通阳法改善肝窦毛细血管化大鼠痰瘀交阻状态的机制研究
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摘要
目的
从阳气失于条达畅通的角度探讨痰瘀同病的发病机理和治疗法则。期望建立一种中医“痰瘀交阻”状态的直观病理模型,观察通阳药物对模型大鼠肝组织病理形态的影响,并进而通过观察其对模型大鼠胶原沉积、基质金属蛋白酶及其抑制因子、肝功能、血脂等指标的影响从阳气的畅通和条达两个层面对通阳法改善痰瘀交阻状态的机制进行探讨。
方法
1.SD雄性大鼠50只,随机选取7只作为正常组,其余大鼠给予酒脂混合物灌胃至第111天后,对剩余大鼠改用40%CCL_4 0.3ml/100g于大鼠大腿内侧皮下注射造模,连续4周后超微电镜下观察模型大鼠肝组织,以评价肝窦毛细血管化模型,作为后续研究的基础。
2.在注射造模的同时,将34只SD大鼠随机分为模型组9只、葱白提取物组(简称葱白组)9只、中药对照组7只、西药对照组9只,并立即分别予生理盐水、葱白混悬液、秋水仙碱混悬液、丹参注射液灌胃。给药19周后采用免疫组化法检测大鼠肝组织CIV的表达,western-blot法检测肝组织MMP-2、TIMP-2的蛋白表达,RT-PCR法检测肝组织中MMP-2mRNA、TIMP-2mRNA的表达,放免法检测大鼠血LN、HA、PIIIP、CIV的含量,样本碱水解法检测肝组织HyP含量,生化法检测大鼠肝功能和血脂的变化。
结果
1.免疫组化法显示CIV在正常组大鼠肝组织有弱表达,在模型组有非常强的表达;各治疗组CIV的表达明显弱于模型组。Western-Blot法显示模型组及各治疗组大鼠肝组织CIV的表达量较正常组均显著增加;各治疗组CIV的表达量较模型组均有明显降低;葱白治疗组大鼠肝组织CIV的表达量较中、西药对照组明显降低。
2.样本碱水解法检测结果表明葱白提取物能明显降低模型大鼠肝组织HyP的含量;对照西药没有明显地降低模型大鼠肝组织HyP的含量。
3.放免法检测结果表明模型组大鼠血中LN、HA、PIIIP、CIV的含量均较正常组均显著升高;各治疗组能显著降低此四项指标的含量。
4.Western-Blot法和RT-PCR法的结果显示模型大鼠肝组织MMP-2的蛋白水平和基因水平较正常组显著增高,葱白提取物能降低其表达。模型大鼠肝组织TIMP-2的蛋白水平和基因水平较正常组显著增高,葱白提取物能降低其表达。
5.生化法检测结果表明模型组大鼠血ALT、AST含量较正常组明显升高;ALB的含量及A/G值较正常组明显降低。对照中药及葱白提取物相比对照西药有更好的改善模型大鼠肝功能的作用。
6.生化法检测结果表明模型组大鼠血TC、TG、HDL-C、LDL-C的含量较正常组明显降低。对照中药及葱白提取物均有升高模型大鼠血TC、TG、HDL-C、LDL-C的含量的作用,其中葱白提取物有非常显著的升高HDL-C的作用。对照西药未能改善上述指标。
结论
1.针对痰瘀同病的成因和治疗提出新观点:①关于痰瘀同病的成因,提出“阳气之失于条达畅通是痰瘀交阻状态发生和发展的关键机制之一”:②关于痰瘀同病的治法:通阳法不失为除化痰、活血之外治疗痰瘀同病的又一治法。③对通阳法的理解:通阳,一指畅通阳气的运行,对有形之痰瘀阻塞能起到推解、疏通的作用;二指通过恢复或激活阳气的条达,来阻断病情的循环加重、引导不良的病理机转向良性循环恢复,进而使各脏腑经络的功能得以正常发挥。
2.率先从组织形态学层面建立了中医“痰瘀交阻”状态的直观病理模型;并围绕上述观点,通过病理学检测证实通阳药物葱白提取物能改善肝窦毛细血管化SD大鼠痰瘀交阻状态。进一步实验证明通阳药物葱白提取物对有形痰瘀的畅通机制可能与其减少模型大鼠肝组织CIV的过度沉积及降低模型大鼠肝组织HyP和血LN、HA、PIIIP、CIV的含量有关。通阳药物葱白提取物条达阳气的作用机制可能与其降低模型大鼠肝组织MMP-2、TIMP-2蛋白和基因的过度表达,促进MMP-2/TIMP-2建立新的平衡;及改善模型大鼠肝功能和脂质代谢有关。
3.本实验为通阳法治疗痰瘀同病提供了直接而客观的证据,给临床治疗痰瘀同病提供了新的思路。
Objective
To confer the mechanism and treatment principles of coexistence of phlegm and blood stasis from the angle of the lose function of yang qi,we want to establish a pathology model for phlegm and blood staiss handing over,and to study the effects and its mechanism of activating yang ameliorating the status of phlegm and blood stasis handing over by observing the changes on livers of model rats and the changes of depositing collagen,Mmp-2,Timp-2,liver function and so on.
Methods
1.50 SD male rats,choose randomly 7 rats as normal group,the remainder were fed the mixture of alcohol and fat for 111 days.Then we gave a hypodermic injection of 40%CCL_4 0.3ml/100g in the legs of the remainder for 4 weeks,and observed the livers of model rats by electron microscopes to evaluat the model of hepatic sinusoid capillarizatin in rats.
2.At the same time of injecting,34 rats were randomly divided into model group(9 rats),fistular onion stalk extraction group (9 rats),Chinese herbal medicine contrast group(7 rats),western medicine group(9 rats).And fed physiological saline,fistular onion stalk extraction,colchicine,Danshen injection immediately for 19 weeks.SABC was used to assay the levels of C-IIIIIIIIV in the livers of rats.Western-blot was used to assay the levels of Mmp-2,Timp-2 in the livers of rats.Radioimmunoassay was used to assay the levels of LN、HA、PIIIP、CIV in the blood of rats.Hydrolysis was used to assay the levels of HyP in the livers of rats and so on.
Results
1.The method of SABC shows:CIV was weakly expressed in the livers of normal group.It was strongly expressed in the livers of model group.The method of Western-blot shows:the levers of CIV were expressed higher in model group and treatment groups than in normal group.The levers of CIVwere expressed lower in treatment groups than in model group.The levers of CIV in fistular onion stalk extraction group were lower expressed than in other treatment groups.
2.The method of hydrolysis shows:fistular onion stalk extraction could reduce the levers of HyP in model group.The levers of HyP in western medicine group were not different from the levers in model group.
3.The method of radioimmunoassay shows:the levers of LN、HA、PIIIP、CIV in the blood of model group were higher than the levers in the blood of normal group.The levers in treatment groups were lower than the levers in model group.
4.The method of western-blot and RT-PCR shows:the levers of protein and gene of Mmp-2 in livers of model group increased obviously.The levers of protein and gene of Timp-2 in livers of model group were increased obviously too.Fistular onion stalk extraction could reduce the levers.
5.The method of biochemistry shows:the levers of ALT、AST in the blood of model group were higher than the levers in the blood of normal group.The levers of ALB、A/G in the blood of model group were lower than the levers in the blood of normal group.Fistular onion stalk extraction and Chinese herbal medicine could finerly ameliorate the liver function of model rats than western medicine.
6.The method of biochemistry shows:the levers of TC、TG、HDL-C、LDL-C in the blood of model group were lower than the levers in the blood of normal group.Fistular onion stalk extraction and Chinese herbal medicine could raise the levers.And Fistular onion stalk extraction could obviously raise the levers of HDL-C.Western medicine had not this function.
Conclusion
1.With regard to the reasons and treatment principles of coexistence of phlegm and blood stasis,we bring up 2 points of view:①Yang qi's deprived of its function of dredging and making fluent is a key to the occurrence and development of phlegm and blood staiss handing over.②Activating yang has 2 meanings:one is dredging the blocked phlegm and blood,the other is to interrupt vicious circle of the state of an illness and turn bad process to virtuous circle by making yang qi fluent.
2.Established successfully a pathology model for phlegm and blood staiss handing over for the first time.And surround those views,verified fistular onion stalk extraction can ameliorates phlegm and blood staiss handing over on rats with hepatic sinusoid capillarizatin.Further experiments proved that the function of dredging of fistular onion stalk extraction maybe have something to do with it could reduce the expressiveness of CIVand the levers of HyP、LN、HA、PIIIP、CIV.The function of making fluent of fistular onion stalk extraction maybe have something to do with it could reduce the expressiveness of Mmp-2x Timp-2,encourage a new balance of Mmp-2/Timp-2,ameliorate the function of model rats.
3.The experiment supplied a visual and objective provement for activating yang ameliorateing phlegm and blood staiss handing over.It enlarges a train of thought for treat coexistence of phlegm and blood stasis.
从阳气失于条达畅通的角度探讨痰瘀同病的发病机理和治疗法则。期望建立一种中医“痰瘀交阻”状态的直观病理模型,观察通阳药物对模型大鼠肝组织病理形态的影响,并进而通过观察其对模型大鼠胶原沉积、基质金属蛋白酶及其抑制因子、肝功能、血脂等指标的影响从阳气的畅通和条达两个层面对通阳法改善痰瘀交阻状态的机制进行探讨。
方法
1.SD雄性大鼠50只,随机选取7只作为正常组,其余大鼠给予酒脂混合物灌胃至第111天后,对剩余大鼠改用40%CCL_4 0.3ml/100g于大鼠大腿内侧皮下注射造模,连续4周后超微电镜下观察模型大鼠肝组织,以评价肝窦毛细血管化模型,作为后续研究的基础。
2.在注射造模的同时,将34只SD大鼠随机分为模型组9只、葱白提取物组(简称葱白组)9只、中药对照组7只、西药对照组9只,并立即分别予生理盐水、葱白混悬液、秋水仙碱混悬液、丹参注射液灌胃。给药19周后采用免疫组化法检测大鼠肝组织CIV的表达,western-blot法检测肝组织MMP-2、TIMP-2的蛋白表达,RT-PCR法检测肝组织中MMP-2mRNA、TIMP-2mRNA的表达,放免法检测大鼠血LN、HA、PIIIP、CIV的含量,样本碱水解法检测肝组织HyP含量,生化法检测大鼠肝功能和血脂的变化。
结果
1.免疫组化法显示CIV在正常组大鼠肝组织有弱表达,在模型组有非常强的表达;各治疗组CIV的表达明显弱于模型组。Western-Blot法显示模型组及各治疗组大鼠肝组织CIV的表达量较正常组均显著增加;各治疗组CIV的表达量较模型组均有明显降低;葱白治疗组大鼠肝组织CIV的表达量较中、西药对照组明显降低。
2.样本碱水解法检测结果表明葱白提取物能明显降低模型大鼠肝组织HyP的含量;对照西药没有明显地降低模型大鼠肝组织HyP的含量。
3.放免法检测结果表明模型组大鼠血中LN、HA、PIIIP、CIV的含量均较正常组均显著升高;各治疗组能显著降低此四项指标的含量。
4.Western-Blot法和RT-PCR法的结果显示模型大鼠肝组织MMP-2的蛋白水平和基因水平较正常组显著增高,葱白提取物能降低其表达。模型大鼠肝组织TIMP-2的蛋白水平和基因水平较正常组显著增高,葱白提取物能降低其表达。
5.生化法检测结果表明模型组大鼠血ALT、AST含量较正常组明显升高;ALB的含量及A/G值较正常组明显降低。对照中药及葱白提取物相比对照西药有更好的改善模型大鼠肝功能的作用。
6.生化法检测结果表明模型组大鼠血TC、TG、HDL-C、LDL-C的含量较正常组明显降低。对照中药及葱白提取物均有升高模型大鼠血TC、TG、HDL-C、LDL-C的含量的作用,其中葱白提取物有非常显著的升高HDL-C的作用。对照西药未能改善上述指标。
结论
1.针对痰瘀同病的成因和治疗提出新观点:①关于痰瘀同病的成因,提出“阳气之失于条达畅通是痰瘀交阻状态发生和发展的关键机制之一”:②关于痰瘀同病的治法:通阳法不失为除化痰、活血之外治疗痰瘀同病的又一治法。③对通阳法的理解:通阳,一指畅通阳气的运行,对有形之痰瘀阻塞能起到推解、疏通的作用;二指通过恢复或激活阳气的条达,来阻断病情的循环加重、引导不良的病理机转向良性循环恢复,进而使各脏腑经络的功能得以正常发挥。
2.率先从组织形态学层面建立了中医“痰瘀交阻”状态的直观病理模型;并围绕上述观点,通过病理学检测证实通阳药物葱白提取物能改善肝窦毛细血管化SD大鼠痰瘀交阻状态。进一步实验证明通阳药物葱白提取物对有形痰瘀的畅通机制可能与其减少模型大鼠肝组织CIV的过度沉积及降低模型大鼠肝组织HyP和血LN、HA、PIIIP、CIV的含量有关。通阳药物葱白提取物条达阳气的作用机制可能与其降低模型大鼠肝组织MMP-2、TIMP-2蛋白和基因的过度表达,促进MMP-2/TIMP-2建立新的平衡;及改善模型大鼠肝功能和脂质代谢有关。
3.本实验为通阳法治疗痰瘀同病提供了直接而客观的证据,给临床治疗痰瘀同病提供了新的思路。
Objective
To confer the mechanism and treatment principles of coexistence of phlegm and blood stasis from the angle of the lose function of yang qi,we want to establish a pathology model for phlegm and blood staiss handing over,and to study the effects and its mechanism of activating yang ameliorating the status of phlegm and blood stasis handing over by observing the changes on livers of model rats and the changes of depositing collagen,Mmp-2,Timp-2,liver function and so on.
Methods
1.50 SD male rats,choose randomly 7 rats as normal group,the remainder were fed the mixture of alcohol and fat for 111 days.Then we gave a hypodermic injection of 40%CCL_4 0.3ml/100g in the legs of the remainder for 4 weeks,and observed the livers of model rats by electron microscopes to evaluat the model of hepatic sinusoid capillarizatin in rats.
2.At the same time of injecting,34 rats were randomly divided into model group(9 rats),fistular onion stalk extraction group (9 rats),Chinese herbal medicine contrast group(7 rats),western medicine group(9 rats).And fed physiological saline,fistular onion stalk extraction,colchicine,Danshen injection immediately for 19 weeks.SABC was used to assay the levels of C-IIIIIIIIV in the livers of rats.Western-blot was used to assay the levels of Mmp-2,Timp-2 in the livers of rats.Radioimmunoassay was used to assay the levels of LN、HA、PIIIP、CIV in the blood of rats.Hydrolysis was used to assay the levels of HyP in the livers of rats and so on.
Results
1.The method of SABC shows:CIV was weakly expressed in the livers of normal group.It was strongly expressed in the livers of model group.The method of Western-blot shows:the levers of CIV were expressed higher in model group and treatment groups than in normal group.The levers of CIVwere expressed lower in treatment groups than in model group.The levers of CIV in fistular onion stalk extraction group were lower expressed than in other treatment groups.
2.The method of hydrolysis shows:fistular onion stalk extraction could reduce the levers of HyP in model group.The levers of HyP in western medicine group were not different from the levers in model group.
3.The method of radioimmunoassay shows:the levers of LN、HA、PIIIP、CIV in the blood of model group were higher than the levers in the blood of normal group.The levers in treatment groups were lower than the levers in model group.
4.The method of western-blot and RT-PCR shows:the levers of protein and gene of Mmp-2 in livers of model group increased obviously.The levers of protein and gene of Timp-2 in livers of model group were increased obviously too.Fistular onion stalk extraction could reduce the levers.
5.The method of biochemistry shows:the levers of ALT、AST in the blood of model group were higher than the levers in the blood of normal group.The levers of ALB、A/G in the blood of model group were lower than the levers in the blood of normal group.Fistular onion stalk extraction and Chinese herbal medicine could finerly ameliorate the liver function of model rats than western medicine.
6.The method of biochemistry shows:the levers of TC、TG、HDL-C、LDL-C in the blood of model group were lower than the levers in the blood of normal group.Fistular onion stalk extraction and Chinese herbal medicine could raise the levers.And Fistular onion stalk extraction could obviously raise the levers of HDL-C.Western medicine had not this function.
Conclusion
1.With regard to the reasons and treatment principles of coexistence of phlegm and blood stasis,we bring up 2 points of view:①Yang qi's deprived of its function of dredging and making fluent is a key to the occurrence and development of phlegm and blood staiss handing over.②Activating yang has 2 meanings:one is dredging the blocked phlegm and blood,the other is to interrupt vicious circle of the state of an illness and turn bad process to virtuous circle by making yang qi fluent.
2.Established successfully a pathology model for phlegm and blood staiss handing over for the first time.And surround those views,verified fistular onion stalk extraction can ameliorates phlegm and blood staiss handing over on rats with hepatic sinusoid capillarizatin.Further experiments proved that the function of dredging of fistular onion stalk extraction maybe have something to do with it could reduce the expressiveness of CIVand the levers of HyP、LN、HA、PIIIP、CIV.The function of making fluent of fistular onion stalk extraction maybe have something to do with it could reduce the expressiveness of Mmp-2x Timp-2,encourage a new balance of Mmp-2/Timp-2,ameliorate the function of model rats.
3.The experiment supplied a visual and objective provement for activating yang ameliorateing phlegm and blood staiss handing over.It enlarges a train of thought for treat coexistence of phlegm and blood stasis.
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