加味达原饮对急性肝损伤湿邪内蕴证模型大鼠的治疗作用研究
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摘要
目的：
在中医理论指导下,探讨大鼠湿邪内蕴证模型的造模过程及检测方法,为中医证型动物造模方法提供理论依据。并研究加味达原饮对D-GalN及CCL4所致的湿邪内蕴证急性肝损伤实验动物模型的治疗效果及作用机制。为中医治疗急性肝损伤提供科学依据。
方法：
选择加味达原饮对D-GalN及CCL4所致的湿邪内蕴证急性肝损伤大鼠模型进行干预,检测生化、免疫、病理、细胞通路等指标,研究达原饮治疗湿邪内蕴证肝损伤大鼠的机制及疗效。
实验一湿邪内蕴证动物模型的建立
SD大鼠,雌性,36只,随机分为空白对照组组、模型1组、模型2组,每组12只。模型1组使用“常规饮食+造模箱”造模。将大鼠置于温度28±2℃,湿度为90±5%的造模箱内饲养15天。造模2组使用“高脂高糖饮食+造模箱”造模。将大鼠置于温度28±2℃,湿度为90±5%的造模箱内饲养15天,并同时予高脂高糖饮食。测量大鼠的饮食量、饮水量、体重、SOD、MDA。
实验二加味达原饮治疗D-GalN所致急性肝损伤湿邪内蕴证大鼠的研究
SD大鼠,雌性,72只,随机分为空白对照组、模型组、阳性(美能)组、加味达原饮低、中、高剂量组,每组12只。除空白对照组外,余各组大鼠置于温度28±2℃,湿度90%±5%的造模箱内饲养15天,并同时给予高脂高糖饮食,15天后一次性腹腔注射D-GalN500mg/kg以造成急性肝损伤模型,造模后立即给予药物灌胃治疗,每日两次,其中阳性(美能)组的日给药量为15.75mg/kg/天,加味达原饮低、中、高剂量组的日给药量分别为：5.89g/kg/天、11.78g/kg／天和23.56g/kg／天。灌药体积为每次10ml/kg/次。造模48h后,所有大鼠股动脉采血,取血浆测ALT、AST、TB, ELISA法检测TNF-α、IL-1、IL-6,肝组织匀浆后荧光PCR法检测NF-κB有关信号传导通路的p65、p50蛋白的表达。处死动物,取肝右叶作常规HE切片,光镜下观察其变化。
实验三加味达原饮治疗CCL4所致急性肝损伤湿邪内蕴证大鼠的研究
SD大鼠,雌性,72只,随机分为空白对照组、模型组、阳性(美能)组、加味达原饮低、中、高剂量组,每组12只。除空白对照组外,余各组大鼠置于温度28±2℃,湿度90%±5%的造模箱内饲养15天,并同时给予高脂高糖饮食,15天后一次性腹腔注射CCL4原液lml/kg体重以造成急性肝损伤模型,造模后立即给予药物灌胃治疗,每日两次,其中阳性(美能)组的日给药量为15.75mg/kg/天,加味达原饮低、中、高剂量组的日给药量分别为：5.89g/kg/天、11.78g/kg/天和23.56g/kg/天。灌药体积为每次10ml/kg。造模48h后,所有大鼠股动脉采血,取血浆测ALT、AST、TB,比色法检测SOD、MDA, ELISA法检测TNF-α、IL-1、IL-6,肝组织匀浆后荧光PCR法检测|NF-κB相关信号传导通路的p65、p50蛋白的表达。处死动物,取肝右叶作常规HE切片,光镜下观察其变化。
结果：
1.湿热内蕴证动物模型的造模结果
造模后15天,模型1组饮食量、体重有明显的下降,与空白对照组相比,差异有统计学意义(P<0.05)。饮水量与空白对照组相比,差异无统计学意义(P>0.05)。SOD、MDA与空白对照组相比,差异无统计学意义(P>0.05)。模型2组大鼠的饮食量、饮水量、体重、SOD明显下降,与空白对照组相比,差异有统计学意义(P<0.05)。MDA明显升高,与空白对照组相比,差异有统计学意义(P<0.05)。
2.加味达原饮对D-GaIN所致急性肝损伤湿邪内蕴证大鼠的治疗作用
(1)造模后48h,模型组ALT、AST、TB含量明显升高,与空白对照组相比,差异有统计学意义(P<0.05)。阳性(美能)组,达原饮中、高剂量组ALT、AST、TB降低,与模型组比较,差异有统计学意义(P<0.05)；加味达原饮低剂量组ALT下降,但与模型组比较,差异无统计学意义(P>0.05)。
(2)造模后48h,模型组血浆TNF-α、IL-1、IL-6含量明显增高,与空白对照组比较,差异有统计学意义(P<0.05)。阳性(美能)组、加味达原饮中、高剂量治疗组血浆TNF-α、IL-1、IL-6明显降低,与模型组相比,差异有统计学意义(P<0.05)。低剂量组的TNF-α、IL-1、IL-6含量有所下降,但与模型组比较,差异无统计学意义(P>0.05)。
(3)NF-κBp50, NF-κBp65 mRNA检测结果：模型组NF-κBp50, NF-κBp65 mRNA的表达明显增高,与空白对照组比较,差异有统计学意义(P<0.05)。阳性(美能)组、加味达原饮中、高剂量治疗组NF-κB p50, NF-κBp65 mRNA表达明显降低,与模型组相比,差异有统计学意义(P<0.05)。低剂量组NF-κBp50,NF-κBp65 mRNA表达与模型组比较,差异无统计学意义(P>0.05)
(4)肝组织HE染色检测结果显示：空白对照组肝窦肝索结构清楚,肝细胞胞质丰富,核大而圆。模型组肝细胞片状坏死,或碎屑状坏死,肝细胞浊肿。加味达原饮低剂量组肝细胞广泛水肿,可见点状坏死和小灶区脂肪变性和点状肝细胞再生。阳性(美能)组,加味达原饮中、高剂量组肝细胞广泛浊肿,可见点状坏死。脂肪变性不明显。
3.加味达原饮对CCL4所致急性肝损伤湿邪内蕴证大鼠的治疗作用
(1)造模后48h,模型组ALT、AST、TB含量明显升高,与空白对照组相比,差异有统计学意义(P<0.05)。阳性(美能)组,加味达原饮中、高剂量组ALT、AST、TB降低,与模型组比较,差异有统计学意义(P<0.05)；加味达原饮低剂量组ALT下降,与模型组比较,差异有统计学意义(P<0.05)
(2)造模后48h,模型组SOD降低,MDA升高,与空白对照组比较有统计学意义(P<0.05)。阳性(美能)组、加味达原饮中、高剂量组的SOD升高,MDA下降,与模型组比较,差异有统计学意义(P<0.05)；加味达原饮低剂量组SOD升高,但与模型组比较,差异无统计学意义(P>0.05)。
(3)造模后48h,模型组血浆TNF-α、IL-1、IL-6含量明显增高,与空白对照组比较,差异有统计学意义(P<0.05)。加味达原饮中、高剂量组的TNF-α下降,与模型组相比有统计学意义(P<0.05)。阳性(美能)组、加味达原饮高剂量组IL-6下降,与模型组比较,差异有统计学意义(P<0.05)。
(4)NF-κBp50, NF-κBp65 mRNA检测结果：模型组NF-κBp50,NF-κBp65 mRNA的表达明显增高,与空白对照组比较,差异有统计学意义(P<0.05)。阳性(美能)组、加味达原饮中、高剂量治疗组NF-κBp50,NF-κBp65 mRNA表达明显降低,与模型组相比,差异有统计学意义(P<0.05)。低剂量组NF-κBp50,NF-κBp65 mRNA表达与模型组比较,差异无统计学意义(P>0.05)。
(5)肝组织HE染色检测结果显示：空白对照组肝窦肝索结构清楚,肝细胞胞质丰富,核大而圆。模型组肝细胞点状坏死,有广泛的肝细胞水肿,明显脂肪变性。加味达原饮低剂量组可见肝细胞部分水肿,脂肪变性和灶区肝细胞再生。阳性(美能)组,加味达原饮中、高剂量组见肝细胞水肿,点状肝细胞再生,肝细胞脂肪变性较模型组轻。
结论
1.“高脂高糖饮食+造模箱”和“常规饮食+造模箱”都可造成湿邪内蕴证动物模型。且造成的大鼠模型偏于湿热内蕴证。造模后大鼠的行动、体重、饮食量、饮水量都有明显改变。但“高脂高糖饮食+造模箱”造模方法的效果更显著,造模后大鼠不仅一般表现发生明显改变,且测量后显示SOD、MDA发生改变。这与中医的内外因致病的理论相一致。
2.加味达原饮中、高剂量治疗组均能显著减轻D-GalN所致湿邪内蕴证大鼠的肝细胞损伤,降低血浆中ALT、AST、TB含量,具有较好的保肝降酶作用。加味达原饮中、高剂量治疗组能显著改善急性肝损伤湿邪内蕴证大鼠肝组织的病理变化,缩小病变面积,减轻肝细胞病变程度。并可降低机体一系列的细胞因子,通过调节机体的免疫反应而起到保肝作用。加味达原饮低剂量组也有一定的保肝降酶作用,但其各指标结果之间差异较大,效果较难评价。
3.加味达原饮的中、高剂量组可明显减轻CCL4所致湿邪内蕴证大鼠的肝细胞损伤,降低血浆中ALT、AST、TB含量,具有较好的保肝降酶作用。并可对SOD、MDA及TNF-α、IL-1、IL-6等细胞因子起到调节作用,并可调节NF-κBp50,NF-κBp65的表达,通过抑制机体的脂质过氧化反应、免疫调节等多重功效而发挥保肝作用。加味达原饮低剂量组保肝作用不明显。
Objective:
This paper will present a new approach to establish the damp accumulation pattern rats model in terms of Traditional Chinese Medicine. At the same time, this article will observe the effects and explore the working mechanism of Da-Yuan-Yin for heat-damp type acute liver injury in rats induced by D-GalN and by CCL4.
Methods:
Supplemented Da-yuan-yin decoction was adopted as an intervention to treat the rats from acute liver injury of damp-heat pattern induced by D-GalN and by CCL4. Its effect and mechanism are accessed by the following outcomes, including index of the biochemistry, immunology, pathology, cellular pathway and so on.
ExperimentⅠ. Establishment of the damp accumulation pattern model of rats
Thirty-six female SD rats were randomized into three groups with 12 in each group:blank control group, model A group, and model B group. In the model A group, the rats were placed in fixed-environmental boxes with the temperature of 28±2℃, and humidity level 90±5% for fifteen days. In model group B, the rats were placed in the same kind of boxes and fed with high-lipid and high-glucose diets. The measurements were amount of food intake, water intake, body weight, SOD and MDA.
Experiment II:Experimental study of supplemented Da-yuan-yin decoction for damp accumulation pattern acute liver injury in rats induced by D-Galn.
72 female rats were randomized into six groups with 12 in each group:blank control group, model group, Compound Glycyrrhizin Tablets group, and low, middle and high dosage group of supplemented Da-Yuan-Yin Decoction. All the rats except in the blank control group were kept in the boxes with the temperature at 28±2℃and humidity level at 90±5% for fifteen days, and were fed with high-lipid, high-glucose food. Ten days later, intraperitoneal injection of D-GalN at a dosage of 500mg/kg was administered to the rats except those in the blank control group to induce acute liver injury. Medications were given orally to each treatment group at the same time, of which the daily dose of Compound Glycyrrhizin Tablets was 23.56mg/kg, and dosage of the three herbal groups were 5.89g/kg,11.78g/kg and 29.40 g/kg respectively. All the medications were given at a volume of 10ml/kg, twice a day for three days.48 hours later, all the rats were sacrificed with their serum ALT, AST and TB being examined. The expression of TNF-α, IL-1 and IL-6 were analyzed with the enzyme-linked immuno sorbent assay. The expression of p65 and p50 related with the NF-KB signal transduction pathway in the liver tissue homogenate were analyzed with the fluorescence PCR method. Right lobe of the liver was applied to make routine HE slices and pathological changes were examined under the light microscope.
Experiment III:Experimental study of supplemented Da-Yuan-Yin decoction for damp accumulation pattern acute liver injury in rats induced by CCL4.
72 female rats were randomized into six groups with 12 in each group:blank control group, model group, Compound Glycyrrhizin Tablets group, and low, middle and high dosage group of supplemented Da-Yuan-Yin Decoction. All the rats except in the blank control group were kept in the boxes with the temperature at 28±2℃and humidity level at 90±5% for fifteen days, and were fed with high-lipid, high-glucose food.Fifteen days later, intraperitoneal injection of CCL4 at a dosage of 1 ml/kg was administered to the rats except those in the blank control group to induce acute liver injury. Medications were given orally to each treatment group at the same time, of which the daily dose of Compound Glycyrrhizin Tablets was 15.75mg/kg, and dosage of the three herbal groups were 5.89g/kg,11.78g/kg and 23.56g/kg respectively. All the medications were given at a volume of 10ml/kg, twice a day for three days.48hours later, all the rats were sacrificed with their serum ALT, AST, TB, being examined.The SOD and MDA were analyzed with the colorimetric method. The expression of TNF-α,IL-1 and IL-6 were analyzed with the enzyme-linked immuno sorbent assay. The expression of p65 and p50 related with the NF-KB signal transduction pathway in the liver tissue homogenate were analyzed with the fluorescence PCR method. Right lobe of the liver was applied to make routine HE slices and pathological changes were examined under the light microscope.
Results:
Results of Experiment I
Fifteen days later, the rats in model A group ate less and lost significant amount of weight. The difference between the model A group and the blank control group was of statistical significance with P<0.05.The differences of water intake amount, SOD and MDA level between the two groups were of no statistical significance with P>0.05.
The rats in model B group ate less and lost significant amount of weight; their MDA levels were significantly lower than that of the blank control group. Their differences between the two groups were of statistical significance with P<0.05. The difference of water intake amount was not statistically significant with P>0.05.
Results of ExperimentⅡ:
(1) 48 hours later, ALT, AST, and TB levels were significantly higher than those in the blank control group (P<0.05). ALT, AST, and TB levels in the Compound Glycyrrhizin Tablets group, middle and high dosage group of supplemented Da-Yuan-Yin group were significantly lower than those in the model group(P<0.05).ALT and AST levels in the low-dose supplemented Da-Yuan-Yin group were lower than model group but the difference was not significant (P>0.05).
(2) 48 hours later, TNF-α, IL-1 and IL-6 levels were significantly higher than those in the blank control group (P<0.05). TNF-α, IL-1 and IL-6 levels in the Compound Glycyrrhizin Tablets group, middle and high dosage group of supplemented Da-Yuan-Yin group were significantly lower than those in the model group(P<0.05). TNF-α, IL-1 and IL-6 levels in the low-dose supplemented Da-Yuan-Yin group were lower than model group but the difference was not significant (P>0.05).
(3) The test results of NF-κBp50, NF-κBp65 mRNA:The model group NF -KBp50, NF-κBp65 mRNA significantly higher, the expression with the blank control group was statistically significant difference (P<0.05). NF-κBp50, NF-κBp65 mRNA in the Compound Glycyrrhizin Tablets group, middle and high dosage group of supplemented Da-Yuan-Yin group were significantly lower than those in the model group(P<0.05).NF-κBp 50, NF-κBp65 mRNA in the low-dose supplemented Da-Yuan-Yin group compared with the model group without obvious difference (P> 0.05).
(4) Pathologic changes from the HE slices:The liver sinus and liver cable's structure clearly, liver cell cytoplasm is plenty, nuclear is big and round rich in the blank control group.The liver cell flake or debris necrosis, turbidity swollen in the model group.The liver cell widely edema in the low dosage of supplemented Da-Yuan-Yin group.And there are liver cell turbidity swollen and stove area fatty degeneration necrosis.The liver cell widely turbidity swollen in the middle and high dosage of supplemented Da-Yuan-Yin group, the Compound Glycyrrhizin Tablets group.Steatosis is not obvious.
Results of ExperimentⅢ
(1) 48 hours later, ALT, AST, and TB levels in the model group were significantly higher than those in the blank control group (P<0.05). ALT, AST, and TB levels in the Compoumd Glycyrrhizin Tablets group middle and high dosage group of supplemented Da-Yuan-Yin group were significantly lower than those in the model group(P<0.05). AST level in the Compound Glycyrrhizin Tablets was significantly lower than that in the model group(P<0.05).ALT levels in the low-dose Da-Yuan-Yin group were lower than model group but the difference was not significant (P>0.05).
(2) 48 hours later, SOD level decreased and MDA level increased in the model group compared to those in the blank control group (P<0.05). SOD elevated and MDA decreased in the Compound Glycyrrhizin Tablets group, middle and high dosage group of supplemented Da-Yuan-Yin group compared to model group(P<0.05). SOD increased in the low-dose supplemented Da-Yuan-Yin group compared to model group but the difference was not significant (P>0.05).
(3) 48 hours later, TNF-α, IL-1 and IL-6 levels in the model group were significantly higher than those in the blank control group (P<0.05). TNF-αdecreased in the middle and high dosage of supplemented Da-Yuan-Yin group compared to those in the model group (P<0.05). IL-6 decreased in the Compound Glycyrrhizin Tablets group, middle and high dosage group in supplemented Da-Yuan-Yin group compared to model group (P<0.05).
(4) The test results of NF-κBp50, NF-κBp65 mRNA:The model group NF-κBp50, NF-κBp65 mRNA significantly higher, the expression with the blank control group was statistically significant difference (P<0.05). NF-κBp50, NF-κBp65 mRNA in the Compound Glycyrrhizin Tablets group, middle and high dosage group of supplemented Da-Yuan-Yin group were significantly lower than those in the model group(P<0.05). NF-κBp 50, NF-κBp65 mRNA in the low-dose supplemented Da-Yuan-Yin group compared with the model group without obvious difference (P> 0.05).
(5) Pathologic changes from the HE slices:The liver sinus and liver cable's structure clearly,liver cell cytoplasm is plenty, nuclear is big and round rich in the blank control group.The liver cell flake or debris necrosis, turbidity swollen in the model group.The liver cell widely edema in the low dosage of supplemented Da-Yuan-Yin group.And there are liver cell turbidity swollen and stove area fatty degeneration necrosis.The liver cell widely turbidity swollen in the middle and high dosage of supplemented Da-Yuan-Yin group, the Compound Glycyrrhizin Tablets group. Steatosis is not obvious.
Conclusions:
(1) High-lipid and high-glucose diet with the damp-heat environment or single damp-heat environment could induce the damp accumulation animal model in rats. The outcomes include general movement, body weight, food and water intake amount. According to this experiment, model B, namely, high-lipid and high-glucose diet plus environment control proves better than single environment exposure method because the SOD and MDA changed in the model B. The result is in consistent with the TCM etiological theory.
(2) The middle and high dosage group of supplemented Da-Yuan-Yin can treat the rats from acute liver injury of damp accumulation pattern induced by D-GalN. It can protect liver by reducing ALT, AST and TB cotent in plasma. The middle and high dosage group of supplemented Da-Yuan-Yin would improve the pathological changes of the liver tissue, narrow lesions, reduce the liver cell pathological changes of degree. And may reduce a series of cell factors, protect liver by regulating the body's immune response. The low-dose supplemented Da-Yuan-Yin group has certain the effect that protect liver. The effect is difficult to evaluate because of the between-group differences.
(3) The middle and high dosage group of supplemented Da-Yuan-Yin can treat the rats from acute liver injury of damp accumulation pattern induced by CCL4. It can protect liver by reducing ALT, AST and TB cotent in plasma. And may reduce SOD, MDA, IL-1 and IL-6;protect liver by reducing lipid peroxidation and regulating the body's immune response. The effect of protecting liver by the low-dose supplemented Da-Yuan-Yin group is insignificance.
在中医理论指导下,探讨大鼠湿邪内蕴证模型的造模过程及检测方法,为中医证型动物造模方法提供理论依据。并研究加味达原饮对D-GalN及CCL4所致的湿邪内蕴证急性肝损伤实验动物模型的治疗效果及作用机制。为中医治疗急性肝损伤提供科学依据。
方法：
选择加味达原饮对D-GalN及CCL4所致的湿邪内蕴证急性肝损伤大鼠模型进行干预,检测生化、免疫、病理、细胞通路等指标,研究达原饮治疗湿邪内蕴证肝损伤大鼠的机制及疗效。
实验一湿邪内蕴证动物模型的建立
SD大鼠,雌性,36只,随机分为空白对照组组、模型1组、模型2组,每组12只。模型1组使用“常规饮食+造模箱”造模。将大鼠置于温度28±2℃,湿度为90±5%的造模箱内饲养15天。造模2组使用“高脂高糖饮食+造模箱”造模。将大鼠置于温度28±2℃,湿度为90±5%的造模箱内饲养15天,并同时予高脂高糖饮食。测量大鼠的饮食量、饮水量、体重、SOD、MDA。
实验二加味达原饮治疗D-GalN所致急性肝损伤湿邪内蕴证大鼠的研究
SD大鼠,雌性,72只,随机分为空白对照组、模型组、阳性(美能)组、加味达原饮低、中、高剂量组,每组12只。除空白对照组外,余各组大鼠置于温度28±2℃,湿度90%±5%的造模箱内饲养15天,并同时给予高脂高糖饮食,15天后一次性腹腔注射D-GalN500mg/kg以造成急性肝损伤模型,造模后立即给予药物灌胃治疗,每日两次,其中阳性(美能)组的日给药量为15.75mg/kg/天,加味达原饮低、中、高剂量组的日给药量分别为：5.89g/kg/天、11.78g/kg／天和23.56g/kg／天。灌药体积为每次10ml/kg/次。造模48h后,所有大鼠股动脉采血,取血浆测ALT、AST、TB, ELISA法检测TNF-α、IL-1、IL-6,肝组织匀浆后荧光PCR法检测NF-κB有关信号传导通路的p65、p50蛋白的表达。处死动物,取肝右叶作常规HE切片,光镜下观察其变化。
实验三加味达原饮治疗CCL4所致急性肝损伤湿邪内蕴证大鼠的研究
SD大鼠,雌性,72只,随机分为空白对照组、模型组、阳性(美能)组、加味达原饮低、中、高剂量组,每组12只。除空白对照组外,余各组大鼠置于温度28±2℃,湿度90%±5%的造模箱内饲养15天,并同时给予高脂高糖饮食,15天后一次性腹腔注射CCL4原液lml/kg体重以造成急性肝损伤模型,造模后立即给予药物灌胃治疗,每日两次,其中阳性(美能)组的日给药量为15.75mg/kg/天,加味达原饮低、中、高剂量组的日给药量分别为：5.89g/kg/天、11.78g/kg/天和23.56g/kg/天。灌药体积为每次10ml/kg。造模48h后,所有大鼠股动脉采血,取血浆测ALT、AST、TB,比色法检测SOD、MDA, ELISA法检测TNF-α、IL-1、IL-6,肝组织匀浆后荧光PCR法检测|NF-κB相关信号传导通路的p65、p50蛋白的表达。处死动物,取肝右叶作常规HE切片,光镜下观察其变化。
结果：
1.湿热内蕴证动物模型的造模结果
造模后15天,模型1组饮食量、体重有明显的下降,与空白对照组相比,差异有统计学意义(P<0.05)。饮水量与空白对照组相比,差异无统计学意义(P>0.05)。SOD、MDA与空白对照组相比,差异无统计学意义(P>0.05)。模型2组大鼠的饮食量、饮水量、体重、SOD明显下降,与空白对照组相比,差异有统计学意义(P<0.05)。MDA明显升高,与空白对照组相比,差异有统计学意义(P<0.05)。
2.加味达原饮对D-GaIN所致急性肝损伤湿邪内蕴证大鼠的治疗作用
(1)造模后48h,模型组ALT、AST、TB含量明显升高,与空白对照组相比,差异有统计学意义(P<0.05)。阳性(美能)组,达原饮中、高剂量组ALT、AST、TB降低,与模型组比较,差异有统计学意义(P<0.05)；加味达原饮低剂量组ALT下降,但与模型组比较,差异无统计学意义(P>0.05)。
(2)造模后48h,模型组血浆TNF-α、IL-1、IL-6含量明显增高,与空白对照组比较,差异有统计学意义(P<0.05)。阳性(美能)组、加味达原饮中、高剂量治疗组血浆TNF-α、IL-1、IL-6明显降低,与模型组相比,差异有统计学意义(P<0.05)。低剂量组的TNF-α、IL-1、IL-6含量有所下降,但与模型组比较,差异无统计学意义(P>0.05)。
(3)NF-κBp50, NF-κBp65 mRNA检测结果：模型组NF-κBp50, NF-κBp65 mRNA的表达明显增高,与空白对照组比较,差异有统计学意义(P<0.05)。阳性(美能)组、加味达原饮中、高剂量治疗组NF-κB p50, NF-κBp65 mRNA表达明显降低,与模型组相比,差异有统计学意义(P<0.05)。低剂量组NF-κBp50,NF-κBp65 mRNA表达与模型组比较,差异无统计学意义(P>0.05)
(4)肝组织HE染色检测结果显示：空白对照组肝窦肝索结构清楚,肝细胞胞质丰富,核大而圆。模型组肝细胞片状坏死,或碎屑状坏死,肝细胞浊肿。加味达原饮低剂量组肝细胞广泛水肿,可见点状坏死和小灶区脂肪变性和点状肝细胞再生。阳性(美能)组,加味达原饮中、高剂量组肝细胞广泛浊肿,可见点状坏死。脂肪变性不明显。
3.加味达原饮对CCL4所致急性肝损伤湿邪内蕴证大鼠的治疗作用
(1)造模后48h,模型组ALT、AST、TB含量明显升高,与空白对照组相比,差异有统计学意义(P<0.05)。阳性(美能)组,加味达原饮中、高剂量组ALT、AST、TB降低,与模型组比较,差异有统计学意义(P<0.05)；加味达原饮低剂量组ALT下降,与模型组比较,差异有统计学意义(P<0.05)
(2)造模后48h,模型组SOD降低,MDA升高,与空白对照组比较有统计学意义(P<0.05)。阳性(美能)组、加味达原饮中、高剂量组的SOD升高,MDA下降,与模型组比较,差异有统计学意义(P<0.05)；加味达原饮低剂量组SOD升高,但与模型组比较,差异无统计学意义(P>0.05)。
(3)造模后48h,模型组血浆TNF-α、IL-1、IL-6含量明显增高,与空白对照组比较,差异有统计学意义(P<0.05)。加味达原饮中、高剂量组的TNF-α下降,与模型组相比有统计学意义(P<0.05)。阳性(美能)组、加味达原饮高剂量组IL-6下降,与模型组比较,差异有统计学意义(P<0.05)。
(4)NF-κBp50, NF-κBp65 mRNA检测结果：模型组NF-κBp50,NF-κBp65 mRNA的表达明显增高,与空白对照组比较,差异有统计学意义(P<0.05)。阳性(美能)组、加味达原饮中、高剂量治疗组NF-κBp50,NF-κBp65 mRNA表达明显降低,与模型组相比,差异有统计学意义(P<0.05)。低剂量组NF-κBp50,NF-κBp65 mRNA表达与模型组比较,差异无统计学意义(P>0.05)。
(5)肝组织HE染色检测结果显示：空白对照组肝窦肝索结构清楚,肝细胞胞质丰富,核大而圆。模型组肝细胞点状坏死,有广泛的肝细胞水肿,明显脂肪变性。加味达原饮低剂量组可见肝细胞部分水肿,脂肪变性和灶区肝细胞再生。阳性(美能)组,加味达原饮中、高剂量组见肝细胞水肿,点状肝细胞再生,肝细胞脂肪变性较模型组轻。
结论
1.“高脂高糖饮食+造模箱”和“常规饮食+造模箱”都可造成湿邪内蕴证动物模型。且造成的大鼠模型偏于湿热内蕴证。造模后大鼠的行动、体重、饮食量、饮水量都有明显改变。但“高脂高糖饮食+造模箱”造模方法的效果更显著,造模后大鼠不仅一般表现发生明显改变,且测量后显示SOD、MDA发生改变。这与中医的内外因致病的理论相一致。
2.加味达原饮中、高剂量治疗组均能显著减轻D-GalN所致湿邪内蕴证大鼠的肝细胞损伤,降低血浆中ALT、AST、TB含量,具有较好的保肝降酶作用。加味达原饮中、高剂量治疗组能显著改善急性肝损伤湿邪内蕴证大鼠肝组织的病理变化,缩小病变面积,减轻肝细胞病变程度。并可降低机体一系列的细胞因子,通过调节机体的免疫反应而起到保肝作用。加味达原饮低剂量组也有一定的保肝降酶作用,但其各指标结果之间差异较大,效果较难评价。
3.加味达原饮的中、高剂量组可明显减轻CCL4所致湿邪内蕴证大鼠的肝细胞损伤,降低血浆中ALT、AST、TB含量,具有较好的保肝降酶作用。并可对SOD、MDA及TNF-α、IL-1、IL-6等细胞因子起到调节作用,并可调节NF-κBp50,NF-κBp65的表达,通过抑制机体的脂质过氧化反应、免疫调节等多重功效而发挥保肝作用。加味达原饮低剂量组保肝作用不明显。
Objective:
This paper will present a new approach to establish the damp accumulation pattern rats model in terms of Traditional Chinese Medicine. At the same time, this article will observe the effects and explore the working mechanism of Da-Yuan-Yin for heat-damp type acute liver injury in rats induced by D-GalN and by CCL4.
Methods:
Supplemented Da-yuan-yin decoction was adopted as an intervention to treat the rats from acute liver injury of damp-heat pattern induced by D-GalN and by CCL4. Its effect and mechanism are accessed by the following outcomes, including index of the biochemistry, immunology, pathology, cellular pathway and so on.
ExperimentⅠ. Establishment of the damp accumulation pattern model of rats
Thirty-six female SD rats were randomized into three groups with 12 in each group:blank control group, model A group, and model B group. In the model A group, the rats were placed in fixed-environmental boxes with the temperature of 28±2℃, and humidity level 90±5% for fifteen days. In model group B, the rats were placed in the same kind of boxes and fed with high-lipid and high-glucose diets. The measurements were amount of food intake, water intake, body weight, SOD and MDA.
Experiment II:Experimental study of supplemented Da-yuan-yin decoction for damp accumulation pattern acute liver injury in rats induced by D-Galn.
72 female rats were randomized into six groups with 12 in each group:blank control group, model group, Compound Glycyrrhizin Tablets group, and low, middle and high dosage group of supplemented Da-Yuan-Yin Decoction. All the rats except in the blank control group were kept in the boxes with the temperature at 28±2℃and humidity level at 90±5% for fifteen days, and were fed with high-lipid, high-glucose food. Ten days later, intraperitoneal injection of D-GalN at a dosage of 500mg/kg was administered to the rats except those in the blank control group to induce acute liver injury. Medications were given orally to each treatment group at the same time, of which the daily dose of Compound Glycyrrhizin Tablets was 23.56mg/kg, and dosage of the three herbal groups were 5.89g/kg,11.78g/kg and 29.40 g/kg respectively. All the medications were given at a volume of 10ml/kg, twice a day for three days.48 hours later, all the rats were sacrificed with their serum ALT, AST and TB being examined. The expression of TNF-α, IL-1 and IL-6 were analyzed with the enzyme-linked immuno sorbent assay. The expression of p65 and p50 related with the NF-KB signal transduction pathway in the liver tissue homogenate were analyzed with the fluorescence PCR method. Right lobe of the liver was applied to make routine HE slices and pathological changes were examined under the light microscope.
Experiment III:Experimental study of supplemented Da-Yuan-Yin decoction for damp accumulation pattern acute liver injury in rats induced by CCL4.
72 female rats were randomized into six groups with 12 in each group:blank control group, model group, Compound Glycyrrhizin Tablets group, and low, middle and high dosage group of supplemented Da-Yuan-Yin Decoction. All the rats except in the blank control group were kept in the boxes with the temperature at 28±2℃and humidity level at 90±5% for fifteen days, and were fed with high-lipid, high-glucose food.Fifteen days later, intraperitoneal injection of CCL4 at a dosage of 1 ml/kg was administered to the rats except those in the blank control group to induce acute liver injury. Medications were given orally to each treatment group at the same time, of which the daily dose of Compound Glycyrrhizin Tablets was 15.75mg/kg, and dosage of the three herbal groups were 5.89g/kg,11.78g/kg and 23.56g/kg respectively. All the medications were given at a volume of 10ml/kg, twice a day for three days.48hours later, all the rats were sacrificed with their serum ALT, AST, TB, being examined.The SOD and MDA were analyzed with the colorimetric method. The expression of TNF-α,IL-1 and IL-6 were analyzed with the enzyme-linked immuno sorbent assay. The expression of p65 and p50 related with the NF-KB signal transduction pathway in the liver tissue homogenate were analyzed with the fluorescence PCR method. Right lobe of the liver was applied to make routine HE slices and pathological changes were examined under the light microscope.
Results:
Results of Experiment I
Fifteen days later, the rats in model A group ate less and lost significant amount of weight. The difference between the model A group and the blank control group was of statistical significance with P<0.05.The differences of water intake amount, SOD and MDA level between the two groups were of no statistical significance with P>0.05.
The rats in model B group ate less and lost significant amount of weight; their MDA levels were significantly lower than that of the blank control group. Their differences between the two groups were of statistical significance with P<0.05. The difference of water intake amount was not statistically significant with P>0.05.
Results of ExperimentⅡ:
(1) 48 hours later, ALT, AST, and TB levels were significantly higher than those in the blank control group (P<0.05). ALT, AST, and TB levels in the Compound Glycyrrhizin Tablets group, middle and high dosage group of supplemented Da-Yuan-Yin group were significantly lower than those in the model group(P<0.05).ALT and AST levels in the low-dose supplemented Da-Yuan-Yin group were lower than model group but the difference was not significant (P>0.05).
(2) 48 hours later, TNF-α, IL-1 and IL-6 levels were significantly higher than those in the blank control group (P<0.05). TNF-α, IL-1 and IL-6 levels in the Compound Glycyrrhizin Tablets group, middle and high dosage group of supplemented Da-Yuan-Yin group were significantly lower than those in the model group(P<0.05). TNF-α, IL-1 and IL-6 levels in the low-dose supplemented Da-Yuan-Yin group were lower than model group but the difference was not significant (P>0.05).
(3) The test results of NF-κBp50, NF-κBp65 mRNA:The model group NF -KBp50, NF-κBp65 mRNA significantly higher, the expression with the blank control group was statistically significant difference (P<0.05). NF-κBp50, NF-κBp65 mRNA in the Compound Glycyrrhizin Tablets group, middle and high dosage group of supplemented Da-Yuan-Yin group were significantly lower than those in the model group(P<0.05).NF-κBp 50, NF-κBp65 mRNA in the low-dose supplemented Da-Yuan-Yin group compared with the model group without obvious difference (P> 0.05).
(4) Pathologic changes from the HE slices:The liver sinus and liver cable's structure clearly, liver cell cytoplasm is plenty, nuclear is big and round rich in the blank control group.The liver cell flake or debris necrosis, turbidity swollen in the model group.The liver cell widely edema in the low dosage of supplemented Da-Yuan-Yin group.And there are liver cell turbidity swollen and stove area fatty degeneration necrosis.The liver cell widely turbidity swollen in the middle and high dosage of supplemented Da-Yuan-Yin group, the Compound Glycyrrhizin Tablets group.Steatosis is not obvious.
Results of ExperimentⅢ
(1) 48 hours later, ALT, AST, and TB levels in the model group were significantly higher than those in the blank control group (P<0.05). ALT, AST, and TB levels in the Compoumd Glycyrrhizin Tablets group middle and high dosage group of supplemented Da-Yuan-Yin group were significantly lower than those in the model group(P<0.05). AST level in the Compound Glycyrrhizin Tablets was significantly lower than that in the model group(P<0.05).ALT levels in the low-dose Da-Yuan-Yin group were lower than model group but the difference was not significant (P>0.05).
(2) 48 hours later, SOD level decreased and MDA level increased in the model group compared to those in the blank control group (P<0.05). SOD elevated and MDA decreased in the Compound Glycyrrhizin Tablets group, middle and high dosage group of supplemented Da-Yuan-Yin group compared to model group(P<0.05). SOD increased in the low-dose supplemented Da-Yuan-Yin group compared to model group but the difference was not significant (P>0.05).
(3) 48 hours later, TNF-α, IL-1 and IL-6 levels in the model group were significantly higher than those in the blank control group (P<0.05). TNF-αdecreased in the middle and high dosage of supplemented Da-Yuan-Yin group compared to those in the model group (P<0.05). IL-6 decreased in the Compound Glycyrrhizin Tablets group, middle and high dosage group in supplemented Da-Yuan-Yin group compared to model group (P<0.05).
(4) The test results of NF-κBp50, NF-κBp65 mRNA:The model group NF-κBp50, NF-κBp65 mRNA significantly higher, the expression with the blank control group was statistically significant difference (P<0.05). NF-κBp50, NF-κBp65 mRNA in the Compound Glycyrrhizin Tablets group, middle and high dosage group of supplemented Da-Yuan-Yin group were significantly lower than those in the model group(P<0.05). NF-κBp 50, NF-κBp65 mRNA in the low-dose supplemented Da-Yuan-Yin group compared with the model group without obvious difference (P> 0.05).
(5) Pathologic changes from the HE slices:The liver sinus and liver cable's structure clearly,liver cell cytoplasm is plenty, nuclear is big and round rich in the blank control group.The liver cell flake or debris necrosis, turbidity swollen in the model group.The liver cell widely edema in the low dosage of supplemented Da-Yuan-Yin group.And there are liver cell turbidity swollen and stove area fatty degeneration necrosis.The liver cell widely turbidity swollen in the middle and high dosage of supplemented Da-Yuan-Yin group, the Compound Glycyrrhizin Tablets group. Steatosis is not obvious.
Conclusions:
(1) High-lipid and high-glucose diet with the damp-heat environment or single damp-heat environment could induce the damp accumulation animal model in rats. The outcomes include general movement, body weight, food and water intake amount. According to this experiment, model B, namely, high-lipid and high-glucose diet plus environment control proves better than single environment exposure method because the SOD and MDA changed in the model B. The result is in consistent with the TCM etiological theory.
(2) The middle and high dosage group of supplemented Da-Yuan-Yin can treat the rats from acute liver injury of damp accumulation pattern induced by D-GalN. It can protect liver by reducing ALT, AST and TB cotent in plasma. The middle and high dosage group of supplemented Da-Yuan-Yin would improve the pathological changes of the liver tissue, narrow lesions, reduce the liver cell pathological changes of degree. And may reduce a series of cell factors, protect liver by regulating the body's immune response. The low-dose supplemented Da-Yuan-Yin group has certain the effect that protect liver. The effect is difficult to evaluate because of the between-group differences.
(3) The middle and high dosage group of supplemented Da-Yuan-Yin can treat the rats from acute liver injury of damp accumulation pattern induced by CCL4. It can protect liver by reducing ALT, AST and TB cotent in plasma. And may reduce SOD, MDA, IL-1 and IL-6;protect liver by reducing lipid peroxidation and regulating the body's immune response. The effect of protecting liver by the low-dose supplemented Da-Yuan-Yin group is insignificance.
引文
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