内皮保护剂治疗川崎病的作用及机制研究
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摘要
目的：
探讨通过耳缘静脉重复注射异种动物蛋白诱导幼兔产生冠状动脉炎，验证其与川崎病冠状动脉病变的相似性，为研究川崎病提供实验模型。
方法：
20只4-6周龄的日本大耳幼兔随机分为模型组和对照组。两组分别给予10%牛血清白蛋白和生理盐水，第1天、第14天各重复注射一次。在首次注射后的第六周，两组幼兔分别行冠脉造影，并在造影结束后一小时之内显微镜下分离冠状动脉行组织病理学检测和超微结构的电镜观察，并留取肝脏、肾脏、肺脏及脾脏行组织病理学检查。
结果：
(1)冠脉造影：仅模型组发现3只兔的冠状动脉出现不同程度的扩张或狭窄（3/10）；(2)组织病理学：模型组所有幼兔冠状动脉均出现内皮增厚、炎性细胞浸润，不连续的冠脉内皮；肺组织、肾脏组织呈现肉芽肿样改变主要由单核细胞组成，且肺组织病变部位小血管腔几乎完全被阻塞，部分肺泡塌陷，肺泡水肿不明显；肝脏组织出现点状坏死，单核细胞聚集；(3)透射电镜结果：模型组兔冠状动脉部分内弹力膜断裂，内皮不连续，伴有内皮细胞脱落和中层平滑肌细胞肿胀变性。
结论：
本研究证实牛血清白蛋白诱导产生的兔免疫性冠状动脉炎，类似川崎病冠状动脉炎改变，可作为模拟川崎病冠状动脉损伤的实验模型。
目的：
内皮细胞保护剂尚未作为川崎病的常规治疗手段，本研究拟在川崎病幼兔模型上，给予内皮保护剂辛伐他汀干预后，观察其对川崎病的发病、病理改变及对内皮功能的影响，并探讨其中的机制，从而为从内皮细胞保护的角度防治川崎病提供初步的实验依据。
方法：
1.实验分组：将30只日本大耳幼兔随机分为模型组、辛伐他汀干预组、对照组三组。模型组及辛伐他汀干预组均予耳缘静脉注射牛血清白蛋白（10%，3ml/kg），对照组给予生理盐水（3ml/kg），第1天、第14天各重复注射一次。辛伐他汀干预组于第2次注射后连续三周每天予辛伐他汀干预（5mg/kg.d）灌胃；三组分别于第2次注射后第7、14、21天（即急性期、亚急性期、恢复期）分别采血一次。
2.检测方法：
（1）评价建模成功的方法：①组织病理学检测各组幼兔的心肌及冠脉组织改变情况；②各组幼兔行冠状动脉造影检查；
（2）ELISA法检测血浆内皮型一氧化氮合成酶（eNOS）的表达；
（3）流式细胞仪计数法测定各组幼兔血浆内皮微颗粒（CD62E+EMPs、CD105+EMPs、CD144+/CD42b-EMPs）的表达水平；
结果：
1.组织病理学结果：模型组和辛伐他汀干预组均出现不同程度的炎症浸润。模型组可见血管内膜局部明显增厚，冠脉内皮不连续；而辛伐他汀干预组幼兔冠状动脉炎性细胞浸润较轻，内膜增厚不明显；对照组冠脉内皮光滑连续。
2. eNOS水平：辛伐他汀干预组eNOS表达水平低于模型组，P＜0.05，差异有统计学意义；辛伐他汀干预组eNOS表达水平与对照组相比，P＞0.05，差异无统计学意义。
3.辛伐他汀干预组KD幼兔急性期、亚急性期、恢复期血浆EMPs表达水平与模型组和对照组的比较：
（1）辛伐他汀干预组及模型组三种表型的EMPs表达水平均高于对照组，P＜0.01，差异有显著的统计学意义；
（2）辛伐他汀干预组与模型组进行比较：①CD62E+EMPs、CD105+EMPs水平比较：辛伐他汀干预组表达均低于模型组，P＜0.01，差异有显著的统计学意义；②CD144+/CD42b-EMPs：急性期辛伐他汀干预组表达低于模型组（P=0.001）P＜0.01，差异有显著的统计学意义；而亚急性期（P=0.199）恢复期（P=0.096）辛伐他汀干预组EMPs表达低于模型组，但差异无统计学意义。
4.模型组幼兔血浆EMPs表达水平：
（1） CD62E+EMPs：急性期明显高于亚急性期、恢复期(P均＜0.05)差异有统计学意义；亚急性期与恢复期比较，P＞0.05，差异无统计学意义；
（2） CD105+EMPs：急性期高于恢复期（P＜0.05）差异有统计学意义；急性期与亚急性期比较及亚急性期与恢复期比较，P均＞0.05，差异无统计学意义；
（3） CD144+/CD42b-EMPs：恢复期表达高于急性期和亚急性期，亚急性期表达高于急性期，P均＜0.05，差异有统计学意义。
结论：
1.辛伐他汀可以降低内皮微颗粒的释放量、改善血管内皮功能障碍，推测辛伐他汀可能通过改善eNOS表达的稳定性，增加一氧化氮的生物利用度来改善内皮功能，eNOS参与了其发挥这一保护作用的机制，为KD血管内皮的保护提供依据。
2. KD兔模型组EMPs持续增高或降低缓慢提示KD恢复期内皮损伤持续存在；EMPs水平的监测尤其是CD144+/CD42b-EMPs可用于KD长期预后评估。
Objective:
To observe the histopathologic characteristics and the Ultrastructure pathologicalfeatures of Coronary Artery vasculitis in rabbit caused by repeated injections of the BovineSerum Albumin(BSA).
Methods:
Twenty weanling rabbits were randomly and equally divided into treatment groups forBSA or normal saline (NS), and administered the respective treatment by intravenousinjection at day1, day14for two cycles. Six weeks after the first treatment, rabbitsunderwent coronary angiography and coronary arteries were removed within one hour.Histopathological examination was performed by light, scanning electron, andtransmission electron microscopy.
Result:
Coronary arteriography revealed that3rabbits in the BSA group had various levels ofdilation and narrowing of the left coronary arteries while, histological examination showedthat10rabbits had infiltration of the coronary arteries by inflammatory cells. Incompleteendothelium, breakage of elastic fiber, and intimal thickening was also observed in theBSA group. Granuloma changes, spotty necrosis composed of mononuclear cells wasobserved in the Lung tissue, kidney tissue and liver of BSA group.Ultrastructurally,3rabbits in the BSA group leukocyte migration, shedding of endothelial microparticles fromthe plasma membranes, abscission of endothelial cells, breakage of the internal elasticlamina (IEL), degeneration of smooth muscle cells in the medial membrane were detected.By contrast, the IEL of the NS control group was continuous and of uniform thickness.
Conclusion:
This rabbit model of coronary arteritis displayed histopathological and ultrastructuralfeatures similar to those of Kawasaki disease in humans. Breakage of the IEL, a key factorin aneurysm formation, was observed in the coronary arteries. Therefore weanling rabbitsmay serve as an experimental model for immune complex vasculitis involving coronaryarteries that mimics Kawasaki disease.
Objective:
To study the effects and mechanism of simvastatin on pathological damage and therelease of endothelial microparticles in the rabbit model of Kawasaki disease, in order toprovide scientific basis for protecting the endothelial cell to prevent and cure Kawasakidisease.
Methods:
Experimental groups:30weanling rabbits were randomly and equally divided intomodel group, simvastatin group, saline control group for BSA or normal saline (NS), andadministered the respective treatment by intravenous injection at day1, day14for twocycles.(model group and simvastatin group for BSA; saline control group for NS)
The simvastatin group, administered intragastrically with (5mg/kg.bw.d) leadsimvastatin for three weeks after the second injection; and at day7,day14and day21afterthe second injection (ie, acute period, sub-acute phase and recovery phase) blood sampleswere collected.
Testing methods:
(1) Examination of modeling method:①Histopathological examination of rabbitsmyocardium and coronary organization;②coronary angiography;
(2) ELISA assay foe plasma endothelial nitric oxide synthase (eNOS);
(3) Flow cytometry method for the determination plasma endothelial microparticles(EMPs:CD62E+EMPs, CD105+EMPs, CD144+/CD42b-EMPs) expression levels.
Result:
1. Histological examination showed that10rabbits (10/10) had infiltration of thecoronary arteries by inflammatory cells. Incomplete endothelium, and intimal thickeningwas also observed in the BSA group and heavier than the simvastatin group; complete andsmooth coronary endothelial was observed in saline control group;
2. eNOS levels: the expression level in simvastatin group level was significantly (P<0.05)lower than the model group; the simvastatin group compared to the saline control group,P>0.05, the difference was not statistically significance.
3. The comparison of plasma EMPs (acute, sub-acute phase and recovery phase)
(1)The EMPs expression level: the model group, simvastatin group was significantly(P <0.01)higher than and the saline group;
(2)The comparison of model group and simvastatin:①CD62E+EMPs andCD105+EMPs(acute phase, sub-acute phase and recovery phase): the model group wassignificantly (P<0.01) higher than and the simvastatin group;.②CD144+/CD42b-EMPs:model group was significantly (P=0.001, P<0.01) higher than and the simvastatin groupinthe acute phase; subacute phase (P=0.199) recovery period (P=0.096) higher than thesimvastatin group, but the difference was not statistically significant;
4. Pairwise comparison of model group plasma EMPs expression levels:
(1) CD62E+EMPs: acute phase was significantly (P<0.05) higher than the sub-acutephase and convalescence.
(2) CD105+EMPs: acute phase was significantly (P<0.05) higher the recovery period;
(3) CD144+/CD42b-EMPs: recovery period was higher than the acute phase,sub-acute phase, and sub-acute phase was higher than the acute phase, and the differencewas statistically significant.
Conclusion:
1.Simvastatin can reduce the release of endothelial microparticles and improveendothelial dysfunction, simvastatin can increase the bioavailability of nitric oxide toimprove endothelial function by improving the stability of eNOS expression, eNOS isinvolved in the mechanism of protection, provide the basis for KD coronary endothelialprotection.
2.CD144+/CD42b-EMPs sustained increases in convalescent prompted endothelialdamage persists in KD. Three phenotypic EMPs, especially CD144+/CD42b-EMPs isavailable for KD long-term prognosis.
探讨通过耳缘静脉重复注射异种动物蛋白诱导幼兔产生冠状动脉炎，验证其与川崎病冠状动脉病变的相似性，为研究川崎病提供实验模型。
方法：
20只4-6周龄的日本大耳幼兔随机分为模型组和对照组。两组分别给予10%牛血清白蛋白和生理盐水，第1天、第14天各重复注射一次。在首次注射后的第六周，两组幼兔分别行冠脉造影，并在造影结束后一小时之内显微镜下分离冠状动脉行组织病理学检测和超微结构的电镜观察，并留取肝脏、肾脏、肺脏及脾脏行组织病理学检查。
结果：
(1)冠脉造影：仅模型组发现3只兔的冠状动脉出现不同程度的扩张或狭窄（3/10）；(2)组织病理学：模型组所有幼兔冠状动脉均出现内皮增厚、炎性细胞浸润，不连续的冠脉内皮；肺组织、肾脏组织呈现肉芽肿样改变主要由单核细胞组成，且肺组织病变部位小血管腔几乎完全被阻塞，部分肺泡塌陷，肺泡水肿不明显；肝脏组织出现点状坏死，单核细胞聚集；(3)透射电镜结果：模型组兔冠状动脉部分内弹力膜断裂，内皮不连续，伴有内皮细胞脱落和中层平滑肌细胞肿胀变性。
结论：
本研究证实牛血清白蛋白诱导产生的兔免疫性冠状动脉炎，类似川崎病冠状动脉炎改变，可作为模拟川崎病冠状动脉损伤的实验模型。
目的：
内皮细胞保护剂尚未作为川崎病的常规治疗手段，本研究拟在川崎病幼兔模型上，给予内皮保护剂辛伐他汀干预后，观察其对川崎病的发病、病理改变及对内皮功能的影响，并探讨其中的机制，从而为从内皮细胞保护的角度防治川崎病提供初步的实验依据。
方法：
1.实验分组：将30只日本大耳幼兔随机分为模型组、辛伐他汀干预组、对照组三组。模型组及辛伐他汀干预组均予耳缘静脉注射牛血清白蛋白（10%，3ml/kg），对照组给予生理盐水（3ml/kg），第1天、第14天各重复注射一次。辛伐他汀干预组于第2次注射后连续三周每天予辛伐他汀干预（5mg/kg.d）灌胃；三组分别于第2次注射后第7、14、21天（即急性期、亚急性期、恢复期）分别采血一次。
2.检测方法：
（1）评价建模成功的方法：①组织病理学检测各组幼兔的心肌及冠脉组织改变情况；②各组幼兔行冠状动脉造影检查；
（2）ELISA法检测血浆内皮型一氧化氮合成酶（eNOS）的表达；
（3）流式细胞仪计数法测定各组幼兔血浆内皮微颗粒（CD62E+EMPs、CD105+EMPs、CD144+/CD42b-EMPs）的表达水平；
结果：
1.组织病理学结果：模型组和辛伐他汀干预组均出现不同程度的炎症浸润。模型组可见血管内膜局部明显增厚，冠脉内皮不连续；而辛伐他汀干预组幼兔冠状动脉炎性细胞浸润较轻，内膜增厚不明显；对照组冠脉内皮光滑连续。
2. eNOS水平：辛伐他汀干预组eNOS表达水平低于模型组，P＜0.05，差异有统计学意义；辛伐他汀干预组eNOS表达水平与对照组相比，P＞0.05，差异无统计学意义。
3.辛伐他汀干预组KD幼兔急性期、亚急性期、恢复期血浆EMPs表达水平与模型组和对照组的比较：
（1）辛伐他汀干预组及模型组三种表型的EMPs表达水平均高于对照组，P＜0.01，差异有显著的统计学意义；
（2）辛伐他汀干预组与模型组进行比较：①CD62E+EMPs、CD105+EMPs水平比较：辛伐他汀干预组表达均低于模型组，P＜0.01，差异有显著的统计学意义；②CD144+/CD42b-EMPs：急性期辛伐他汀干预组表达低于模型组（P=0.001）P＜0.01，差异有显著的统计学意义；而亚急性期（P=0.199）恢复期（P=0.096）辛伐他汀干预组EMPs表达低于模型组，但差异无统计学意义。
4.模型组幼兔血浆EMPs表达水平：
（1） CD62E+EMPs：急性期明显高于亚急性期、恢复期(P均＜0.05)差异有统计学意义；亚急性期与恢复期比较，P＞0.05，差异无统计学意义；
（2） CD105+EMPs：急性期高于恢复期（P＜0.05）差异有统计学意义；急性期与亚急性期比较及亚急性期与恢复期比较，P均＞0.05，差异无统计学意义；
（3） CD144+/CD42b-EMPs：恢复期表达高于急性期和亚急性期，亚急性期表达高于急性期，P均＜0.05，差异有统计学意义。
结论：
1.辛伐他汀可以降低内皮微颗粒的释放量、改善血管内皮功能障碍，推测辛伐他汀可能通过改善eNOS表达的稳定性，增加一氧化氮的生物利用度来改善内皮功能，eNOS参与了其发挥这一保护作用的机制，为KD血管内皮的保护提供依据。
2. KD兔模型组EMPs持续增高或降低缓慢提示KD恢复期内皮损伤持续存在；EMPs水平的监测尤其是CD144+/CD42b-EMPs可用于KD长期预后评估。
Objective:
To observe the histopathologic characteristics and the Ultrastructure pathologicalfeatures of Coronary Artery vasculitis in rabbit caused by repeated injections of the BovineSerum Albumin(BSA).
Methods:
Twenty weanling rabbits were randomly and equally divided into treatment groups forBSA or normal saline (NS), and administered the respective treatment by intravenousinjection at day1, day14for two cycles. Six weeks after the first treatment, rabbitsunderwent coronary angiography and coronary arteries were removed within one hour.Histopathological examination was performed by light, scanning electron, andtransmission electron microscopy.
Result:
Coronary arteriography revealed that3rabbits in the BSA group had various levels ofdilation and narrowing of the left coronary arteries while, histological examination showedthat10rabbits had infiltration of the coronary arteries by inflammatory cells. Incompleteendothelium, breakage of elastic fiber, and intimal thickening was also observed in theBSA group. Granuloma changes, spotty necrosis composed of mononuclear cells wasobserved in the Lung tissue, kidney tissue and liver of BSA group.Ultrastructurally,3rabbits in the BSA group leukocyte migration, shedding of endothelial microparticles fromthe plasma membranes, abscission of endothelial cells, breakage of the internal elasticlamina (IEL), degeneration of smooth muscle cells in the medial membrane were detected.By contrast, the IEL of the NS control group was continuous and of uniform thickness.
Conclusion:
This rabbit model of coronary arteritis displayed histopathological and ultrastructuralfeatures similar to those of Kawasaki disease in humans. Breakage of the IEL, a key factorin aneurysm formation, was observed in the coronary arteries. Therefore weanling rabbitsmay serve as an experimental model for immune complex vasculitis involving coronaryarteries that mimics Kawasaki disease.
Objective:
To study the effects and mechanism of simvastatin on pathological damage and therelease of endothelial microparticles in the rabbit model of Kawasaki disease, in order toprovide scientific basis for protecting the endothelial cell to prevent and cure Kawasakidisease.
Methods:
Experimental groups:30weanling rabbits were randomly and equally divided intomodel group, simvastatin group, saline control group for BSA or normal saline (NS), andadministered the respective treatment by intravenous injection at day1, day14for twocycles.(model group and simvastatin group for BSA; saline control group for NS)
The simvastatin group, administered intragastrically with (5mg/kg.bw.d) leadsimvastatin for three weeks after the second injection; and at day7,day14and day21afterthe second injection (ie, acute period, sub-acute phase and recovery phase) blood sampleswere collected.
Testing methods:
(1) Examination of modeling method:①Histopathological examination of rabbitsmyocardium and coronary organization;②coronary angiography;
(2) ELISA assay foe plasma endothelial nitric oxide synthase (eNOS);
(3) Flow cytometry method for the determination plasma endothelial microparticles(EMPs:CD62E+EMPs, CD105+EMPs, CD144+/CD42b-EMPs) expression levels.
Result:
1. Histological examination showed that10rabbits (10/10) had infiltration of thecoronary arteries by inflammatory cells. Incomplete endothelium, and intimal thickeningwas also observed in the BSA group and heavier than the simvastatin group; complete andsmooth coronary endothelial was observed in saline control group;
2. eNOS levels: the expression level in simvastatin group level was significantly (P<0.05)lower than the model group; the simvastatin group compared to the saline control group,P>0.05, the difference was not statistically significance.
3. The comparison of plasma EMPs (acute, sub-acute phase and recovery phase)
(1)The EMPs expression level: the model group, simvastatin group was significantly(P <0.01)higher than and the saline group;
(2)The comparison of model group and simvastatin:①CD62E+EMPs andCD105+EMPs(acute phase, sub-acute phase and recovery phase): the model group wassignificantly (P<0.01) higher than and the simvastatin group;.②CD144+/CD42b-EMPs:model group was significantly (P=0.001, P<0.01) higher than and the simvastatin groupinthe acute phase; subacute phase (P=0.199) recovery period (P=0.096) higher than thesimvastatin group, but the difference was not statistically significant;
4. Pairwise comparison of model group plasma EMPs expression levels:
(1) CD62E+EMPs: acute phase was significantly (P<0.05) higher than the sub-acutephase and convalescence.
(2) CD105+EMPs: acute phase was significantly (P<0.05) higher the recovery period;
(3) CD144+/CD42b-EMPs: recovery period was higher than the acute phase,sub-acute phase, and sub-acute phase was higher than the acute phase, and the differencewas statistically significant.
Conclusion:
1.Simvastatin can reduce the release of endothelial microparticles and improveendothelial dysfunction, simvastatin can increase the bioavailability of nitric oxide toimprove endothelial function by improving the stability of eNOS expression, eNOS isinvolved in the mechanism of protection, provide the basis for KD coronary endothelialprotection.
2.CD144+/CD42b-EMPs sustained increases in convalescent prompted endothelialdamage persists in KD. Three phenotypic EMPs, especially CD144+/CD42b-EMPs isavailable for KD long-term prognosis.
引文
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3. Mouthon L.Causes and mechanisms of systemic vasculitides. Rev Prat.2008;Mar15;58(5):487-91.
4. Mason WH, Jordan SC, Sakai R, Takahashi M, Bernstein B. Circulating immunecomplexes in Kawasaki syndrome. Pediatr Infect Dis.1985;4:48-51.
5. Alqahtani M, Mukundan D. Current understanding of fever and host immunity. CurrOpin Pediatr.2011;23(1):115-20.
6. Rowley AH, Miura M. Immunoglobulin A deficiency and Kawasaki disease. PediatrInt.2010;52(2):330.
7. Keren G, Wolman M. Can Pseudomonas infection in experimental animals mimicKawasaki disease? J Infect.1984;9:22-29.
8. Murata H. Experimental Candida-induced arteritis in mice: relation to arteritis in themucocutaneous lymph node syndrome. Microbiol Immunol.1970;23:825-831.
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10. Felsburg PJ, HogenEsch H, Somberg RL, Snyder PW, Glickman LT. Immunologicabnormalities in canine juvenile polyarteritis syndrome: a naturally occurring animalmodel of Kawasaki disease. Clin Immunol Immunopathol.1992;65:110-118.
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12. Philip S, Lee WC, Liu SK, Wu MH, Lue HC. A swine model of horse serum-inducedcoronary vasculitis:an implication for Kawasaki disease. Pediatr Res.2004;55(2):211-219
13. Murata, H. Experimental candida-induced arteritis in mice. Relation to arteritis in themucocutaneous lymph node syndrome. Microbiol Immunol.1979;23:825-831.
14. Takahashi K, Oharaseki T, Yokouchi Y, Miura NN, Ohno N, Okawara AI, Murata H,Naoe S, Suzuki K. Administration of human immunoglobulin suppressesdevelopment of murine systemic vasculitis induced with Candida albicanswater-soluble fraction: an animal model of Kawasaki disease. Mod Rheumatol.2010;20(2):160-7.
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