氧化苦参碱对溃疡性结肠炎大鼠细胞因子和核因子-κBp65表达的影响
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摘要
目的:用2,4,6-三硝基苯磺酸(TNBS)建立溃疡性结肠炎大鼠模型,给予氧化苦参碱注射液肌注治疗,观察其治疗效果。检测大鼠结肠黏膜细胞因子白细胞介素-2,白细胞介素-10的水平以及核因子(NF)-κBp65的表达,初步探讨其作用机制。
方法:将40只SD大鼠随机分为正常对照组、模型组、美沙拉嗪组、氧化苦参碱组,每组10只。除正常组外,其余三组均用TNBS造模。模型组给予生理盐水肌注,美沙拉嗪组给予美沙拉嗪混悬液灌胃,氧化苦参碱组给予氧化苦参碱肌注,治疗15天。观察各组大鼠腹泻、便血等一般临床症状。治疗结束后观察结肠黏膜损伤情况,HE染色后光镜观察结肠黏膜组织炎症程度,戊二醛固定后透射电镜观察其超微病理改变。用ELISA法检测结肠黏膜IL-2、IL-10水平。以及应用免疫组化技术检测大鼠结肠黏膜NF-κBp65的表达。
结果:①TNBS模型组大鼠结肠黏膜损伤可见水肿、充血、糜烂、溃疡以及瘢痕形成,造模成功。②氧化苦参碱组大鼠腹泻、便血症状较快得到控制。③氧化苦参碱组结肠黏膜组织损伤积分明显小于模型组(p<0.01);氧化苦参碱组结肠黏膜炎症程度明显轻于模型组(p<0.05);氧化苦参碱组结肠黏膜超微病理结构明显改善。④结肠黏膜组织中促炎因子IL-2的水平:模型组较正常组大鼠升高(p<0.01),氧化苦参碱组较模型组含量减少(p<0.05);⑤结肠黏膜组织中抑炎因子IL-10的水平:模型组的含量较正常组减少(p<0.01),经过氧化苦参碱治疗后含量较模型组增多(p<0.05);⑥模型组结肠黏膜NF-κBp65阳性细胞表达率明显高于正常组(p<0.01),氧化苦参碱组结肠黏膜NF-κBp65阳性细胞表达率明显低于模型组(p<0.01)。⑦与美沙拉嗪组比较,结肠黏膜组织中IL-2和IL-10的水平,NF-κBp65的表达无显著性差别(p>0.05)。
结论:氧化苦参碱注射液可以较快缓解溃疡性结肠炎大鼠临床症状,改善结肠黏膜组织损伤,减轻炎症程度,促进超微病理结构的修复,治疗溃疡性结肠炎大鼠有明显效果。其作用机制可能是通过减少促炎因子IL-2的生成、促进抑炎因子IL-10分泌和阻断NF-κBp65的激活发挥治疗作用。
Objective:
To establish the ulcerative colitis(UC) model rats induced by 2, 4, 6-trinitro-benzene-sulfonic acid (TNBS).To detect the levels of interleukin-2(IL-2) and interleukin-10(IL-10) and expression of nuclear factor-kappa Bp65 (NF-κBp65) in UC rats colonic intestinal mucosa after the treatment for UC rats with Oxymatrine (OMT) Injection. And to evaluate the efficacy, to study and research the anti-inflammatory mechanism of Oxymatrine Injection.
Methods:
40 male rats were randomized into the following groups (n=10 per group): normal control, experimental colitis, experimental colitis with Mesalazine, experimental colitis with OMT treatment. Ulcerative colitis was induced by the mixing of TNBS and 50% alcohol in each group except for normal control. The rats in experimental colitis were injected 0.9% saline in an equal volume as OMT treatment for 15 days. The rats in Mesalazine group were lavaged by Mesalazine at the dosage of 0.42g*kg-1 *d-1 for 15days. And the rats in OMT treatment were intramuscular injected with OMT at the dosage of 63mg*kg-1 *d-1 for 15days.the rats in normal control drank water and feed food normally. Diarrhea and bloody stool as well as colonic mucosa damage observed. After stainning with hematoxylineosin (HE), the degrees of inflammation in colonic mucosa were graded with microscopic observation. Retained in Glutaral for few hours, ultramicro-pathology change of UC rats colonic mucosa was observed by electron microscope. The levels of IL-2 and IL-10 were determined by ELISA, and NF-κBp65 activity were detected by immunohistochemistry method
Results:
①Oedema, anabrosis, hyperemia, and cicatricle was observed in the colonic mucosa of experimental colitis. And the the ulcerative colitis model of rats was made successfully.②The inflammatory symptoms (diarrhea, bloody purulent stool, et al)of colonic mucosa in OMT-treated group were significantly improved.③Compared with experimental colitis, the colonic mucosa damage index as well as the degrees of inflammation of colonic mucosa in OMT-treated group was significantly decreased(p<0.01). And ultramicro-pathology damage of colonic mucosa in OMT-treated group was relieved obviously.④Compared with normal control, the level of IL-2 in the experimental colitis rats was increased(p<0.01). Compared with experimental colitis , the level of IL-2 in OMT-treated group was decreased(p<0.05).⑤Compared with normal control, the level of IL-10 in the experimental colitis rats was reduced(p<0.01). Compared with experimental colitis, the level of IL-10 in OMT-treated group was increased(p<0.05).⑥Compared with normal control, there was increased expression of NF-κBp65 in the experimental colitis rats(p<0.01). Compared with experimental colitis, the expression of NF-κBp65 in OMT-treated group was significantly reduced(p<0.01).⑦And the expression of NF-κBp65, IL-2 and IL-10 in the OMT-treated group was similar(no statistical difference, p>0.05) as Mesalazine-treated group.
Conclusion:
Oxymatrine Injection is effective obviously to treat ulcerative colitis in rats. With the administration of Oxymatrine Injection, the clinical symptom of ulcerative colitis rats was relieved rapidly, the degrees of inflammation as well as colon injury were alleviated, and ultramicro-pathology damage of colonic mucosa was restored. Inhibiting the expression of NF-κBp65, IL-2 and promoting the expression of IL-10 may be the anti-inflammatory mechanism of Oxymatrine Injection.
方法:将40只SD大鼠随机分为正常对照组、模型组、美沙拉嗪组、氧化苦参碱组,每组10只。除正常组外,其余三组均用TNBS造模。模型组给予生理盐水肌注,美沙拉嗪组给予美沙拉嗪混悬液灌胃,氧化苦参碱组给予氧化苦参碱肌注,治疗15天。观察各组大鼠腹泻、便血等一般临床症状。治疗结束后观察结肠黏膜损伤情况,HE染色后光镜观察结肠黏膜组织炎症程度,戊二醛固定后透射电镜观察其超微病理改变。用ELISA法检测结肠黏膜IL-2、IL-10水平。以及应用免疫组化技术检测大鼠结肠黏膜NF-κBp65的表达。
结果:①TNBS模型组大鼠结肠黏膜损伤可见水肿、充血、糜烂、溃疡以及瘢痕形成,造模成功。②氧化苦参碱组大鼠腹泻、便血症状较快得到控制。③氧化苦参碱组结肠黏膜组织损伤积分明显小于模型组(p<0.01);氧化苦参碱组结肠黏膜炎症程度明显轻于模型组(p<0.05);氧化苦参碱组结肠黏膜超微病理结构明显改善。④结肠黏膜组织中促炎因子IL-2的水平:模型组较正常组大鼠升高(p<0.01),氧化苦参碱组较模型组含量减少(p<0.05);⑤结肠黏膜组织中抑炎因子IL-10的水平:模型组的含量较正常组减少(p<0.01),经过氧化苦参碱治疗后含量较模型组增多(p<0.05);⑥模型组结肠黏膜NF-κBp65阳性细胞表达率明显高于正常组(p<0.01),氧化苦参碱组结肠黏膜NF-κBp65阳性细胞表达率明显低于模型组(p<0.01)。⑦与美沙拉嗪组比较,结肠黏膜组织中IL-2和IL-10的水平,NF-κBp65的表达无显著性差别(p>0.05)。
结论:氧化苦参碱注射液可以较快缓解溃疡性结肠炎大鼠临床症状,改善结肠黏膜组织损伤,减轻炎症程度,促进超微病理结构的修复,治疗溃疡性结肠炎大鼠有明显效果。其作用机制可能是通过减少促炎因子IL-2的生成、促进抑炎因子IL-10分泌和阻断NF-κBp65的激活发挥治疗作用。
Objective:
To establish the ulcerative colitis(UC) model rats induced by 2, 4, 6-trinitro-benzene-sulfonic acid (TNBS).To detect the levels of interleukin-2(IL-2) and interleukin-10(IL-10) and expression of nuclear factor-kappa Bp65 (NF-κBp65) in UC rats colonic intestinal mucosa after the treatment for UC rats with Oxymatrine (OMT) Injection. And to evaluate the efficacy, to study and research the anti-inflammatory mechanism of Oxymatrine Injection.
Methods:
40 male rats were randomized into the following groups (n=10 per group): normal control, experimental colitis, experimental colitis with Mesalazine, experimental colitis with OMT treatment. Ulcerative colitis was induced by the mixing of TNBS and 50% alcohol in each group except for normal control. The rats in experimental colitis were injected 0.9% saline in an equal volume as OMT treatment for 15 days. The rats in Mesalazine group were lavaged by Mesalazine at the dosage of 0.42g*kg-1 *d-1 for 15days. And the rats in OMT treatment were intramuscular injected with OMT at the dosage of 63mg*kg-1 *d-1 for 15days.the rats in normal control drank water and feed food normally. Diarrhea and bloody stool as well as colonic mucosa damage observed. After stainning with hematoxylineosin (HE), the degrees of inflammation in colonic mucosa were graded with microscopic observation. Retained in Glutaral for few hours, ultramicro-pathology change of UC rats colonic mucosa was observed by electron microscope. The levels of IL-2 and IL-10 were determined by ELISA, and NF-κBp65 activity were detected by immunohistochemistry method
Results:
①Oedema, anabrosis, hyperemia, and cicatricle was observed in the colonic mucosa of experimental colitis. And the the ulcerative colitis model of rats was made successfully.②The inflammatory symptoms (diarrhea, bloody purulent stool, et al)of colonic mucosa in OMT-treated group were significantly improved.③Compared with experimental colitis, the colonic mucosa damage index as well as the degrees of inflammation of colonic mucosa in OMT-treated group was significantly decreased(p<0.01). And ultramicro-pathology damage of colonic mucosa in OMT-treated group was relieved obviously.④Compared with normal control, the level of IL-2 in the experimental colitis rats was increased(p<0.01). Compared with experimental colitis , the level of IL-2 in OMT-treated group was decreased(p<0.05).⑤Compared with normal control, the level of IL-10 in the experimental colitis rats was reduced(p<0.01). Compared with experimental colitis, the level of IL-10 in OMT-treated group was increased(p<0.05).⑥Compared with normal control, there was increased expression of NF-κBp65 in the experimental colitis rats(p<0.01). Compared with experimental colitis, the expression of NF-κBp65 in OMT-treated group was significantly reduced(p<0.01).⑦And the expression of NF-κBp65, IL-2 and IL-10 in the OMT-treated group was similar(no statistical difference, p>0.05) as Mesalazine-treated group.
Conclusion:
Oxymatrine Injection is effective obviously to treat ulcerative colitis in rats. With the administration of Oxymatrine Injection, the clinical symptom of ulcerative colitis rats was relieved rapidly, the degrees of inflammation as well as colon injury were alleviated, and ultramicro-pathology damage of colonic mucosa was restored. Inhibiting the expression of NF-κBp65, IL-2 and promoting the expression of IL-10 may be the anti-inflammatory mechanism of Oxymatrine Injection.
引文
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2.Macdonald TT, Monteleone G, Pender SL. Recent developments in the immunology of inflammtory bowel disease [J]. Scand J Immul, 2000, 51(1): 2～9
3.Papadakis KA, Targan SR. Role of cytokines in the pathogenesis of inflammatory bowel disease [J].Annu Rev Med, 2000, 51: 289～298
4.Ardizzone S, Porro GB. inflammtory bowel disease: new insights into pathogenesis and treatment[J]. J Int Med,2002,252:475～496
5.范恒,寿折星,吕建芳.复方苦参结肠溶胶囊治疗溃疡性结肠炎11例.中国中西结合消化杂志, 2007,15(1):60～61
6.刘芬,刘洁,陈霞,等.氧化苦参碱的抗炎作用及其机制.吉林大学学报,2005,31(3):728～730
7.陈霞,刘芬,吕文伟,等.氧化苦参碱的镇痛作用及其机制研究.中草药,2006,37(2):255～257
8.黄秀梅,李波.氧化苦参碱对TNF-α、IL-6和IL-8的影响.中成药,2001,25(11):903～906
9.郑萍,牛凤丽,彭延生,等.氧化苦参碱对葡聚糖硫酸钠诱导结肠炎影响的初步研究.胃肠病学,2001,6(4):209～210
10.郑萍,牛凤丽,刘文忠,等.氧化苦参碱对葡聚糖硫酸钠诱导大鼠结肠炎的抗炎作用机制研究.中华消化杂志,2003,23(4):207～210
11.Morris GP, Beck PL, et al. Hapten-induced model of chronic inflammation and ulceration in the rat colon[J].Gastroenterology, 1989, 96: 795～811
12.朱峰,钱家鸣,潘国宗.细胞免疫反应性炎症性肠病动物模型的建立.中国医学科学院学报,1998,20(4):271
13.李小军,张晓峰,马贵同.大鼠实验性溃疡性结肠炎动物模型的复制.河北医学,2003,9(6):528～530
14.苗明三.主编实验动物学用量的确定及计算方法,实验动物和动物实验技术.中国中医药出版社,1995,142～150
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16.郑家驹.结肠炎症性疾病手册.北京:科学出版社,2007:8～11
17.全国慢性非感染肠道疾病学术研讨会.溃疡性结肠炎的诊断及疗效标准[C].中华消化杂志,1993, 13(6): 354～356
18. Jiang XL, Cui HF. Analysis of 10218 Ulcerative Colitis Cases in China. World [J]. Gastroenterol, 2002, 8: 158～161
19.朱元民,王勤河,刘玉兰.溃疡性结肠炎环境因素致病作用研究.中华消化杂志,2002,22(9):571～572
20.江学良,权启镇,刘涛,等.溃疡性结肠炎研究的新进展[J].世界华人消化杂志,2000,8(2):217
21. Campieri M, Gionchetti P . Bacteria as the cause of ulcerative colitis [J]. Gut, 2001, 48: 132～135
22. Madsen KL, Doyle JS, Jewell LD, et al. Lactobacillus species prevents colitis in interleukin-10 gene-deficient mice. Gastroenterology, 1999, 116: 1107
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24.Neurath MF. Immunotherapy of inflammatory bowel disease : current concepts and future perspectives[J]. Arch Immunol Ther Exp(Warsz), 2000, 48(2): 81～84
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2.Macdonald TT, Monteleone G, Pender SL. Recent developments in the immunology of inflammtory bowel disease [J]. Scand J Immul, 2000, 51(1): 2～9
3.Papadakis KA, Targan SR. Role of cytokines in the pathogenesis of inflammatory bowel disease [J].Annu Rev Med, 2000, 51: 289～298
4.Ardizzone S, Porro GB. inflammtory bowel disease: new insights into pathogenesis and treatment[J]. J Int Med,2002,252:475～496
5.范恒,寿折星,吕建芳.复方苦参结肠溶胶囊治疗溃疡性结肠炎11例.中国中西结合消化杂志, 2007,15(1):60～61
6.刘芬,刘洁,陈霞,等.氧化苦参碱的抗炎作用及其机制.吉林大学学报,2005,31(3):728～730
7.陈霞,刘芬,吕文伟,等.氧化苦参碱的镇痛作用及其机制研究.中草药,2006,37(2):255～257
8.黄秀梅,李波.氧化苦参碱对TNF-α、IL-6和IL-8的影响.中成药,2001,25(11):903～906
9.郑萍,牛凤丽,彭延生,等.氧化苦参碱对葡聚糖硫酸钠诱导结肠炎影响的初步研究.胃肠病学,2001,6(4):209～210
10.郑萍,牛凤丽,刘文忠,等.氧化苦参碱对葡聚糖硫酸钠诱导大鼠结肠炎的抗炎作用机制研究.中华消化杂志,2003,23(4):207～210
11.Morris GP, Beck PL, et al. Hapten-induced model of chronic inflammation and ulceration in the rat colon[J].Gastroenterology, 1989, 96: 795～811
12.朱峰,钱家鸣,潘国宗.细胞免疫反应性炎症性肠病动物模型的建立.中国医学科学院学报,1998,20(4):271
13.李小军,张晓峰,马贵同.大鼠实验性溃疡性结肠炎动物模型的复制.河北医学,2003,9(6):528～530
14.苗明三.主编实验动物学用量的确定及计算方法,实验动物和动物实验技术.中国中医药出版社,1995,142～150
15.王良静,陈淑洁,等.云母对大鼠溃疡性结肠炎的肠黏膜保护作用,中国中药杂志,2005,30(23):1840～1844
16.郑家驹.结肠炎症性疾病手册.北京:科学出版社,2007:8～11
17.全国慢性非感染肠道疾病学术研讨会.溃疡性结肠炎的诊断及疗效标准[C].中华消化杂志,1993, 13(6): 354～356
18. Jiang XL, Cui HF. Analysis of 10218 Ulcerative Colitis Cases in China. World [J]. Gastroenterol, 2002, 8: 158～161
19.朱元民,王勤河,刘玉兰.溃疡性结肠炎环境因素致病作用研究.中华消化杂志,2002,22(9):571～572
20.江学良,权启镇,刘涛,等.溃疡性结肠炎研究的新进展[J].世界华人消化杂志,2000,8(2):217
21. Campieri M, Gionchetti P . Bacteria as the cause of ulcerative colitis [J]. Gut, 2001, 48: 132～135
22. Madsen KL, Doyle JS, Jewell LD, et al. Lactobacillus species prevents colitis in interleukin-10 gene-deficient mice. Gastroenterology, 1999, 116: 1107
23. Cameron EA , Binnie JA , Balan K, et al. Oral prednisonoe metasulphobenzoate in the treatment of active ulcerative colitis[J]. Scand J Gastroenterol, 2003,38:535～537
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25.Abreu MT, Vora P, Fature E , et al. Decreasel expression of Toll-like recepter-4 and MD-2 correlates with intestinal epithial cell protection against dysregulated proinflammatory gene expression in response to bacterialimanatory gene expression in response to bacterial lipopolysaccharide.J Immunol , 2001, 167(3): 1609～1616
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