加味茵陈蒿汤对急性肝损伤大鼠肝组织TLR4信号转导通路及Th1/Th2影响的实验研究
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摘要
目的：探讨以加味茵陈蒿汤为代表的基本治法—解毒利湿、养阴益气法对D-氨基半乳糖所致的急性肝损伤实验动物模型肝组织TLR4信号转导通路及Th1/Th2的影响与作用机制,为临床推广应用中医药防治急性肝损伤提供理论依据。
方法：选择清洁级SD大鼠,雌性,72只,随机分为空白对照组、模型组、阳性组(复方甘草酸苷,商品名：美能)、中药加味茵陈蒿汤低剂量组、加味茵陈蒿汤中剂量组和加味茵陈蒿汤高剂量组。所有大鼠均适应性喂养在室温15-20℃,相对湿度60-80%的实验室7天。7天后给模型组、西药组、中药组予一次性腹腔注射D-Ga1N600mg/kg以造成急性肝损伤模型,造模后除模型组外余各组立即给予药物灌胃,每日两次,其中阳性(美能)组的日给药量为15.75mg/kg/天,加味茵陈蒿汤低、中、高剂量组的日给药量分别为：14.7g/kg,29.4g/kg,58.8g/kg,空白对照组予以0.9%的生理盐水灌胃,灌药体积为10ml/kg/次,一日两次,共灌胃治疗2天。在此期间观察动物一般状况、摄食及饮水等。实验结束时,所有大鼠股动脉采血,取血浆测丙氨酸氨基转移酶(Alanine aminotransferase, ALT)天冬氨酸氨基转移酶(Aspartate aminotransferase, AST)、总胆红素(TBIL);双抗体夹心ABC-ELISA法测定肿瘤坏死因子-α (Tumor necrosis factor alpha,TNF-α)、白细胞介素-2(Interleukin-2, IL-2)、白细胞介素-4(Interleukin-4, IL-4)、白细胞介素-10(Interleukin-10, IL-10)、γ干扰素(Interferon-γ, IFN-y)及巨噬细胞炎性蛋白2(Macrophage inflammatory protein2,MIP-2)含量；免疫组化法测髓样分化因子-88(myeloid ddifferentiation factor88,MyD88)、肿瘤坏死因子受体相关因子-6(tumor necrosis factor receptor-associated factor, TRAF6)、IκB蛋白-α(inhibitory of NF-κB, IkB-α)、丝裂原活化蛋白激酶(mitogen-activated protein kinase p38MAPK)、(Toll-like-receptor4、TLR4)等指标的含量,处死动物,取肝右叶作常规HE切片,光镜下观察其变化。实时荧光定量PCR技术检测肝组织TLR4mRNA (Toll-like-receptor4)的转录水平,蛋白印迹(Western blot)法检测肝组织TLR4的蛋白表达水平。
结果：
(1)造模后48h,模型组大鼠ALT、AST及TB含量明显升高,与正常组相比差异有统计学意义(p<0.05)。阳性(复方甘草酸苷)组,加味茵陈蒿汤低、中、高剂量组ALT、AST、TB均有所降低,与模型组比较,差异有统计学意义(p<0.05)。
(2)造模后48h,模型组血浆TNF-α、MIP-2、MyD88、TRAF6、IkB-α、p38MAPK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、加味茵陈蒿汤低、中、高剂量治疗组血浆TNF-α、MyD88、TRAF6、IkB-α、 p38MAPK均明显降低,与模型组相比,差异有统计学意义(p<0.05)。
(3)造模后48h,模型组血浆IL-2、IL-4、IFN-y及IL-10含量均明显增高,与空白对照组比较,差异有统计学意义(p<0.05)。阳性(美能)组、加味茵陈蒿汤低、中、高剂量治疗组血浆IL-2、IL-4、IFN-y及IL-10含量明显降低,与模型组相比,差异有统计学意义(p<0.05)。
(4) TLR4mRNA检测结果：模型组TLR4mRNA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、加味茵陈蒿汤低、中、高剂量组TLR4mRNA表达明显降低,与模型组相比,差异有统计学意义(p<0.05)
(5) Western blot检测TLR4结果：模型组TLR4的蛋白表达明显增高,与空白对照组比较,差异有统计学意义(p<0.05)。阳性(美能)组、加味茵陈蒿汤低、中、高剂量组TLR4蛋白表达明显降低,与模型组相比,差异有统计学意义(p<0.05)。
(6)肝组织HE染色检测结果显示：正常对照组大鼠肝细胞结构清楚,着色均匀,无肿胀、挤压、脆裂,无细胞变性、坏死及炎性细胞浸润。模型组大鼠肝脏结构破坏较明显,肝小叶结构欠清,肝细胞索排列紊乱,肝细胞变性、溶解坏死、肝汇管区炎性细胞浸润明显,肝细胞呈弥漫性空泡样变。加味茵陈蒿汤高剂量组肝小叶结构较模型组清楚,只有散在脂肪小滴浸润,肝细胞仅弥漫性轻度水肿。加味茵陈蒿汤中剂量组肝组织结构较模型组尚清楚,肝细胞变性、坏死较模型组有明显减轻。加味茵陈蒿汤低剂量组大鼠肝组织结构部分破坏,肝细胞变性、溶解坏死、炎性细胞润较模型组轻,呈中度弥漫性空泡样变。阳性组大鼠肝细胞结构部分破坏,肝细胞变性、坏死、出血较模型组略有减轻。
结论
1.加味茵陈蒿汤低、中、高剂量治疗组均能显著减轻D-氨基半乳糖所致大鼠的肝细胞损伤,降低血浆中ALT、AST、TB含量,具有较好的保肝降酶作用。同时在病理方面,均能显著改善肝组织的病理变化,缩小病变的面积,减轻肝细胞的损伤程度。
2.加味茵陈蒿汤低、中、高剂量治疗组均能显著减轻D-氨基半乳糖所致大鼠的肝细胞损伤,通过调节Th1、Th2类细胞因子,纠正Th1/Th2的免疫失衡状态,调节机体的免疫反应而起到保肝作用。
3.加味茵陈蒿汤高剂量和中剂量治疗组对D-氨基半乳糖所致急性肝损伤大鼠的TLR4信号转导通路均有一定的影响,可能通过调节细胞因子-细胞信号转导通路起到保肝的作用。
Objective: To research the mechanisms of supplemented Yin-Chen-Hao decotion representing the methods of detoxification and removing dampness, nourishing yin and yi qi that affects TLR4signal transduction of the rats liver tissue and Thl/Th2for acute liver injury of rats induced by D-GalN.
Method:72female SD rats of clean class were randomized into six groups with12in each group:blank control group, model group, Compound Glycyrrhizin Tablets group, and low, middle and high dosage group of supplemented Yin-Chen-Hao decotion. All the rats were fed adaptedly with common feed and clean water in the15-20degrees and humidity level at60-80%of laboratory for seven days, seven days later, single intraperitoneal injection of D-GalN at a dosage of600mg/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 was15.75mg/kg, and dosage of the three herbal groups were14.7g/kg,29.4g/kg and58.8g/kg respectively. The blank control group was fed with the0.9%physiological saline.All the medications were given at a volume of lOml/kg, twice a day for two days.48hours later, all the rats were sacrificed with their serum ALT, AST and TB being examined. The expression of TNF-a, MIP-2, IL-2, IL-4, IL-10and IFN-y were analyzed with the enzyme-linked immuno sorbent assay. Immunohistochemical method is used to measure the content of MyD88、TRAF6、IkB-α、P38MAPK and TLR4. The expression of TLR4related with the Toll-like receptor signal transduction pathway in the liver tissue homogenate were analyzed with the fluorescence PCR method and western blot. Right lobe of the liver was applied to make routine HE slices and pathological changes were examined under the light microscope.
Result:
(1)48hours later, ALT, AST and TB for the rats in model group were significantly increased. compared with the normal group the differences were statistically significant (P<0.05).Positive (SNMC) group, modified Yinchenhao Decoction in low, middle and high dose groups, ALT, AST, TB decreased, compared with the model group, the difference was statistically significant (P<0.05).
(2) Plasma levels of TNF-α, MIP-2, MyD88, TRAF6, IkB-α, P38MAPK were significantly increased in model group, compared with the blank control group, the difference was statistically significant (P<0.05).Positive (SNMC) group. low. middle and high dose of modified Yinchenhao Decoction in the treatment groups, the plasma TNF-a, MIP-2,MyD88, TRAF6, IkB-a, P38MAPK were all significantly decreased, compared with the model group, the difference was statistically significant (P<0.05).
(3) after the model of48h, plasma IL-2, IL-4, IFN-y and IL-10of model group were significantly increased, compared with the blank control group, the difference was statistically significant (P<0.05).Positive (SNMC) group, low, middle and high dose of modified Yin-chen-hao Decoction in the treatment groups, the plasma IL-2. IL-4,IFN-y and IL-10were all significantly decreased, compared with the model group, the difference was statistically significant (P<0.05).
(4) TLR4mRNA results:model group. TLR4mRNA expression was significantly increased, compared with the blank control group, the difference was statistically significant (P<0.05).Positive (SNMC) group, modified Yin-chen-hao Decoction in low, middle and high dose group, the expression of TLR4mRNA were all significantly decreased, compared with the model group, the difference was statistically significant (P<0.05).
(5) WB detection of TLR4results:model group TLR4protein expression was significantly increased, compared with the blank control group, the difference was statistically significant (P<0.05).Positive (SNMC), modified Yin-chen-hao Decoction group, every dose group of TLR4protein expression was significantly decreased, compared with the model group, the difference was statistically significant (P<0.05).
(6) Liver tissue HE staining results showed: The normal structure of liver cell group rats were clear, uniform color, no swelling, extrusion, brittle, no cell degeneration, necrosis and inflammatory cell infiltration. Obvious liver structure of rats in model group, hepatic lobule structure was not clear, liver cells arranged in disorder, liver cell degeneration, necrosis, hepatic periportal inflammatory cell infiltration, liver cell diffuse vacuolar degeneration. Jiawei Yinchenhao Decoction high dose group compared with model group, the hepatic lobule structure clear, only scattered infiltration in the fat droplets, liver cells only diffuse mild edema. Jiawei Yinchenhao Decoction of liver tissue dose group structure is clearly compared with the model group, liver cell degeneration, necrosis was significantly reduced compared with the model group. Jiawei Yinchenhao Decoction low dose group of rat liver tissue structure failure, liver cell degeneration, necrosis, inflammatory cell run lighter than in the model group, showed moderate diffuse vacuolar degeneration. Positive group structure of liver cells of rat partial destruction, liver cell degeneration, necrosis, bleeding was slightly reduced compared with model group.
Conclusion:1. Low, middle and high dosage groups of supplemented Yin-Chen-Hao decotion can treat the rats from acute liver injury rats induced by D-GalN. It can protect liver by reducing ALT, AST and TB content in plasma. The middle and high dosage group of supplemented Yin-Chen-Hao decotion 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 Yin-Chen-Hao decotion has certain the effect in protecting liver.2. Low, middle and high dosage group of supplemented Yin-Chen-Hao decotion can treat the rats from acute liver injury rats induced by D-GalN. It can protect liver by reducing ALT, AST and TB content in plasma. And may reduce TNF-a, IFN-y, IL-2inflammatory factors et al; protect liver by regulating the body's immune response.3. Modified Yin-chen-hao Decoction in every dose group on D-galactosamine induced acute liver injury in rats of the TLR4signal transduction pathways have a certain influence, possibly through the regulation of cytokine signal transduction pathway plays a role.
方法：选择清洁级SD大鼠,雌性,72只,随机分为空白对照组、模型组、阳性组(复方甘草酸苷,商品名：美能)、中药加味茵陈蒿汤低剂量组、加味茵陈蒿汤中剂量组和加味茵陈蒿汤高剂量组。所有大鼠均适应性喂养在室温15-20℃,相对湿度60-80%的实验室7天。7天后给模型组、西药组、中药组予一次性腹腔注射D-Ga1N600mg/kg以造成急性肝损伤模型,造模后除模型组外余各组立即给予药物灌胃,每日两次,其中阳性(美能)组的日给药量为15.75mg/kg/天,加味茵陈蒿汤低、中、高剂量组的日给药量分别为：14.7g/kg,29.4g/kg,58.8g/kg,空白对照组予以0.9%的生理盐水灌胃,灌药体积为10ml/kg/次,一日两次,共灌胃治疗2天。在此期间观察动物一般状况、摄食及饮水等。实验结束时,所有大鼠股动脉采血,取血浆测丙氨酸氨基转移酶(Alanine aminotransferase, ALT)天冬氨酸氨基转移酶(Aspartate aminotransferase, AST)、总胆红素(TBIL);双抗体夹心ABC-ELISA法测定肿瘤坏死因子-α (Tumor necrosis factor alpha,TNF-α)、白细胞介素-2(Interleukin-2, IL-2)、白细胞介素-4(Interleukin-4, IL-4)、白细胞介素-10(Interleukin-10, IL-10)、γ干扰素(Interferon-γ, IFN-y)及巨噬细胞炎性蛋白2(Macrophage inflammatory protein2,MIP-2)含量；免疫组化法测髓样分化因子-88(myeloid ddifferentiation factor88,MyD88)、肿瘤坏死因子受体相关因子-6(tumor necrosis factor receptor-associated factor, TRAF6)、IκB蛋白-α(inhibitory of NF-κB, IkB-α)、丝裂原活化蛋白激酶(mitogen-activated protein kinase p38MAPK)、(Toll-like-receptor4、TLR4)等指标的含量,处死动物,取肝右叶作常规HE切片,光镜下观察其变化。实时荧光定量PCR技术检测肝组织TLR4mRNA (Toll-like-receptor4)的转录水平,蛋白印迹(Western blot)法检测肝组织TLR4的蛋白表达水平。
结果：
(1)造模后48h,模型组大鼠ALT、AST及TB含量明显升高,与正常组相比差异有统计学意义(p<0.05)。阳性(复方甘草酸苷)组,加味茵陈蒿汤低、中、高剂量组ALT、AST、TB均有所降低,与模型组比较,差异有统计学意义(p<0.05)。
(2)造模后48h,模型组血浆TNF-α、MIP-2、MyD88、TRAF6、IkB-α、p38MAPK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、加味茵陈蒿汤低、中、高剂量治疗组血浆TNF-α、MyD88、TRAF6、IkB-α、 p38MAPK均明显降低,与模型组相比,差异有统计学意义(p<0.05)。
(3)造模后48h,模型组血浆IL-2、IL-4、IFN-y及IL-10含量均明显增高,与空白对照组比较,差异有统计学意义(p<0.05)。阳性(美能)组、加味茵陈蒿汤低、中、高剂量治疗组血浆IL-2、IL-4、IFN-y及IL-10含量明显降低,与模型组相比,差异有统计学意义(p<0.05)。
(4) TLR4mRNA检测结果：模型组TLR4mRNA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、加味茵陈蒿汤低、中、高剂量组TLR4mRNA表达明显降低,与模型组相比,差异有统计学意义(p<0.05)
(5) Western blot检测TLR4结果：模型组TLR4的蛋白表达明显增高,与空白对照组比较,差异有统计学意义(p<0.05)。阳性(美能)组、加味茵陈蒿汤低、中、高剂量组TLR4蛋白表达明显降低,与模型组相比,差异有统计学意义(p<0.05)。
(6)肝组织HE染色检测结果显示：正常对照组大鼠肝细胞结构清楚,着色均匀,无肿胀、挤压、脆裂,无细胞变性、坏死及炎性细胞浸润。模型组大鼠肝脏结构破坏较明显,肝小叶结构欠清,肝细胞索排列紊乱,肝细胞变性、溶解坏死、肝汇管区炎性细胞浸润明显,肝细胞呈弥漫性空泡样变。加味茵陈蒿汤高剂量组肝小叶结构较模型组清楚,只有散在脂肪小滴浸润,肝细胞仅弥漫性轻度水肿。加味茵陈蒿汤中剂量组肝组织结构较模型组尚清楚,肝细胞变性、坏死较模型组有明显减轻。加味茵陈蒿汤低剂量组大鼠肝组织结构部分破坏,肝细胞变性、溶解坏死、炎性细胞润较模型组轻,呈中度弥漫性空泡样变。阳性组大鼠肝细胞结构部分破坏,肝细胞变性、坏死、出血较模型组略有减轻。
结论
1.加味茵陈蒿汤低、中、高剂量治疗组均能显著减轻D-氨基半乳糖所致大鼠的肝细胞损伤,降低血浆中ALT、AST、TB含量,具有较好的保肝降酶作用。同时在病理方面,均能显著改善肝组织的病理变化,缩小病变的面积,减轻肝细胞的损伤程度。
2.加味茵陈蒿汤低、中、高剂量治疗组均能显著减轻D-氨基半乳糖所致大鼠的肝细胞损伤,通过调节Th1、Th2类细胞因子,纠正Th1/Th2的免疫失衡状态,调节机体的免疫反应而起到保肝作用。
3.加味茵陈蒿汤高剂量和中剂量治疗组对D-氨基半乳糖所致急性肝损伤大鼠的TLR4信号转导通路均有一定的影响,可能通过调节细胞因子-细胞信号转导通路起到保肝的作用。
Objective: To research the mechanisms of supplemented Yin-Chen-Hao decotion representing the methods of detoxification and removing dampness, nourishing yin and yi qi that affects TLR4signal transduction of the rats liver tissue and Thl/Th2for acute liver injury of rats induced by D-GalN.
Method:72female SD rats of clean class were randomized into six groups with12in each group:blank control group, model group, Compound Glycyrrhizin Tablets group, and low, middle and high dosage group of supplemented Yin-Chen-Hao decotion. All the rats were fed adaptedly with common feed and clean water in the15-20degrees and humidity level at60-80%of laboratory for seven days, seven days later, single intraperitoneal injection of D-GalN at a dosage of600mg/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 was15.75mg/kg, and dosage of the three herbal groups were14.7g/kg,29.4g/kg and58.8g/kg respectively. The blank control group was fed with the0.9%physiological saline.All the medications were given at a volume of lOml/kg, twice a day for two days.48hours later, all the rats were sacrificed with their serum ALT, AST and TB being examined. The expression of TNF-a, MIP-2, IL-2, IL-4, IL-10and IFN-y were analyzed with the enzyme-linked immuno sorbent assay. Immunohistochemical method is used to measure the content of MyD88、TRAF6、IkB-α、P38MAPK and TLR4. The expression of TLR4related with the Toll-like receptor signal transduction pathway in the liver tissue homogenate were analyzed with the fluorescence PCR method and western blot. Right lobe of the liver was applied to make routine HE slices and pathological changes were examined under the light microscope.
Result:
(1)48hours later, ALT, AST and TB for the rats in model group were significantly increased. compared with the normal group the differences were statistically significant (P<0.05).Positive (SNMC) group, modified Yinchenhao Decoction in low, middle and high dose groups, ALT, AST, TB decreased, compared with the model group, the difference was statistically significant (P<0.05).
(2) Plasma levels of TNF-α, MIP-2, MyD88, TRAF6, IkB-α, P38MAPK were significantly increased in model group, compared with the blank control group, the difference was statistically significant (P<0.05).Positive (SNMC) group. low. middle and high dose of modified Yinchenhao Decoction in the treatment groups, the plasma TNF-a, MIP-2,MyD88, TRAF6, IkB-a, P38MAPK were all significantly decreased, compared with the model group, the difference was statistically significant (P<0.05).
(3) after the model of48h, plasma IL-2, IL-4, IFN-y and IL-10of model group were significantly increased, compared with the blank control group, the difference was statistically significant (P<0.05).Positive (SNMC) group, low, middle and high dose of modified Yin-chen-hao Decoction in the treatment groups, the plasma IL-2. IL-4,IFN-y and IL-10were all significantly decreased, compared with the model group, the difference was statistically significant (P<0.05).
(4) TLR4mRNA results:model group. TLR4mRNA expression was significantly increased, compared with the blank control group, the difference was statistically significant (P<0.05).Positive (SNMC) group, modified Yin-chen-hao Decoction in low, middle and high dose group, the expression of TLR4mRNA were all significantly decreased, compared with the model group, the difference was statistically significant (P<0.05).
(5) WB detection of TLR4results:model group TLR4protein expression was significantly increased, compared with the blank control group, the difference was statistically significant (P<0.05).Positive (SNMC), modified Yin-chen-hao Decoction group, every dose group of TLR4protein expression was significantly decreased, compared with the model group, the difference was statistically significant (P<0.05).
(6) Liver tissue HE staining results showed: The normal structure of liver cell group rats were clear, uniform color, no swelling, extrusion, brittle, no cell degeneration, necrosis and inflammatory cell infiltration. Obvious liver structure of rats in model group, hepatic lobule structure was not clear, liver cells arranged in disorder, liver cell degeneration, necrosis, hepatic periportal inflammatory cell infiltration, liver cell diffuse vacuolar degeneration. Jiawei Yinchenhao Decoction high dose group compared with model group, the hepatic lobule structure clear, only scattered infiltration in the fat droplets, liver cells only diffuse mild edema. Jiawei Yinchenhao Decoction of liver tissue dose group structure is clearly compared with the model group, liver cell degeneration, necrosis was significantly reduced compared with the model group. Jiawei Yinchenhao Decoction low dose group of rat liver tissue structure failure, liver cell degeneration, necrosis, inflammatory cell run lighter than in the model group, showed moderate diffuse vacuolar degeneration. Positive group structure of liver cells of rat partial destruction, liver cell degeneration, necrosis, bleeding was slightly reduced compared with model group.
Conclusion:1. Low, middle and high dosage groups of supplemented Yin-Chen-Hao decotion can treat the rats from acute liver injury rats induced by D-GalN. It can protect liver by reducing ALT, AST and TB content in plasma. The middle and high dosage group of supplemented Yin-Chen-Hao decotion 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 Yin-Chen-Hao decotion has certain the effect in protecting liver.2. Low, middle and high dosage group of supplemented Yin-Chen-Hao decotion can treat the rats from acute liver injury rats induced by D-GalN. It can protect liver by reducing ALT, AST and TB content in plasma. And may reduce TNF-a, IFN-y, IL-2inflammatory factors et al; protect liver by regulating the body's immune response.3. Modified Yin-chen-hao Decoction in every dose group on D-galactosamine induced acute liver injury in rats of the TLR4signal transduction pathways have a certain influence, possibly through the regulation of cytokine signal transduction pathway plays a role.
引文
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