CD34rose persistently and was different obviously with the model group and electroacupuncture group at each time point. Conclusion: Electroacupuncture and the pre-electroacupuncture can obviously increase the expression of bFGF and CD34in ischemic cerebral cortex of cerebral ischemia-reperfusion rat, contribute to angiogenesis.
PART TWO SD rat bone marrow-derived endothelial progenitor cells isolation, culture and characterization
Objective:To study the isolation, culture and identification of Sprague Dawley (SD)rat bone marrow-derived EPCs.
Methods:Bone marrow mononuclear cells (BMMNCs) were isolated"from bone, marrow of SD rats (4weeks old) by density gradient centri fugation, and cultured by EGM-2MV medium. Then identified the cell by observing the morphology, the assay of "ptaking Dil-Ac-LDL and combining with FITC-UEA-1,the expression of surface (?)igens CD133and VEGFR2by fluorescent immunocytochemistry, and evaluating the formation capillary ability through the tube formation assay on matrigel.
Results:
(l)Morphology:After culturing of the separated BMMNCs, the shape was different in the early (about8th day) and later (about10th day) of growth stage. In the early, they were spindle, triangle and round;In the later, they showed round and short spindle appearance
(2)The assay of uptaking Dil-Ac-LDL and combing with FITC-UEA-1:Both the8th and21th cells were all positive;
(3)Fluorescent immunocytochemistry:The8th cells expressed CD133and VFGFR2;
(4)Tube formation assay:FPCs formed capillary-like formations after about15hours when plated on matrigel.
Conclusion: We can isolate the rat BMMNCs using density gradient centri fugation and then culture them with EGM-2MV medium. The aquired colls were proved to be consistent with the characteristics of EPCs. This method is simple, quick, reliable to get enough EPCs.
PART THREE Effects of acupuncture serum on proliferation, migration, adhesion of rat bone marrow-derived EPCs
Objective: To study and investigate the effect of electroaeupuncture scrum and pre-electroacupuncture serum on the proliferation, migration, adhesion of cultured EPCs.
Methods: In experiment one, we got the serum after cerebral ischemia-reperfusion48hours from the model group,the electroacupuncture group and the pre-electroacupuncture group, meanwhile obtained the normal serum. Adding different serum to the cultured rat bone marrow-derived EPCs, and set the control group, using MTT method to determi ne the su itabl e concent ration of serum in vitro intervention, then using the MTT assay, migration assay, adhesion assay to observe the effect of electroacupuncture.
Results:
(1) In vitro, the most significant proliferal ion of EPCs was the concern rat ion of20%which came from pre-electroacupuncture
(2) Pre-electroacupuncture serum had the most sigrnficanl effect on EPCs proliferation, migration, adhesion, which was different significantly from the normal group, model group, and electroacupuncture group;
(3) Electroacupuncture serum can enhance the proliferation, migration, adhesion of EPCs in vitro. The migration and adhesion was di fferent significantly from the normal group and model group; The proliferation was different significantly from the normal group.
(4) Model group serum can enhance the proliferation, migration, adhesion of EPCs in vitro, which was significantly different with the normal group;
(5) In normal group, EPCs prol i ferat ion, migration, adhesi on abilit y was higher than the control group, also had obvious difference compared with control group.
Conclusion: ElecLroacupuncture and pro-electroacupuncturc serum can obviously enhance the proliferation, migration, adhesion of EPCs, this may be one of the factors that the Electroacupuncture therapy can promote tissue repair and neovascularization after injury and ischemia, also may be the effect of acupuncture can " move the Qi and blood, smooth t ho main and col lateral channels".
引文
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