[1]汪倩倩,刘春芳,姜宜妮,等.补肾方对激素性股骨头坏死大鼠股骨头血管形态和血液状态的影响[J].中医正骨,2016,28(06):1-11.
　WANG Qianqian,LIU Chunfang,JIANG Yini,et al.Effect of Bushen Fang(补肾方)on blood vessel morphous of femoral head and blood state in rats with steroid-induced necrosis of femoral head[J].The Journal of Traditional Chinese Orthopedics and Traumatology,2016,28(06):1-11.
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补肾方对激素性股骨头坏死大鼠股骨头血管形态和血液状态的影响()
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《中医正骨》[ISSN:1001-6015/CN:41-1162/R]

卷:
第28卷
期数:
2016年06期
页码:
1-11
栏目:
基础研究
出版日期:
2016-06-20

文章信息/Info

Title:
Effect of Bushen Fang(补肾方)on blood vessel morphous of femoral head and blood state in rats with steroid-induced necrosis of femoral head
作者:
汪倩倩1; 刘春芳2; 姜宜妮2; 王慧2; 陈卫衡3; 林娜2
1.广州中医药大学,广州 510006;
2.中国中医科学院中药研究所,北京 100700;
3.中国中医科学院望京医院,北京 100102
Author(s):
WANG Qianqian1; LIU Chunfang2; JIANG Yini2; WANG Hui2; CHEN Weiheng3; LIN Na2
1.Guangzhou University of Chinese Medicine,Guangzhou 510006,China
2.Institute of Chinese materia medica of China Academy of Chinese Medical sciences,Beijing 100700,China
3.Wangjing Hospital of China Academy of Chinese Medical Sciences,Beijing 100102,China
关键词:
股骨头坏死;  大鼠; Wistar;  补肾方;  血管形态;  血液状态;  动物实验
Keywords:
femur head necrosis;  rats; wistar;  Bushen Fang;  morphous of blood vessel;  state of blood;  animal experimentation
摘要:
目的:探讨补肾方对激素性股骨头坏死(osteonecroois of the femoral head,ONFH)大鼠股骨头血管形态和血液状态的影响。方法:将120只雄性 Wistar大鼠随机分为空白组、模型组、健骨生丸组、补肾方高剂量组、补肾方中剂量组和补肾方低剂量组,每组20只。除空白组外,其余5组大鼠臀肌注射甲泼尼龙琥珀酸钠,连续注射3 d,建立激素性ONFH模型。甲泼尼龙琥珀酸钠注射完后,空白组、模型组自由饮食; 健骨生丸组按1.68 g·kg-1以健骨生丸灌胃,每天1次,连续6周; 补肾方高、中、低剂量组分别按21.2 g·kg-1、10.6 g·kg-1、5.3 g·kg-1以补肾方灌胃,每天1次,连续6周。药物干预结束后,先从各组随机选取10只大鼠,麻醉后腹主动脉取血,动物死亡后,取双侧股骨头制成石蜡切片。将所取腹主动脉血分成2份,一份取血清测定甘油三酯(triglyceride,TG)、总胆固醇(total cholesterol,TC)、高密度脂蛋白(high density lipoprotein,HDL)、低密度脂蛋白(low density lipoprotein,LDL)、载脂蛋白A1(apolipoprotein A1,ApoA1)及ApoB; 另一份取全血以旋转法测定全血黏度低切值、中切值和高切值,取血浆检测血浆黏度。制成的股骨头组织切片分成2份,一份进行HE染色,光学显微镜下观察骨组织形态; 另一份进行免疫组织化学染色,测定血管内皮生长因子(vascular endothelial growth factor,VEGF)和FLK1蛋白表达情况。各组剩余的10只大鼠应用血管造影结合Micro-CT扫描技术测定股骨头中血管体积、血管表面积、血管体积分数及血管厚度。结果:①血脂检测结果。6组大鼠血清TG、TC、LDL、HDL、ApoA1和ApoB含量比较,组间差异均有统计学意义(F=4.538,P=0.004; F=3.322,P=0.018; F=2.681,P=0.043; F=2.621,P=0.047; F=2.400,P=0.035; F=3.741,P=0.010)。空白组、健骨生丸组、补肾方中剂量组和补肾方高剂量组TG、TC、LDL、ApoB含量均低于模型组(P=0.000,P=0.021,P=0.009,P=0.032; P=0.008,P=0.016,P=0.031,P=0.030; P=0.009,P=0.017,P=0.036,P=0.031; P=0.005,P=0.013,P=0.031,P=0.025),HDL、ApoA1含量均高于模型组(P=0.019,P=0.034; P=0.041,P=0.034; P=0.040,P=0.031; P=0.035,P=0.029); 补肾方低剂量组TC含量低于模型组(P=0.023),TG、LDL、HDL、ApoA1、ApoB含量与模型组比较,组间差异均无统计学意义(P=0.297,P=0.315,P=0.189,P=0.084,P=0.333); 补肾方低剂量组血清TG、TC、LDL、ApoB含量均高于健骨生丸组(P=0.037,P=0.018,P=0.041,P=0.047),HDL、ApoA1含量均低于健骨生丸组(P=0.046,P=0.043); 补肾方中剂量组和健骨生丸组血清TG、TC、LDL、HDL、ApoA1、ApoB含量比较,组间差异均无统计学意义(P=0.080,P=0.440,P=0.375,P=0.204,P=0.130,P=0.389); 补肾方高剂量组血清TG、TC、LDL、ApoB含量均低于健骨生丸组(P=0.019,P=0.022,P=0.024,P=0.039),HDL含量高于健骨生丸组(P=0.043),2组ApoA1含量比较,差异无统计学意义(P=0.094); 补肾方中剂量组和高剂量组血清TG、TC、LDL、ApoB含量均低于低剂量组(P=0.033,P=0.021,P=0.042,P=0.042; P=0.021,P=0.019,P=0.018,P=0.034),HDL含量均高于低剂量组(P=0.048; P=0.042),2组ApoA1含量与补肾方低剂量组比较,组间差异均无统计学意义(P=0.053; P=0.057); 补肾方高剂量组血清TG、TC、LDL、ApoB含量均低于中剂量组(P=0.029,P=0.020,P=0.020,P=0.035),HDL含量高于中剂量组(P=0.045),2组ApoA1含量比较,组间差异无统计学意义(P=0.239)。②血液流变学指标检测结果。6组大鼠全血黏度低切值、全血黏度中切值及血浆黏度比较,组间差异均有统计学意义(F=3.291,P=0.019; F=3.256,P=0.020; F=3.779,P=0.010); 6组全血黏度高切值比较,差异无统计学意义(F=2.460,P=0.059)。空白组、健骨生丸组、补肾方中剂量组和补肾方高剂量组全血黏度低切值、全血黏度中切值及血浆黏度均低于模型组(P=0.017,P=0.033,P=0.011; P=0.026,P=0.043,P=0.040; P=0.028,P=0.012,P=0.028; P=0.023,P=0.010,P=0.022); 补肾方低剂量组全血黏度低切值、全血黏度中切值及血浆黏度与模型组比较,差异均无统计学意义(P=0.085,P=0.069,P=0.094); 补肾方低剂量组血浆黏度高于健骨生丸组(P=0.049),2组全血黏度低切值、全血黏度中切值比较,组间差异均无统计学意义(P=0.054,P=0.057); 补肾方中剂量组和健骨生丸组全血黏度低切值、全血黏度中切值及血浆黏度比较,组间差异均无统计学意义(P=0.091,P=0.083,P=0.055); 补肾方高剂量组全血黏度中切值和血浆黏度 均低于健骨生丸组(P=0.045,P=0.014),2组全血黏度低切值比较,差异无统计学意义(P=0.214); 补肾方中剂量组全血黏度低切值、血浆黏度均低于低剂量组(P=0.048,P=0.032),2组全血黏度中切值比较,组间差异均无统计学意义(P=0.051); 补肾方高剂量组全血黏度低切值、全血黏度中切值及血浆黏度均低于低剂量组(P=0.030,P=0.048,P=0.013); 补肾方高剂量组全血黏度低切值、血浆黏度均低于中剂量组(P=0.049,P=0.027),2组全血黏度中切值比较,组间差异无统计学意义(P=0.052)。③VEGF蛋白和FLK1蛋白测定结果。6组大鼠股骨头内VEGF蛋白和FLK1蛋白表达量比较,组间差异均有统计学意义(F=9.519,P=0.000; F=5.317,P=0.009)。空白组、健骨生丸组、补肾方中剂量组和补肾方高剂量组VEGF蛋白和FLK1蛋白表达量均高于模型组(P=0.000,P=0.000; P=0.005,P=0.009; P=0.004,P=0.008; P=0.000,P=0.000); 补肾方低剂量组VEGF蛋白表达量与模型组比较,差异无统计学意义(P=0.051),FLK1蛋白表达量高于模型组(P=0.047); 补肾方低剂量组VEGF蛋白和FLK1蛋白表达量均低于健骨生丸组(P=0.041,P=0.036); 补肾方中剂量组VEGF蛋白和FLK1蛋白表达量与健骨生丸组比较,组间差异均无统计学意义(P=0.175; P=0.221); 补肾方高剂量组VEGF蛋白和FLK1蛋白表达量均高于健骨生丸组(P=0.045; P=0.047); 补肾方中剂量组和高剂量组VEGF蛋白、FLK1蛋白表达量均高于低剂量组(P=0.047,P=0.044; P=0.016,P=0.011); 补肾方高剂量组FLK1蛋白表达量高于中剂量组(P=0.042),2组VEGF蛋白表达量比较,组间差异无统计学意义(P=0.051)。④股骨头内血管Micro-CT检查结果。6组大鼠股骨头血管体积、血管表面积、血管体积分数、血管厚度比较,组间差异均有统计学意义(F=36.442,P=0.000; F=7.080,P=0.000; F=27.869,P=0.000; F=8.371,P=0.000)。空白组、健骨生丸组、补肾方中剂量组、补肾方高剂量组血管体积、血管表面积、血管体积分数、血管厚度均大于模型组(P=0.000,P=0.000,P=0.000,P=0.000; P=0.009,P=0.003,P=0.002,P=0.001; P=0.000,P=0.001,P=0.001,P=0.000; P=0.007,P=0.015,P=0.011,P=0.005); 补肾方低剂量组与模型组血管体积、血管表面积、血管体积分数、血管厚度比较,组间差异均无统计学意义(P=0.051,P=0.052,P=0.082,P =0.064); 补肾方低剂量组、补肾方中剂量组与健骨生丸组血管体积、血管表面积、血管体积分数、血管厚度比较,组间差异均无统计学意义(P=0.057,P=0.063,P=0.051,P=0.052; P=1.000,P=0.222,P=1.000,P=0.813); 补肾方高剂量组血管体积、血管表面积、血管体积分数、血管厚度均大于健骨生丸组(P=0.000,P=0.017,P=0.000,P=0.010); 补肾方中剂量组和高剂量组血管体积、血管表面积、血管体积分数、血管厚度均大于低剂量组(P=0.000,P=0.023,P=0.001,P=0.021; P=0.000,P=0.015,P=0.000,P=0.007); 补肾方高剂量组血管体积、血管表面积、血管体积分数、血管厚度均大于中剂量组(P=0.000,P=0.019,P=0.000,P=0.009)。结论:补肾方能促进激素性ONFH大鼠股骨血管修复,改善股骨头血液微循环状态,其作用可能与补肾方增加股骨头内VEGF和FLK1蛋白表达有关,且中剂量补肾方的疗效与健骨生丸相当,高剂量补肾方的疗效优于健骨生丸。
Abstract:
Objective:To explore the effect of Bushen Fang(补肾方,BSF)on blood vessel morphous of femoral head and blood state in rats with steroid-induced necrosis of femoral head(SNFH).Methods:One hundred and twenty Wistar male rats were randomly divided into blank group,model group,Jiangusheng Wan(健骨生丸,JGSW)group,BSF high-dose group,BSF middle-dose group and BSF low-dose group,20 cases in each group.The rats in model group,JGSW group,BSF high-dose group,BSF middle-dose group and BSF low-dose group were treated with intra-gluteal injection of methylprednisolone sodium succinate for consecutive 3 days to build the SNFH models.Then the rats in blank group and model group were permitted to drink and eat freely.The rats in JGSW group were intragastric administrated with JGSW(1.68 g/kg),once a day for consecutive 6 weeks; while the others in BSF high-dose group,BSF middle-dose group and BSF low-dose group were intragastric administrated with BSF(21.2,10.6 and 5.3 g/kg,respectively),once a day for consecutive 6 weeks.After the end of drug intervention,10 rats were randomly selected from each group,and their blood were fetched out from aorta abdominalis after anesthesia and the bilateral femoral heads were fetched out for making paraffin sections after the rats died.The blood were divided into 2 parts,and one of them were applied to measure the serum contents of triglyceride(TG),total cholesterol(TC),high density lipoprotein(HDL),low density lipoprotein(LDL),apolipoprotein A1(ApoA1)and ApoB; while the other portion were applied to measure the high,medium and low shear whole blood viscosity and the plasma viscosity.The acquired tissue sections of femoral head were divided into 2 parts,and one of them were received HE staining for observing the bone tissue morphology under optical microscope,while the other portion were received immunohistochemical staining for detecting the expression of vascular endothelial growth factor(VEGF)protein and FLK1 protein.The remaining 10 rats in each group were used to measure the volume, surface area,volume fraction and thickness of blood vessel in femoral head by using angiography combined with Micro-CT scanning technique.Results:There was statistical difference in serum content of TG,TC,LDL,HDL,ApoA1 and ApoB between the 6 groups(F=4.538,P=0.004; F=3.322,P=0.018; F=2.681,P=0.043; F=2.621,P=0.047; F=2.400,P=0.035; F=3.741,P=0.010).The serum content of TG,TC,LDL and ApoB were lower and the serum content of HDL and ApoA1 were higher in blank group,JGSW group,BSF middle-dose group and BSF high-dose group compared to model group(P=0.000,P=0.021,P=0.009,P=0.032; P=0.008,P=0.016,P=0.031,P=0.030; P=0.009,P=0.017,P=0.036,P=0.031; P=0.005,P=0.013,P=0.031,P=0.025; P=0.019,P=0.034; P=0.041,P=0.034; P=0.040,P=0.031; P=0.035,P=0.029).The serum content of TC were lower in BSF low-dose group compared to model group(P=0.023),and there was no statistical difference in serum content of TG,LDL,HDL,ApoA1 and ApoB between BSF low-dose group and model group(P=0.297,P=0.315,P=0.189,P=0.084,P=0.333).The serum content of TG,TC,LDL and ApoB were higher and the serum content of HDL and ApoA1 were lower in BSF low-dose group compared to JGSW group(P=0.037,P=0.018,P=0.041,P=0.047,P=0.046,P=0.043).There was no statistical difference in serum content of TG,TC,LDL,HDL,ApoA1 and ApoB between BSF middle-dose group and JGSW group(P=0.080,P=0.440,P=0.375,P=0.204,P=0.130,P=0.389).The serum content of TG,TC,LDL and ApoB were lower and the serum content of HDL was higher in BSF high-dose group compared to JGSW group(P=0.019,P=0.022,P=0.024,P=0.039,P=0.043),and there was no statistical difference in serum content of ApoA1 between the two groups(P=0.094).The serum content of TG,TC,LDL and ApoB were lower and the serum content of HDL was higher in BSF middle-dose group and high-dose group compared to low-dose group(P=0.033,P=0.021,P=0.042,P=0.042; P=0.021,P=0.019,P=0.018,P=0.034; P=0.048; P=0.042),and there was no statistical difference in serum content of ApoA1 between BSF middle-dose group and BSF low-dose group and between BSF high-dose group and BSF low-dose group(P=0.053; P=0.057).The serum content of TG,TC,LDL and ApoB were lower and the serum content of HDL was higher in BSF high-dose group compared to BSF middle-dose group(P=0.029,P=0.020,P=0.020,P=0.035,P=0.045),and there was no statistical difference in serum content of ApoA1 between the two groups(P=0.239).The detection results of hemorheological indexs showed that there was statistical difference in low and medium shear whole blood viscosity and plasma viscosity between the 6 groups(F=3.291,P=0.019; F=3.256,P=0.020; F=3.779,P=0.010),and there was no statistical difference in the high shear whole blood viscosity between the 6 groups(F=2.460,P=0.059).The low and medium shear whole blood viscosity and plasma viscosity were lower in blank group,JGSW group,BSF middle-dose group and BSF high-dose group compared to model group(P=0.017,P=0.033,P=0.011; P=0.026,P=0.043,P=0.040; P=0.028,P=0.012,P=0.028; P=0.023,P=0.010,P=0.022).There was no statistical difference in low and medium shear whole blood viscosity and plasma viscosity between BSF low-dose group and model group(P=0.085,P=0.069,P=0.094).The plasma viscosity was higher in BSF low-dose group compared to JGSW group(P=0.049),and there was no statistical difference in low and medium shear whole blood viscosity between the two groups(P=0.054,P=0.057).There was no statistical difference in low and medium shear whole blood viscosity and plasma viscosity between BSF middle-dose group and JGSW group(P=0.091,P=0.083,P=0.055).The medium shear whole blood viscosity and plasma viscosity were lower in BSF high-dose group compared to JGSW group(P=0.045,P=0.014),and there was no statistical difference in the low shear whole blood viscosity between the two groups(P=0.214).The low shear whole blood viscosity and plasma viscosity were lower in BSF middle-dose group compared to BSF low-dose group(P=0.048,P=0.032),and there was no statistical difference in the medium shear whole blood viscosity between the two groups(P=0.051).The low and medium shear whole blood viscosity and plasma viscosity were lower in BSF high-dose group compared to BSF low-dose group(P=0.030,P=0.048,P=0.013).The low shear whole blood viscosity and plasma viscosity were lower in BSF high-dose group compared to BSF middle-dose group(P=0.049,P=0.027),and there was no statistical difference in the medium shear whole blood viscosity between the two groups(P=0.052).There was statistical difference in the expression of VEGF protein and FLK1 protein in femoral heads between the 6 groups(F=9.519,P=0.000; F=5.317,P=0.009).The VEGF and FLK1 protein expression were higher in blank group,JGSW group,BSF middle-dose group and BSF high-dose group compared to model group(P=0.000,P=0.000; P=0.005,P=0.009; P=0.004,P=0.008; P=0.000,P=0.000).There was no statistical difference in the VEGF protein expression between BSF low-dose group and model group(P=0.051),while the FLK1 protein expression were higher in BSF low-dose group comared to model group(P=0.047).The VEGF and FLK1 protein expression were lower in BSF low-dose group compared to JGSW group(P=0.041,P=0.036).There was no statistical difference in the VEGF and FLK1 protein expression between BSF middle-dose group and JGSW group(P=0.175; P=0.221).The VEGF and FLK1 protein expression were higher in BSF high-dose group compared to JGSW group(P=0.045; P=0.047).The VEGF and FLK1 protein expression were higher in BSF middle-dose group and high-dose group compared to low-dose group(P=0.047,P=0.044; P=0.016,P=0.011).The FLK1 protein expression was higher in BSF high-dose group compared to middle-dose group(P=0.042),and there was no statistical difference in the VEGF protein expression between the two groups(P=0.051).The results of Micro-CT examination showed that there was statistical difference in the volumes,surface area,volume fraction and thickness of blood vessels in femoral head between the 6 groups(F=36.442,P=0.000; F=7.080,P=0.000; F=27.869,P=0.000; F=8.371,P=0.000).The volumes,surface area,volume fraction and thickness of blood vessels were larger in blank group,JGSW group,BSF middle-dose group and BSF high-dose group compared to model group(P=0.000,P=0.000,P=0.000,P=0.000; P=0.009,P=0.003,P=0.002,P=0.001; P=0.000,P=0.001,P=0.001,P=0.000; P=0.007,P=0.015,P=0.011,P=0.005).There was no statistical difference in the volumes,surface area,volume fraction and thickness of blood vessels between BSF low-dose group and model group(P=0.051,P=0.052,P=0.082,P=0.064).There was no statistical difference in the volumes,surface area,volume fraction and thickness of blood vessels between BSF low-dose group and JGSW group and between BSF middle-dose group and JGSW group(P=0.057,P=0.063,P=0.051,P=0.052; P=1.000,P=0.222,P=1.000,P=0.813).The volumes,surface area,volume fraction and thickness of blood vessels were larger in BSF high-dose group compared to JGSW group(P=0.000,P=0.017,P=0.000,P=0.010).The volumes,surface area,volume fraction and thickness of blood vessels were larger in BSF middle-dose group and high-dose group compared to low-dose group(P=0.000,P=0.023,P=0.001,P=0.021; P=0.000,P=0.015,P=0.000,P=0.007).The volumes,surface area,volume fraction and thickness of blood vessels were larger in BSF high-dose group compared to middle-dose group(P=0.000,P=0.019,P=0.000,P=0.009).Conclusion:Application of BSF can promote femoral blood vessel repair and improve blood microcirculation of femoral head in rats with SNFH,and the effect may be related to the increase of expression of VEGF protein and FLK1 protein in the femoral head.The middle-dose BSF is similar to JGSW while the high-dose BSF surpasses JGSW in the curative effect.

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备注/Memo

备注/Memo:
基金项目:国家自然科学基金项目( 81173417,81373656 )
通讯作者:林娜 E-mail:linna888@163.com
更新日期/Last Update: 2016-06-30