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Rotective Effects of Quercetin Against the Triptolide Induced Liver Injury and Relevant Mechanism Study
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摘要:目的 探究槲皮素(quercetin，QE)对雷公藤甲素(triptolide，TP)诱发肝损伤的拮抗机制。方法 取40只C57BL/6小鼠，随机平均分为正常对照组、TP模型组、低剂量QE(20 mg/kg)组和高剂量QE(80 mg/kg)组。低剂量QE组和高剂量QE组进行预处理给药，按0.2 mL/10 g量连续灌胃10 d，2次/d，其余各组灌胃等量生理盐水。末次给药4 h后，除正常对照组外，各组单次灌胃500 μg/kg TP进行造模。造模22 h后取血，处死小鼠，肝切片HE染色观察肝组织病理学改变；检测小鼠血清中谷草转氨酶(AST)和谷丙转氨酶(ALT)活性；测定肝匀浆液中还原型谷胱甘肽(GSH)、超氧化物歧化酶(SOD)和丙二醛(MDA)水平；采用ELISA方法检测肝匀浆液中白细胞介素(IL)-17、IL-10和IL-6分泌情况；Western blot测定Toll样受体4(TLR4)蛋白表达水平。结果 与正常对照组比较，TP模型组肝小叶结构萎缩甚至消失，肝细胞坏死明显，炎性细胞浸润；小鼠血清中ALT、AST和MDA水平异常升高，SOD和GSH水平降低，IL-6和IL-17分泌水平升高，IL-10分泌水平下降，TLR4蛋白水平升高(P < 0.05)。与TP模型组相比，QE组肝组织损伤和炎症细胞浸润减轻，血清中ALT、AST、MDA、IL-6和IL-17水平均下降，TLR4表达水平下调(P < 0.05)，且高剂量QE组改变更为明显(P < 0.05，与低剂量QE组比较)。结论 槲皮素可通过减轻氧化损伤促进抗氧化，调控细胞因子的分泌，减轻TP诱导的肝损伤。Abstract:Objective To explore the protective effects of quercetin (QE) on triptolide (TP) induced liver injury and the relevant mechanism.Methods Forty C57BL/6 mice were equally divided into 4 groups, control group, TP model group, 20 mg/kg QE treatment group and 80 mg/kg QE treatment group randomly. The 20 mg/kg and 80 mg/kg QE groups were gastrointestinal administration with QE at the dose of 0.2 mL/10 g for 10 d, twice daily, while other groups were administrated with equivalent normal saline. Four hours post the last dose, animals were gastrointestinal administered with TP at a dose of 500 μg/kg per mouse, except for NS control. All the mice were sacrificed 22 h later, blood and liver tissue samples were collected. The pathologic change of liver tissue was detected by HE staining. The level of aminotransferase (AST) and aspartate alanine aminotransferase (ALT) in serum, and the level of glutathione (GSH), malondialdehyde (MDA) and superoxide dismutase (SOD) in liver tissue homogenates were detected using the commercial kits. The level of interleukin (IL)-17, IL-10 and IL-6 in liver tissue homogenates was measured by ELISA. Hepatic expression of Toll-like receptor 4 (TLR4) was detected by Western blot.Results Compared with the control group, in the TP model group, hepatic lobule structure atrophied and even disappeared, hepatic cell necrosis and inflammatory cell infiltration are obvious. Additionally, in TP model group, serum ALT, AST and MDA levels were significantly increased, SOD and GSH levels were decreased, IL-6 and IL-17 levels were increased, IL-10 levels were decreased, and TLR4 protein levels were increased (P < 0.05). Compared with the TP model group, liver tissue injury and inflammatory cell infiltration were reduced in the QE group, and serum levels of ALT, AST, MDA, IL-6 and IL-17 were all decreased. TLR4 expression was down-regulated (P < 0.05) in both QE groups, and the decease levle was more significant in the high-dose QE group (P < 0.05, compared with the low-dose QE group).Conclusion Quercetin can reduce TP-induced liver injury by reducing oxidative damage, promoting antioxidant and regulating cytokine secretion.
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Keywords:
- Triptolide /
- Quercetin /
- Liver injury /
- Cytokine /
- Oxidative stress
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雷公藤甲素(triptolide，TP)为卫矛科植物雷公藤的主要有效成分，属于二萜内酯类化合物，具有抗炎、抗氧化、抗类风湿、抗老年性痴呆症、抗癌等活性，常被用于自身免疫病和癌症的辅助治疗手段[1-5]。由于雷公藤毒性较强，可对脏器造成实质性损伤，故非疑难杂症或重大疾病者应慎用之[6-7]。研究表明，300~1 000 μg/kg TP可引起脂质氧化、诱导肝细胞坏死，从而引起TP肝损伤[8-9]；且白介素(IL)-6、IL-10和IL-17等细胞因子参与了TP肝损伤过程，并最终导致肝脏炎症和功能受损[10-12]，而且这一过程与Toll样受体4(TLR4)的作用直接相关[13-14]。
槲皮素(quercetin，QE)是天然黄酮类物质之一，广泛存在于植物的花、叶、果实中，具有抗炎、抗氧化、抗癌等作用[15-16]。研究表明，QE可减轻由CCl4[17]、全氟辛酸[18]等引起的肝损伤。本实验拟用TP诱导小鼠肝损伤模型[19]，检测不同剂量QE预处理后TP肝损伤小鼠的肝脏病理学改变，肝脏酶学、氧化应激水平以及细胞细胞因子及受体的表达的变化，从氧化应激和细胞因子的调控探讨QE拮抗TP诱导的肝损伤的作用机制。
1. 材料和方法
1.1 器材与试剂
重庆医科大学提供SPF级雌性C57BL/6小鼠(18~20 g)。TP和QE标准品购于四川维克奇有限公司购买(雷公藤甲素和槲皮素)，生化试剂盒〔谷草转氨酶(AST)、谷丙转氨酶(ALT)、还原型谷胱甘肽(GSH)、超氧化物歧化酶(SOD)和丙二醛(MDA)〕购自建成生物工程研究所；细胞因子试剂盒(IL-6、IL-10和IL-17)购于桥杜生物科技有限公司；ECL化学发光试剂盒、SDS-PAGE试剂盒和BCA检测试剂盒购于碧云天生物技术有限公司；β-actin和TLR4抗体购于万类生物科技有限公司。
1.2 方法
1.2.1 构建TP肝损伤模型
将C57BL/6小鼠随机均分4组：正常对照组、TP模型组、低剂量QE组和高剂量QE组。低剂量QE(20 mg/kg)组和高剂量QE(80 mg/kg)组按0.2 mL/10 g连续灌胃10 d，2次/d，进行预处理，其余各组灌胃等量生理盐水。末次给药4 h后，除正常对照组外，各组单次灌胃500 μg/kg的TP进行造模。文献[6, 19]和预实验结果均表明TP造模22 h后实验结果较为稳定，故此选择此时间点取血，然后脱臼处死实验小鼠，取肝脏组织，制作切片和制备10%肝脏匀浆液。
1.2.2 小鼠肝组织病理学检测
肝组织经体积分数4%多聚甲醛溶液固定，石蜡包埋，切片，经HE染色，在光学显微镜下观察并拍照，观察小鼠的肝脏病理学损伤。
1.2.3 小鼠血清和肝组织生化指标检测
各组小鼠血液静置5 min，2 000 r/min离心10 min，制备血清，采用赖氏法检测ALT和AST活性。操作步骤严格按照说明书进行。制备10%肝脏组织匀浆，按MDA、SOD和GSH试剂盒说明测定各生化指标的水平。取10%肝匀浆液，按ELISA试剂盒说明测定IL-6、IL-10和IL-17分泌水平。
1.2.4 Western blot检测小鼠肝组织TLR4蛋白表达
取10%肝匀浆液加裂解液，12 000 r/ min离心10 min，采用BCA法测定TLR4蛋白含量，经SDS-PAGE分离后湿法转膜，封闭2 h后分别孵育抗TLR4(1:200)，以β-actin(1:2 000)为内参，经化学发光法检测，图像采集，Quantity one软件进行图像分析灰度值，以目的条带与内参条带灰度值的比值为各组TLR4蛋白的表达量。
1.2.5 统计学方法
数据以x±s表示。首先进行ANOVA分析，进一步行t检验，P＜0.05为差异有统计学意义。
2. 结果
2.1 各组小鼠肝组织病理学改变
见图 1。正常对照组小鼠呈现组织完整、汇管区正常分布、肝小叶清晰可见、结构规则的肝脏组织；TP模型组多发炎性细胞浸润，肝细胞大面积坏死、肝小叶结构呈明显不规则分布；低剂量QE组小鼠肝组织局部发生炎性细胞浸润，肝细胞呈现少量变性和坏死；高剂量QE组小鼠肝小叶结构趋于正常，肝索及汇管区规则排布，几无炎性细胞浸润，整体形态趋于正常。
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图 1 QE对各组小鼠肝组织病理学形态的影响Figure 1. Effect of QE on liver in mice with immunological liver injuryA: Control group; B: TP group; C: Low dose QE group; D: High dose QE group2.2 各组小鼠血清中肝脏酶学的改变
与正常对照组相比，TP模型组小鼠血清中ALT和AST水平升高(P < 0.05)，说明成功诱导TP肝损伤模型。与TP模型组比较，低剂量QE组ALT和AST水平降低不明显(P>0.05)，高剂量QE组小鼠血清中ALT和AST水平降低(P < 0.05)，高、低剂量QE组间差异有统计学意义(P < 0.05)。见表 1。
表 1 各组血清酶学指标的比较Table 1. Enzymatic indexes of serumGroup n ALT/(nmol/mg) AST/(U/mg) Control 10 4.58±1.09 19.16±3.47 TP 10 67.18±6.83 # 73.47±4.96 # Low dose QE 10 66.68±3.93 #，△ 70.18±5.68 #，△ High dose QE 10 14.45±4.27 #，* 16.65±3.71 * #P＜0.05, vs. control group；* P＜0.05, vs. TP group；△P＜0.05，vs. high dose QE group 2.3 各组小鼠肝脏中氧化水平的改变
见表 2。与对照组相比，TP模型组肝匀浆液中SOD和GSH含量偏低(P < 0.05)，而MDA含量升高(P < 0.05)；低剂量QE组与TP组MDA、SOD和GSH的水平无明显差异；而高剂量QE组小鼠较TP模型组GSH和SOD水平升高(P < 0.05)，MDA水平降低(P < 0.05), 高、低剂量QE组间上述指标差异有统计学意义(P < 0.05)。
表 2 槲皮素对TP肝损伤小鼠的MDA、GSH、SOD水平影响Table 2. Effect of QE on hepatic MDA, GSH and SOD in mice with immunological liver injuryGroup n MDA/(nmol/mg) SOD/(U/mg) GSH/(nmol/mg) Control 10 1.35±0.23 384.26±18.47 6.13±0.59 TP 10 4.98±0.63# 263.47±32.96# 2.19±0.66# Low dose QE 10 4.04±0.13#，△ 287.88±19.28#，△ 3.43±0.18#，△ High dose QE 10 1.45±0.27* 390.65±24.71* 5.96±0.59* #P＜0.05, vs. control group; * P＜0.05, vs.TP group; △ P＜0.05，vs.high dose QE group 2.4 各组小鼠肝脏中细胞因子水平的改变
见表 3。与正常对照组相比，TP造模组小鼠的IL-17和IL-6的分泌水平上升，IL-10分泌水平下降(P < 0.05)。低剂量QE组小鼠各项指标与TP模型组比较均无明显差异；高剂量QE组与TP模型组比较，小鼠的IL-17和IL-6的分泌水平降低(P < 0.05)，IL-10分泌水平升高(P < 0.05), 高、低剂量QE组之间上述指标的差异有统计学意义(P < 0.05)。
表 3 槲皮素对TP肝损伤小鼠IL-10、IL-17、IL-6水平影响Table 3. Effect of QE on hepatic IL-10, IL-17 and IL-6 in mice with immunological liver injuryGroup n IL-10/(pg/mL) IL-17/(pg/mL) IL-6/(pg/mL) Control 10 309.51±18.22 191.74±47.49 129.99±5.15 TP 10 224.43±25.32# 399.97±19.24# 199.94±11.69# Low dose QE 10 249.31±9.22#，△ 375.38±16.73#，△ 180.57±7.59#，△ High dose QE 10 320.64±33.56* 224.05±22.70* 120.17±31.77* #P＜0.05, vs.control group; * P＜0.05, vs.TP group; △ P＜0.05，vs.high dose QE group 2.5 各组小鼠肝脏TLR4蛋白表达的改变
Western blot结果(图 2)显示，正常对照组小鼠中TLR4仅呈现本底表达；与正常对照组比较，TP模型组中TLR4表达水平升高；低剂量QE组预处理后，TLR4蛋白表达水平下降，与正常对照组和TP模型组相比，差异有统计学意义(P < 0.05)；而高剂量QE组预处理后，TLR4蛋白表达进一步降低，恢复至正常对照组水平(P>0.05)，与TP模型组及低剂量QE组相比，差异有统计学意义(P < 0.05)。
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图 2 各组小鼠TLR4蛋白表达比较Figure 2. The protein expression of TLR4 in 4 groupsA: Control group; B: TP group; C: Low dose QE group; D: High dose QE group; #P < 0.05, vs.A; *P < 0.05, ** P < 0.005, vs. B; ▲P < 0.05, vs. D3. 讨论
药物性肝损伤[20]是临床上最常见的药物不良反应之一，严重者可导致急性肝衰竭, 甚至死亡。近年来，随着社会的发展和医疗水平的提高，我国用药种类和频次逐年增多，药物性肝损伤发生概率[21]亦逐渐增加。TP是一种二萜内酯类化合物[22]，它具有免疫抑制、抗炎、抗生育及抗肿瘤等生物活性[23]，因此在临床上特别是治疗自身免疫性疾病等难治性疾病中得到广泛的运用，但其毒性和不良反应，尤其是肝毒性在使用过程中不容忽视[24]。因此，关于TP肝损伤的机制研究逐渐成为肝病研究学者关注的热点。QE是一种黄酮类化合物，表现出极强的抗氧化和清除氧自由基能力，以及抗炎和抗癌等活性[25]。本研究采用TP诱导肝损伤模型，观察QE拮抗肝损伤的作用，并探究其机制。造模后，经病理检测显示肝小叶结构萎缩甚至消失，肝脏实质细胞坏死明显，炎性细胞浸润多发，小鼠血清中ALT、AST和MDA水平异常升高，一系列指标显示肝组织和细胞损伤严重，氧化应激反应强烈。同时，SOD和GSH水平降低，表明小鼠的自身抗氧化能力受到抑制。综上所述，TP诱导造模可诱发实验小鼠的急性肝损伤。
经高剂量QE(80 mg/kg)预处理，急性肝损伤发生后，小鼠血清中ALT、AST和MDA水平较TP模型组下降，SOD和GSH水平较TP模型组升高。数据显示，高剂量QE对TP肝损伤发挥修复作用，此过程可能与抑制氧化应激和促进抗氧化作用有关。
本研究继续从细胞因子层面进行剖析。IL是由多种细胞产生并作用于多种细胞的一类细胞因子，在传递信息，激活与调节免疫细胞，介导T和B细胞活化、增殖与分化及在炎症反应中发挥重要的作用[26]。Th17细胞分泌的IL-17通过与IL-17R结合，可以刺激上皮细胞、内皮细胞、成纤维细胞产生IL-6、IL-8等多种细胞因子，增强细胞间黏附分子的表达。IL-10可由Treg细胞分泌，主要功能是调节其他免疫细胞的功能并抑制免疫反应，从而介导自身免疫耐受和维持免疫平衡[27]。相关研究已证明Th17/Treg失衡参与了肝损伤的发病过程[28-30]，故而Th17/Treg失衡情况、TLR-4、IL-6和IL-17以及IL-10等细胞因子可客观反应出TP诱导肝损伤情况。本研究发现，与TP模型组比较，高剂量QE可显著上调Treg细胞应答相关的IL-10水平，抑制Th17细胞应答相关的IL-17、IL-6和TLR4等的表达，由此可推测高剂量QE通过细胞因子和受体的表达影响Th17/Treg失衡，从而对TP肝损伤起到拮抗作用。
综上所述，本研究证实TP诱导可触发Th17/Treg失衡和氧化应激发生，从而引起严重的急性肝损伤；而高剂量QE预处理则通过减少氧化应激，激发自身抗氧化能力，调控与Th17/Treg平衡相关细胞因子等一系列过程，启动肝脏保护作用。本研究为药物性肝损伤的发生机制和修复方法探索了一条新路径。
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图 1 QE对各组小鼠肝组织病理学形态的影响
Figure 1. Effect of QE on liver in mice with immunological liver injury
A: Control group; B: TP group; C: Low dose QE group; D: High dose QE group
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图 2 各组小鼠TLR4蛋白表达比较
Figure 2. The protein expression of TLR4 in 4 groups
A: Control group; B: TP group; C: Low dose QE group; D: High dose QE group; #P < 0.05, vs.A; *P < 0.05, ** P < 0.005, vs. B; ▲P < 0.05, vs. D
表 1 各组血清酶学指标的比较
Table 1 Enzymatic indexes of serum
Group n ALT/(nmol/mg) AST/(U/mg) Control 10 4.58±1.09 19.16±3.47 TP 10 67.18±6.83 # 73.47±4.96 # Low dose QE 10 66.68±3.93 #，△ 70.18±5.68 #，△ High dose QE 10 14.45±4.27 #，* 16.65±3.71 * #P＜0.05, vs. control group；* P＜0.05, vs. TP group；△P＜0.05，vs. high dose QE group 
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表 2 槲皮素对TP肝损伤小鼠的MDA、GSH、SOD水平影响
Table 2 Effect of QE on hepatic MDA, GSH and SOD in mice with immunological liver injury
Group n MDA/(nmol/mg) SOD/(U/mg) GSH/(nmol/mg) Control 10 1.35±0.23 384.26±18.47 6.13±0.59 TP 10 4.98±0.63# 263.47±32.96# 2.19±0.66# Low dose QE 10 4.04±0.13#，△ 287.88±19.28#，△ 3.43±0.18#，△ High dose QE 10 1.45±0.27* 390.65±24.71* 5.96±0.59* #P＜0.05, vs. control group; * P＜0.05, vs.TP group; △ P＜0.05，vs.high dose QE group
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表 3 槲皮素对TP肝损伤小鼠IL-10、IL-17、IL-6水平影响
Table 3 Effect of QE on hepatic IL-10, IL-17 and IL-6 in mice with immunological liver injury
Group n IL-10/(pg/mL) IL-17/(pg/mL) IL-6/(pg/mL) Control 10 309.51±18.22 191.74±47.49 129.99±5.15 TP 10 224.43±25.32# 399.97±19.24# 199.94±11.69# Low dose QE 10 249.31±9.22#，△ 375.38±16.73#，△ 180.57±7.59#，△ High dose QE 10 320.64±33.56* 224.05±22.70* 120.17±31.77* #P＜0.05, vs.control group; * P＜0.05, vs.TP group; △ P＜0.05，vs.high dose QE group
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