泻火补肾汤对脑出血神经干细胞移植后大鼠脑微血管内皮细胞的保护作用
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摘要
研究背景：脑出血后多遗留有不同程度的偏瘫、失语等残疾，致使患者生活质量严重下降。神经干细胞(neural stem cells，NSCs)的发现给脑血管疾病的治疗带来新的希望，但由于脑出血后内源性神经干细胞发生的数目有限，不足以修复脑出血后神经损伤，因此采用外源性神经干细胞移植治疗脑出血很有必要。然而脑出血后血脑屏障破坏，大量血液细胞侵入脑内。其中免疫细胞激活导致细胞因子释放，改变了脑内原有的“免疫豁免”环境。出血后脑内存在的大量细胞因子既可促进小胶质细胞等细胞主要组织相容性复合物(MHC)分子的表达，促进抗原递呈及识别；又可诱导神经干细胞MHC分子的表达，诱发免疫排斥反应，加重组织损伤。
根据免疫反应理论，脑出血血脑屏障损伤后用NSCs移植治疗可能发生移植物抗宿主反应(GVHD)。即以TH1为主，TH2、CTL参与的细胞免疫反应。TH1释放的IFN-γ、TNF-α等细胞因子可诱导血管内皮细胞(Endothelial cell，EC)血管细胞黏附分子-1(vascular cell adhesion molecule，VCAM-1)的表达，促进白细胞黏附、变形、游出，侵入脑组织引起炎症反应。因此血管内皮细胞无论在脑出血的炎症反应或免疫排斥过程中，均起着关键作用。
目的：本研究旨在通过观察泻火补肾汤对脑出血NSCs移植后大鼠及干扰素-γ(interferon gamma，IFN-γ)干预后大鼠脑微血管内皮细胞(rat cerebral microvascular endothelial cells，RCMECs)血管细胞粘附分子-1、转化生长因子-β1(transforming growth factor-β1，TGF-β1)、Fas、FasL表达及细胞凋亡的影响，探讨泻火补肾汤在NSCs移植免疫反应中对微血管内皮细胞的保护作用及可能机制。
方法：1)体外实验：用新生7-10天SD乳鼠分离原代鼠脑微血管内皮细胞，培养、传代后以Ⅷ相关抗原抗体鉴定。取2-8代细胞进行分组实验。分空白组、IFN-γ刺激组、正常血清组、泻火补肾汤血清组共四组进行处理。分别用RT-PCR及ELISA检测VCAM-1、TGF-β1的mRNA和蛋白表达水平，TUNEL检测细胞凋亡，RT-PCR及免疫细胞化学方法观察Fas、FasL mRNA及蛋白表达。2)体内实验：90只SD大鼠随机分为正常组(n=10)、假手术组(n=20)、脑出血组(n=20)、NSCs移植组(n=20)及泻火补肾汤组(n=20)，用Ⅶ型胶原酶注入苍白球复制脑出血模型，术后2d进行NSCs移植，移植后第4d、7d分两批处死动物。分别采用RT-PCR及ELISA检测VCAM-1、TGF-β1 mRNA和蛋白表达水平，TUNEL检测细胞凋亡，RT-PCR及免疫组织化学方法观察Fas、FasL mRNA及蛋白的表达。
结果：
体外实验：
1．RT-PCR及ELISA检测显示：IFN-γ刺激后可见RCMECs形态改变，细胞活力下降，VCAM-1、TGF-β1 mRNA及蛋白表达水平均升高(P＜0.01)。泻火补肾汤血清处理后细胞形态及活力改善，VCAM-1及TGF-β1表达降低，与正常血清组、IFN-γ刺激组比较差异显著(P＜0.05)。
2．TUNEL检测显示：IFN-γ刺激后RCMECs大量凋亡，泻火补肾汤处理后TUNEL阳性细胞明显减少，与正常血清组、IFN-γ刺激组比较差异有显著性(P＜0.01)。
3．免疫组化及RT-PCR检测显示：IFN-γ刺激后，RCMECs Fas、FasL蛋白及mRNA表达均增加(P＜0.01)。泻火补肾汤组处理后Fas表达降低(P＜0.05)，FasL表达明显增加，与正常血清组、IFN-γ刺激组比较差异显著(P＜0.01)。
体内实验：
1．RT-PCR显示正常组及假手术组大鼠脑内见微量VCAM-1mRNA表达，脑出血组大鼠VCAM-1 mRNA表达较正常组、假手术组增多(P＜0.05)，NSCs移植后VCAM-1 mRNA表达明显增加(P＜0.05)，泻火补肾汤组表达明显低于NSCs移植组(P＜0.01)，除正常组外各组7d VCAM-1mRNA表达较4d均有下降(P＜0.05)。血清VCAM-1表达与脑内VCAM-1 mRNA表达趋势一致。TGF-β1mRNA在正常大鼠脑内有微量表达，NSCs移植组较脑出血组表达增强(P＜0.01)，泻火补肾汤组表达更强，与其它各组比较有显著性差异(P＜0001)；除正常组和假手术组外，各组7d TGF-β1mRNA表达较4d均有下降(P＜0.05)。ELISA检测显示各组血清TGF-β1水平较正常组下降，以NSCs移植组最低。7d与4d比较，除正常组外各组TGF-β1均有回升，以泻火补肾汤组最明显。
2．TUNEL检测显示：正常鼠脑中未见凋亡细胞，脑出血后出血区周围可见凋亡细胞。NSCs移植后凋亡细胞增多(P＜0.05)；泻火补肾汤干预后TUNEL阳性细胞明显减少(P＜0.05)；除正常组外，各组7d时TUNEL阳性细胞较4d减少。
3．免疫组化定性检测示脑出血组及NSCs移植组脑内均有Fas、FasL蛋白的表达。RT-PCR半定量检测示正常组大鼠脑内有少量FasmRNA表达，假手术组、脑出血组、NSCs移植组Fas mRNA表达增加，以NSCs移植组最强(P＜0.05)，泻火补肾汤组明显低于NSCs移植组(P＜0.05)。除正常组外7d时各组Fas mRNA表达较4d下降。正常组及假手术组大鼠脑内仅见微量FasL mRNA表达，脑出血组、NSCs移植组、泻火补肾汤组FasL mRNA表达增强，以泻火补肾汤组最强(P＜0.05)。且同组内前后比较表达下降(P＜0.05)。
结论
1．IFN-γ体外干预大鼠脑微血管内皮细胞，建立的的免疫损伤反应模型中存在细胞活力下降，VCAM-1、TGF-β1和Fas、FasL表达上调；
2．脑出血大鼠移植NSCs后出王见VCAM-1、TGF-β1和Fas、FasL表达上调，细胞凋亡增加；提示脑内存在炎症和免疫反应增强，
3．泻火补肾汤能抑制脑出血NSCs移植后的炎症和免疫反应，保护脑微血管内皮细胞。其机制可能是通过：1)下调VCAM-1表达、上调TGF-β1的表达；2)调节Fas、FasL表达，通过Fas／FasL通路促进免疫细胞凋亡，诱导免疫耐受。
Background and Objective
The study aimed to observe the effects of Xiehuo Bushen Decoction on the expression of vascular cell adhesion molecule(VCAM-1), transforming growth factor beta (TGF-β1), Fas, Fas Ligand and apoptosis in rats brain of neural stem cells (NSCs)-transplanted experimental intracerebral hemorrhage and cultured interferon(IFN-γ)-induced cerebral microvascular endothelial cells (RCMECs), to explore the mechanism of Xiehuo Bushen Decoction (XHBS) in protecting RCMECs in NSCs-transplanted intracerebral hemorrhagic rat brains.
Methods
1. RCMECs were obtained from 7-10 days old neonate SD rats. The cultured RCMECs were randomly divided into control group, IFN-γgroup, serum control group and XHBS serum group. We observed the expression of VCAM-1 and TGF-β1 by enzyme-linked immunosorbent assay (ELISA) and reverse transcriptase polymerase chain reaction (RT-PCR), the expression of Fas and FasL by immunohistochemistry and RT-PCR, as well as the apoptosis by TdT-mediated dUTP-biotin nick end labeling (TUNEL).
2. Ninety rats were randomly divided into five groups including normal group (n=10), sham operation group (n=20), intracerebral hemorrhage group (n=20), NSCs-transplanted group (n=20) and XHBS-treated group(n=20). The intracerebral hemorrhage model was induced by injecting 0.4UⅦcollagenase into right globus pallidus(1.4mm posterior, 3.2mm lateral to bregma, and 5.6mm depth from the cortical surface) with stereotaxic apparatus. BrdU-labled NSCs were transplanted to subventricle zone (SVZ) 2 days later. The expression of VCAM-1 and TGF-β1, Fas, FasL and apoptosis was assayed by the same technique as those in in vitro respectively.
Results
1. VCAM-land TGF-β1 mRNA expressed remarkably in cultured RCMECs after induced with IFN-γ(P＜0.01 vs control group). Their expression were decreased after treated with XHBS serum (P＜0.05 vs IFN-γgroup), The concentration of VCAM-1 and TGF-β1 in supernatant changed similar to that of the mRNA. The cell viability of XHBS serum group were higher than that of IFN-γgroup by MTT (P＜0.05).
2. The number of TUNEL positive cells which was very small in control group, increased markedly in IFN-γgroup (P＜0.01 vs control group) and decreased in XHBS serum group (P＜0.05 vs serum control group).
3. The expression of Fas mRNA and protein in RCMECs was increased remarkably after induced by IFN-γ(P＞0.05 vs control group) and decreased in XHBS serum group (P＜0.01 vs serum control group). The expression of FasL was gradually up-regulated in IFN-γgroup, serum control group and XHBS serum group, and there is significant difference between IFN-γgroup and XHBS serum group (P＜0.05).
4. VCAM-1 expressed at low level in normal group and sham operation group, it was up-regulated remarkably in intracerebral hemorrhage group and NSCs transplanted group. The expression of VCAM-1 was down-regulated significantly in XHBS-treated group (P＜0.05 vs NSCs-transplanted group). TGF-β1 mRNA also can be seen mildly in normal group and sham operation group (P＜0.05). It was higher in intracerebral hemorrhage group than in sham operation group (P＜0.05). The expression was up-regulated markedly in XHBS-treated group (P＜0.05 vs NSCs-transplanted group).
5. There was no TUNEL positive cells in the rat brains of normal group and some in sham operation group. The number of TUNEL positive cells increased significantly in model group and NSCs-transplanted group, and there was no difference between the two groups. The number of apoptosis cells decreased markedly in XHBS-treated group(P＜0.05 vs NSCs-transplanted group).
6. Fas expressed at low level in the rat brains of normal group and sham operation group. The expression of Fas mRNA and protein in intracerebral hemorrhage group and NSCs-transplanted group increased at 4d (P＜0.01 vs normal group and sham operation group). It expressed mainly in neurons and endothelial cells around hematoma. it was down-regulated remarkably in XHBS-treated group(P＜0.05 vs NSCs-transplanted group). There was little FasL mRNA expressed in normal group and sham operation group. The trend of FasL expression increased gradually in intracerebral hemorrhage group, NSCs-transplanted group and XHBS-treated group. The expression of FasL from 4d to 7d is ascendant.
Conclusions
1. Expression of VCAM-1, TGF-β1, Fas and FasL was up-regulated in IFN-γ-treated rat cerebral microvascular endothelial cells to simulate host-rejection in vitro, accompanied by celluar morphological change and viability reduction.
2. Expression of VCAM-1, TGF-β1 and Fas/FasL was up-regulated in brain of NSCs-transplanted intracerebral hemorrhagic rats, which indicated intensification of inflammatory and immunological reaction.
3. Xiehuobushen decoction can ameliorate host rejection following NSCs-transplantation in intracerebral hemorrhagic rat brains, which may be attributed to its inhibition of inflammation by reducing VCAM-1 activation and promoting TGF-β1 expression, and protection of rat brain microvascular endothelial cells by modifying Fas/FasL pathway.
根据免疫反应理论，脑出血血脑屏障损伤后用NSCs移植治疗可能发生移植物抗宿主反应(GVHD)。即以TH1为主，TH2、CTL参与的细胞免疫反应。TH1释放的IFN-γ、TNF-α等细胞因子可诱导血管内皮细胞(Endothelial cell，EC)血管细胞黏附分子-1(vascular cell adhesion molecule，VCAM-1)的表达，促进白细胞黏附、变形、游出，侵入脑组织引起炎症反应。因此血管内皮细胞无论在脑出血的炎症反应或免疫排斥过程中，均起着关键作用。
目的：本研究旨在通过观察泻火补肾汤对脑出血NSCs移植后大鼠及干扰素-γ(interferon gamma，IFN-γ)干预后大鼠脑微血管内皮细胞(rat cerebral microvascular endothelial cells，RCMECs)血管细胞粘附分子-1、转化生长因子-β1(transforming growth factor-β1，TGF-β1)、Fas、FasL表达及细胞凋亡的影响，探讨泻火补肾汤在NSCs移植免疫反应中对微血管内皮细胞的保护作用及可能机制。
方法：1)体外实验：用新生7-10天SD乳鼠分离原代鼠脑微血管内皮细胞，培养、传代后以Ⅷ相关抗原抗体鉴定。取2-8代细胞进行分组实验。分空白组、IFN-γ刺激组、正常血清组、泻火补肾汤血清组共四组进行处理。分别用RT-PCR及ELISA检测VCAM-1、TGF-β1的mRNA和蛋白表达水平，TUNEL检测细胞凋亡，RT-PCR及免疫细胞化学方法观察Fas、FasL mRNA及蛋白表达。2)体内实验：90只SD大鼠随机分为正常组(n=10)、假手术组(n=20)、脑出血组(n=20)、NSCs移植组(n=20)及泻火补肾汤组(n=20)，用Ⅶ型胶原酶注入苍白球复制脑出血模型，术后2d进行NSCs移植，移植后第4d、7d分两批处死动物。分别采用RT-PCR及ELISA检测VCAM-1、TGF-β1 mRNA和蛋白表达水平，TUNEL检测细胞凋亡，RT-PCR及免疫组织化学方法观察Fas、FasL mRNA及蛋白的表达。
结果：
体外实验：
1．RT-PCR及ELISA检测显示：IFN-γ刺激后可见RCMECs形态改变，细胞活力下降，VCAM-1、TGF-β1 mRNA及蛋白表达水平均升高(P＜0.01)。泻火补肾汤血清处理后细胞形态及活力改善，VCAM-1及TGF-β1表达降低，与正常血清组、IFN-γ刺激组比较差异显著(P＜0.05)。
2．TUNEL检测显示：IFN-γ刺激后RCMECs大量凋亡，泻火补肾汤处理后TUNEL阳性细胞明显减少，与正常血清组、IFN-γ刺激组比较差异有显著性(P＜0.01)。
3．免疫组化及RT-PCR检测显示：IFN-γ刺激后，RCMECs Fas、FasL蛋白及mRNA表达均增加(P＜0.01)。泻火补肾汤组处理后Fas表达降低(P＜0.05)，FasL表达明显增加，与正常血清组、IFN-γ刺激组比较差异显著(P＜0.01)。
体内实验：
1．RT-PCR显示正常组及假手术组大鼠脑内见微量VCAM-1mRNA表达，脑出血组大鼠VCAM-1 mRNA表达较正常组、假手术组增多(P＜0.05)，NSCs移植后VCAM-1 mRNA表达明显增加(P＜0.05)，泻火补肾汤组表达明显低于NSCs移植组(P＜0.01)，除正常组外各组7d VCAM-1mRNA表达较4d均有下降(P＜0.05)。血清VCAM-1表达与脑内VCAM-1 mRNA表达趋势一致。TGF-β1mRNA在正常大鼠脑内有微量表达，NSCs移植组较脑出血组表达增强(P＜0.01)，泻火补肾汤组表达更强，与其它各组比较有显著性差异(P＜0001)；除正常组和假手术组外，各组7d TGF-β1mRNA表达较4d均有下降(P＜0.05)。ELISA检测显示各组血清TGF-β1水平较正常组下降，以NSCs移植组最低。7d与4d比较，除正常组外各组TGF-β1均有回升，以泻火补肾汤组最明显。
2．TUNEL检测显示：正常鼠脑中未见凋亡细胞，脑出血后出血区周围可见凋亡细胞。NSCs移植后凋亡细胞增多(P＜0.05)；泻火补肾汤干预后TUNEL阳性细胞明显减少(P＜0.05)；除正常组外，各组7d时TUNEL阳性细胞较4d减少。
3．免疫组化定性检测示脑出血组及NSCs移植组脑内均有Fas、FasL蛋白的表达。RT-PCR半定量检测示正常组大鼠脑内有少量FasmRNA表达，假手术组、脑出血组、NSCs移植组Fas mRNA表达增加，以NSCs移植组最强(P＜0.05)，泻火补肾汤组明显低于NSCs移植组(P＜0.05)。除正常组外7d时各组Fas mRNA表达较4d下降。正常组及假手术组大鼠脑内仅见微量FasL mRNA表达，脑出血组、NSCs移植组、泻火补肾汤组FasL mRNA表达增强，以泻火补肾汤组最强(P＜0.05)。且同组内前后比较表达下降(P＜0.05)。
结论
1．IFN-γ体外干预大鼠脑微血管内皮细胞，建立的的免疫损伤反应模型中存在细胞活力下降，VCAM-1、TGF-β1和Fas、FasL表达上调；
2．脑出血大鼠移植NSCs后出王见VCAM-1、TGF-β1和Fas、FasL表达上调，细胞凋亡增加；提示脑内存在炎症和免疫反应增强，
3．泻火补肾汤能抑制脑出血NSCs移植后的炎症和免疫反应，保护脑微血管内皮细胞。其机制可能是通过：1)下调VCAM-1表达、上调TGF-β1的表达；2)调节Fas、FasL表达，通过Fas／FasL通路促进免疫细胞凋亡，诱导免疫耐受。
Background and Objective
The study aimed to observe the effects of Xiehuo Bushen Decoction on the expression of vascular cell adhesion molecule(VCAM-1), transforming growth factor beta (TGF-β1), Fas, Fas Ligand and apoptosis in rats brain of neural stem cells (NSCs)-transplanted experimental intracerebral hemorrhage and cultured interferon(IFN-γ)-induced cerebral microvascular endothelial cells (RCMECs), to explore the mechanism of Xiehuo Bushen Decoction (XHBS) in protecting RCMECs in NSCs-transplanted intracerebral hemorrhagic rat brains.
Methods
1. RCMECs were obtained from 7-10 days old neonate SD rats. The cultured RCMECs were randomly divided into control group, IFN-γgroup, serum control group and XHBS serum group. We observed the expression of VCAM-1 and TGF-β1 by enzyme-linked immunosorbent assay (ELISA) and reverse transcriptase polymerase chain reaction (RT-PCR), the expression of Fas and FasL by immunohistochemistry and RT-PCR, as well as the apoptosis by TdT-mediated dUTP-biotin nick end labeling (TUNEL).
2. Ninety rats were randomly divided into five groups including normal group (n=10), sham operation group (n=20), intracerebral hemorrhage group (n=20), NSCs-transplanted group (n=20) and XHBS-treated group(n=20). The intracerebral hemorrhage model was induced by injecting 0.4UⅦcollagenase into right globus pallidus(1.4mm posterior, 3.2mm lateral to bregma, and 5.6mm depth from the cortical surface) with stereotaxic apparatus. BrdU-labled NSCs were transplanted to subventricle zone (SVZ) 2 days later. The expression of VCAM-1 and TGF-β1, Fas, FasL and apoptosis was assayed by the same technique as those in in vitro respectively.
Results
1. VCAM-land TGF-β1 mRNA expressed remarkably in cultured RCMECs after induced with IFN-γ(P＜0.01 vs control group). Their expression were decreased after treated with XHBS serum (P＜0.05 vs IFN-γgroup), The concentration of VCAM-1 and TGF-β1 in supernatant changed similar to that of the mRNA. The cell viability of XHBS serum group were higher than that of IFN-γgroup by MTT (P＜0.05).
2. The number of TUNEL positive cells which was very small in control group, increased markedly in IFN-γgroup (P＜0.01 vs control group) and decreased in XHBS serum group (P＜0.05 vs serum control group).
3. The expression of Fas mRNA and protein in RCMECs was increased remarkably after induced by IFN-γ(P＞0.05 vs control group) and decreased in XHBS serum group (P＜0.01 vs serum control group). The expression of FasL was gradually up-regulated in IFN-γgroup, serum control group and XHBS serum group, and there is significant difference between IFN-γgroup and XHBS serum group (P＜0.05).
4. VCAM-1 expressed at low level in normal group and sham operation group, it was up-regulated remarkably in intracerebral hemorrhage group and NSCs transplanted group. The expression of VCAM-1 was down-regulated significantly in XHBS-treated group (P＜0.05 vs NSCs-transplanted group). TGF-β1 mRNA also can be seen mildly in normal group and sham operation group (P＜0.05). It was higher in intracerebral hemorrhage group than in sham operation group (P＜0.05). The expression was up-regulated markedly in XHBS-treated group (P＜0.05 vs NSCs-transplanted group).
5. There was no TUNEL positive cells in the rat brains of normal group and some in sham operation group. The number of TUNEL positive cells increased significantly in model group and NSCs-transplanted group, and there was no difference between the two groups. The number of apoptosis cells decreased markedly in XHBS-treated group(P＜0.05 vs NSCs-transplanted group).
6. Fas expressed at low level in the rat brains of normal group and sham operation group. The expression of Fas mRNA and protein in intracerebral hemorrhage group and NSCs-transplanted group increased at 4d (P＜0.01 vs normal group and sham operation group). It expressed mainly in neurons and endothelial cells around hematoma. it was down-regulated remarkably in XHBS-treated group(P＜0.05 vs NSCs-transplanted group). There was little FasL mRNA expressed in normal group and sham operation group. The trend of FasL expression increased gradually in intracerebral hemorrhage group, NSCs-transplanted group and XHBS-treated group. The expression of FasL from 4d to 7d is ascendant.
Conclusions
1. Expression of VCAM-1, TGF-β1, Fas and FasL was up-regulated in IFN-γ-treated rat cerebral microvascular endothelial cells to simulate host-rejection in vitro, accompanied by celluar morphological change and viability reduction.
2. Expression of VCAM-1, TGF-β1 and Fas/FasL was up-regulated in brain of NSCs-transplanted intracerebral hemorrhagic rats, which indicated intensification of inflammatory and immunological reaction.
3. Xiehuobushen decoction can ameliorate host rejection following NSCs-transplantation in intracerebral hemorrhagic rat brains, which may be attributed to its inhibition of inflammation by reducing VCAM-1 activation and promoting TGF-β1 expression, and protection of rat brain microvascular endothelial cells by modifying Fas/FasL pathway.
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