“退行性”钙化性主动脉瓣膜病临床病理组织学及相关发病机制研究
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摘要
目的:寻找退行性钙化性主动脉瓣膜病(Degenerative calcific aorticvalve disease,DCAVD)不同病变阶段的病理组织学特征,及与病变进展相关的临床危险因素;通过高脂血症动物模型,寻找高脂血症可能参与DCAVD病变形成的依据以及阿托伐他汀干预对病变的影响;利用原子力显微镜(AtomicForce Microscope,AFM)动态观察高脂血症及阿托伐他汀干预对主动脉瓣膜内皮细胞表面纳米水平超微结构的影响。
方法:第一部分:选择来自尸检和经外科手术的成人主动脉瓣膜总计55例,检测正常及不同程度大体病变的瓣膜中弹力纤维,钙盐,磷酸盐,脂质,蛋白聚糖,以及血管的分布及变化;对瓣膜内各层组织结构的变化进行测量;检测炎症细胞,血管内皮细胞,以及骨母细胞标记物在瓣膜中的表达情况。回顾各例中与心血管疾病危险因素有关的临床记录。第二部分:选择健康新西兰纯种雄性白兔30只,随机分为正常对照组(N组),高脂饮食组(HC组),高脂饮食加阿托伐他汀干预组(AI组)。喂养8周后,取静脉血测定血浆脂质水平;取主动脉瓣膜标本,行脂质,钙盐,炎症细胞,骨母细胞,血管内皮细胞等相关的病理学检测。第三部分:选择健康新西兰纯种雄性白兔60只,随机分为正常对照组(N组),高脂饮食组(HC组),高脂饮食加阿托伐他汀干预组(AI组)。分别于实验开始及随后第2、4、6、8周末5个时间点,随机获取各组兔的主动脉瓣膜标本。制样后,在大气和室温条件下对内皮细胞表面结构进行AFM直接观察。利用AFM图像分析软件,对瓣膜内皮细胞表面的结构形貌特征进行测量和分析。
结果:第一部分:不同程度主动脉瓣膜病变均以瓣膜基底部增厚明显,增厚区病灶及附近的纤维层内蛋白质,脂肪和钙盐聚集。免疫组化染色示,不同程度病变中,可见单核巨噬细胞浸润,偶尔可见T淋巴细胞;还可见由CD31表达阳性的血管内皮细胞围绕而成的新生毛细血管结构,以及骨母细胞特异性标记物——骨桥蛋白(Osteopontin,OPN)表达,上述标记物随瓣膜病变程度加重表达量增加,而在正常主动脉瓣膜中均无或很少表达。心血管疾病危险因素,包括吸烟史,高脂血症,高血压,冠心病,在重度病变中的发生率显著高于轻中度病变。第二部分:HC组和AI组血浆脂质水平在第8周末时,较实验前及N组均明显升高;同期AI组的各项血脂水平明显低于HC组(p＜0.05)。HC组主动脉瓣膜出现与DCAVD早期病变相似的病理组织学改变,包括瓣膜基底部增厚,主动脉面内皮下间隙增宽,其中可见脂质及单核细胞源性的泡沫细胞聚集;纤维层增厚,可见被茜素红染成橘红色的钙盐沉积其中;免疫组化染色示,病变内单核细胞和T淋巴细胞浸润,OPN广泛表达。AI组病变程度较HC组明显减轻,N组主动脉瓣膜内未见上述改变。第三部分:当AFM的扫描范围为50um×50um时,随着高脂饮食时间的延长,主动脉瓣膜基底部内皮细胞的排列从规则的栅栏状紧密极向排列,变为无序紊乱的疏松排列。细胞形态从长梭形变为短圆形,细胞之间的间隙从紧密变为疏松。阿托伐他汀干预能够减轻上述改变。当AFM的扫描范围在内皮细胞表面缩小为500nm×500nm时,正常主动脉瓣膜基底部内皮细胞表面出现大小比较均匀一致,中央呈孔洞状凹陷的球形隆起结构,隆起结构直径约为54～60nm,中央孔径约为11～19nm,细胞膜表面高度约为51～69nm。随着高脂饮食时间的延长,该结构变得低平,稀疏,融合,紊乱。当AFM扫描范围进一步缩小时,随着高脂饮食时间的延长,瓣膜内皮细胞表面球形隆起中央孔洞状结构彼此融合,形成裂隙,裂隙逐渐增宽扩大,球形隆起被分隔,结构紊乱。阿托伐他汀干预能够显著减轻上述改变。
结论:
(1)DCAVD的病理组织学特征与动脉粥样硬化具有相似之处,包括炎症反应,毛细血管增生,脂质与钙盐共沉积,骨母细胞标志物表达等。
(2)高脂饮食能够诱导兔主动脉瓣膜发生与早期DCAVD相似的病理组织学改变,阿托伐他汀能够在多个环节上发挥阻断作用。
(3)AFM能够在瓣膜组织原位清晰显示损伤保护作用后,内皮细胞膜表面纳米水平三维结构变化;高脂血症致内皮细胞表面受体样结构的改变,可能是DCAVD发生的始动因素;阿托伐他汀能够缓解上述改变。
Objectives:To analyze the histopathological features of degenerative calcific aortic valve disease(DCAVD) and to find related clinical risk factors.To find the roles of hypercholesterolemia and atorvastatin intervention in the pathological changes of rabbit aortic valves.To observe the effects of hypercholesterolemia and atorvastatin on the nano-structures of rabbit aortic valvular endothelial cells by atomic force microscope(AFM).
Methods:Histological and immunohistochemical studies were performed on aortic valve leaflets obtained at autopsy from 18 adults with normal leaflets(n=3), mild and moderate leaflet thickening(n=15),or obtained at aortic valve replacement surgery from 37 patients with clinical severe DCAVD. Cardiovascular diseases risk factors were recorded for each case.New Zealand white rabbits(n=30) were randomly divided into three groups:control group (Group N),high cholesterol diet group(Group HC),and high cholesterol diet plus atorvastatin group(Group AI).After 8 weeks,plasma cholesterol,triglyceride, lipoprotein,aminopherase,and phosphocreatine kinase were measured by standard assays.The aortic valves obtained from each groups were examined histologically and immunohistochemicaUy.New Zealand white rabbits(n=60) were randomly divided into 3 groups:control group,high cholesterol diet group, and high cholesterol diet plus atorvastatin group.After feeding for 2,4,6,or 8 weeks,5 rabbits selected randomly from each groups were executed separately. Fresh aortic valves were dissected from the hearts.After processing,they were loaded on the platform of NanoScopeⅢa AFM and scanned in tapping mode. Image analysis system integrated in the AFM was applied to measure the topography structures.
Results:Significant thickening in the third basal leaflets could be seen for each case of DCAVD.Thickening was characterized by the presence of intracellular and extracellular neutral lipids,protein and fine,stippled mineralization in subendothelial space on the aortic side of the leaflets and adjacent fibrosa. Accumulation of the materials increased with the degree of lesions. Immunohistochemical studies showed that clustered mono-macrophages,T lymphocytes,neo-formative capillaries,and osteoblasts could be seen both in mild to moderate lesions and in severe lesions of DCAVD.Control valves showed none of these abnormalities.Expression of above mentioned antibodies increased from mild to severe cases.Prevalence of smoking,hyperlipidemia,hypertension,and coronary heart disease in DCAVD with clinical aortic stenosis were significantly higher than that in mild to moderate DCAVD.Plasma cholesterol,triglyceride,and lipoprotein increased in group HC when compared with group AI.Oil red, Von-kossa,and alizarin red histochemical staining were positive in group HC whereas all negative in group N.Immunohistochemistry staining of CD68,CD3, CD31,and osteopontin were positive in group HC,whereas negative or seldom positive in group N.All these characteristics were diminished or weakened in group AI.Under the scanning of AFM,arrangement of endothelial cells changed from intensive regular paliform alignment to disorder scattered alignment when high cholesterol diet was administrated.The shape of endothelial cell transformed from long fusiform to short round shape.Interstitial areas between endothelial cells were enlarged.When the scanning dimention of AFM on the surface of endothelial cells was decreased further to nanometer scale,receptor-like globular bulged structures with center hollow became low,fused,and diminished gradually. The extent of structure changes of endothelial cells of high cholesterol diet plus atorvastatin group was between those of the other two groups.
Conclusions:DCAVD is an active inflammatory process with similarities to atherosclerosis.Experimental hypercholesterolemia could induce histopathological changes of early DCAVD that could be transversed by atorvastatin.AFM could display the 3-Dimentional morphology of the surface of aortic valve endothelial cells.High cholesterol diet could influence the arrangement,distribution,and shape of endothelial cells,which might be the basis for DCAVD,and treatment with atorvastatin could modify this transformation.
方法:第一部分:选择来自尸检和经外科手术的成人主动脉瓣膜总计55例,检测正常及不同程度大体病变的瓣膜中弹力纤维,钙盐,磷酸盐,脂质,蛋白聚糖,以及血管的分布及变化;对瓣膜内各层组织结构的变化进行测量;检测炎症细胞,血管内皮细胞,以及骨母细胞标记物在瓣膜中的表达情况。回顾各例中与心血管疾病危险因素有关的临床记录。第二部分:选择健康新西兰纯种雄性白兔30只,随机分为正常对照组(N组),高脂饮食组(HC组),高脂饮食加阿托伐他汀干预组(AI组)。喂养8周后,取静脉血测定血浆脂质水平;取主动脉瓣膜标本,行脂质,钙盐,炎症细胞,骨母细胞,血管内皮细胞等相关的病理学检测。第三部分:选择健康新西兰纯种雄性白兔60只,随机分为正常对照组(N组),高脂饮食组(HC组),高脂饮食加阿托伐他汀干预组(AI组)。分别于实验开始及随后第2、4、6、8周末5个时间点,随机获取各组兔的主动脉瓣膜标本。制样后,在大气和室温条件下对内皮细胞表面结构进行AFM直接观察。利用AFM图像分析软件,对瓣膜内皮细胞表面的结构形貌特征进行测量和分析。
结果:第一部分:不同程度主动脉瓣膜病变均以瓣膜基底部增厚明显,增厚区病灶及附近的纤维层内蛋白质,脂肪和钙盐聚集。免疫组化染色示,不同程度病变中,可见单核巨噬细胞浸润,偶尔可见T淋巴细胞;还可见由CD31表达阳性的血管内皮细胞围绕而成的新生毛细血管结构,以及骨母细胞特异性标记物——骨桥蛋白(Osteopontin,OPN)表达,上述标记物随瓣膜病变程度加重表达量增加,而在正常主动脉瓣膜中均无或很少表达。心血管疾病危险因素,包括吸烟史,高脂血症,高血压,冠心病,在重度病变中的发生率显著高于轻中度病变。第二部分:HC组和AI组血浆脂质水平在第8周末时,较实验前及N组均明显升高;同期AI组的各项血脂水平明显低于HC组(p＜0.05)。HC组主动脉瓣膜出现与DCAVD早期病变相似的病理组织学改变,包括瓣膜基底部增厚,主动脉面内皮下间隙增宽,其中可见脂质及单核细胞源性的泡沫细胞聚集;纤维层增厚,可见被茜素红染成橘红色的钙盐沉积其中;免疫组化染色示,病变内单核细胞和T淋巴细胞浸润,OPN广泛表达。AI组病变程度较HC组明显减轻,N组主动脉瓣膜内未见上述改变。第三部分:当AFM的扫描范围为50um×50um时,随着高脂饮食时间的延长,主动脉瓣膜基底部内皮细胞的排列从规则的栅栏状紧密极向排列,变为无序紊乱的疏松排列。细胞形态从长梭形变为短圆形,细胞之间的间隙从紧密变为疏松。阿托伐他汀干预能够减轻上述改变。当AFM的扫描范围在内皮细胞表面缩小为500nm×500nm时,正常主动脉瓣膜基底部内皮细胞表面出现大小比较均匀一致,中央呈孔洞状凹陷的球形隆起结构,隆起结构直径约为54～60nm,中央孔径约为11～19nm,细胞膜表面高度约为51～69nm。随着高脂饮食时间的延长,该结构变得低平,稀疏,融合,紊乱。当AFM扫描范围进一步缩小时,随着高脂饮食时间的延长,瓣膜内皮细胞表面球形隆起中央孔洞状结构彼此融合,形成裂隙,裂隙逐渐增宽扩大,球形隆起被分隔,结构紊乱。阿托伐他汀干预能够显著减轻上述改变。
结论:
(1)DCAVD的病理组织学特征与动脉粥样硬化具有相似之处,包括炎症反应,毛细血管增生,脂质与钙盐共沉积,骨母细胞标志物表达等。
(2)高脂饮食能够诱导兔主动脉瓣膜发生与早期DCAVD相似的病理组织学改变,阿托伐他汀能够在多个环节上发挥阻断作用。
(3)AFM能够在瓣膜组织原位清晰显示损伤保护作用后,内皮细胞膜表面纳米水平三维结构变化;高脂血症致内皮细胞表面受体样结构的改变,可能是DCAVD发生的始动因素;阿托伐他汀能够缓解上述改变。
Objectives:To analyze the histopathological features of degenerative calcific aortic valve disease(DCAVD) and to find related clinical risk factors.To find the roles of hypercholesterolemia and atorvastatin intervention in the pathological changes of rabbit aortic valves.To observe the effects of hypercholesterolemia and atorvastatin on the nano-structures of rabbit aortic valvular endothelial cells by atomic force microscope(AFM).
Methods:Histological and immunohistochemical studies were performed on aortic valve leaflets obtained at autopsy from 18 adults with normal leaflets(n=3), mild and moderate leaflet thickening(n=15),or obtained at aortic valve replacement surgery from 37 patients with clinical severe DCAVD. Cardiovascular diseases risk factors were recorded for each case.New Zealand white rabbits(n=30) were randomly divided into three groups:control group (Group N),high cholesterol diet group(Group HC),and high cholesterol diet plus atorvastatin group(Group AI).After 8 weeks,plasma cholesterol,triglyceride, lipoprotein,aminopherase,and phosphocreatine kinase were measured by standard assays.The aortic valves obtained from each groups were examined histologically and immunohistochemicaUy.New Zealand white rabbits(n=60) were randomly divided into 3 groups:control group,high cholesterol diet group, and high cholesterol diet plus atorvastatin group.After feeding for 2,4,6,or 8 weeks,5 rabbits selected randomly from each groups were executed separately. Fresh aortic valves were dissected from the hearts.After processing,they were loaded on the platform of NanoScopeⅢa AFM and scanned in tapping mode. Image analysis system integrated in the AFM was applied to measure the topography structures.
Results:Significant thickening in the third basal leaflets could be seen for each case of DCAVD.Thickening was characterized by the presence of intracellular and extracellular neutral lipids,protein and fine,stippled mineralization in subendothelial space on the aortic side of the leaflets and adjacent fibrosa. Accumulation of the materials increased with the degree of lesions. Immunohistochemical studies showed that clustered mono-macrophages,T lymphocytes,neo-formative capillaries,and osteoblasts could be seen both in mild to moderate lesions and in severe lesions of DCAVD.Control valves showed none of these abnormalities.Expression of above mentioned antibodies increased from mild to severe cases.Prevalence of smoking,hyperlipidemia,hypertension,and coronary heart disease in DCAVD with clinical aortic stenosis were significantly higher than that in mild to moderate DCAVD.Plasma cholesterol,triglyceride,and lipoprotein increased in group HC when compared with group AI.Oil red, Von-kossa,and alizarin red histochemical staining were positive in group HC whereas all negative in group N.Immunohistochemistry staining of CD68,CD3, CD31,and osteopontin were positive in group HC,whereas negative or seldom positive in group N.All these characteristics were diminished or weakened in group AI.Under the scanning of AFM,arrangement of endothelial cells changed from intensive regular paliform alignment to disorder scattered alignment when high cholesterol diet was administrated.The shape of endothelial cell transformed from long fusiform to short round shape.Interstitial areas between endothelial cells were enlarged.When the scanning dimention of AFM on the surface of endothelial cells was decreased further to nanometer scale,receptor-like globular bulged structures with center hollow became low,fused,and diminished gradually. The extent of structure changes of endothelial cells of high cholesterol diet plus atorvastatin group was between those of the other two groups.
Conclusions:DCAVD is an active inflammatory process with similarities to atherosclerosis.Experimental hypercholesterolemia could induce histopathological changes of early DCAVD that could be transversed by atorvastatin.AFM could display the 3-Dimentional morphology of the surface of aortic valve endothelial cells.High cholesterol diet could influence the arrangement,distribution,and shape of endothelial cells,which might be the basis for DCAVD,and treatment with atorvastatin could modify this transformation.
引文
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