骨桥蛋白在实验性变态反应性脑脊髓炎发病中作用的研究
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摘要
目的：探讨骨桥蛋白(osteopontin, OPN)在实验性变态反应性脑脊髓炎(experimental allergic encephalomyelitis, EAE)大鼠发病中的作用及其免疫学机制,探讨阿托伐他汀对EAE大鼠中枢神经系统(central nervous system, CNS) OPN表达的影响以及对EAE的治疗作用。方法：将40只雌性Wistar大鼠随机分成4组：正常对照组、EAE对照组、大剂量阿托伐他汀组和小剂量阿托伐他汀组,每组各10只。采用粗制髓鞘碱性蛋白(myelin basic protein, MBP)抗原注入EAE对照组及大、小剂量阿托伐他汀组大鼠后足掌皮下(0.2ml/100g)制作EAE模型,正常对照组注射等量生理盐水。自造模之日开始,小剂量阿托伐他汀组每日灌胃阿托伐他汀1mg/kg.d,大剂量阿托伐他汀组每日灌胃阿托伐他汀4mg/kg.d,正常对照组及EAE对照组每日灌胃等体积生理盐水,直至整个实验结束。EAE对照组、大小剂量阿托伐他汀组连续3天症状评分无加重或四肢瘫痪、死亡时作为EAE发病高峰期。记录发病大鼠的潜伏期、进展期和高峰期神经功能障碍评分；于发病高峰期处死大鼠,正常对照组4周后处死,留取大鼠脑及脊髓组织,经处理切片行HE染色,光学显微镜下观察病理变化；免疫组化技术和平均光密度测定法检测各组大鼠脑和脊髓白质组织内OPN和CD44的表达情况；留取各组大鼠眶静脉血,用酶联免疫吸附(enzyme-linked immunosorbent assay, ELISA)法检测外周血单个核细胞(peripheral blood mononuclear cell, PBMC)分泌IFN-γ、IL-10的能力。结果：(1)大鼠发病情况：正常对照组大鼠未发病。EAE对照组及大、小剂量阿托伐他汀组均有不同程度发病。EAE对照组发病潜伏期为12.5±1.1天,小剂量阿托伐他汀组潜伏期(14.2±1.3天)较EAE对照组延长,差异有统计学意义(P＜0.05),大剂量阿托伐他汀组潜伏期(19.4±2.2天)较EAE对照组及小剂量阿托伐他汀组均明显延长(P＜0.01,P＜0.05)；EAE对照组发病进展期为6.9±1.4天,小剂量阿托伐他汀组进展期(4.7±0.6天)较EAE对照组缩短(P＜0.01),大剂量阿托伐他汀组进展期(4.4±0.8天)较EAE对照组明显缩短(P＜0.01),而同小剂量阿托伐他汀组比较,差异没有统计学意义(P＞0.05)；EAE对照组发病高峰期神经功能障碍评分为3.6±0.5分,小剂量阿托伐他汀组神经功能障碍评分(1.8±0.8分)较EAE对照组明显降低(P＜0.01),大剂量阿托伐他汀组神经功能障碍评分(1.6±0.8分)较EAE对照组明显降低(P＜0.01),而同小剂量阿托伐他汀组比较,差异没有统计学意义(P＞0.05)。(2)EAE对照组、大小剂量阿托伐他汀组大鼠脑及脊髓病理学改变：正常对照组大鼠脑和脊髓无异常。EAE对照组大鼠高峰期可见脑及脊髓实质内小血管充血,血管周围主要是小静脉周围有大量炎性细胞浸润,主要为单个核细胞浸润,形成“袖套”状改变,血管周围白质明显脱髓鞘改变。而小剂量阿托伐他汀组病理改变较轻,大剂量组最轻。(3)EAE对照组、大小剂量阿托伐他汀组大鼠CNS内OPN和CD44表达情况：OPN、CD44表达部位主要在大脑、脑干、脊髓白质及灰白质交界的小血管周围。OPN主要分布在神经细胞胞核,部分胞浆亦有表达；CD44主要分布在神经细胞胞浆,两者高表达部位的炎症表现较重。正常对照组大鼠CNS内未发现OPN、CD44阳性细胞；EAE对照组大鼠CNS白质及灰白质交界处可见大量阳性细胞,棕黄色颗粒浓染,着色深；大剂量阿托伐他汀组和小剂量阿托伐他汀组大鼠CNS内仅有少量散在淡染的阳性细胞,小剂量阿托伐他汀组CD44表达高于大剂量阿托伐他汀组。图像分析结果显示,与大剂量阿托伐他汀组及小剂量阿托伐他汀组比较,EAE对照组CNS白质OPN、CD44表达水平均明显升高(P＜0.01)；与小剂量阿托伐他汀组比较,大剂量阿托伐他汀组CNS白质的OPN、CD44表达水平显著降低(P＜0.05)。(4)EAE对照组、大小剂量阿托伐他汀组大鼠PBMC分泌IFN-γ、IL-10能力：正常对照组PBMC分泌的IFN-y水平为0.21±0.02ng/ml,EAE对照组分泌的IFN-γ水平为0.38±0.04ng/ml,EAE对照组较正常对照组明显升高(P＜0.01),大、小剂量阿托伐他汀组分泌的IFN-γ水平分别为0.24±0.01ng/ml、0.27±0.02ng/ml,均较EAE对照组显著下降(P＜0.01),大剂量阿托伐他汀组较小剂量阿托伐他汀组下降更明显(P＜0.05)；正常对照组PBMC分泌的IL-10水平为2.25±0.28pg/ml,EAE对照组分泌的IL-10水平为2.91±0.39pg/ml,EAE对照组较正常对照组无明显改变(P＞0.05),大、小剂量阿托伐他汀组分泌的IL-10水平分别为7.05±1.46pg/ml、5.80±1.10pg/ml,均较EAE对照组显著升高(P＜0.01),大剂量阿托伐他汀组较小剂量阿托伐他汀组升高明显(P＜0.05)；EAE对照组IFN-γ/IL-10比值(105.5±15.85)较正常对照组(92.82±13.63)明显升高(P＜0.05),大、小剂量阿托伐他汀组IFN-γ/IL-10比值分别是31.13±9.69、47.06±7.51,均较EAE对照组显著下降(P＜0.01),大剂量阿托伐他汀组IFN-γ/IL-10比值较小剂量阿托伐他汀组显著降低(P＜0.05)。(5)相关性分析：EAE对照组及大小剂量阿托伐他汀组发病高峰期OPN、CD44表达与发病潜伏期呈负相关(P＜0.01),与发病进展期、高峰期神经功能障碍评分呈正相关(P＜0.05)。EAE对照组及大小剂量阿托伐他汀组发病高峰期外周血IFN-γ/IL-10比值与发病潜伏期呈负相关(P<0.01),与发病进展期、神经功能障碍评分呈正相关(P＜0.01)。EAE对照组及大小剂量阿托伐他汀组发病高峰期OPN、CD44表达与外周血IFN-γ/IL-10比值呈正相关(P＜0.05)。EAE对照组及大小剂量阿托伐他汀组发病高峰期OPN与CD44表达呈相正关(P＜0.05)。结论：1.本实验以豚鼠脊髓粗制MBP为免疫原诱导大鼠EAE模型,EAE大鼠神经功能障碍明显,脑和脊髓血管周围炎性细胞浸润、白质脱髓鞘,说明本法造模成功,可靠,稳定。2.EAE大鼠体内存在着免疫失衡。EAE对照组大鼠发病高峰期体内Th1型细胞因子IFN-γ增多,Th2型细胞因子IL-10减少,Th1/Th2细胞比例失衡,免疫格局向Th1型偏移。3.EAE大鼠发病期OPN表达上调,OPN表达与EAE潜伏期呈负相关,与进展期、神经功能障碍评分呈正相关,经阿托伐他汀治疗后降低,提示OPN与EAE发生发展有关。4.OPN在EAE发病中作用的机制可能通过与CD44相结合后发挥细胞信号分子作用,诱导Th1/Th2失衡有关。5．阿托伐他汀对EAE有一定的治疗作用,可有效改善EAE的临床症状,延缓发病时间,抑制中枢神经系统的炎症细胞浸润、髓鞘脱失和轴突损伤,并对中枢神经系统的轴索再生有一定促进作用,但其机制可能是通过影通过CD44途径影响OPN表达实现的。
Abstract:bjective:To explore the effect and possible mechanism of osteopontin(OPN) on experimental allergic encephalomyelitis(EAE),to explore the atorvastatin's effect on OPN and treatment on EAE. By observing the OPN on the EAE about its incidence, pathology, immunohistochemistry, expression of CD44 and OPN, peripheral blood IL-10, IFN-γexpression, Th1/Th2 balance,to explore the effect of OPN on the possible immunological mechanisms of EAE.Method:40 female rats were randomly divided into four groups:normal control group, EAE control group, high-dose atorvastatin treatment group and the low-dose atorvastatin treatment group, n= 10. Myelin basic protein(myelin basic protein, MBP) by crude antigen were injectde(0.2ml/100g) into the EAE control group, atorvastatin high and low dose treatment groups, normal control group was injected with equivalent saline. Since the date of modeling, low-dose atorvastatin treatment group was administered atorvastatin 1mg/kg daily, high-dose atorvastatin treatment group administered 4mg/kg daily, normal control group and the EAE control group administered equivalent saline daily until the end of the experiment. EAE control group, all dose of atorvastatin treatment groups had the symptom for 3 consecutive days without aggravating or quadriplegia,or the rats being dead, would be considered as the peak of EAE disease. Record onset latency, advanced and peak disease score; the rats would be killed at he peak incidence, normal control group were killed 4 weeks later. Then we would keep the brain and spinal cord tissue,and they would be used for HE staining, to observe the pathological changes; Immunohistochemical method and the mean optical density measurement to detect the rat brain and spinal cord white matter tissue OPN and CD44 expression,the capacity of peripheral blood mononuclear cells (peripheral blood mononuclear cell, PBMC) secretion of IFN-γ, IL-10 would be teasted by enzyme-linked immunosorbent assay (ELISA).Result:(1) The incidence of rats:normal control rats did not have the disease. EAE control group, atorvastatin high, low-dose treatment group had varying degrees of disease. EAE control group, the delitescence was 12.5±1.1 days, atorvastatin treatment group,14.2±1.3 days was longer than the EAE control group,this was statistically significant (P＜0.05), high-dose atorvastatin treatment group was 19.4±2.2 days, compared with EAE control group and low-dose group were significantly longer (P＜0.01, P＜0.05); the progression of EAE control group was 6.9±1.4days, low-dose atorvastatin treatment group was 4.7±0.6days,this was shorter than the EAE control group (P＜0.01), high-dose atorvastatin. treatment group was 4.4±0.8 days, was significantly shorter than the EAE control group (P＜0.01),but compared with the low-dose atorvastatin treatment group,this was not statistically significant (P＞0.05); EAE control group, the peak incidence of disease score was 3.6±0.5, low-dose atorvastatin group disease scored 1.8±0.8, compared with EAE,this was significantly decreased (P＜0.01), high-dose atorvastatin group disease scored 1.6±0.8,this was lower than the EAE control group (P＜0.01), but not statistically significant when compared with the low-dose(P＞0.05). (2) Pathological changes in brain and spinal cord:By light microscope, we found the slice of cerebrum, cerebellum, brain stem and spinal cord in the normal group normal.The pathological changes of EAE in the process of maximal disease showed inflammatory cuff around small blood vessels, perivascular inflammatory cell infiltration and demyelination in white matter, especially in spinal cord. The pathological changes of atorvastatin treatment group lessened. (3) OPN and CD44 immunohistochemistry and image analysis:OPN, CD44 was mainly expressed in the brain, brain stem, spinal cord,white matter and gray matter around the junction of the small blood vessels. OPN mainly expressed in the nerve cell nucleus and the part of the cytoplasm also expressed; CD44 mainly e-xpressed in the cytoplasm of nerve cells. Expression of these two parts had heavier inflammation. Normal control group had no OPN and CD44 positive cells. White matter and gray matter could be seen at the junction of a large number of positive cells whith was dark brown in EAE control group; high-dose atorvastatin and low-doses atorvastatin groups had only sparsely stained positive cells, low-dose atorvastatin group was higher than high-dose atorvastatin group. Image analysis showed that with high-dose atorvastatin group and low-dose atorvastatin group, EAE group of CNS white matter of OPN, CD44 expression level was significantly increased (P＜0.01);the expression of OPN and CD44 expression in low-dose and high-dose atorvastatin group was significantly different (P＜0.05). (4) IFN-γand IL-10 of each group:IFN-y of normal control group was 0.21±0.02ng/ml, IFN-γof EAE control group 0.38±0.04ng/ml,whith were significantly higher than the normal control group (P＜0.01), IFN-γof the high-dose and low-dose atorvastatin groups were 0.24±0.01ng/ml,0.27±0.02ng/ml, compared with EAE control group, these were significantly decreased (P＜0.05, P＜0.01), high-dose atorvastatin group was decreased significantly than the low-dose(P＜0.05); IL-10 of normal control group was 2.25±0.28pg/ml, IL-10 of EAE control group was 2.91±0.39pg/ml, compared with the nomal group whith was decreased significantly (P＜0.01), IL-10 of high-dose and low-doses atorvastatin groups were 7.05±1.46pg/ml,5.80±1.10pg/ml, compared with EAE control group whith were significantly increased (P＜0.01), low-dose atorvastatin group compared with high dose atorvastatin group, was obvious (P＜0.05); EAE control group IFN-γ/IL-10 ratio was significantly higher than the normal control group (P＜0.01), high-dose and low-dose atorvastatin groups of IFN-γ/IL-10 ratio compared with EAE control group were significantly decreased (P＜0.01), high-dose and low-dose group had significant difference (P＜0.05). (5) Correlative analysis:the expression of OPN and CD44 in EAE contral group, the low-dose atorvastatin group and the high-dose atorvastatin group were significantly negatively correlated with the delitescence and positive with the progression and miximal disease scores;the ratio of IFN-y/IL-10 were significantly positively correlated with and the maximal disease score and the progression and negetive with delitescence;the ratio of IFN-y/IL-10 were significantly positively correlated with the expression of CD44 and OPN;the expression of OPN was positive with the expression of CD44.Conclusion:1.In this experiment, crude spinal cord of guinea pigs were used to induce EAE model.EAE rats had obvious nerve dysfunction, brain and spinal cord perivascular inflammatory cell had infiltration and demyelination. The EAE model in this study was successful, reliable and stable.2.EAE rats existed immune imbalance. EAE rats had increased Th1 type cytokines IFN-γ, and decreased Th2 type cytokines IL-10.Th1/Th2 cell had imbalance, immune style shifted to the Thl type pattern.3.EAE rats had upregulation of OPN. OPN expression was negatively correlated with delitescence, and positively correlated with progression, disease score.After atorvastatin treatment,OPN expression reduced, whith indicated that OPN had a relationship with the development of EAE.4.The possible reason that OPN was important in the mechanism of EAE was OPN had combined with CD44.The combination of OPN and CD44 might cause Thl/Th2 imbalance.5.Atorvastatin on EAE had a therapeutic effect, whith could improve the clinical symptoms, delay the onset time, improve the central CNS inflammation,decrease the demyelination and axonal injury, and even promote the regeneration of neuraxon. But the mechanism might be achieved through the CD44 pathway of OPN.
Abstract:bjective:To explore the effect and possible mechanism of osteopontin(OPN) on experimental allergic encephalomyelitis(EAE),to explore the atorvastatin's effect on OPN and treatment on EAE. By observing the OPN on the EAE about its incidence, pathology, immunohistochemistry, expression of CD44 and OPN, peripheral blood IL-10, IFN-γexpression, Th1/Th2 balance,to explore the effect of OPN on the possible immunological mechanisms of EAE.Method:40 female rats were randomly divided into four groups:normal control group, EAE control group, high-dose atorvastatin treatment group and the low-dose atorvastatin treatment group, n= 10. Myelin basic protein(myelin basic protein, MBP) by crude antigen were injectde(0.2ml/100g) into the EAE control group, atorvastatin high and low dose treatment groups, normal control group was injected with equivalent saline. Since the date of modeling, low-dose atorvastatin treatment group was administered atorvastatin 1mg/kg daily, high-dose atorvastatin treatment group administered 4mg/kg daily, normal control group and the EAE control group administered equivalent saline daily until the end of the experiment. EAE control group, all dose of atorvastatin treatment groups had the symptom for 3 consecutive days without aggravating or quadriplegia,or the rats being dead, would be considered as the peak of EAE disease. Record onset latency, advanced and peak disease score; the rats would be killed at he peak incidence, normal control group were killed 4 weeks later. Then we would keep the brain and spinal cord tissue,and they would be used for HE staining, to observe the pathological changes; Immunohistochemical method and the mean optical density measurement to detect the rat brain and spinal cord white matter tissue OPN and CD44 expression,the capacity of peripheral blood mononuclear cells (peripheral blood mononuclear cell, PBMC) secretion of IFN-γ, IL-10 would be teasted by enzyme-linked immunosorbent assay (ELISA).Result:(1) The incidence of rats:normal control rats did not have the disease. EAE control group, atorvastatin high, low-dose treatment group had varying degrees of disease. EAE control group, the delitescence was 12.5±1.1 days, atorvastatin treatment group,14.2±1.3 days was longer than the EAE control group,this was statistically significant (P＜0.05), high-dose atorvastatin treatment group was 19.4±2.2 days, compared with EAE control group and low-dose group were significantly longer (P＜0.01, P＜0.05); the progression of EAE control group was 6.9±1.4days, low-dose atorvastatin treatment group was 4.7±0.6days,this was shorter than the EAE control group (P＜0.01), high-dose atorvastatin. treatment group was 4.4±0.8 days, was significantly shorter than the EAE control group (P＜0.01),but compared with the low-dose atorvastatin treatment group,this was not statistically significant (P＞0.05); EAE control group, the peak incidence of disease score was 3.6±0.5, low-dose atorvastatin group disease scored 1.8±0.8, compared with EAE,this was significantly decreased (P＜0.01), high-dose atorvastatin group disease scored 1.6±0.8,this was lower than the EAE control group (P＜0.01), but not statistically significant when compared with the low-dose(P＞0.05). (2) Pathological changes in brain and spinal cord:By light microscope, we found the slice of cerebrum, cerebellum, brain stem and spinal cord in the normal group normal.The pathological changes of EAE in the process of maximal disease showed inflammatory cuff around small blood vessels, perivascular inflammatory cell infiltration and demyelination in white matter, especially in spinal cord. The pathological changes of atorvastatin treatment group lessened. (3) OPN and CD44 immunohistochemistry and image analysis:OPN, CD44 was mainly expressed in the brain, brain stem, spinal cord,white matter and gray matter around the junction of the small blood vessels. OPN mainly expressed in the nerve cell nucleus and the part of the cytoplasm also expressed; CD44 mainly e-xpressed in the cytoplasm of nerve cells. Expression of these two parts had heavier inflammation. Normal control group had no OPN and CD44 positive cells. White matter and gray matter could be seen at the junction of a large number of positive cells whith was dark brown in EAE control group; high-dose atorvastatin and low-doses atorvastatin groups had only sparsely stained positive cells, low-dose atorvastatin group was higher than high-dose atorvastatin group. Image analysis showed that with high-dose atorvastatin group and low-dose atorvastatin group, EAE group of CNS white matter of OPN, CD44 expression level was significantly increased (P＜0.01);the expression of OPN and CD44 expression in low-dose and high-dose atorvastatin group was significantly different (P＜0.05). (4) IFN-γand IL-10 of each group:IFN-y of normal control group was 0.21±0.02ng/ml, IFN-γof EAE control group 0.38±0.04ng/ml,whith were significantly higher than the normal control group (P＜0.01), IFN-γof the high-dose and low-dose atorvastatin groups were 0.24±0.01ng/ml,0.27±0.02ng/ml, compared with EAE control group, these were significantly decreased (P＜0.05, P＜0.01), high-dose atorvastatin group was decreased significantly than the low-dose(P＜0.05); IL-10 of normal control group was 2.25±0.28pg/ml, IL-10 of EAE control group was 2.91±0.39pg/ml, compared with the nomal group whith was decreased significantly (P＜0.01), IL-10 of high-dose and low-doses atorvastatin groups were 7.05±1.46pg/ml,5.80±1.10pg/ml, compared with EAE control group whith were significantly increased (P＜0.01), low-dose atorvastatin group compared with high dose atorvastatin group, was obvious (P＜0.05); EAE control group IFN-γ/IL-10 ratio was significantly higher than the normal control group (P＜0.01), high-dose and low-dose atorvastatin groups of IFN-γ/IL-10 ratio compared with EAE control group were significantly decreased (P＜0.01), high-dose and low-dose group had significant difference (P＜0.05). (5) Correlative analysis:the expression of OPN and CD44 in EAE contral group, the low-dose atorvastatin group and the high-dose atorvastatin group were significantly negatively correlated with the delitescence and positive with the progression and miximal disease scores;the ratio of IFN-y/IL-10 were significantly positively correlated with and the maximal disease score and the progression and negetive with delitescence;the ratio of IFN-y/IL-10 were significantly positively correlated with the expression of CD44 and OPN;the expression of OPN was positive with the expression of CD44.Conclusion:1.In this experiment, crude spinal cord of guinea pigs were used to induce EAE model.EAE rats had obvious nerve dysfunction, brain and spinal cord perivascular inflammatory cell had infiltration and demyelination. The EAE model in this study was successful, reliable and stable.2.EAE rats existed immune imbalance. EAE rats had increased Th1 type cytokines IFN-γ, and decreased Th2 type cytokines IL-10.Th1/Th2 cell had imbalance, immune style shifted to the Thl type pattern.3.EAE rats had upregulation of OPN. OPN expression was negatively correlated with delitescence, and positively correlated with progression, disease score.After atorvastatin treatment,OPN expression reduced, whith indicated that OPN had a relationship with the development of EAE.4.The possible reason that OPN was important in the mechanism of EAE was OPN had combined with CD44.The combination of OPN and CD44 might cause Thl/Th2 imbalance.5.Atorvastatin on EAE had a therapeutic effect, whith could improve the clinical symptoms, delay the onset time, improve the central CNS inflammation,decrease the demyelination and axonal injury, and even promote the regeneration of neuraxon. But the mechanism might be achieved through the CD44 pathway of OPN.
引文
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