图1 各组大鼠肝脏外观形态图
Published:30 March 2024,
Received:19 August 2023,
Revised:29 December 2023
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To investigate the intervention effect and potential mechanism of breviscapine on hepatic fibrosis (HF) in rats based on the transforming growth factor-β1(TGF-β1)/Smad2/extracellular signal-regulated protein kinase 1(ERK1) and Kelch-like epichlorohydrin-associated protein 1(Keap1)/nuclear factor-erythroid 2-related factor 2(Nrf2)/heme oxygenase-1(HO-1) pathways.
Totally 60 rats were randomly divided into normal control group, model group, breviscapine low-dose, medium-dose and high-dose groups (5.4, 10.8, 21.6 mg/kg), and colchicine group (positive control, 0.45 mg/kg), with 10 rats in each group, half male and half female. Except for the normal control group, HF model of the other groups was induced by carbon tetrachloride. Subsequently, each drug group was given corresponding medicine by gavage once a day for 28 days. The liver appearance of rats in each group was observed and their liver coefficients were calculated. The levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum, those of ALT, AST, superoxide dismutase (SOD), malondialdehyde (MDA) and glutathione peroxidase (GSH-Px) in liver tissue were detected. The liver tissue inflammatory and fibrotic changes were observed. The protein and mRNA expressions of TGF-β1, Smad2, ERK1, Nrf2, Keap1 and HO-1 in liver tissue were detected.
Compared with the normal control group, the model group showed large areas of white nodular lesions in the liver, obvious inflammatory cell infiltration and collagen fiber deposition. The body weight, the levels of SOD and GSH-Px in liver tissue, the protein and mRNA expressions of Nrf2 and HO-1 were significantly lowered in the model group (P<0.05); the liver coefficient, the percentage of Masson staining positive area, ALT and AST levels of serum and liver tissue, MDA level of liver tissue, the protein and mRNA expressions of TGF-β1, Smad2, ERK1 and Keap1 were significantly increased (P<0.05). Compared with the model group, the liver lesions of rats in each drug group were improved, and the above quantitative indexes were generally reversed (P<0.05).
Breviscapine has a good intervention effect on HF rats, which may be related to inhibiting TGF-β1/Smad2/ERK1 pathway for anti-fibrosis and regulating Keap1/Nrf2/HO-1 pathway to inhibit oxidative stress.
肝纤维化(hepatic fibrosis,HF)是慢性肝病发展到肝硬化乃至肝癌的共同途径[1―2]。当肝损伤发生时,受损的上皮细胞和纤维化组织可激活肝星状细胞(hepatic stellate cells,HSCs),并使HSCs转化为肌成纤维细胞(myofibroblast,MFB)表型,合成大量肝细胞外基质(extracellular matrix,ECM),致使ECM合成与降解失衡,形成瘢痕组织,最终引发HF[
中医学将HF归为“积聚”“胁痛”范畴[
本研究所用主要仪器有FlexA-200型酶标仪(杭州奥盛仪器有限公司)、CX41型光学显微镜(日本Olympus公司)、StepOneTM plus型实时荧光定量聚合酶链式反应(PCR)仪(美国ABI公司)、HY1508型石蜡切片机(金华惠友仪器设备有限公司)等。
灯盏花素片(批号20220732,每片含灯盏花素20 mg)购自云南生物谷药业股份有限公司;秋水仙碱片(批号210715,每片含秋水仙碱0.5 mg)购自西双版纳版纳药业有限责任公司;四氯化碳(CCl4,批号20210612)购自天津市富宇精细化工有限公司;羧甲基纤维素钠(CMC-Na,批号20160704)购自国药集团化学试剂有限公司;丙氨酸转氨酶(alanine aminotransferase,ALT)试剂盒(批号C009-1-1)、天冬氨酸转氨酶(aspartate aminotransferase,AST)试剂盒(批号C010-1-1)、超氧化物歧化酶(superoxide dismutase,SOD)试剂盒(批号A001-1-2)、丙二醛(malondialdehyde,MDA)试剂盒(批号A003-1-2)、谷胱甘肽过氧化物酶(glutathione peroxidase,GSH-Px)试剂盒(批号A005-1-2)均购自南京建成生物工程研究所;兔免疫组化试剂盒(批号SP-9001),DAB显色试剂盒(批号ZLI-9018),兔抗大鼠TGF-β1、Smad2、ERK1、Keap1、Nrf2、HO-1抗体(批号分别为GB13028、GB11511、GB13003、GB11847、GB113808、GB11104),辣根过氧化物酶标记的山羊抗兔IgG二抗(批号G1213-100UL),TriQuick总RNA提取试剂(批号R1100),cDNA合成试剂盒(批号G3330),实时荧光定量PCR扩增试剂(批号G3320)均购自武汉赛维尔生物科技有限公司。
SPF级健康SD大鼠60只,雌雄各半,体重180~200 g,由郑州市惠济区华兴实验动物养殖场提供,动物生产许可证号为SCXK(豫)2019-0002。所有动物均饲养于河南中医药大学医学机能实验室(室温20~22 ℃,相对湿度55%~60%,正常光照),自由饮水、采食。本实验方案获河南中医药大学第一附属医院伦理委员会批准(编号DWLL202201010)。
将60只大鼠按随机数字表法分为正常对照组,模型组,灯盏花素低、中、高剂量组(5.4、10.8、21.6 mg/kg)和秋水仙碱组(阳性对照,0.45 mg/kg),每组10只,雌雄各半。除正常对照组外,其余各组大鼠均按1 mL/kg腹腔注射50%CCl4-橄榄油溶液,每周2次,连续4周。若大鼠血清中ALT、AST水平显著升高,且肝组织可见明显纤维化病变和炎症细胞浸润,则表明HF模型复制成功[
末次给药24 h后,称取各组大鼠体重,麻醉后于腹主动脉取血,血样于常温下静置1~2 h,低温离心,取上层血清,于-80 ℃下储存,备用。取血后,脱颈椎处死各组大鼠并剖取肝脏,去除周围组织,以生理盐水洗涤,观察其外观形态,用滤纸吸尽其表面液体后称重;随后,将肝脏一分为二,其中一份用4%多聚甲醛固定,另一份用液氮速冻后于-80 ℃下储存,备用。
根据大鼠体重、肝脏质量,按下式计算各组大鼠的肝脏系数:肝脏系数=肝脏质量/体重。
采用酶联免疫吸附测定(ELISA)法检测。取“2.2”项下各组大鼠血清样品适量,按照相应试剂盒说明书方法操作,以酶标仪检测血清中ALT、AST水平。
采用ELISA法检测。称取“2.2”项下各组大鼠冻存的肝组织适量,加入冰生理盐水0.9 mL制备10%匀浆液,以3 000 r/min离心10 min,取上清液适量,按照相应试剂盒说明书方法操作,以酶标仪检测肝组织中ALT、AST、SOD、MDA、GSH-Px水平。
取“2.2”项下各组大鼠固定好的肝组织,经脱水、透明、包埋后,切片,进行常规苏木精-伊红(HE)染色,置于显微镜下观察肝组织病理变化。同法制作切片,进行Masson染色,置于显微镜下观察肝组织纤维化情况,并采用Image-Pro Plus 6.0软件检测Masson染色阳性(呈蓝色)面积百分比(即阳性面积与总面积的百分比值),用以评价肝组织的纤维化水平。
采用免疫组化法检测。取“2.6”项下各组大鼠的肝组织切片,经脱蜡、水化、封闭(H2O2)、清洗、抗原修复(柠檬酸盐缓冲液)后,滴加山羊血清封闭液,室温孵育;弃去上清液,分别滴加TGF-β1、Smad2、ERK1、Nrf2、Keap1、HO-1一抗(稀释比例均为1∶1 000),4 ℃孵育过夜;加入相应二抗(稀释比例为1∶100),常温孵育20~30 min,以DAB显色;冲洗后,以苏木精复染,再以盐酸乙醇溶液分化;冲洗后,脱水、透明、封片,置于显微镜下观察,并采用Image-Pro Plus 6.0软件检测阳性(呈棕黄色)区域的积分光密度(integrated optical density,IOD)值,用以评价目的蛋白的表达水平。
采用实时荧光定量PCR法检测。取“2.2”项下各组大鼠冻存的肝组织适量,加入TriQuick试剂1 mL,充分研磨匀浆后提取总RNA并检测RNA浓度及纯度。按cDNA合成试剂盒说明书方法操作,合成cDNA;以此cDNA为模板,进行PCR扩增。反应体系(共15 μL)包括cDNA模板2 μL,上、下游引物共1.5 μL,2×qPCR Mix 7.5 μL,无核酸酶水4 μL。扩增条件如下:95 ℃预变性10 min;95 ℃变性15 s,60 ℃退火30 s,72 ℃延伸30 s,共40个循环。反应结束后,根据扩增曲线及熔解曲线判断扩增结果,以甘油醛-3-磷酸脱氢酶(GAPDH)为内参,采用2-ΔΔCt法计算目的基因的相对表达水平(结果以正常对照组为参照进行归一化处理)。PCR引物序列及扩增产物片段长度见
目的基因 | 引物序列(5′→3′) | 扩增产物片段长度/bp |
---|---|---|
TGF-β1 | 上游引物:GCTGAACCAAGGAGACGGAATA | 194 |
下游引物:GCAGGTGTTGAGCCCTTTCC | ||
Smad2 | 上游引物:ACTGCCGCCTCTGGATGACTAT | 197 |
下游引物:AGAGAGTGGTAGGAGACAGTTCAGC | ||
ERK1 | 上游引物:GAGAGATGTTTACATTGTTCAGGACC | 273 |
下游引物:GCCACATACTCGGTAAGAAAGC | ||
Nrf2 | 上游引物:AATTGCCACCGCCAGGACT | 100 |
下游引物:TCAAACACTTCTCGACTTACCCC | ||
Keap1 | 上游引物:GAGATATGAGCCAGATCGAGACG | 183 |
下游引物:GGTGTAATCATCCGCCACTCAT | ||
HO-1 | 上游引物:CAGCATGTCCCAGGATTTGTC | 104 |
下游引物:CCTGACCCTTCTGAAAGTTCCTC | ||
GAPDH | 上游引物:CTGGAGAAACCTGCCAAGTATG | 138 |
下游引物:GGTGGAAGAATGGGAGTTGCT |
采用SPSS 24.0软件对数据进行统计分析。计量资料以x±s表示,多组间比较采用单因素方差分析,组间两两比较采用LSD-t检验(方差齐)或Dunnett检验(方差不齐)。检验水准α=0.05。
正常对照组大鼠肝脏形态正常,外观红润;模型组大鼠肝脏稍增大,颜色深,可见大面积白色结节灶;秋水仙碱组和灯盏花素低、中、高剂量组大鼠肝脏颜色较模型组浅,白色结节灶面积有所缩小。结果见
图1 各组大鼠肝脏外观形态图
与正常对照组比较,模型组大鼠的体重显著降低,而肝脏系数显著升高(P<0.05);与模型组比较,秋水仙碱组、灯盏花素高剂量组大鼠的肝脏质量和各药物组大鼠的肝脏系数均显著降低(P<0.05)。结果见
组别 | 体重/g | 肝脏质量/mg | 肝脏系数/(mg/g) |
---|---|---|---|
正常对照组 | 279.22±14.60 | 10 455.93±484.11 | 37.47±1.12 |
模型组 | 202.17±50.27a | 11 705.33±3 139.52 | 57.79±3.98a |
秋水仙碱组 | 223.17±32.07 | 8 612.87±1 401.42b | 38.57±1.97b |
灯盏花素低剂量组 | 222.33±64.32 | 10 899.48±3 149.85 | 49.21±2.35b |
灯盏花素中剂量组 | 235.83±38.77 | 10 635.57±1 579.16 | 45.20±1.20b |
灯盏花素高剂量组 | 237.50±16.63 | 9 969.07±701.04b | 41.98±0.92b |
a:与正常对照组比较,P<0.05;b:与模型组比较,P<0.05。
与正常对照组比较,模型组大鼠血清及肝组织中ALT、AST水平均显著升高(P<0.05);与模型组比较,各药物组大鼠血清及肝组织中ALT(灯盏花素低剂量组肝组织除外)、AST水平均显著降低(P<0.05)。结果见
组别 | 血清 | 肝组织 | ||
---|---|---|---|---|
ALT/(U/L) | AST/(U/L) | ALT/(U/L) | AST/(U/L) | |
正常对照组 | 28.78±5.35 | 131.22±7.44 | 207.87±16.82 | 129.17±6.85 |
模型组 | 167.87±11.79a | 362.29±27.17a | 371.53±6.64a | 506.00±83.80a |
秋水仙碱组 | 38.26±4.24b | 140.46±7.06b | 277.85±18.38b | 156.60±4.53b |
灯盏花素低剂量组 | 74.08±7.69b | 269.43±41.96b | 359.32±2.35 | 334.41±50.54b |
灯盏花素中剂量组 | 61.24±7.96b | 168.98±8.73b | 348.86±11.11b | 213.23±13.84b |
灯盏花素高剂量组 | 38.62±2.92b | 148.52±4.89b | 315.53±8.44b | 165.67±12.82b |
a:与正常对照组比较,P<0.05;b:与模型组比较,P<0.05。
与正常对照组比较,模型组大鼠肝组织中SOD、GSH-Px水平均显著降低,MDA水平显著升高(P<0.05);与模型组比较,各药物组大鼠肝组织中SOD、GSH-Px水平均显著升高,MDA水平均显著降低(P<0.05)。结果见
组别 | SOD/(U/mg) | MDA/(nmol/mg) | GSH-Px/(U/mL) |
---|---|---|---|
正常对照组 | 273.08±10.33 | 3.87±0.61 | 759.44±71.25 |
模型组 | 213.90±18.61a | 11.42±1.36a | 262.27±28.97a |
秋水仙碱组 | 279.57±4.89b | 3.86±0.48b | 709.10±77.66b |
灯盏花素低剂量组 | 253.06±1.58b | 8.57±0.58b | 446.40±40.02b |
灯盏花素中剂量组 | 268.21±7.13b | 5.95±0.80b | 586.76±61.34b |
灯盏花素高剂量组 | 282.68±11.00b | 4.31±0.70b | 694.41±98.19b |
a:与正常对照组比较,P<0.05;b:与模型组比较,P<0.05。
HE染色结果显示,正常对照组大鼠肝细胞围绕中央静脉呈放射状排列,形态正常,未见炎症细胞浸润;模型组大鼠肝细胞排列紊乱,呈空泡状脂肪变性,细胞间纤维结缔组织增生,呈条状纤维间隔,可见大量炎症细胞浸润;灯盏花素低剂量组大鼠肝细胞大量空泡状变性,细胞间有少量纤维组织增生;灯盏花素中、高剂量组和秋水仙碱组大鼠肝细胞排列基本正常,细胞间纤维组织少,未见明显炎症细胞浸润,病变程度有所缓解。Masson染色结果显示,正常对照组大鼠肝小叶结构完整,仅在肝静脉管壁周有少量蓝色胶原纤维沉积;模型组大鼠肝小叶结构遭到破坏,肝静脉与汇管区周围可见广泛而致密的蓝色胶原纤维沉积,并延伸形成纤维间隔;各药物组大鼠肝组织纤维化改变均有不同程度缓解。与正常对照组[(9.70±0.92)%]比较,模型组大鼠肝组织Masson染色阳性面积百分比[(35.03±1.12)%]显著增加(P<0.05);与模型组比较,秋水仙碱组和灯盏花素低、中、高剂量组大鼠肝组织Masson染色阳性面积百分比[(13.66±2.33)%、(14.25±0.68)%、(11.51±1.80)%、(8.97±1.31)%]均显著减小(P<0.05)。结果见
图2 各组大鼠肝组织病理形态观察的显微图(标尺=5 μm)
黑色箭头:炎症细胞浸润区域或胶原纤维聚集区域。
与正常对照组比较,模型组大鼠肝组织中可见大量TGF-β1、Smad2、ERK1、Keap1蛋白阳性表达,其阳性区域IOD值均显著升高(P<0.05);可见少量Nrf2、HO-1蛋白阳性表达,其阳性区域IOD值均显著降低(P<0.05)。与模型组比较,各药物组大鼠肝组织中TGF-β1、Smad2、ERK1、Keap1蛋白阳性表达均有所减少,其阳性区域IOD值均显著降低(P<0.05);Nrf2、HO-1蛋白阳性表达均有所增加,其阳性区域IOD值均显著升高(P<0.05)。结果见
图3 各组大鼠肝组织中TGF-β1、Nrf2蛋白表达的免疫组化图(标尺=5 μm)
黑色箭头:目的蛋白阳性表达区域。
组别 | TGF-β1(×102) | Smad2(×102) | ERK1(×102) | Nrf2(×102) | Keap1(×102) | HO-1(×102) |
---|---|---|---|---|---|---|
正常对照组 | 893.63±3.45 | 885.44±2.83 | 884.84±2.35 | 844.60±2.79 | 875.54±2.73 | 1 035.10±3.40 |
模型组 | 1 732.32±1.49a | 1 641.08±2.65a | 2 238.45±3.20a | 205.74±2.94a | 5 426.68±27.04a | 466.01±2.16a |
秋水仙碱组 | 825.44±3.93b | 842.21±3.49b | 844.56±3.39b | 827.52±2.67b | 957.10±1.76b | 1 203.21±2.74b |
灯盏花素低剂量组 | 803.84±2.05b | 882.69±2.07b | 1 036.74±10.64b | 766.92±3.48b | 935.81±2.01b | 1 086.45±3.20b |
灯盏花素中剂量组 | 794.30±3.48b | 791.98±1.32b | 944.77±2.32b | 874.26±3.13b | 926.22±3.20b | 1 155.17±2.81b |
灯盏花素高剂量组 | 794.57±0.66b | 778.12±1.19b | 903.77±2.87b | 893.56±3.19b | 963.18±2.19b | 1 117.90±3.29b |
a:与正常对照组比较,P<0.05;b:与模型组比较,P<0.05。
与正常对照组比较,模型组大鼠肝组织中TGF-β1、Smad2、ERK1、Keap1 mRNA表达水平均显著升高,Nrf2、HO-1 mRNA表达水平均显著降低(P<0.05);与模型组比较,各药物组大鼠肝组织中TGF-β1、Smad2、ERK1、Keap1 mRNA表达水平均显著降低,Nrf2、HO-1(灯盏花素低剂量组除外) mRNA水平均显著升高(P<0.05)。结果见
组别 | TGF-β1 | Smad2 | ERK1 | Nrf2 | Keap1 | HO-1 |
---|---|---|---|---|---|---|
正常对照组 | 1 | 1 | 1 | 1 | 1 | 1 |
模型组 | 2.51±0.84a | 2.36±0.26a | 3.64±0.73a | 0.22±0.03a | 2.66±0.24a | 0.59±0.04a |
秋水仙碱组 | 0.20±0.13b | 0.47±0.19b | 0.54±0.18b | 0.80±0.22b | 0.61±0.12b | 1.57±0.31b |
灯盏花素低剂量组 | 0.54±0.37b | 0.32±0.08b | 0.57±0.14b | 0.20±0.03 | 0.15±0.03b | 0.83±0.14 |
灯盏花素中剂量组 | 0.76±0.21b | 0.28±0.04b | 0.49±0.14b | 0.84±0.08b | 0.38±0.06b | 1.69±0.43b |
灯盏花素高剂量组 | 0.52±0.17b | 0.33±0.10b | 0.56±0.19b | 1.34±0.33b | 0.39±0.04b | 1.98±0.40b |
a:与正常对照组比较,P<0.05;b:与模型组比较,P<0.05。
HF是肝脏功能减退的关键环节,动物模型可由化学诱导、饮食诱导、手术和病毒感染等途径构建,其中由CCl4诱导构建的HF模型应用较为广泛。CCl4对啮齿类动物具有广泛的肝脏毒性,可通过灌胃或腹腔注射的方式进入机体,由门静脉入肝后被肝细胞吸收,从而使细胞膜磷脂分子过氧化,引起肝细胞坏死和炎症反应;同时,CCl4还可作用于HSCs,使其活化并转化为MFB,MFB大量增殖并合成ECM,使得ECM在短时间内成倍堆积,从而形成HF[
HF是各种慢性肝病发展的常见病理过程,对该过程进行干预是治疗慢性肝病、防止其转化为肝硬化和肝癌的重要环节。研究指出,除晚期肝硬化外的多种慢性肝病的纤维化均可逆[
本研究结果显示,低、中、高剂量的灯盏花素能不同程度地缩小肝脏白色结节灶,降低HF大鼠血清和肝组织中ALT、AST水平和肝脏指数,提示灯盏花素能有效延缓HF进展,具有较好的肝保护作用;同时,病理染色观察结果显示,经灯盏花素干预后,HF大鼠肝细胞排列趋于正常,细胞间纤维组织和炎症细胞浸润减少,且Masson染色阳性面积百分比较模型组显著降低,提示该成分能减轻HF大鼠肝组织的炎症反应,并改善其纤维化损伤。
TGF-β1蛋白是纤维化的主要因子,与HF的发生、发展密切相关;Smad2作为TGF-β1下游调节因子,可通过磷酸化来促进TGF-β1介导的HF[
氧化应激是体内氧化与抗氧化作用失衡的一种状态,能促进动脉硬化和纤维化的进程。研究证实,受Keap1/Nrf2/HO-1通路调控的氧化应激相关指标SOD、GSH-Px、MDA与HF的发生、发展密切相关[
综上所述,灯盏花素对大鼠HF有较好的干预作用,其作用可能与抑制TGF-β1/Smad2/ERK1通路来抗纤维化,调控Keap1/Nrf2/HO-1通路来抑制氧化应激有关。
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