基础研究 Open Access
Copyright ©The Author(s) 2005. Published by Baishideng Publishing Group Inc. All rights reserved.
世界华人消化杂志. 2005-09-28; 13(18): 2205-2209
在线出版日期: 2005-09-28. doi: 10.11569/wcjd.v13.i18.2205
草苁蓉乙醇提取物对二甲基亚硝胺诱导大鼠肝纤维化的治疗作用
朴熙绪, 黄红果, 朴东明
朴熙绪, 黄红果, 延边大学医学院附属医院消化内科 吉林省延吉市 133000
朴东明, 延边大学医学院附属医院病理科 吉林省延吉市 133000
朴熙绪, 男, 1951-10-25生, 吉林省双阳县人, 朝鲜族, 1978年白求恩医科大学本科毕业, 1984年延边大学医学院硕士研究生, 主任医师, 主要从事肝脏疾病的基础与临床研究, 发表论文60余篇.
基金项目: 吉林省卫生厅医学科研基金资助项目, No. 114.
通讯作者: 朴熙绪, 133000, 吉林省延吉市局子街119号, 延边大学医学院消化内科. piaoxixu1951@yahoo.com.cn.
电话: 0433-2660061 传真: 0433-2513610
收稿日期: 2005-07-15
修回日期: 2005-07-24
接受日期: 2005-08-03
在线出版日期: 2005-09-28

目的: 探讨草苁蓉乙醇提取物对二甲基亚硝胺(DMN)诱导大鼠肝纤维化的治疗作用及其机制.

方法: 将健康♂Wistar大鼠35只随机分为空白对照组(A组)10只, 模型组(B组)15只, 草苁蓉组(C组)10只. B、C组每周1-3 d腹腔内注射1% DMN 1 mL/kg体质量, A组用相同剂量生理盐水代替DMN, 4-7 d休息, 共3 wk. 造模结束后A组及B组生理盐水10 mL/kg体质量, C组50 g/L草苁蓉乙醇提取物10 mL/kg体质量, 每日一次灌胃, 共4 wk(实验4-7 wk). 实验第八周第一天从全部实验大鼠采血, 取肝组织, 分别检测血清SOD、GSH-PX活性、MDA、HA、PCⅢ、Ⅳ.C含量, 肝组织SOD、GSH-PX活性及MDA含量, 并做肝脏组织病理学检查及α-SMA的表达的检测.

结果: 模型组的血清及肝组织SOD(98.58±17.36 kNU/L, 9.99±1.69 kNU/L)、GSH-PX活性(117.37±45.24 U, 12.43±2.99 U)显著低于对照组(129.05±18.55 kNU/L, 19.94±5.87 kNU/L和173.79±25.76 U, 22.66±6.99 U, P<0.01), MDA含量(10.87±1.23 μmol/L, 1.38±0.37 μmol/L)高于对照组(6.63±1.05 μmol/L, 0.91±0.25 μmol/L, P<0.01). 模型组血清HA(394.83±103.28 μg/L)、PCⅢ(13.30±1.88 mg/L)、Ⅳ.C的含量(2.43±1.32 mg/L)也显著高于对照组(186.54±39.87 μg/L, 6.99±1.55 mg/L, 1.18±0.79 mg/L, P<0.01). 草苁蓉组的血清和肝组织SOD(134.29±21.93 kNU/L, 18.99±6.86 kNU/L), GSH-PX活性(171.82±37.50 U, 23.57±7.19 U)显著高于模型组(P<0.01), MDA含量(8.68±2.32 μmol/L, 0.97±0.22 μmol/L)则低于模型组(10.87±1.23, 1.38±0.37 μmol/L)(P<0.01). 草苁蓉组血清HA(115.87±13.96 μg/L)、PCⅢ(6.67±1.86 μg/L)、Ⅳ.C的含量(1.62±0.50 mg/L)也低于模型组(P<0.05). 与模型组比较草苁蓉组的肝纤维化分期程度明显减轻(P<0.01), 肝组织α-SMA的表达降低.

结论: 草苁蓉对DMN所致大鼠肝纤维化有治疗作用, 其机制可能与抗脂质过氧化物作用和抑制肝星状细胞的激活有关.

关键词: 草苁蓉; 二甲基亚硝胺; 肝纤维化
引文著录: 朴熙绪, 黄红果, 朴东明. 草苁蓉乙醇提取物对二甲基亚硝胺诱导大鼠肝纤维化的治疗作用. 世界华人消化杂志 2005; 13(18): 2205-2209
Therapeutic role of ethanolic extract of Boschniakia Rossica in dimethylnitrosamine-induced liver fibrosis in rats
Xi-Xu Piao, Hong-Guo Huang, Dong-Ming Piao
Xi-Xu Piao, Hong-Guo Huang, Department of Gastroenterology, the Affiliated Hospital of Medical College of Yanbian University, Yanji 133000, Jilin Province, China
Dong-Ming Piao, Department of Pathology, the Affiliated Hospital of Medical College of Yanbian University, Yanji 133000, Jilin Province, China
Supported by: the Fund from Medical Scientific Research of Health Department of Jilin Province, No. 114.
Correspondence to: Xi-Xu Piao, Department of Gastroenterology, the Affiliated Hospital of Medical College of Yanbian University, 119 Juzi Street, Yanji 133000, Jilin Province, China. piaoxixu1951@yahoo.com
Received: July 15, 2005
Revised: July 24, 2005
Accepted: August 3, 2005
Published online: September 28, 2005

AIM: To study the effect of Boschniakia Rossica ethanolic extract (BREE) in rat liver fibrosis induced by dimethylnitrosamine (DMN).

METHODS: Hepatic fibrosis was induced by DMN administration intraperitoneally. Thirty-five male Wistar rats were randomly divided into three groups: normal control group (GA, n = 10), hepatic fibrosis model group (GB, n = 15) and BREE treatment group (GC, n = 10). From the 1st to 3rd wk, rats in GB and GC were treated with DMN (10 g/L) intraperitoneally in the first three days of each week, while rats in GA were treated with normal saline. From the 4th to 7th wk, rats in GC were treated with 50 g/L BREE (10 mL/kg) intragastrically each day, while rats in GA and GB were treated with normal saline. At the 1st d of the 8th wk, all the rats were sacrificed and the activity of superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX), the contents of malondialdehyde (MDA), hyaluronic acid (HA), type Ⅲ procollagen (PC Ⅲ), type Ⅳ collagen (Ⅳ.C) in serum were examined. The expression of alpha smooth muscle actin (α-SMA) in liver was also analyzed.

RESULTS: The activity of SOD (98.58±17.36 kNU/L, 9.99±1.69 kNU/L) and GSH-PX (117.37±45.24 U, 12.43±2.99 U) in serum and liver tissue in GB was significantly lower than those in GA (SOD: 129.05±18.55 kNU/L, 19.94±5.87 kNU/L; GSH-PX: 173.79±25.76 U, 22.66±6.99 U)(P < 0.01), while the contents of MDA in GB (10.87±1.23 μmol/L, 1.38±0.37 μmol/L) were higher than those in GA (6.63±1.05 μmol/L, 0.91±0.25 μmol/L)(P < 0.01). The concentrations of serum HA (394.83±103.28 μg/L), PC Ⅲ (13.30±1.88 mg/L) and Ⅳ.C (2.43±1.32 mg/L) in GB were markedly higher than those in GA (186.54±39.87 μg/L, 6.99±1.55 mg/L, 1.18±0.79 mg/L, P < 0.01). The concentrations of serum HA (115.87±13.96 μg/L), PC Ⅲ (6.67±1.86 mg/L) and Ⅳ.C (1.62±0.50 mg/L) in GC were significantly lower than those in GB (P < 0.05), while the activity of SOD (134.29±21.93 kNU/L, 18.99±6.86 kNU/L) and GSH-PX (171.82±37.50 U, 23.57±7.19 U) in serum and liver tissue increased significantly (P < 0.01). The contents of MDA in serum and tissue in GC (8.68±2.32 μmol/L, 0.97±0.22 μmol/L) was lower than those in GB (10.87±1.23, 1.38±0.37 μmol/L)(P < 0.01). The fibrosis index and α-SMA expression in liver decreased in GC too.

CONCLUSION: BREE plays an anti-fibrogenic role in the DMN-induced liver fibrosis of rat by its anti-oxidative effect and inhibition on hepatic stellate cells activation.

Key Words: Boschniakia Rossica; Dimethylnitrosamine; Liver fibrosis
0 引言

近年的研究表明, 草苁蓉具有清除自由基、抗脂质过氧化、抗肿瘤、抗炎、增强四氯化碳所致损伤肝枯否细胞的免疫活性等作用, 并对大鼠实验性急性肝损伤有保护作用[1-3], 但其对肝纤维化有无治疗作用尚未见研究报告. 本实验采用腹腔内注射二甲基亚硝胺的方法建立大鼠实验性肝纤维化模型, 探讨了草苁蓉乙醇提取物灌胃对大鼠肝纤维化的治疗作用.

1 材料和方法
1.1 动物模型制备及分组

健康Wistar大鼠35只, ♂, 体质量180-220 g(延边大学医学院实验动物科提供), 随机分为3组, 空白对照组(A组)10只, 模型组(B组)15只, 草苁蓉组(C组)10只. B、C组每周1-3 d腹腔内注射1% DMN 1 mL/kg体质量, A组用相同剂量生理盐水代替DMN, 4-7 d休息, 共3 wk. 造模结束后A组及B组生理盐水10 mL/kg体质量, C组5%草苁蓉乙醇提取物10 mL/kg体质量, 每日一次灌胃[2,3], 共4 wk(实验4-7 wk).

1.2 检测指标及方法

实验第8周第一天将所有大鼠用乙醚麻醉后心脏采血, 分离血清, 待测SOD、GSH-PX活性、MDA、HA、PCⅢ、Ⅳ.C含量. 采血完毕后立即处死动物, 取肝脏左叶用40 g/L福尔马林固定, 做病理组织学检查及图象分析, 其余肝组织留做检测肝匀浆中SOD、GSH-PX活性及MDA含量. 检测血清及肝组织SOD、GSH-PX及MDA生化试剂盒由南京建成生物工程研究所生产; 血清HA、PCⅢ、Ⅳ.C放免试剂盒均由上海海研医学生物技术中心生产, 在DFM-96型10管放射免疫γ计数器(日本产)检测. 肝组织平滑肌动蛋白(α-smooth muscle actin, α-SMA)试剂盒由北京中山生物技术有限公司生产, 用免疫组化法检测. 肝组织常规石蜡包埋切片, HE染色, 光镜下观察肝脏组织病理改变. 用0.1%天狼猩红苦味酸饱和溶液染色, 参照文献[4]确定肝纤维化分期.

统计学处理 计量资料用方差分析, 两样本均数之间比较用q检验, 计数资料用Kruskal-Wallis检验.

2 结果
2.1 各组动物一般情况

实验过程中, B组大鼠死亡7只, 存活的小鼠体质量较A组明显减轻, 毛质粗糙, 日进食量明显减少, 精神萎靡, 动作迟钝. C组大鼠体质量增长, 毛质光滑, 进食良好, 活泼好动, 与A组相比无明显差别.

2.2 各组动物血清和肝组织SOD、GSH-PX活性及MDA含量检测结果

如表1所示, 模型组的血清SOD、GSH-PX活性显著低于对照组, MDA含量高于对照组; 但草苁蓉组的血清SOD和GSH-PX活性则显著高于模型组, MDA含量低于模型组. 如表2所示, 模型组的肝组织SOD、GSH-PX活性显著低于对照组, MDA含量高于对照组; 但草苁蓉组的肝组织SOD和GSH-PX活性则显著高于模型组, MDA含量低于模型组.

表1 各组大鼠血清SOD、GSH-PX活性及MDA含量检测结果 (mean±SD).
组别nSOD(NU/mL)GSH-PX(活力单位/mg蛋白)MDA(nmol/mL)
A组10129.05±18.55173.79±25.766.63±1.05
B组898.58±17.36a117.37±45.24a10.87±1.23a
C组10134.29±21.93b171.82±37.50b8.68±2.32b
aP < 0.01 vs 正常对照组;
bP < 0.01 vs 模型组. A组(空白对照组), B组(模型组), C组(草苁蓉组).
表2 各组大鼠肝匀浆SOD、GSH-PX活性及MDA含量检测结果 (mean±SD).
组别nSOD(NU/mL)GSH-PX(活力单位/mg蛋白)MDA(nmol/mL)
A组1019.94±5.8722.66±6.990.91±0.25
B组89.99±1.69a12.43±2.99a1.38±0.37a
C组1018.99±6.86b23.57±7.19b0.97±0.22b
aP < 0.01 vs 正常对照组;
bP < 0.01 vs 模型组. A组(空白对照组), B组(模型组), C组(草苁蓉组).
2.3 各组大鼠血清HA、PCⅢ及Ⅳ.C含量检测结果

如表3所示, 模型组血清HA、PCⅢ、Ⅳ.C的含量显著高于对照组, 而草苁蓉组血清HA、PCⅢ、Ⅳ.C的含量则低于模型组.

表3 各组大鼠血清HA、PCIII及IV.c含量检测结果 (mean±SD).
组别nHA(ng/mL)PCⅢ(μg/mL)Ⅳ.C(μg/mL)
A组10186.54±39.876.99±1.551.18±0.79
B组8394.83±103.28a13.30±1.88a2.43±1.32a
C组10115.87±13.96b6.67±1.86b1.62±0.50b
aP < 0.01 vs 正常对照组;
bP < 0.01 vs 模型组. A组(空白对照组), B组(模型组), C组(草苁蓉组).
2.4 各组大鼠肝脏组织病理学变化

(1)HE染色: 光镜下正常对照组大鼠未见肝细胞变性及坏死, 门脉区不增宽, 未见胶原纤维增生. 模型组大鼠可见大量肝细胞变性、坏死, 大量胶原纤维增生, 伸入到肝实质中, 汇管区周围大量炎症细胞浸润, 可见含铁血黄素颗粒. 草苁蓉组大鼠肝细胞变性坏死, 胶原纤维增生及炎症细胞浸润程度较模型组明显减轻; (2)天狼猩红染色: 各组肝纤维化分期如表4所示, 草苁蓉组的肝纤维化程度比模型组明显减轻(P<0.01); (3)α-SMA免疫组化染色结果: 空白对照组肝中央静脉, 小血管壁上可见少量阳性反应, 汇管区、胆囊壁周围及肝实质内为阴性反应(图A). 模型组纤维间隔及汇管区可见大量的α-SMA阳性细胞, 肝实质内也有较多阳性反应(图B). 草苁蓉组仅在汇管区及纤细的纤维间隔处仅见少量α-SMA阳性细胞, 明显少于模型组(图C).

表4 各组大鼠肝纤维化分期.
组别n纤维化分期
01234
A组10100000
B组802231
C组a1017110
Kruskal-Wallis检验,
aP < 0.01 vs模型组. A组(空白对照组), B组(模型组), C组(草苁蓉组).
3 讨论

肝纤维化是各种急慢性肝病向肝硬化发展的必经阶段, 是肝损伤持续存在, 组织发生修复反应时细胞外基质合成, 降解与沉积不平衡而引起的动态病理过程. 阻止这一病理过程的发生和发展对于改善各种病因的急慢性肝病的预后具有重要意义. 因此, 开发毒副作用少, 高效的抗肝纤维化药物是肝病临床研究领域的重大课题.

近年来中药抗肝纤维化的疗效及机制研究令人瞩目, 并已展示良好的应用前景[3-9]. 已有的研究提示, 天然中药草苁蓉具有清除自由基、抗脂质过氧化、抗肿瘤、抗炎、增强四氯化碳所致损伤肝枯否细胞的免疫活性等作用, 并对实验动物的急性肝损伤有治疗作用[1-3]. 本实验通过二甲基亚硝胺诱导的大鼠肝纤维化模型研究表明, 草苁蓉组的肝纤维化分期明显低于模型组, 两组间差异有统计学意义(P<0.01), 说明草苁蓉对DMN诱导的实验大鼠肝纤维化确有治疗作用.

迄今研究的肝纤维化的血清标记物种类较多, 其中HA、PCⅢ及IV.C的检测是比较常用方法[10-14]. 本实验中DMN诱导的肝纤维化模型组血清HA、PCⅢ及IV.C含量显著升高, 而草苁蓉组的HA、PCⅢ及IV.C的含量则显著低于模型组, 从一个侧面提示草苁蓉对DMN诱导的实验大鼠肝纤维化有抑制作用. 肝细胞受损伤时, 通过不同途径使肝星状细胞激活并转化为肌成纤维样细胞和成纤维细胞, 合成大量的胶原等细胞外基质, 并沉积于肝脏而形成肝纤维化. 因此, 肝星状细胞的激活是肝纤维化发生、发展的核心环节. 激活的肝星状细胞的特点之一是表达α-SMA, 后者常作为肝星状细胞激活的标记物[15-29]. 本研究中, α-SMA免疫组织化学染色结果显示模型组大鼠肝组织纤维间隔、汇管区及肝实质内可见大量的α-SMA阳性细胞, 而草苁蓉组大鼠肝组织内α-SMA的表达明显减少, 提示草苁蓉具有抑制肝星状细胞激活的作用. 研究表明, 氧化应激可能是诱导肝星状细胞激活的重要因素之一[30-40]. 本实验结果显示草苁蓉治疗组血清和肝组织SOD, GXH-PX活性明显高于模型组, MDA含量则明显低于模型组, 提示草苁蓉的抗肝纤维化作用机制可能还有赖于其抗脂质过氧化物作用, 从而抑制肝星状细胞的激活及胶原的增生. 肝纤维化的发生机制错综复杂, 草苁蓉抗肝纤维化的机制尚不完全清楚, 有必要从分子生物学水平进行更深入的研究.

电编:张敏 编辑:潘伯荣 审读:张海宁

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