从“湿热变证”论治急性肝损伤的动物实验研究及机制初探
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摘要
目的：
在中医理论指导下,试探性地寻找适合相应中医治法的造模方式。从中医药防治湿热变证的方法入手,对急性肝损伤进行防治。分别观察两种不同的治疗湿热变证的中医治法对两种不同类型的急性肝损伤动物模型的疗效,并初步探讨其保肝作用机制。特别研究中药复方对肝细胞胀亡的影响,拓宽对中药保肝机制的研究,期望为中医药防治急性肝损伤提供更多新的理论依据和有效方药。
方法：
根据湿热病邪导致的中医不同证型：湿热之邪从热化或湿热之邪从寒化,分别选择相应方药,选择适合该证型的造模方法,对其疗效及作用机制进行探讨。针对湿热之邪从热化,选用具有和解少阳、清热祛湿、滋阴活血的中药复方柴胡愈肝汤方进行研究,观察其对D-Gal造成的化学性急性肝损伤大鼠的影响。对于湿热之邪从寒化,选用具有补火助阳,散寒止痛的单味中药附子振奋阳气,温化寒湿,观察其对卡介苗(BCG)／脂多糖(LPS)造成的免疫性急性肝损伤大鼠模型的影响。
1.柴胡愈肝汤方治疗D-Galn所致大鼠急性肝损伤：SD大鼠,雌性,60只,随机分为空白对照组、模型组、联苯双酯组、中药低、中、高剂量组,每组10只。除空白对照组外,一次性腹腔注射D-Galn600mg/kg以造成肝损伤模型,造模后立即给予药物灌胃治疗,每日两次,其中联苯双酯组的日给药量为4.5mg/kg,中药低中高剂量组的日给药量分别为：11.8g/kg、23.6g/kg和47 g/kg。造模48h后,所有大鼠股动脉采血,取血浆测ALT、AST、TB、Calpain、TNF-α、IL-18。处死动物,取肝右叶作常规HE切片,透射电镜下观察肝细胞形态结构。免疫组化法检测肝组织中bcl-2、bax的表达。
2.附子防治BCG/LPS所致大鼠急性肝损伤：将50只SD大鼠随机分为5组：正常组10只,模型组10只(采用卡介苗联合脂多糖法建立免疫性肝损伤的大鼠模型),低、中、高剂量治疗组各10只(治疗组采用附片免煎剂进行干预)。造模成功后24h取大鼠血清观察ALT、AST、TBIL、MDA、SOD的改变情况,取肝组织进行病理组织学检查,用核磁共振法对肝组织中的小分子代谢产物进行检测。
结果：
1.柴胡愈肝汤方对D-Galn所致大鼠急性肝损伤的治疗作用：
(1)造模后48h,模型组血浆中ALT、AST、TB含量明显升高,与正常组相比差异有统计学意义(P<0.05)。DDB组、柴胡愈肝汤方低、高剂量治疗组、阳性对照组血浆中ALT、AST、TB含量与模型组相比均降低,差异有统计学意义(P<0.05)；中剂量组血浆中ALT、TB下降,与模型组相比有统计学意义(P<0.05)。
(2)造模后48h,模型组血浆Calpain、TNF-α、IL-18表达明显增高,差异显著(P<0.05)。与模型组相比,DDB组、低剂量治疗组血浆TNF-α、Calpain、IL-18表达明显降低,中剂量组血浆TNF-α表达降低,高剂量组血浆TNF-α、Calpain表达降低,差异均具有统计学意义(P<0.05)。中剂量组对血浆Calpain、IL-18影响不显著(P>0.05),高剂量组对血浆IL-18影响不显著(P>0.05)。
(3)模型组肝组织bcl-2表达明显下降,bax表达明显增高,与正常组相比差异有统计学意义(P<0.05)。与模型组相比,DDB组、柴胡愈肝汤低、高剂量组均能有效降低造模后肝组织中bax表达,增强肝组织中bcl-2的表达,有明显差异(P<0.05)。中剂量组对肝组织中bax、bcl-2表达水平的影响不显著(P>0.05)。
(4)肝组织HE染色检测结果显示：模型组脂肪样变、空泡样变明显,并存在散在的点灶状坏死,治疗组脂变、空泡样变程度及面积均较模型组减轻,其中柴胡愈肝汤高剂组和DDB组病变最轻,低剂组病变次之,中剂量组变性程度与模型组差别不明显。
(5)肝组织电镜结果表明：模型组肝细胞同时出现胀亡、凋亡两种不同的死亡形态,明显可见肝细胞内线粒体肿胀、破损,嵴退化或消失,内质网扩张或崩解。高剂组和DDB组肝细胞坏死程度较轻,肝细胞内线粒体肿胀不明显。中剂量组与模型组相比病变改善程度不明显。
2.附子对BCG/LPS所致大鼠急性肝损伤的保护作用：
(1)各用药组均能明显降低BCG/LPS所致免疫性肝损伤大鼠血清的ALT、AST、TBIL、MDA,与模型组比较有显著性差异(P<0.05)。
(2)肝组织病理学检查,低、中、高剂量治疗组肝组织肝小叶结构基本正常,肝窦充血与炎性细胞浸润明显减轻,肝细胞坏死亦显著减少。其中以高剂量治疗组损伤的程度最轻。
(3)用核磁共振的方法检测各组肝组织的小分子代谢产物,检测结果表明附子免煎剂能减轻肝损伤所造成的肝组织小分子代谢物的改变,其中以高剂量治疗组样本点偏向正常组更为明显。
结论：
1.柴胡愈肝汤低、高剂量治疗组均能显著降低D-Gal所致的肝细胞损伤,降低血浆中ALT、AST、TB含量,具有一定的保肝降酶作用。同时该方能显著改善急性肝损伤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,具有对抗细胞凋亡和细胞胀亡双重作用。其作用途径可能与减轻线粒体损伤,降低bax、Calpain、TNF-α,升高bcl-2表达密切相关。
2.中药附子免煎剂能够减轻免疫性肝损伤大鼠的肝损害,具有一定的保肝降酶作用,其作用机制可能与减少脂质过氧化有关。同时借用核磁共振的检测手段帮助评价药物疗效是一种直观、全面、行之有效的新方法。
3.两种不同的治法的方药,分别对化学性急性损伤和免疫性急性肝损伤的实验动物模型有不同程度的防治作用。
Objective:
To search for the suitable model to the therapeutical principle and method under the guidenece of TCM theory. Observe the liver protection respectively by two different methods for curting deterioration of damp-heat syndrome, and explore the action mechanism. To study specially the the effect of prescription on oncosis, and investigate the action mechanism of liver protection. Hope that it can provide more new theoretical basis and effective prescriptions for treatment of acute liver injury.
Methods:
Choose suitable prescriptions and model according chinese medicine syndrome types to study the curative effect and action mechanism. Select the prescription of Chaihu Yugan Detection that helps to clear heat, dispel dampness, promote blood flow, nourish yin targeting at predominance of heat, to remedy acute liver injury rats caused by D-Gal rats with acute liver injury.And select the chinese herb of radix aconiti carmichaeli that helps to warming yang,dipel cold,and relieve the pain to remedy acute liver injury rats that caused by BCG/LPS.To investigate the curative effection and action mechanism.
1.Chaihu Yugan Detection remedy the acute liver injury caused by D-Galn:Sixty female SD rats were randomized into six groups with 10 in each group, normal control group, model group, diphenyl dimethyl bicarboxylate (DDB) group, low-dose group, middle-dose group and high-dose group. Intraperitoneal injection of D-Galn at a dose of 600mg/kg was administered to the rats except those in the normal 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 DDB is 4.5mg/kg, and dosage of the three herbal groups was 11.8g/kg,23.6g/kg and 47g/kg respectively,2 daily. All the medications were given at a volume of 10ml/kg, twice a day for two days.48 hours later, all the rats were sacrificed with their serum ALT, AST, TB, Calpain, TNF- αand IL-18 being examined. Right lobe of the liver was applied to make routine HE slices and pathological changes were examined under the microscope. The expression of bcl-2 and bax were analyzed by immunohistochemical.
2. Radix aconiti carmichaeli remedy the acute liver injury caused by BCG/LPS: Divide 50 rats into 5 groups randomly:normal control group(group A), model group (group B), low-dose group (group C), middle-dose group (group D) and high-dose group (group E). BCG and LPS were injected intrapefitoneally(ip) to rats in Gb、Gc、Gd and Ge to induce acute immune liver injury. And then Gc、Gd and Ge were treated with different doses of traditional Chinese medicine respective. Observe the changes of ALT、AST、TBIL、MDA、SOD in serum of rats and the diseased tissues. Verify the smaller molecule metabolites in liver tissue by nuclear magnetic resonance.
Results:
1. The curative effect of Chaihu Yugan Decoction on acute liver injury caused by D-Galn:
(1)The Chaihu Yugan Decoction at an oral dose of 11.8g/kg and 47g/kg exhibited a significant (P<0.05 for all) curative effect by normalizing the levels of alanine amino transferase (ALT), aspartate amino transferase (AST) and total bilirubin (TB) which were significantly (P<0.05) increased at 48h later in rats by treatment with 600 mg/kg D-Galn. DDB (4.5 mg/kg), a known hepatoprotective drug used for comparison exhibited significant curative effect in terms of ALT, AST and TB (P<0.05). The Chaihu Yugan Decoction at an oral dose of 23.6g/kg exhibited significant curative effect in terms of ALT and TB (P<0.05).
(2) Calpain、Tumor necrosis factor alpha (TNF-α) and interleukin-18(IL-18) levels in human plusma increased significantly in the model group compared to that of normal group (P<0.05). DDB group and low dose group exhibited a significant (P<0.05 for all) curative effect by normalizing the levels of Calpain、TNF-αand IL-18 compared to model group.
(3) The expression of bax levels decreased significantly, whereas bcl-2 increased significantly in the model group compared to that of normal group (P<0.05). DDB group, low dose group and high dose group exhibited a significant (P<0.05 for all) curative effect by normalizing the levels of bax and increasing the levels of bcl-2 compared to modle group. Middle dose group did not affect bcl-2 or bax levels in liver tissue significantly (P> 0.05)
(4)Pathologic changes from the HE slices suggested that size of fatty degeneration, hydropic degeneration and focal necrosis in the model group was much larger than that of the treatment group in which the high dose group and DDB group exhibited the better protective effects.
(5) The ultrastructure of the hepatocyte showed that:liver cells in model group appeared simultaneous death of oncosis and apoptosis. There were swollen nad deformed mitochondrias in liver cells, some of which were destroyed in structure. Endoplasmic reticulum expanded or collapsed. High dose group and DDB group exhibited the better protective effect. Middle dose group was not significantly difference than modle group.
2. Curative effect and metabonomic of radix aconiti carmichaeli to acute liver injury caused by BCG/LPS:
(1)All the treatment groups exhibited a significant (P<0.01 for all) curative effect by normalizing the levels of alanine amino transferase (ALT), aspartate amino transferase (AST), total bilirubin (TB) and MDA which were significantly (P<0.05) increased in rats by treatment with BCG/LPS.
(2) Pathologic changes from the HE slices suggested that size of lobular architecture were almost normal in all treatment groups. Hydropic degeneration and focal necrosis in treatment groups was much larger than that of the treatment group in which the high dose group and DDB group exhibited the better protective effects
Conclusions:
1. Chaihu Yugan Decoction could lower down the increased serum ALT, AST and TB levels in D-Galn-induced hepatotoxic rats and decrease the size of degeneration and necrosis in the liver due to D-Galn hepatotoxicity which indicates its prominent curative effect. The antagonism of Chaihu Yugan Decoction on necrosis may be correlated with an increase Bcl-2 and a decrease expression of Bax,Calpain and TNF-α.
2. Radix aconiti carmichaeli can abate the liver injury in immune liver injury model rats and and possess a certain action of protecting liver and lowering transaminase. To use metabolomic method to help evaluate drug efficacy is a direct, comprehensive, and effective new method.
3. Two different treatment methods Targeting at heat and dampness, cold and dampness both exhibited varying degree curative effect.
在中医理论指导下,试探性地寻找适合相应中医治法的造模方式。从中医药防治湿热变证的方法入手,对急性肝损伤进行防治。分别观察两种不同的治疗湿热变证的中医治法对两种不同类型的急性肝损伤动物模型的疗效,并初步探讨其保肝作用机制。特别研究中药复方对肝细胞胀亡的影响,拓宽对中药保肝机制的研究,期望为中医药防治急性肝损伤提供更多新的理论依据和有效方药。
方法：
根据湿热病邪导致的中医不同证型：湿热之邪从热化或湿热之邪从寒化,分别选择相应方药,选择适合该证型的造模方法,对其疗效及作用机制进行探讨。针对湿热之邪从热化,选用具有和解少阳、清热祛湿、滋阴活血的中药复方柴胡愈肝汤方进行研究,观察其对D-Gal造成的化学性急性肝损伤大鼠的影响。对于湿热之邪从寒化,选用具有补火助阳,散寒止痛的单味中药附子振奋阳气,温化寒湿,观察其对卡介苗(BCG)／脂多糖(LPS)造成的免疫性急性肝损伤大鼠模型的影响。
1.柴胡愈肝汤方治疗D-Galn所致大鼠急性肝损伤：SD大鼠,雌性,60只,随机分为空白对照组、模型组、联苯双酯组、中药低、中、高剂量组,每组10只。除空白对照组外,一次性腹腔注射D-Galn600mg/kg以造成肝损伤模型,造模后立即给予药物灌胃治疗,每日两次,其中联苯双酯组的日给药量为4.5mg/kg,中药低中高剂量组的日给药量分别为：11.8g/kg、23.6g/kg和47 g/kg。造模48h后,所有大鼠股动脉采血,取血浆测ALT、AST、TB、Calpain、TNF-α、IL-18。处死动物,取肝右叶作常规HE切片,透射电镜下观察肝细胞形态结构。免疫组化法检测肝组织中bcl-2、bax的表达。
2.附子防治BCG/LPS所致大鼠急性肝损伤：将50只SD大鼠随机分为5组：正常组10只,模型组10只(采用卡介苗联合脂多糖法建立免疫性肝损伤的大鼠模型),低、中、高剂量治疗组各10只(治疗组采用附片免煎剂进行干预)。造模成功后24h取大鼠血清观察ALT、AST、TBIL、MDA、SOD的改变情况,取肝组织进行病理组织学检查,用核磁共振法对肝组织中的小分子代谢产物进行检测。
结果：
1.柴胡愈肝汤方对D-Galn所致大鼠急性肝损伤的治疗作用：
(1)造模后48h,模型组血浆中ALT、AST、TB含量明显升高,与正常组相比差异有统计学意义(P<0.05)。DDB组、柴胡愈肝汤方低、高剂量治疗组、阳性对照组血浆中ALT、AST、TB含量与模型组相比均降低,差异有统计学意义(P<0.05)；中剂量组血浆中ALT、TB下降,与模型组相比有统计学意义(P<0.05)。
(2)造模后48h,模型组血浆Calpain、TNF-α、IL-18表达明显增高,差异显著(P<0.05)。与模型组相比,DDB组、低剂量治疗组血浆TNF-α、Calpain、IL-18表达明显降低,中剂量组血浆TNF-α表达降低,高剂量组血浆TNF-α、Calpain表达降低,差异均具有统计学意义(P<0.05)。中剂量组对血浆Calpain、IL-18影响不显著(P>0.05),高剂量组对血浆IL-18影响不显著(P>0.05)。
(3)模型组肝组织bcl-2表达明显下降,bax表达明显增高,与正常组相比差异有统计学意义(P<0.05)。与模型组相比,DDB组、柴胡愈肝汤低、高剂量组均能有效降低造模后肝组织中bax表达,增强肝组织中bcl-2的表达,有明显差异(P<0.05)。中剂量组对肝组织中bax、bcl-2表达水平的影响不显著(P>0.05)。
(4)肝组织HE染色检测结果显示：模型组脂肪样变、空泡样变明显,并存在散在的点灶状坏死,治疗组脂变、空泡样变程度及面积均较模型组减轻,其中柴胡愈肝汤高剂组和DDB组病变最轻,低剂组病变次之,中剂量组变性程度与模型组差别不明显。
(5)肝组织电镜结果表明：模型组肝细胞同时出现胀亡、凋亡两种不同的死亡形态,明显可见肝细胞内线粒体肿胀、破损,嵴退化或消失,内质网扩张或崩解。高剂组和DDB组肝细胞坏死程度较轻,肝细胞内线粒体肿胀不明显。中剂量组与模型组相比病变改善程度不明显。
2.附子对BCG/LPS所致大鼠急性肝损伤的保护作用：
(1)各用药组均能明显降低BCG/LPS所致免疫性肝损伤大鼠血清的ALT、AST、TBIL、MDA,与模型组比较有显著性差异(P<0.05)。
(2)肝组织病理学检查,低、中、高剂量治疗组肝组织肝小叶结构基本正常,肝窦充血与炎性细胞浸润明显减轻,肝细胞坏死亦显著减少。其中以高剂量治疗组损伤的程度最轻。
(3)用核磁共振的方法检测各组肝组织的小分子代谢产物,检测结果表明附子免煎剂能减轻肝损伤所造成的肝组织小分子代谢物的改变,其中以高剂量治疗组样本点偏向正常组更为明显。
结论：
1.柴胡愈肝汤低、高剂量治疗组均能显著降低D-Gal所致的肝细胞损伤,降低血浆中ALT、AST、TB含量,具有一定的保肝降酶作用。同时该方能显著改善急性肝损伤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,具有对抗细胞凋亡和细胞胀亡双重作用。其作用途径可能与减轻线粒体损伤,降低bax、Calpain、TNF-α,升高bcl-2表达密切相关。
2.中药附子免煎剂能够减轻免疫性肝损伤大鼠的肝损害,具有一定的保肝降酶作用,其作用机制可能与减少脂质过氧化有关。同时借用核磁共振的检测手段帮助评价药物疗效是一种直观、全面、行之有效的新方法。
3.两种不同的治法的方药,分别对化学性急性损伤和免疫性急性肝损伤的实验动物模型有不同程度的防治作用。
Objective:
To search for the suitable model to the therapeutical principle and method under the guidenece of TCM theory. Observe the liver protection respectively by two different methods for curting deterioration of damp-heat syndrome, and explore the action mechanism. To study specially the the effect of prescription on oncosis, and investigate the action mechanism of liver protection. Hope that it can provide more new theoretical basis and effective prescriptions for treatment of acute liver injury.
Methods:
Choose suitable prescriptions and model according chinese medicine syndrome types to study the curative effect and action mechanism. Select the prescription of Chaihu Yugan Detection that helps to clear heat, dispel dampness, promote blood flow, nourish yin targeting at predominance of heat, to remedy acute liver injury rats caused by D-Gal rats with acute liver injury.And select the chinese herb of radix aconiti carmichaeli that helps to warming yang,dipel cold,and relieve the pain to remedy acute liver injury rats that caused by BCG/LPS.To investigate the curative effection and action mechanism.
1.Chaihu Yugan Detection remedy the acute liver injury caused by D-Galn:Sixty female SD rats were randomized into six groups with 10 in each group, normal control group, model group, diphenyl dimethyl bicarboxylate (DDB) group, low-dose group, middle-dose group and high-dose group. Intraperitoneal injection of D-Galn at a dose of 600mg/kg was administered to the rats except those in the normal 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 DDB is 4.5mg/kg, and dosage of the three herbal groups was 11.8g/kg,23.6g/kg and 47g/kg respectively,2 daily. All the medications were given at a volume of 10ml/kg, twice a day for two days.48 hours later, all the rats were sacrificed with their serum ALT, AST, TB, Calpain, TNF- αand IL-18 being examined. Right lobe of the liver was applied to make routine HE slices and pathological changes were examined under the microscope. The expression of bcl-2 and bax were analyzed by immunohistochemical.
2. Radix aconiti carmichaeli remedy the acute liver injury caused by BCG/LPS: Divide 50 rats into 5 groups randomly:normal control group(group A), model group (group B), low-dose group (group C), middle-dose group (group D) and high-dose group (group E). BCG and LPS were injected intrapefitoneally(ip) to rats in Gb、Gc、Gd and Ge to induce acute immune liver injury. And then Gc、Gd and Ge were treated with different doses of traditional Chinese medicine respective. Observe the changes of ALT、AST、TBIL、MDA、SOD in serum of rats and the diseased tissues. Verify the smaller molecule metabolites in liver tissue by nuclear magnetic resonance.
Results:
1. The curative effect of Chaihu Yugan Decoction on acute liver injury caused by D-Galn:
(1)The Chaihu Yugan Decoction at an oral dose of 11.8g/kg and 47g/kg exhibited a significant (P<0.05 for all) curative effect by normalizing the levels of alanine amino transferase (ALT), aspartate amino transferase (AST) and total bilirubin (TB) which were significantly (P<0.05) increased at 48h later in rats by treatment with 600 mg/kg D-Galn. DDB (4.5 mg/kg), a known hepatoprotective drug used for comparison exhibited significant curative effect in terms of ALT, AST and TB (P<0.05). The Chaihu Yugan Decoction at an oral dose of 23.6g/kg exhibited significant curative effect in terms of ALT and TB (P<0.05).
(2) Calpain、Tumor necrosis factor alpha (TNF-α) and interleukin-18(IL-18) levels in human plusma increased significantly in the model group compared to that of normal group (P<0.05). DDB group and low dose group exhibited a significant (P<0.05 for all) curative effect by normalizing the levels of Calpain、TNF-αand IL-18 compared to model group.
(3) The expression of bax levels decreased significantly, whereas bcl-2 increased significantly in the model group compared to that of normal group (P<0.05). DDB group, low dose group and high dose group exhibited a significant (P<0.05 for all) curative effect by normalizing the levels of bax and increasing the levels of bcl-2 compared to modle group. Middle dose group did not affect bcl-2 or bax levels in liver tissue significantly (P> 0.05)
(4)Pathologic changes from the HE slices suggested that size of fatty degeneration, hydropic degeneration and focal necrosis in the model group was much larger than that of the treatment group in which the high dose group and DDB group exhibited the better protective effects.
(5) The ultrastructure of the hepatocyte showed that:liver cells in model group appeared simultaneous death of oncosis and apoptosis. There were swollen nad deformed mitochondrias in liver cells, some of which were destroyed in structure. Endoplasmic reticulum expanded or collapsed. High dose group and DDB group exhibited the better protective effect. Middle dose group was not significantly difference than modle group.
2. Curative effect and metabonomic of radix aconiti carmichaeli to acute liver injury caused by BCG/LPS:
(1)All the treatment groups exhibited a significant (P<0.01 for all) curative effect by normalizing the levels of alanine amino transferase (ALT), aspartate amino transferase (AST), total bilirubin (TB) and MDA which were significantly (P<0.05) increased in rats by treatment with BCG/LPS.
(2) Pathologic changes from the HE slices suggested that size of lobular architecture were almost normal in all treatment groups. Hydropic degeneration and focal necrosis in treatment groups was much larger than that of the treatment group in which the high dose group and DDB group exhibited the better protective effects
Conclusions:
1. Chaihu Yugan Decoction could lower down the increased serum ALT, AST and TB levels in D-Galn-induced hepatotoxic rats and decrease the size of degeneration and necrosis in the liver due to D-Galn hepatotoxicity which indicates its prominent curative effect. The antagonism of Chaihu Yugan Decoction on necrosis may be correlated with an increase Bcl-2 and a decrease expression of Bax,Calpain and TNF-α.
2. Radix aconiti carmichaeli can abate the liver injury in immune liver injury model rats and and possess a certain action of protecting liver and lowering transaminase. To use metabolomic method to help evaluate drug efficacy is a direct, comprehensive, and effective new method.
3. Two different treatment methods Targeting at heat and dampness, cold and dampness both exhibited varying degree curative effect.
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