调胃承气汤证和小承气汤证兔动物模型的研制
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摘要
目的:研制出符合中医阳明腑实证中的调胃承气汤证和小承气汤证的兔动物模型,建立稳定的造模方法,并初步制定出该证的客观证候指标,探讨承气轻下法的治疗机理及意义。
方法:将105只白兔随机分为正常对照组(1组)、调胃承气汤证组(2组)、小承气汤证组(3组),2、3组再各分为病理模型组A、模型治疗组B、模型验证组C,即(1、2A、2B、2C、3A、3B、3C),共七组。正常对照组给以正常饲料喂养,自由饮水。调胃承气汤证组和小承气汤证组在实验前48小时分别给予拌有不同剂量次碳酸铋的饲料喂养2天,第2天禁水24小时。然后在自然状态下,调胃承气汤证组和小承气汤证组分别注射不同剂量的大肠杆菌内毒素。其中2A、3A组于攻毒前1小时、攻毒后2小时给予生理盐水,2B、3B组在攻毒前1小时、攻毒后2小时分别灌胃以调胃承气汤、小承气汤,2C、3C组则在造模的同时分别给予调胃承气汤和小承气汤,直至实验结束。正常对照组给予相应比例的生理盐水。在实验中,观测家兔的精神状态、呼吸、耳血管、体温、腹围等一般情况。于攻毒后6小时心脏采血,检测各项血液指标。随后处死动物,取肺、肝、肾、结肠等重要脏器作病理切片,光镜观察。
结果:正常对照组未见明显的变化。模型组家兔(2A、3A)体温明显升高,以2A组升高最多;2A、3A组家兔腹围显著增大,以3A组增大更明显。模型组的实验指标与正常对照组相比均有显著差异(P＜0.01或P＜0.05),其中WBC、NO、MDA和MMS含量有不同程度的增高,SOD含量明显下降;电解质中钠含量略有降低,钾含量则显著降低;全血粘度、血浆粘度升高,红细胞变形指数降低;TXB_2、TM值和PAI-1含量明显升高,同时t-PA含量明显降低。治疗组(2B、3B)、验证组(2C、3C)与模型组比较均有显著差异(P＜0.01或P＜0.05),与正常对照组比较,部分指标无显著差异,部分指标仍有显著差异(P＜0.01或P＜0.05)。病理形态大体观察:模型组(2A、3A)大部分家兔的肺脏表面可见点状或片状出血点,大肠膨隆胀气,肠管增粗,其余脏器未见明显病变。光镜观察:模型组家兔肺脏均有改变,2A组家兔的肺可见局灶性肺实变,3A组稍轻,可见肺泡间隔增宽,炎细胞浸润、充血。肠粘膜可见不同程度的炎细胞浸润、充血、水肿。肝脏也可见不同程度的炎细胞浸润,肾脏基本正常。治疗组与验证组家兔仅有轻微变化,或大致正常。
结论:采用次碳酸铋、禁水和大肠杆菌内毒素多因素联合造模方法,通过控制给药剂量,制作出不同的家兔病理模型,其主要症状、体征和病理变化符合《伤寒论》中调胃承气汤证、小承气汤证,故可以认为用此种造模方法所复制的调胃承气汤证、小承气汤证动物模型是成功的。2、调胃承气汤、小承气汤可以有效降低模型组家兔的体温,腹围、减轻其症状和体征,改善各种实验指标和病理改变,保护脏器组织。因此可以反证此种造模方法切实可靠,所制作的调胃承气汤证、小承气汤证家兔动物模型是成功的。
The objectives of this study were to(a) develop animal models that could be adequately used to show the syndromes suitable for Tiaoweichengqi Decoction(SSTD) and Xiaochengqi Decoction(SSXD),which are the "Excess-Syndrome of yangming disease" as described in the traditional Chinese medical literature;(b) establish applicable methodology for the model-building using lab rabbits;(c) define objective criteria for the syndrome observation;and(d) discuss the possible mechanism and meaning of the drug's medicinal effects.
The study was carried out with 105 lab rabbits by equally and randomly dividing the animals into 7 groups.The groups included Control(1),Pathological Model of SSTD(2A), Model-Treating of SSTD(2B),Model-Proving of SSTD(2C),Pathological Model of SSXD (3A),Model-Treating of SSXD(3B),and Model-Proving of SSXD(3C).Normal feed was given to the rabbits in the Control group.Feed containing varying amounts of bismuth subcarbonate were given to the Model groups for 2 days,no water for 24 hours on the second day,then intravenously injected E.coli endotoxin.An hour before and 2 hours after the endotoxin injection,physiological saline was given orally to Groups 2A and 3A.For Group 2B and 3B,Tiaoweichengqi Decoction(TD) and Xiaochengqi Decoction(XD),respectively, were given orally.In the 2C and 3C groups,TD or XD was given when the bismuth subcarbonate containing diet and the endotoxin were administered.During the experiment,a rabbit's spirit,breath,ear blood vessel,body temperature and abdominal circumference were observed or measured regularly.Blood samples were collected for testing from the rabbits 6 hours after endotoxin injection.At the end,air was injected into the vein to kill the animals. Pathological changes in lung,liver,intestines and kidney were examined under microscope.
The results indicated that no changes incurred to the animals in the Control group. There was a rise in body temperature among the rabbits in Group 2A and 3A,with those in 2A the most significant.The abdominal circumference of the animals in Group 2A and 3A significantly enlarged,with those in 3A the greatest increase.There were significant differences(P＜0.01 or P＜0.05) on all indices between the Control and Model groups.The WBC counts and the contents of NO,MDA and MMS in 2A and 3A animals increased in various degrees,whereas the SOD decreased.The K and Na contents decreased in varying amounts in the Model groups.The viscosities of the whole blood and plasma increased while erythrocyte deformation index decreased in the Model groups.In Group 2A and 3A,t-PA content decreased,as PAI-1,TXB_2 and TM contents increased.Comparing Group 2A and 3A to the other groups,there existed significant differences(p＜0.05 or p＜0.01).Certain indices showed significant differences(p＜0.05 or p＜0.01) and others no difference in Model-Treating groups and Model-Proving groups as compared to the Control.Pathological observations during the experiment included(a) most of the animals in Group 2A and 3A had bleeding spots in the lungs;(b) large bowels were distended with gas;and,(c) there was no apparent change in other viscera.Microscopic observations were:(a) local lung consolidation seen in Group 2A,and to a lesser degree in Group 3A animals;(b) congestion and leukocytes infiltration existed in lung tissue with pulmonary septal thickened;(c) varying degrees of congestion and leukocytes infiltration found in the intestinal mucosa;(d) some leukocytes infiltration observed in the liver but no changes in the kidney;(e) either slight or no changes found in the rabbits in the Model-Treating or Model-Proving groups.
It was concluded that the multifactor intervention approach with varying dosages of bismuth subcarbonate,water deprivation and endotoxin injection could create the major symptoms,physiological signs and pathological changes in lab rabbits strikingly close to what described by the TCM theories.Thus,this method of developing models seemed appropriate for the purpose.In addition,TD and XD showed to be effective in lowering body temperature, reducing abdominal circumference,and alleviating disease symptoms and abnormal physiological signs on the infected rabbits.They could also improve various testing indices and pathological changes.These,again,correspond well with the TCM theories.Thus,the reliability of the model-developing method was proven.
方法:将105只白兔随机分为正常对照组(1组)、调胃承气汤证组(2组)、小承气汤证组(3组),2、3组再各分为病理模型组A、模型治疗组B、模型验证组C,即(1、2A、2B、2C、3A、3B、3C),共七组。正常对照组给以正常饲料喂养,自由饮水。调胃承气汤证组和小承气汤证组在实验前48小时分别给予拌有不同剂量次碳酸铋的饲料喂养2天,第2天禁水24小时。然后在自然状态下,调胃承气汤证组和小承气汤证组分别注射不同剂量的大肠杆菌内毒素。其中2A、3A组于攻毒前1小时、攻毒后2小时给予生理盐水,2B、3B组在攻毒前1小时、攻毒后2小时分别灌胃以调胃承气汤、小承气汤,2C、3C组则在造模的同时分别给予调胃承气汤和小承气汤,直至实验结束。正常对照组给予相应比例的生理盐水。在实验中,观测家兔的精神状态、呼吸、耳血管、体温、腹围等一般情况。于攻毒后6小时心脏采血,检测各项血液指标。随后处死动物,取肺、肝、肾、结肠等重要脏器作病理切片,光镜观察。
结果:正常对照组未见明显的变化。模型组家兔(2A、3A)体温明显升高,以2A组升高最多;2A、3A组家兔腹围显著增大,以3A组增大更明显。模型组的实验指标与正常对照组相比均有显著差异(P＜0.01或P＜0.05),其中WBC、NO、MDA和MMS含量有不同程度的增高,SOD含量明显下降;电解质中钠含量略有降低,钾含量则显著降低;全血粘度、血浆粘度升高,红细胞变形指数降低;TXB_2、TM值和PAI-1含量明显升高,同时t-PA含量明显降低。治疗组(2B、3B)、验证组(2C、3C)与模型组比较均有显著差异(P＜0.01或P＜0.05),与正常对照组比较,部分指标无显著差异,部分指标仍有显著差异(P＜0.01或P＜0.05)。病理形态大体观察:模型组(2A、3A)大部分家兔的肺脏表面可见点状或片状出血点,大肠膨隆胀气,肠管增粗,其余脏器未见明显病变。光镜观察:模型组家兔肺脏均有改变,2A组家兔的肺可见局灶性肺实变,3A组稍轻,可见肺泡间隔增宽,炎细胞浸润、充血。肠粘膜可见不同程度的炎细胞浸润、充血、水肿。肝脏也可见不同程度的炎细胞浸润,肾脏基本正常。治疗组与验证组家兔仅有轻微变化,或大致正常。
结论:采用次碳酸铋、禁水和大肠杆菌内毒素多因素联合造模方法,通过控制给药剂量,制作出不同的家兔病理模型,其主要症状、体征和病理变化符合《伤寒论》中调胃承气汤证、小承气汤证,故可以认为用此种造模方法所复制的调胃承气汤证、小承气汤证动物模型是成功的。2、调胃承气汤、小承气汤可以有效降低模型组家兔的体温,腹围、减轻其症状和体征,改善各种实验指标和病理改变,保护脏器组织。因此可以反证此种造模方法切实可靠,所制作的调胃承气汤证、小承气汤证家兔动物模型是成功的。
The objectives of this study were to(a) develop animal models that could be adequately used to show the syndromes suitable for Tiaoweichengqi Decoction(SSTD) and Xiaochengqi Decoction(SSXD),which are the "Excess-Syndrome of yangming disease" as described in the traditional Chinese medical literature;(b) establish applicable methodology for the model-building using lab rabbits;(c) define objective criteria for the syndrome observation;and(d) discuss the possible mechanism and meaning of the drug's medicinal effects.
The study was carried out with 105 lab rabbits by equally and randomly dividing the animals into 7 groups.The groups included Control(1),Pathological Model of SSTD(2A), Model-Treating of SSTD(2B),Model-Proving of SSTD(2C),Pathological Model of SSXD (3A),Model-Treating of SSXD(3B),and Model-Proving of SSXD(3C).Normal feed was given to the rabbits in the Control group.Feed containing varying amounts of bismuth subcarbonate were given to the Model groups for 2 days,no water for 24 hours on the second day,then intravenously injected E.coli endotoxin.An hour before and 2 hours after the endotoxin injection,physiological saline was given orally to Groups 2A and 3A.For Group 2B and 3B,Tiaoweichengqi Decoction(TD) and Xiaochengqi Decoction(XD),respectively, were given orally.In the 2C and 3C groups,TD or XD was given when the bismuth subcarbonate containing diet and the endotoxin were administered.During the experiment,a rabbit's spirit,breath,ear blood vessel,body temperature and abdominal circumference were observed or measured regularly.Blood samples were collected for testing from the rabbits 6 hours after endotoxin injection.At the end,air was injected into the vein to kill the animals. Pathological changes in lung,liver,intestines and kidney were examined under microscope.
The results indicated that no changes incurred to the animals in the Control group. There was a rise in body temperature among the rabbits in Group 2A and 3A,with those in 2A the most significant.The abdominal circumference of the animals in Group 2A and 3A significantly enlarged,with those in 3A the greatest increase.There were significant differences(P＜0.01 or P＜0.05) on all indices between the Control and Model groups.The WBC counts and the contents of NO,MDA and MMS in 2A and 3A animals increased in various degrees,whereas the SOD decreased.The K and Na contents decreased in varying amounts in the Model groups.The viscosities of the whole blood and plasma increased while erythrocyte deformation index decreased in the Model groups.In Group 2A and 3A,t-PA content decreased,as PAI-1,TXB_2 and TM contents increased.Comparing Group 2A and 3A to the other groups,there existed significant differences(p＜0.05 or p＜0.01).Certain indices showed significant differences(p＜0.05 or p＜0.01) and others no difference in Model-Treating groups and Model-Proving groups as compared to the Control.Pathological observations during the experiment included(a) most of the animals in Group 2A and 3A had bleeding spots in the lungs;(b) large bowels were distended with gas;and,(c) there was no apparent change in other viscera.Microscopic observations were:(a) local lung consolidation seen in Group 2A,and to a lesser degree in Group 3A animals;(b) congestion and leukocytes infiltration existed in lung tissue with pulmonary septal thickened;(c) varying degrees of congestion and leukocytes infiltration found in the intestinal mucosa;(d) some leukocytes infiltration observed in the liver but no changes in the kidney;(e) either slight or no changes found in the rabbits in the Model-Treating or Model-Proving groups.
It was concluded that the multifactor intervention approach with varying dosages of bismuth subcarbonate,water deprivation and endotoxin injection could create the major symptoms,physiological signs and pathological changes in lab rabbits strikingly close to what described by the TCM theories.Thus,this method of developing models seemed appropriate for the purpose.In addition,TD and XD showed to be effective in lowering body temperature, reducing abdominal circumference,and alleviating disease symptoms and abnormal physiological signs on the infected rabbits.They could also improve various testing indices and pathological changes.These,again,correspond well with the TCM theories.Thus,the reliability of the model-developing method was proven.
引文
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