青藤碱对三硝基苯磺酸诱导的实验性大鼠结肠炎作用及其作用机制的研究
|
摘要
研究背景炎症性肠病(inflammatory bowel disease,IBD)在发达国家和发展中国家中是一个非常突出的健康问题,尤其在发达国家更为突出。IBD为胃肠道慢性反复发作与缓解的炎症性疾病,是一种非特异性胃肠道疾病,主要包括溃疡性结肠炎(ulcerative colitis,UC)和克罗恩病(Crohn's disease,CD)。其病因和发病机制迄今尚未阐明,目前认为IBD受遗传、感染、环境、免疫和精神心理等因素影响,属于难治性疾病。随着IBD发病率和患病率的增高,预防和治疗的难题引起同行的高度重视。目前,炎症性肠病的治疗主要依赖5-氨基水杨酸、糖皮质激素、免疫抑制剂等,包括嘌呤类抗代谢物和环孢霉素,然而激素抵抗和依赖已成重要的临床问题,其它免疫抑制剂如硫唑嘌呤和环孢霉素A也表现出严重的副作用。近年来,生物制剂如抗肿瘤坏死因子抗体和抗白细胞介素抗体应用于治疗炎症性肠病,虽取得一些成功,但也有其不足之处,而且其治疗方案复杂,价格又昂贵。因此,寻找新型有效的药物一直是该领域的研究热点。青藤碱(sinomenine)是从青风藤中提取出来的选择性生物碱单体,研究表明青藤碱具有显著的抗炎和免疫抑制作用,清除自由基等作用,发挥免疫调节功能,并且毒副作用小,肠道易吸收。临床广泛应用于关节炎的治疗,并取得良好疗效。在IBD的研究中,报道较少。
目的观察青藤碱(sinomenine)对2,4,6-三硝基苯磺酸(2,4,6-trinitrobenzenesulfonic acid,TNBS)/乙醇诱导结肠炎大鼠的抗炎和保护作用,并初步探讨其作用机制,为临床应用青藤碱治疗炎症性肠病提供一定的实验理论依据。
方法60只成年雄性健康清洁级Sprague-Dawley(SD)大鼠随机均分为正常对照组(Normal group,N group,N组)、结肠炎模型组(Model group,M group,M组)、5-氨基水杨酸治疗组(5-aminosalicylic acid group,5-ASA group,C组)、青藤碱高剂量治疗组(High dose sinomenine group,HD group,HD组)、青藤碱中剂量治疗组(Middle dose sinomenine group,MD group,MD组)以及青藤碱低剂量治疗组(Low dose sinomenine group,LD group,LD组)。除正常对照组外,余5组采用三硝基苯磺酸/乙醇灌肠法制备结肠炎模型,造模24 h后,开始灌胃,正常对照组和结肠炎模型组每只大鼠给予2 mL生理盐水灌胃,5-ASA治疗组每只大鼠给予100mg/kg·d 5-ASA灌胃,青藤碱高、中、低剂量治疗组每只大鼠分别给予120、80、40 mg/kg·d青藤碱灌胃。评价各组大鼠疾病活动指数(disease activity index,DAI)、结肠大体形态损伤指数(colon macroscopic damage index,CMDI)及组织学损伤指数(tissues damage index,TDI)。ELISA法检测大鼠血清IL-1β、TNF-α、MMP-2以及MMP-9的含量,免疫组织化学SP法检测大鼠结肠组织MMP-2、MMP-9以及pp38MAPK的表达。
结果正常对照组、结肠炎模型组、5-ASA治疗组以及青藤碱高、中、低剂量治疗组的DAI评分分别为0.00±0.00、3.47±0.48、1.00±0.55、0.93±0.54、1.60±0.81和2.43±0.75;CMDI评分分别为0.30±0.48、6.50±1.27、1.30±1.16、1.00±0.82、2.30±1.70和4.40±2.01;TDI评分分别为0.20±0.42、5.10±0.74、1.10±1.20、0.90±0.99、2.80±1.40和4.10±1.10;大鼠血清IL-1β含量分别为24.39±5.08 pg/mL、88.48±5.12 pg/mL、35.44±4.31 pg/mL、35.80±3.05 pg/mL、51.77±2.73 pg/mL和62.20±5.07 pg/mL;大鼠血清TNF-α含量分别为23.54±4.20 pg/mL、74.72±5.30pg/mL、35.37±4.44 pg/mL、32.50±4.91 pg/mL、49.76±4.38 pg/mL和61.63±7.16 pg/mL;大鼠血清MMP-2的含量分别为0.76±0.44 ng/mL、10.40±2.10 ng/mL、2.44±0.83ng/mL、2.50±0.82 ng/mL、3.76±1.44 ng/mL和5.34±1.07 ng/mL;大鼠血清MMP-9的含量分别为2.83±1.15 ng/mL、15.85±2.39 ng/mL、5.88±1.84 ng/mL、5.32±1.81ng/mL、7.69±2.16 ng/mL和10.14±2.61 ng/mL;大鼠结肠组织MMP-2的表达分别为0.60±0.52、5.00±1.41、1.30±1.25、1.00±0.94、2.20±1.03和3.50±1.58;大鼠结肠组织MMP-9的表达分别为0.50±0.53、6.30±0.67、1.50±1.35、1.40±0.97、2.90±1.20和4.50±1.43;大鼠结肠组织pp38MAPK的表达分别为1.30±0.48、5.80±1.03、2.10±0.74、2.00±0.82、3.10±1.37和4.30±0.95。与正常对照组大鼠进行比较,上述指标在结肠炎模型组中显著升高,差异具有统计学意义(P值均＜0.01)。与结肠炎模型组比较,5-ASA治疗组和青藤碱高、中剂量组的大鼠DAI、CMDI和TDI显著降低;大鼠血清中的IL-1β、TNF-α、MMP-2和MMP-9的含量显著降低;大鼠结肠组织MMP-2、MMP-9和pp38MAPK的表达也显著降低,经单因素方差分析及t检验,差异有统计学意义(P值均＜0.01);而青藤碱高剂量治疗组大鼠与5-ASA治疗组大鼠进行比较,二者作用相当(P＞0.05)。青藤碱高剂量治疗组大鼠与青藤碱低剂量治疗组大鼠进行比较,上述指标均显著降低,差异有统计学意义(P值均＜0.01),提示青藤碱对TNBS诱导的结肠炎大鼠干预存在剂量反应关系。
结论青藤碱可改善大鼠结肠炎症情况,显著降低血清和结肠组织IL-1β、TNF-α、MMP-2和MMP-9,其作用机制可能与抑制细胞因子的表达,同时抑制基质金属蛋白酶和pp38MAPK的表达,减轻上皮细胞破坏,保护肠黏膜屏障有关。
Research background Inflammatory bowel disease(IBD),a significant health problem both in the developed and developing countries,especially in the developed countries,which comprised two chronic relapsing and remitting inflammatory disorders of the gastrointestinal tract,which was a non-specificity inflammatory disease in gastrointestinal tract,mainly included ulcerative colitis(UC) and Crohn's disease(CD). Up to now,little was known about the underlying pathogenesis of IBD,however,it was considered a disease of multifactorial origin reflecting an interplay of genetic, immunological,infection,psychology and environmental factors,which might underlie the initiation and perpetuation of gastrointestinal inflammation.With the heightening of incidence and prevalence in IBD,the difficulty of prevention and therapeutics evoked extensive attention.At present,pharmacologic management of IBD had relied mainly on 5-aminosalicylates,corticosteroids,and immunosuppressants,including purine antimetabolites and cyclosporine.However,corticosteroid dependence was a clinically important problem,and other immunosuppressive agents such as azathioprine and cyclosporine A also exhibited serious side effects.Recently,biological products such as anti-TNF-αand anti-IL-12 antibody had been used with some success in IBD.This approach,however,was also not without side effects,and treatment protocols were complicated and expensive.Therefore,additional studies were warranted to identify new anti-inflammatory agents to treat IBD.Sinomenine was a selective alkaloidal monomer which extracted from sinomenium acutum.Sinomenine possessed anti-inflammatory effects,depressed humoral immunity and cellular immunity,removed nitric oxide free radicals,produced anti-inflammatory effection,and almost without toxic and side-effect,was easily absorbed in intestinal tract.Extensively clinically applying sinomenine in therapeutics of arthritis,and acquired good therapeutic effects. But in the study of IBD,there was almost no report which be concerned with sinomenine.
Objective To observe the anti-inflammatory and protective effects of sinomenine on experimental colitis-induced by 2,4,6-trinitrobenzene sulfonic acid(TNBS)/ alcohol in rats,and investigate it's mechanism of action on colitis.In order to supply determinate experimental theory for clinical application of sinomenine in therapeutics of IBD
Methods Sixty Sprague-Dawley(SD) rats were randomly divided into six groups (n=10):normal control group(N group),model colitis group(M group),5-aminosalicylic acid treatment group(5-ASA treatment group,C group),High dose sinomenine treatment group(HD group),Middle dose sinomenine treatment group(MD group) and Low dose treatment sinomenine group(LD group).Excepted normal control group,other group were colitis models of rats which were established by intracolon enema with trinitrobenzene sulfonic acid(TNBS)/ ethanol.In the normal control group,no colitis induction was performed,but colitis was induced in all other groups.Followed the induction of colitis,5-ASA and sinomenine were applied to homologous treatment groups of rats.Began to proceeding intragastric administration, after twenty-four hours by establishing colitis models.The each of rats in normal control group and model colitis group with physiological saline(2 mL);the each of rats in 5-ASA treatment group with 5-ASA(100 mg/kg·d);the each of rats in High、Middle and Low sinomenine treatment group with sinomenine in dose of 120、80 and 40 mg/kg·d respectively.Disease activity index(DAI) and colon macroscopic damage index(CMDI) as well as tissues damage index(TDI) of rats in each group were evaluated respectively.The serum levels of IL-1β,TNF-α,MMP-2 as well as MMP-9 were detected by enzyme-linked immunosorbent assay(ELISA).The expressions of MMP-2,MMP-9 as well as pp38MAPK in colonic tissues were detected using immunohistochemical method.
Results In normal control group,model colitis group,5-ASA treatment group, High、Middle and Low dose of sinomenine treatment group,the DAI were 0.00±0.00, 3.47±0.48,1.00±0.55,0.93±0.54,1.60±0.81 and 2.43±0.75,respectively;the CMDI were 0.30±0.48,6.50±1.27,1.30±1.16,1.00±0.82,2.30±1.70 and 4.40±2.01 respectively;the TDI were 0.20±0.42,5.10±0.74,1.10±1.20,0.90±0.99,2.80±1.40 and 4.10±1.10 respectively;the serum levels of IL-1βwere 24.39±5.08 pg/mL, 88.48±5.12 pg/mL,35.44±4.31 pg/mL,35.80±3.05 pg/mL,51.77±2.73 pg/mL and 62.20±5.07 pg/mL respectively;the serum levels of TNF-αwere 23.54±4.20 pg/mL, 74.72±5.30 pg/mL,35.37±4.44 pg/mL,32.50±4.91 pg/mL,49.76±4.38 pg/mL and 61.63±7.16pg/ mL respectively;the serum levels of MMP-2 were 0.76±0.44 ng/mL, 10.40±2.10 ng/mL,2.44±0.83 ng/mL,2.50±0.82 ng/mL,3.76±1.44 ng/mL and 5.34±1.07 ng/mL respectively;the serum levels of MMP-9 were 2.83±1.15 ng/mL, 15.85±2.39 ng/mL,5.88±1.84 ng/mL,5.32±1.81 ng/mL,7.69±2.16 ng/mL and 10.14±2.61ng/mL respectively;the expressions of MMP-2 in colonic tissues of rats were 0.60±0.52,5.00±1.41,1.30±1.25,1.00±0.94,2.20±1.03 and 3.50±1.58 respectively;the expressions of MMP-9 in colonic tissues of rats were 0.50±0.53,6.30±0.67,1.50±1.35,1.40±0.97,2.90±1.20 and 4.50±1.43 respectively;the expressions of PP38MAPK in colonic tissues of rats were 1.30±0.48,5.80±1.03,2.10±0.74,2.00±0.82,3.10±1.37 and 4.30±0.95 respectively.Compared with normal control group,all index above-mentioned significantly increased in model colitis group (all P＜0.01).Compared with model colitis group,the DAI,CMDI as well as TDI in 5-ASA treatment group,High and Middle dose of sinomenine treatment group were significantly ameliorated(all P＜0.01);The serum levels of IL-1β,TNF-α,MMP-2 as well as MMP-9 were significantly reduced(all P＜0.01).The expressions of MMP-2, MMP-9 as well as pp38MAPK in colonic tissues of rats in 5-ASA treatment group, High and Middle dose of sinomenine treatment group significantly decreased(all P＜0.01),however,equalitily effects between 5-ASA treatment group and High dose sinomenine treatment group(P＞0.05).Compared with High dose sinomenine treatment group,all index above-mentioned in Low dose sinomenine treatment group significantly increased(all P＜0.01),suggested that the therapeutics of sinomenine on experimental colitis-induced by 2,4,6-trinitrobenzene sulfonic acid(TNBS)/ alcohol in rats presented dose-response relationship.All above results were determined by using one-way analysis of variance(ANOVA) and Student's t test.
Conclusions The present results of study indicates that sinomenine can ameliorate the colonic inflammation,reduce the serum levels of IL-1β,TNF-α,MMP-2 and MMP-9, and decrease the expression of MMP-2,MMP-9,pp38MAPK.It's mechanism of anti-inflammatory effects is possiblely related with reducing the expression of cytokine, MMP-2,MMP-9,as well as pp38MAPK,alleviating epithelial cells cytoclasis,and protecting intestines mucous membrane barrier.
目的观察青藤碱(sinomenine)对2,4,6-三硝基苯磺酸(2,4,6-trinitrobenzenesulfonic acid,TNBS)/乙醇诱导结肠炎大鼠的抗炎和保护作用,并初步探讨其作用机制,为临床应用青藤碱治疗炎症性肠病提供一定的实验理论依据。
方法60只成年雄性健康清洁级Sprague-Dawley(SD)大鼠随机均分为正常对照组(Normal group,N group,N组)、结肠炎模型组(Model group,M group,M组)、5-氨基水杨酸治疗组(5-aminosalicylic acid group,5-ASA group,C组)、青藤碱高剂量治疗组(High dose sinomenine group,HD group,HD组)、青藤碱中剂量治疗组(Middle dose sinomenine group,MD group,MD组)以及青藤碱低剂量治疗组(Low dose sinomenine group,LD group,LD组)。除正常对照组外,余5组采用三硝基苯磺酸/乙醇灌肠法制备结肠炎模型,造模24 h后,开始灌胃,正常对照组和结肠炎模型组每只大鼠给予2 mL生理盐水灌胃,5-ASA治疗组每只大鼠给予100mg/kg·d 5-ASA灌胃,青藤碱高、中、低剂量治疗组每只大鼠分别给予120、80、40 mg/kg·d青藤碱灌胃。评价各组大鼠疾病活动指数(disease activity index,DAI)、结肠大体形态损伤指数(colon macroscopic damage index,CMDI)及组织学损伤指数(tissues damage index,TDI)。ELISA法检测大鼠血清IL-1β、TNF-α、MMP-2以及MMP-9的含量,免疫组织化学SP法检测大鼠结肠组织MMP-2、MMP-9以及pp38MAPK的表达。
结果正常对照组、结肠炎模型组、5-ASA治疗组以及青藤碱高、中、低剂量治疗组的DAI评分分别为0.00±0.00、3.47±0.48、1.00±0.55、0.93±0.54、1.60±0.81和2.43±0.75;CMDI评分分别为0.30±0.48、6.50±1.27、1.30±1.16、1.00±0.82、2.30±1.70和4.40±2.01;TDI评分分别为0.20±0.42、5.10±0.74、1.10±1.20、0.90±0.99、2.80±1.40和4.10±1.10;大鼠血清IL-1β含量分别为24.39±5.08 pg/mL、88.48±5.12 pg/mL、35.44±4.31 pg/mL、35.80±3.05 pg/mL、51.77±2.73 pg/mL和62.20±5.07 pg/mL;大鼠血清TNF-α含量分别为23.54±4.20 pg/mL、74.72±5.30pg/mL、35.37±4.44 pg/mL、32.50±4.91 pg/mL、49.76±4.38 pg/mL和61.63±7.16 pg/mL;大鼠血清MMP-2的含量分别为0.76±0.44 ng/mL、10.40±2.10 ng/mL、2.44±0.83ng/mL、2.50±0.82 ng/mL、3.76±1.44 ng/mL和5.34±1.07 ng/mL;大鼠血清MMP-9的含量分别为2.83±1.15 ng/mL、15.85±2.39 ng/mL、5.88±1.84 ng/mL、5.32±1.81ng/mL、7.69±2.16 ng/mL和10.14±2.61 ng/mL;大鼠结肠组织MMP-2的表达分别为0.60±0.52、5.00±1.41、1.30±1.25、1.00±0.94、2.20±1.03和3.50±1.58;大鼠结肠组织MMP-9的表达分别为0.50±0.53、6.30±0.67、1.50±1.35、1.40±0.97、2.90±1.20和4.50±1.43;大鼠结肠组织pp38MAPK的表达分别为1.30±0.48、5.80±1.03、2.10±0.74、2.00±0.82、3.10±1.37和4.30±0.95。与正常对照组大鼠进行比较,上述指标在结肠炎模型组中显著升高,差异具有统计学意义(P值均＜0.01)。与结肠炎模型组比较,5-ASA治疗组和青藤碱高、中剂量组的大鼠DAI、CMDI和TDI显著降低;大鼠血清中的IL-1β、TNF-α、MMP-2和MMP-9的含量显著降低;大鼠结肠组织MMP-2、MMP-9和pp38MAPK的表达也显著降低,经单因素方差分析及t检验,差异有统计学意义(P值均＜0.01);而青藤碱高剂量治疗组大鼠与5-ASA治疗组大鼠进行比较,二者作用相当(P＞0.05)。青藤碱高剂量治疗组大鼠与青藤碱低剂量治疗组大鼠进行比较,上述指标均显著降低,差异有统计学意义(P值均＜0.01),提示青藤碱对TNBS诱导的结肠炎大鼠干预存在剂量反应关系。
结论青藤碱可改善大鼠结肠炎症情况,显著降低血清和结肠组织IL-1β、TNF-α、MMP-2和MMP-9,其作用机制可能与抑制细胞因子的表达,同时抑制基质金属蛋白酶和pp38MAPK的表达,减轻上皮细胞破坏,保护肠黏膜屏障有关。
Research background Inflammatory bowel disease(IBD),a significant health problem both in the developed and developing countries,especially in the developed countries,which comprised two chronic relapsing and remitting inflammatory disorders of the gastrointestinal tract,which was a non-specificity inflammatory disease in gastrointestinal tract,mainly included ulcerative colitis(UC) and Crohn's disease(CD). Up to now,little was known about the underlying pathogenesis of IBD,however,it was considered a disease of multifactorial origin reflecting an interplay of genetic, immunological,infection,psychology and environmental factors,which might underlie the initiation and perpetuation of gastrointestinal inflammation.With the heightening of incidence and prevalence in IBD,the difficulty of prevention and therapeutics evoked extensive attention.At present,pharmacologic management of IBD had relied mainly on 5-aminosalicylates,corticosteroids,and immunosuppressants,including purine antimetabolites and cyclosporine.However,corticosteroid dependence was a clinically important problem,and other immunosuppressive agents such as azathioprine and cyclosporine A also exhibited serious side effects.Recently,biological products such as anti-TNF-αand anti-IL-12 antibody had been used with some success in IBD.This approach,however,was also not without side effects,and treatment protocols were complicated and expensive.Therefore,additional studies were warranted to identify new anti-inflammatory agents to treat IBD.Sinomenine was a selective alkaloidal monomer which extracted from sinomenium acutum.Sinomenine possessed anti-inflammatory effects,depressed humoral immunity and cellular immunity,removed nitric oxide free radicals,produced anti-inflammatory effection,and almost without toxic and side-effect,was easily absorbed in intestinal tract.Extensively clinically applying sinomenine in therapeutics of arthritis,and acquired good therapeutic effects. But in the study of IBD,there was almost no report which be concerned with sinomenine.
Objective To observe the anti-inflammatory and protective effects of sinomenine on experimental colitis-induced by 2,4,6-trinitrobenzene sulfonic acid(TNBS)/ alcohol in rats,and investigate it's mechanism of action on colitis.In order to supply determinate experimental theory for clinical application of sinomenine in therapeutics of IBD
Methods Sixty Sprague-Dawley(SD) rats were randomly divided into six groups (n=10):normal control group(N group),model colitis group(M group),5-aminosalicylic acid treatment group(5-ASA treatment group,C group),High dose sinomenine treatment group(HD group),Middle dose sinomenine treatment group(MD group) and Low dose treatment sinomenine group(LD group).Excepted normal control group,other group were colitis models of rats which were established by intracolon enema with trinitrobenzene sulfonic acid(TNBS)/ ethanol.In the normal control group,no colitis induction was performed,but colitis was induced in all other groups.Followed the induction of colitis,5-ASA and sinomenine were applied to homologous treatment groups of rats.Began to proceeding intragastric administration, after twenty-four hours by establishing colitis models.The each of rats in normal control group and model colitis group with physiological saline(2 mL);the each of rats in 5-ASA treatment group with 5-ASA(100 mg/kg·d);the each of rats in High、Middle and Low sinomenine treatment group with sinomenine in dose of 120、80 and 40 mg/kg·d respectively.Disease activity index(DAI) and colon macroscopic damage index(CMDI) as well as tissues damage index(TDI) of rats in each group were evaluated respectively.The serum levels of IL-1β,TNF-α,MMP-2 as well as MMP-9 were detected by enzyme-linked immunosorbent assay(ELISA).The expressions of MMP-2,MMP-9 as well as pp38MAPK in colonic tissues were detected using immunohistochemical method.
Results In normal control group,model colitis group,5-ASA treatment group, High、Middle and Low dose of sinomenine treatment group,the DAI were 0.00±0.00, 3.47±0.48,1.00±0.55,0.93±0.54,1.60±0.81 and 2.43±0.75,respectively;the CMDI were 0.30±0.48,6.50±1.27,1.30±1.16,1.00±0.82,2.30±1.70 and 4.40±2.01 respectively;the TDI were 0.20±0.42,5.10±0.74,1.10±1.20,0.90±0.99,2.80±1.40 and 4.10±1.10 respectively;the serum levels of IL-1βwere 24.39±5.08 pg/mL, 88.48±5.12 pg/mL,35.44±4.31 pg/mL,35.80±3.05 pg/mL,51.77±2.73 pg/mL and 62.20±5.07 pg/mL respectively;the serum levels of TNF-αwere 23.54±4.20 pg/mL, 74.72±5.30 pg/mL,35.37±4.44 pg/mL,32.50±4.91 pg/mL,49.76±4.38 pg/mL and 61.63±7.16pg/ mL respectively;the serum levels of MMP-2 were 0.76±0.44 ng/mL, 10.40±2.10 ng/mL,2.44±0.83 ng/mL,2.50±0.82 ng/mL,3.76±1.44 ng/mL and 5.34±1.07 ng/mL respectively;the serum levels of MMP-9 were 2.83±1.15 ng/mL, 15.85±2.39 ng/mL,5.88±1.84 ng/mL,5.32±1.81 ng/mL,7.69±2.16 ng/mL and 10.14±2.61ng/mL respectively;the expressions of MMP-2 in colonic tissues of rats were 0.60±0.52,5.00±1.41,1.30±1.25,1.00±0.94,2.20±1.03 and 3.50±1.58 respectively;the expressions of MMP-9 in colonic tissues of rats were 0.50±0.53,6.30±0.67,1.50±1.35,1.40±0.97,2.90±1.20 and 4.50±1.43 respectively;the expressions of PP38MAPK in colonic tissues of rats were 1.30±0.48,5.80±1.03,2.10±0.74,2.00±0.82,3.10±1.37 and 4.30±0.95 respectively.Compared with normal control group,all index above-mentioned significantly increased in model colitis group (all P＜0.01).Compared with model colitis group,the DAI,CMDI as well as TDI in 5-ASA treatment group,High and Middle dose of sinomenine treatment group were significantly ameliorated(all P＜0.01);The serum levels of IL-1β,TNF-α,MMP-2 as well as MMP-9 were significantly reduced(all P＜0.01).The expressions of MMP-2, MMP-9 as well as pp38MAPK in colonic tissues of rats in 5-ASA treatment group, High and Middle dose of sinomenine treatment group significantly decreased(all P＜0.01),however,equalitily effects between 5-ASA treatment group and High dose sinomenine treatment group(P＞0.05).Compared with High dose sinomenine treatment group,all index above-mentioned in Low dose sinomenine treatment group significantly increased(all P＜0.01),suggested that the therapeutics of sinomenine on experimental colitis-induced by 2,4,6-trinitrobenzene sulfonic acid(TNBS)/ alcohol in rats presented dose-response relationship.All above results were determined by using one-way analysis of variance(ANOVA) and Student's t test.
Conclusions The present results of study indicates that sinomenine can ameliorate the colonic inflammation,reduce the serum levels of IL-1β,TNF-α,MMP-2 and MMP-9, and decrease the expression of MMP-2,MMP-9,pp38MAPK.It's mechanism of anti-inflammatory effects is possiblely related with reducing the expression of cytokine, MMP-2,MMP-9,as well as pp38MAPK,alleviating epithelial cells cytoclasis,and protecting intestines mucous membrane barrier.
引文
1.中华医学会消化病学分会炎症性肠病协作组.对我国炎症性肠病诊断治疗规范的共识意见[J].现代消化及介入诊疗,2008,13(2):139-145.
2.郑家驹.遵循“共识意见”更好地规范炎症性肠病的治疗[J].医学新知杂志,2008,18(3):160-163.
3.Zheng JJ,Zhu XS,Huang FZ,et al.Crohn's disease in mainland China:a systematic analysis of 50 years of research[J].Chin J Dig Dis,2005,6(4):175-181.
4.Heuschkel RB,MacDonald TT,Monteleone G,et al.Imbalance of stromelysin-1and TIMP-1 in the mucosal lesions of children with inflammatory bowel disease [J].Gut,2000,47(1):57-62.
5.郭长存,吴开春.难治性炎症性肠病的治疗[J].中国实用内科杂志,2007,27(18):1418-1422.
6.Faubion WA Jr,Loftus EV Jr,Harmsen WS,et al.The natural history of corticoste -roid therapy for inflammatory bowel disease:a population-based study[J].Gastro -enterology,2001,121(2):255-260.
7.Seegers D,Bouma G,Pena AS.Review article:a critical approach to new forms of treatment of Crohn's disease and ulcerative colitis[J].Aliment Pharmacol Ther.2002,16 Suppl 4:53-58.
8.Ogata H,Hibi T.Cytokine and anti-cytokine therapies for inflammatory bowel diseases[J].Curr Pharm Des,2003,9(14):1107-1113.
9.Poggioli G,Laureti S,Campieri M,et al.Infliximab in the treatment of Crohn's disease[J].Ther Clin Risk Manag,2007,3(2):301-308.
10.王文君,王培训,李晓娟.青藤碱抗炎机理-青藤碱对人外周血单个核细胞环氧化酶活性及其基因表达的影响[J].中国中药杂志,2003,28(4):352-355.
11.Zeng Y,Gu B,Ji X,et al.Sinomenine,an antirheumatic alkaloid,ameliorates clinical signs of disease in the Lewis rat model of acute experimental auto immune encephalolmyelitis[J].Biol Pharm Bull,2007,30(8):1438-1444.
12.Feng H,Yamaki K,Takano H,et al.Suppression of Th1 and Th2 immune responses in mice by Sinomenine,an alkaloid extracted from the chinese medicinal plant Sin -omenium acutum[J].Planta Med,2006,72(15):1383-1388.
13.刘刚,王辉,张先洲,等.青藤碱清除氧自由基和抗脂质过氧化作用[J].中草药,2006,37(1):84-87.
14.Liu Z,Zheng JF,Yang LQ,et al.Effects of sinomenine on NO/nNOS system in cerebellum and spinal cord of morphine-dependent and withdrawal mice[J].Sheng Li Xue Bao,2007,59(3):285-292.
15.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[J].中国 医学科学院学报, 1998, 20(4):271-278.
16. Murano M, Maemura K, Hirata I, et al.Therapeutic effect of intracolonically administered nuclear factorκB(P65) antisense oligonucleotide on mouse dextran sulphate sodium(DSS)-induced colitis[J]. Clin Exp Immunol, 2000,120(1): 51- 58.
17. Zingarelli B, Hake PW, Burroughs TJ, et al. Activator protein-1 signalling pathwa -y and apoptosis are modulated by poly(ADP-ribose)polymerase-1 in experimental colitis[J]. Immunology, 2004,113 (4): 509-517.
18. Akcan A, Muhtaroglu S, Akgun H, et al. Ameliorative effects of bombesin and neurotensin on trinitrobenzene sulphonic acid-induced colitis, oxidative damage and apoptosis in rats[J]. World J Gastroenterol, 2008,14(8): 1222-1230.
19. Koga H, Sakisaka S, Ohishi M, et al. Expression of cyclooxygenase-2 in human hepatocellular carcinoma:relevance to tumor dedifferentiation[J]. Hepatology,19-99,29(3):688-696.
20. Choi PM, Zelig MP. Similarity of colorectal cancer in Crohn's disease and ulcerat -ive colitis:implications for carcinogenesis and prevention[J].Gut, 1994,35(7):950-954.
21. Eaden JA, Abrams KR, Mayberry JF. The risk of colorectal cancer in Ulcerative colitis:a meta-analysis[J]. Gut, 2001,48(4):526-535.
22. Rutter MD, Saunders BP, Wilkinson KH, et al. Thirty year analysis of a colonos -copic surveillance program for neoplasia in Ulcerative colitis[J]. Gastroenter-ology, 2006,130(4):1030-1038.
23. Jess T, Loftus EV Jr, Velayos FS, et al. Risk of intestinal cancer in inflammatory bowel disease: a population-based study from Olmsted county, Minnesota [J]. Gastroenterology, 2006, 130(4): 1039-1046.
24. Balding J, Livingstone WJ, Conroy J, et al. Inflammatory bowel disease:the role of inflammatory cytokine gene polymorphisms[J]. Mediators Inflamm, 2004, 13(3):181-187.
25.Arseneau KO,Pizarro TT,Cominelli F.Discovering the cause of inflammatory bowel disease:lessons from animal models[J].Curr Opin Gastroenterol,2000,16(4):310-317.
26.王皓,欧阳钦,胡仁伟.三硝基苯磺酸结肠炎动物模型的建立[J].胃肠病学,2001,6(1):7-10.
27.杨德森,刘芳,曾繁典,等.青藤碱对大鼠佐剂性关节炎治疗作用及机制的研究[J].中国中药杂志,2005,30(17):1361-1363.
28.Cao W,Vrees MD,Potenti FM,et al.Interleukin 1beta-induced production of H2O2 contributes to reduced sigmoid colonic circular smooth muscle contractil -ity in ulcerative colitis[J].J Pharmacol Exp Ther,2004,311(1):60-70.
29.Malo MS,Biswas S,Abedrapo MA,et al.The pro-inflammatory cytokine,IL-1"beta and TNF-alpha,inhibit intestinal alkaline phosphatase gene expression[J].DNA Cell Biol,2006,5(12):684-695.
30.贾百灵,候晓华.溃疡性结肠炎患者血清白细胞介素1β检测[J].郑州大学学报(医学版),2004,39(2):306-308.
31.贾百灵,侯晓华.溃疡性结肠炎患者血清TNF-α的变化[J].第四军医大学学报,2004,25(9):849-850.
32.Murch SH,Braegger CP,Walker-Smith JA,et al.Location of tumour necrosis fa -ctor alpha by immunohistochemistry in chronic inflammatory bowel disease[J].Gut,1993,34(12):1705-1709.
33.Whittall T,Wang Y,Kelly CG,et al.Tumor necrosis factor-alpha production sti -mulated by heat shock protein 70 and its inhibition in circulating dendritic cells and cells eluted from mucosal tissues in Crohn's disease[J].Clin Exp Immunol,2006,143(3):550-559.
34.Zhou YH,Yu JP,Liu YF,et al.Effects of Ginkgo biloba extract on inflammatory mediators(SOD,MDA,TNF-alpha,NF-kappaBp65,IL-6) in TNBS-induced col -itis in rats[J].Mediators Inflamm,2006,2006(5):92642.
35.Noguchi M,Hiwatashi N,Liu Z,et al.Secretion imbalance between tumour necr -osis factor and its inhibitor in inflammatory bowel disease[J].Gut,1998,43(2):203-209.
36.Ebert EC.Tumour necrosis factor-alpha enhances intraepithelial lymphocyte pro -liferation and migration[J].Gut,1998,42(5):650-655.
37.Wang F,Graham WV,Wang Y,et al.Interferon-gamma and tumor necrosis fac -tor-alpha synergize to induce intestinal epithelial barrier dysfunction by upregulating myosin light chain kinase expression[J].Am J Pathol,2005,166(2):409-419.
38.崔巍,刘冬妍,马力,等.TNF-α对肠上皮细胞紧密连接蛋白表达的作用[J].世界华人消化杂志,2007,15(16):1788-1793.
39.Qian L,Xu Z,Zhang W,et al.Sinomenine,a natural dextrorotatory morphinan a -nalog,is anti-inflammatory and neuroprotective through inhibition of microglial NADPH oxidase[J].J Neuroinflammation,2007,4:23.
40.李晓娟,王培训,刘良,等.青藤碱对T淋巴细胞活化及TH1类细胞内细胞因子表达的影响[J].中国免疫学杂志,2004,20(4):249-252,258.
41.Huang F,Yamaki K,Tong X,et al.Inhibition of the antigen-induced activation of RBL-2H3 cells by sinomenine[J].Int Immunopharmacol,2008,8(3):502-507.
42.Huang J,Lin Z,Luo M,et al.Sinomenine suppresses TNF-alpha-induced VCA -M-1expression in human umbilical vein endothelial cells[J].J Ethnopharmacol,2007,114(2):180-185.
43.金晓琨,李卫东,滕慧玲,等.青藤碱对核转录因子-κB及其抑制因子IκB 的影响[J].中国药理学通报,2004,20(7):788-791.
44.Wang AL,Li Z,Yuan M,et al.Sinomenine inhibits activation of rat retinal mi -croglia induced by advanced glycation end products[J].Int Immunopharmacol,2007,7(12):1552-1558.
45.方勇飞,王勇,周新,等.青藤碱对佐剂性关节炎大鼠滑膜细胞核因子κB信号转导的影响及其机制[J].中国临床康复,2005,9(7):204-205.
46.Medina C,Videla S,Radomski A,et al.Increased activity and expression of mat -rix metalloproteinase-9 in a rat model of distal colitis[J].Am J Physiol Gastr -ointest Liver Physiol,2003,284(1):116-122.
47.Stallmach A,Chan CC,Ecker K-W,et al.Comparable expression of matrix meta -lloproteinases 1 and 2 in pouchitis and ulcerative colitis[J].Gut,2000,47(3):415-422.
48.Gao Q,Meijer MJ,Kubben FJ,et al.Expression of matrix metalloproteinases -2 and -9 in intestinal tissue of patients with inflammatory bowel diseases[J].Dig Liver Dis,2005,37(8):584-592.
49.Piril(a|¨) E,Ramamurthy NS,Sorsa T,et al.Gelatinase A(MMP-2),collagenase-2(MMP-8),and laminin-5 gamma2-chain expression in murine inflammatory bo -wel disease(ulcerative colitis)[J].Dig Dis Sci,2003,48(1):93-98.
50.杨汝春,王永钧,林京莲,等.青藤碱对白介素1β诱导的肾小管上皮细胞骨架变化和明胶酶活性的影响[J].中华肾脏病杂志,2006,22(8):499-502.
51.Von Lampe B,Barthel B,Coupland SE,et al.Differential expression of matrix metalloproteinases and their tissue inhibitors in colon mucosa of patients with inflammatory bowel disease[J].Gut,2000,47(1):63-73.
52.Medina C,Santana A,Paz MC,et al.Matrix metalloproteinase-9 modulates intes -tinal injury in rats with transmural colitis[J].J Leukoc Biol,2006,79(5):954-962.
53.Zhou H,Wong YF,Wang J,et al.Sinomenine ameliorates arthritis via MMPs,TIMPs,and cytokines in rats[J].Biochem Biophys Res Commun,2008,376(2):352-357.
54.Waetzig GH,Seegert D,Rosenstiel P,et al.p38 mitogen-activated protein kinase is activated and linked to TNF-alpha signaling in inflammatory bowel disease[J]. J Immunol,2002,168(10):5342-5351.
55.Hollenbach E,Neumann M,Vieth M,et al.Inhibition of p38MAP kinase-and RI -CK/NF-kappaB-signaling suppresses inflammatory bowel disease[J].FASEB J,2004,18(13):1550-1552.
56.王峻,郭德玉.TNF-α对胃癌细胞MMP-2和MMP-9表达的诱导作用[J].世界华人消化杂志,2007,15(11):1208-1212.
57.Han YP,Tuan TL,Wu H,et al.TNF-alpha stimulates activation of pro-MMP-2in human skin through NF-(kappa)B mediated induction of MT1-MMP[J].J Ce -ll Sci,2001,114(pt 1):131-139.
58.朱军华,陶凯雄,王国斌.TNF-α对肝癌细胞VEGF和MMP-9表达的影响[J].中国普外基础与临床杂志,2005,12(4):384-389.
59.Lee CW,Lin CC,Lin WN,et al.TNF-alpha induces MMP-9 expression via ac.-tivation of Src/EGFR,PDGFR/PI3K/AKt cascade and promotion of NF-kappa B/p300 binding in human tracheal smooth muscle cells[J].Am J Physiol Lung Cell Mol Physiol,2007,292(3):L799-L812.
60.Meijer MJ,Mieremet-Ooms MA,van Duijn W,et al.Effect of the anti-tumor necrosis factor-alpha antibody infliximab on the ex vivo mucosal matrix meta -lloproteinase-proteolytic phenotype in inflammatory bowel disease[J].Inflamm Bowel Dis,2007,13(2):200-210.
61.Gao Q,Meijer MJ,Schl(u|¨)ter UG,et al.Infliximab treatment influences the serolo -gical expression of matrix metalloproteinase(MMP)-2 and -9 in Crohn's disease [J].Inflamm Bowel Dis,2007,13(6):693-702.
62.Lin CC,Tseng HW,Hsieh HL,et al.Tumor necrosis factor-alpha induces MM -P-9 expression via p42/p44 MAPK,JNK,and nuclear factor-kappaB in A549 ce -lls[J].Toxicol Appl Pharmacol,2008,229(3):386-398.
63.Wiehler S,Cuvelier SL,Chakrabarti S,et al.p38 MAP kinase regulates rapid ma -trix metalloproteinase-9 release from eosinophils[J].Biochem Biophys Res Co -mmun,2004,315(2):463-470.
1 Ishiguro Y.Mucosal proinflammatory cytokine production correlates with endoscopic activity of ulcerative colitis[J].J Gastroenterol,1999,34(1):66-74.
2 贾百灵,侯晓华.溃疡性结肠炎患者血清白细胞介素1β检测[J].郑州大学学报(医学版),2004,39(2):306-308.
3 张文俊,许国铭,李兆申,等.血清白细胞介素1β与溃疡性结肠炎的关系[J].第二军医大学学报,2002,23(12):1345-1346.
4 Zou K,Liu S,Xie X,et al.Clinical significance and assessment of cytokines in various stages of ulcerative colitis[J].J Tongji Med Univ,2001,21(4):308-309.
5 Yamamoto T,Maruyama Y,Umegae S,et al.Mucosal inflammation in the terminal ileum of ulcerative colitis patients:endoscopic findings and cytokine profiles[J]. Dig Liver Dis,2008,40(4):253-259.
6 Wedrychowicz A,Stopyrowa J,Fyderek K,et al.Stool interleukin 1beta and interleukin 1 receptor antagonist concentrations in children with active ulcerative colitis and during recovery[J].Eur J Pediatr,2003,162(7-8):541-542.
7 Evgenikos N,Bartolo DC,Hamer-Hodges DW,et al.Assessment of ileoanal pouch inflammation by interleukin-1 beta and interleukin-8 concentration in the gut lumen[J].Dis Colon Rectum,2002,45(2):249-255.
8 Sawa Y,Oshitani N,Adachi K,et al.Comprehensive analysis of intestinal cyto -kine messenger RNA profile by real-time quantitative polymerase chain reaction in patients with inflammatory bowel disease[J].Int J Mol Med,2003,11(2):175-179.
9 Arai F,Takahashi T,Furukawa K,et al.Mucosal expression of interleukin-6 and interleukin-8 messenger RNA in ulcerative colitis and in Crohn's disease[J].Dig Dis Sci,1998,43(9):2071-2079.
10 Ashwood P,Harvey R,Verjee T,et al.FunctionaL interactions between mucosal IL-1,IL-1ra and TGF-β beta 1 in ulcerative colitis[J].Inflamm res,2004,53(2):53-59.
11 Witkin SS,Gerber S,Ledger WJ.Influence of interleukin-1 receptor antagonist gene polymorphism on disease[J].Clin Infect Dis,2002,34(2):204-209.
12 Dinarello CA.Biologic basis for interleukin-1 in disease[J].Blood,1996,87(6):2095-2147.
13 杨幼林,刘芳,李宝杰,等.IL-1β和IL-1Ra基因单核苷酸多态性同溃疡性结肠炎的相关性[J].胃肠病学和肝病学杂志,2007,16(4):377-340.
14 薛惠平,倪培华,吴洁敏,等.炎症性肠病IL-1β基因多态性及连锁不平衡研究[J].上海交通大学学报(医学版),2006,26(8):912-915.
15 Balding J,Livingstone WJ,Conrov J,et al.Inflammatory bowel disease:the role of inflammatory cytokine gene polymorphisms[J].Mediators Inflamm,2004,13(3): 181-187.
16 彭仲生,胡品津,崔毅,等.溃疡性结肠炎的IL-1β、IL-1RA、LMP2基因多态性研究[J].中国免疫学杂志,2002,18(12):852-855.
17 Cao W,Vrees MD,Potenti FM,et al.Interleukin 1beta-induced production of H2O2 contributes to reduced sigmoid colonic circular smooth muscle contractility in ulcerative colitis[J].J Pharmacol Exp Ther,2004,311(1):60-70.
18 Cao W,Fiocchi C,Pricolo VE.Production of IL-1beta,hydrogen peroxide,and nitric oxide by colonic mucosa decreases sigmoid smooth muscle contractility in ulcerative colitis[J].Am J Physiol cell Physiol,2005,289(6):C1408-C1416.
19 Malo MS,Biswas S,Abedrapo MA,et al.The pro-inflammatory cytokines,IL-1beta and TNF-alpha,inhibit intestinal alkaline phosphatase gene expression[J].DNA Cell Biol,2006,5(12):684-695.
20 贾百灵,侯晓华.溃疡性结肠炎患者血清TNF-α的变化[J].第四军医大学学报,2004,25(9):849-850.
21 Murch SH,Braegger CP,Walker-Smith JA,et al.Location of tumour necrosis factor alpha by immunohistochemistry in chronic inflammatory bowel disease[J].Gut,1993,34(12):1705-1709.
22 Whittall T,Wang Y,Kelly CG,et al.Tumor necrosis factor-alpha production stimulated by heat shock protein 70 and its inhibition in circulating dendritic cells and cells eluted from mucosal tissues in Crohn's disease[J].Clin Exp Immunol,2006,143(3):550-559.
23 Zhou YH,Yu JP,Liu YF,et al.Effects of Ginkgo biloba extract on inflammatory mediators(SOD,MDA,TNF-alpha,NF-kappaBp65,IL-6) in TNBS-induced colitis in rats[J].Mediators Inflamm.,2006,2006(5):92642.
24 Noguchi M,Hiwatashi N,Liu Z,et al.Secretion imbalance between tumour necrosis factor and its inhibitor in inflammatory bowel disease[J].Gut,1998,43(2):203-209.
25 Saiki T,Mitsuvama K,Tovonaga A,et al.Detection of pro-and anti-inflammatory cytokines in stools of patient with inflammatory bowel[J].Scand J Gastroenterol,1998,33(6):616-622.
26 Hadziselimovic F,Emmons LR,Gallati H,et al.Soluble tumour necrosis factor receptors p55、p75 in the urine monitor disease activity and the efficacy of treatment of inflammatory bowel disease[J].Gut,1995,37(2):260-263.
27 崔静,刘占举,唐芙爱.炎症性肠病患者血清肿瘤坏死因子和白介素8检测[J].郑州大学学报(医学版),2006,41(5):825-827.
28 Wang YD,Mao JW.Expression of matrix metalloproteinase-1 and tumor necrosis factor-alpha in ulcerative colitis[J].World J Gastroenterol,2007,13(44):5926-5932.
29 Baena A,Leung JY,Sullivan AD,et al.TNF-alpha promoter single nucleotide polymorphisms are markers of human ancestry[J].Genes Immun,2002,3(8):482-487.
30 Koss K,Satsangi J,Fanning GC,et al.Cytokine(TNF alpha,LT alpha and IL-10)polymorphisms in inflammatory bowel diseases and normal controls:differential effects on production and allele frequencies[J].Genes Immun,2000,1(3):185-190.
31 Gonzalez S,Rodrigo L,Martinez-Borra J,et al.TNF-alpha-308A promoter poly -morphism is associated with enhanced TNF-alpha production and inflammatory activity in Crohn's patients with fistulizing disease[J].Am J Gastroenterol,2003,98(5):1101-1106.
32 Linderson Y,Bresso F,Buentke E,et al.Functional interaction of CARD15/NOD2and Crohn's disease-associated TNF alpha polymorphisms[J].Int J Colorectal Dis,2005,20(4):305-311.
33 宋瑛,吴开春,张沥,等.肿瘤坏死因子基因多态性与炎症性肠病的相关性分析[J].中华消化杂志 2005,25(4):202-206.
34 曹倩,高敏,周刚,等.肿瘤坏死因子基因多态性与溃疡性结肠炎相关性研究 [J].中华消化杂志,2006,26(7):460-463.
35 Cucchiara S,Latiano A,Palmieri O,et al.Polymorphisms of tumor necrosis factor-alpha but not MDR1 influence response to medical therapy in pediatriconset inflammatory bowel disease[J].J Pediatr Gastroenterol Nutr,2007,44(2):171-179.
36 项利鹃,陈春晓.肿瘤坏死因子α基因多态性与炎症性肠病的关系[J].浙江医学,2006,28(4):261-263.
37 Zipperlen K,Peddle L,Melay B,et al.Association of TNF-alpha polymorphisms in Crohn disease[J].Hum Immunol,2005,66(1):56-59.
38 袁岸龙,夏冰,侯炜,等.肿瘤坏死因子-α基因多态性与炎症性肠病的相关性研究[J].中华消化杂志,2004,24(4):243-244.
39 Yamamoto-Furusho JK,Uscanga LF,Vargas-Alarcon G,et al.Polymorphisms in the promoter region of tumor necrosis factor alpha(TNF-alpha)and the HLA-DRB1locus in Mexican Mestizo patients with ulcerative colitis[J].Immunol Lett,2004,95(1):31-35.
40 Louis E,Peeters M,Franchimont D,et al.Tumor necrosis factor(TNF)gene poly -morphism in Crohn's disease(CD):influence on disease behaviour?[J].Clin Exp Immunol,2000,119(1):64-68.
41 Araujo F,Pereira AC,Mota GF,et al.The influence of tumor necrosis factor-308and C-reactive protein G1059C gene variants on serum concentration of C-reactive protein:evidence for an age-dependent association[J].Clin Chim Acta,2004,349(1-2):129-134.
42 Jeanmonod P,von K(a|¨)nel R,Maly FE,et al.Elevated plasma C-reactive protein in chronically distressed subjects who carry the A allel of the TNF-alpha-308G/A polymorphism[J].Psychosom Med,2004,66(4):501-506.
43 Vatay A,Bene L,Kovacs A,et al.Relationship between the tumor necrosis factor alpha polymorphism and the serum C-reactive protein levels in inflammatory bowel disease[J].Immunogenetics,2003,55(4):247-252.
44 Mittal RD,Manchanda PK,Bid HK,et al.Analysis of polymorphisms of tumor necrosis factor-alpha and polymorphic xenobiotic metabolizing enzymes in infla -mmatory bowel disease:Study from northern India[J].J Gastroenterol Hepatol,2007,22(6):920-924.
45 Meijer MJ,Mieremet-Ooms MA,van Hogezand RA,et al.Role of matrix metall -oproteinase,tissue inhibitor of metalloproteinase and tumor necrosis factor-alpha single nucleotide gene polymorphisms in inflammatory bowel disease[J].World J Gastroenterol,2007,13(21):2960-2966.
46 Wang F,Graham WV,Wang Y,et al.Interferon-gamma and tumor necrosis factor-alpha synergize to induce intestinal epithelial barrier dysfunction by up-regulating myosin light chain kinase expression[J].Am J Pathol,2005,166(2):409-419.
47 崔巍,刘冬妍,马力,等.TNF-α对肠上皮细胞紧密连接蛋白表达的作用[J].世界华人消化杂志,2007,15(16):1788-1793.
48 Szlosarek PW,Balkwill FR.Tumour necrosis factor alpha:a potential target for the therapy of solid tumours[J].Lancet Oncol,2003,4(9):567-573.
49 Ebert EC.Tumor necrosis factor-αenhances intraepithelial lymphocyte proliferatio -n and migration[J].J Gut,1998,42(5):650-665.
50 Medina C,Videla S,Radomski A,et al.Increased activity and expression of matri -x metalloproteinase-9 in a rat model of distal colitis[J].Am J Physiol Gastrointest Liver Physiol,2003,284(1):116-122.
51 McKaig BC,McWilliams D,Watson SA,et al.Expression and regulation of tissue inhibitor of metalloproteinase-1 and matrix metalloproteinases by intestinal myofi -broblasts in inflammatory bowel disease[J].Am J Pathol,2003,162(4):1355-1360.
52 Von Lampe B,Barthel B,Coupland SE,et al.Differential expression of matrix metalloproteinases and their tissue inhibitors in colon mucosa of patients with inflammatory bowel disease[J].Gut,2000,47(1):63-73.
53 Heuschkel RB,MacDonald TT,Monteleone G,et al.Imbalance of stromelysin-1and TIMP-1 in the mucosal lesion of children with inflammatory bowel disease[J].Gut,2000,47(1):57-62.
54 Matsuno K,Adachi Y,Yamamoto H,et al.The expression of matrix metallopro -teinase matrilysin indicates the degree of inflammation in ulcerative colitis[J].J Gastroenterol,2003,38(4):348-354.
55 缪应雷,欧阳钦,段丽平,等.基质金属蛋白酶-1、基质金属蛋白酶-2和基质金属蛋白酶-3在溃疡性结肠炎患者肠黏膜的表达[J].临床内科杂志,2005,22(10):682-684.
56 Newell KJ,Matrisian LM,Driman DK.Matrilysin(matrix metalloproteinase-7)expression in ulcerative colitis-related tumorigenesis[J].Mol Carcinog,2002,34(2):59-63.
57 Piril(a|¨).E,Ramamurthy NS,Sorsa T,et al.Gelatinase A(MMP-2),collagenase-2(MMP-8),and laminin gamma2-chain expression in murine inflammatory bowel disease(ulcerative colitis)[J].Dig Dis Sci,2003,48(1):93-98.
58 张文俊,许国铭,李兆申,等.基质金属蛋白酶3和9在溃疡性结肠炎中表达的研究[J].中华消化杂志,2003,23(3):187-188.
59 陈锡美,刘文滨,陈文骏,等.溃疡性结肠炎患者基质金属蛋白酶-2,9和抑制因子-1,2的表达及其意义[J].临床内科杂志,2003,20(7):384-386.
60 Gao Q,Meijer MJ,Kubben FJ,et al.Expression of matrix metalloproteinases-2and -9 in intestinal tissue of patients with inflammatory bowel diseases[J].Dig Liver Dis,2005,37(8):584-592.
61 Medina C,Santana A,Paz MC,et al.Matrix metalloproteinase-9 modulates intestinal injury in rats with transmural colitis[J].J Leukoc Biol,2006,79(5):954-962.
62 Brinkman BM, Telliez JB, Schievella AR, et al. Engagement of tumor necrosis factor(TNF)receptor 1 leads to ATF-2 and P38 mitogen-activated protein kinase-dependent TNF-alpha gene expression[J]. J Biol Chem, 1999, 274(43): 30882-308806.
63 Hoffmeyer A, Grosse-wilde A, Flory E, et al. Differene mitogen-activated protein kinase signaling pathways cooperate to regulate tumor necrosis factor alpha gene expression in T lymphocytes[J]. J Biol Chem, 1999,274(7):4319-4327.
64 Waetzig GH, Seegert D, Rosenstiel P, et al. p38 mitogen-activated protein kinase is activated and linked to TNF-alpha signaling in inflammatory bowel disease[J]. J Immunol, 2002,168(10):5342-5351.
65 Hollenbach E, Neumann M, Vieth M, et al. Inhibition of p38MAP kinase- and RICK/NF-kappaB-signaling suppresses inflammatory bowel disease[J]. FASEB J, 2004,18(13):1550-1552.
66 Rutault K, Hazzalin CA, Mahadevan LC. Combinations of ERK and P38MAPK inhibitors ablate tumor necrosis factor-alpha(TNF-alpha) mRNA induction: Evidence for selective destabilization of TNF-alpha transcripts[J]. J Biol Chem, 2001,276(9):6666-6674.
2.郑家驹.遵循“共识意见”更好地规范炎症性肠病的治疗[J].医学新知杂志,2008,18(3):160-163.
3.Zheng JJ,Zhu XS,Huang FZ,et al.Crohn's disease in mainland China:a systematic analysis of 50 years of research[J].Chin J Dig Dis,2005,6(4):175-181.
4.Heuschkel RB,MacDonald TT,Monteleone G,et al.Imbalance of stromelysin-1and TIMP-1 in the mucosal lesions of children with inflammatory bowel disease [J].Gut,2000,47(1):57-62.
5.郭长存,吴开春.难治性炎症性肠病的治疗[J].中国实用内科杂志,2007,27(18):1418-1422.
6.Faubion WA Jr,Loftus EV Jr,Harmsen WS,et al.The natural history of corticoste -roid therapy for inflammatory bowel disease:a population-based study[J].Gastro -enterology,2001,121(2):255-260.
7.Seegers D,Bouma G,Pena AS.Review article:a critical approach to new forms of treatment of Crohn's disease and ulcerative colitis[J].Aliment Pharmacol Ther.2002,16 Suppl 4:53-58.
8.Ogata H,Hibi T.Cytokine and anti-cytokine therapies for inflammatory bowel diseases[J].Curr Pharm Des,2003,9(14):1107-1113.
9.Poggioli G,Laureti S,Campieri M,et al.Infliximab in the treatment of Crohn's disease[J].Ther Clin Risk Manag,2007,3(2):301-308.
10.王文君,王培训,李晓娟.青藤碱抗炎机理-青藤碱对人外周血单个核细胞环氧化酶活性及其基因表达的影响[J].中国中药杂志,2003,28(4):352-355.
11.Zeng Y,Gu B,Ji X,et al.Sinomenine,an antirheumatic alkaloid,ameliorates clinical signs of disease in the Lewis rat model of acute experimental auto immune encephalolmyelitis[J].Biol Pharm Bull,2007,30(8):1438-1444.
12.Feng H,Yamaki K,Takano H,et al.Suppression of Th1 and Th2 immune responses in mice by Sinomenine,an alkaloid extracted from the chinese medicinal plant Sin -omenium acutum[J].Planta Med,2006,72(15):1383-1388.
13.刘刚,王辉,张先洲,等.青藤碱清除氧自由基和抗脂质过氧化作用[J].中草药,2006,37(1):84-87.
14.Liu Z,Zheng JF,Yang LQ,et al.Effects of sinomenine on NO/nNOS system in cerebellum and spinal cord of morphine-dependent and withdrawal mice[J].Sheng Li Xue Bao,2007,59(3):285-292.
15.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[J].中国 医学科学院学报, 1998, 20(4):271-278.
16. Murano M, Maemura K, Hirata I, et al.Therapeutic effect of intracolonically administered nuclear factorκB(P65) antisense oligonucleotide on mouse dextran sulphate sodium(DSS)-induced colitis[J]. Clin Exp Immunol, 2000,120(1): 51- 58.
17. Zingarelli B, Hake PW, Burroughs TJ, et al. Activator protein-1 signalling pathwa -y and apoptosis are modulated by poly(ADP-ribose)polymerase-1 in experimental colitis[J]. Immunology, 2004,113 (4): 509-517.
18. Akcan A, Muhtaroglu S, Akgun H, et al. Ameliorative effects of bombesin and neurotensin on trinitrobenzene sulphonic acid-induced colitis, oxidative damage and apoptosis in rats[J]. World J Gastroenterol, 2008,14(8): 1222-1230.
19. Koga H, Sakisaka S, Ohishi M, et al. Expression of cyclooxygenase-2 in human hepatocellular carcinoma:relevance to tumor dedifferentiation[J]. Hepatology,19-99,29(3):688-696.
20. Choi PM, Zelig MP. Similarity of colorectal cancer in Crohn's disease and ulcerat -ive colitis:implications for carcinogenesis and prevention[J].Gut, 1994,35(7):950-954.
21. Eaden JA, Abrams KR, Mayberry JF. The risk of colorectal cancer in Ulcerative colitis:a meta-analysis[J]. Gut, 2001,48(4):526-535.
22. Rutter MD, Saunders BP, Wilkinson KH, et al. Thirty year analysis of a colonos -copic surveillance program for neoplasia in Ulcerative colitis[J]. Gastroenter-ology, 2006,130(4):1030-1038.
23. Jess T, Loftus EV Jr, Velayos FS, et al. Risk of intestinal cancer in inflammatory bowel disease: a population-based study from Olmsted county, Minnesota [J]. Gastroenterology, 2006, 130(4): 1039-1046.
24. Balding J, Livingstone WJ, Conroy J, et al. Inflammatory bowel disease:the role of inflammatory cytokine gene polymorphisms[J]. Mediators Inflamm, 2004, 13(3):181-187.
25.Arseneau KO,Pizarro TT,Cominelli F.Discovering the cause of inflammatory bowel disease:lessons from animal models[J].Curr Opin Gastroenterol,2000,16(4):310-317.
26.王皓,欧阳钦,胡仁伟.三硝基苯磺酸结肠炎动物模型的建立[J].胃肠病学,2001,6(1):7-10.
27.杨德森,刘芳,曾繁典,等.青藤碱对大鼠佐剂性关节炎治疗作用及机制的研究[J].中国中药杂志,2005,30(17):1361-1363.
28.Cao W,Vrees MD,Potenti FM,et al.Interleukin 1beta-induced production of H2O2 contributes to reduced sigmoid colonic circular smooth muscle contractil -ity in ulcerative colitis[J].J Pharmacol Exp Ther,2004,311(1):60-70.
29.Malo MS,Biswas S,Abedrapo MA,et al.The pro-inflammatory cytokine,IL-1"beta and TNF-alpha,inhibit intestinal alkaline phosphatase gene expression[J].DNA Cell Biol,2006,5(12):684-695.
30.贾百灵,候晓华.溃疡性结肠炎患者血清白细胞介素1β检测[J].郑州大学学报(医学版),2004,39(2):306-308.
31.贾百灵,侯晓华.溃疡性结肠炎患者血清TNF-α的变化[J].第四军医大学学报,2004,25(9):849-850.
32.Murch SH,Braegger CP,Walker-Smith JA,et al.Location of tumour necrosis fa -ctor alpha by immunohistochemistry in chronic inflammatory bowel disease[J].Gut,1993,34(12):1705-1709.
33.Whittall T,Wang Y,Kelly CG,et al.Tumor necrosis factor-alpha production sti -mulated by heat shock protein 70 and its inhibition in circulating dendritic cells and cells eluted from mucosal tissues in Crohn's disease[J].Clin Exp Immunol,2006,143(3):550-559.
34.Zhou YH,Yu JP,Liu YF,et al.Effects of Ginkgo biloba extract on inflammatory mediators(SOD,MDA,TNF-alpha,NF-kappaBp65,IL-6) in TNBS-induced col -itis in rats[J].Mediators Inflamm,2006,2006(5):92642.
35.Noguchi M,Hiwatashi N,Liu Z,et al.Secretion imbalance between tumour necr -osis factor and its inhibitor in inflammatory bowel disease[J].Gut,1998,43(2):203-209.
36.Ebert EC.Tumour necrosis factor-alpha enhances intraepithelial lymphocyte pro -liferation and migration[J].Gut,1998,42(5):650-655.
37.Wang F,Graham WV,Wang Y,et al.Interferon-gamma and tumor necrosis fac -tor-alpha synergize to induce intestinal epithelial barrier dysfunction by upregulating myosin light chain kinase expression[J].Am J Pathol,2005,166(2):409-419.
38.崔巍,刘冬妍,马力,等.TNF-α对肠上皮细胞紧密连接蛋白表达的作用[J].世界华人消化杂志,2007,15(16):1788-1793.
39.Qian L,Xu Z,Zhang W,et al.Sinomenine,a natural dextrorotatory morphinan a -nalog,is anti-inflammatory and neuroprotective through inhibition of microglial NADPH oxidase[J].J Neuroinflammation,2007,4:23.
40.李晓娟,王培训,刘良,等.青藤碱对T淋巴细胞活化及TH1类细胞内细胞因子表达的影响[J].中国免疫学杂志,2004,20(4):249-252,258.
41.Huang F,Yamaki K,Tong X,et al.Inhibition of the antigen-induced activation of RBL-2H3 cells by sinomenine[J].Int Immunopharmacol,2008,8(3):502-507.
42.Huang J,Lin Z,Luo M,et al.Sinomenine suppresses TNF-alpha-induced VCA -M-1expression in human umbilical vein endothelial cells[J].J Ethnopharmacol,2007,114(2):180-185.
43.金晓琨,李卫东,滕慧玲,等.青藤碱对核转录因子-κB及其抑制因子IκB 的影响[J].中国药理学通报,2004,20(7):788-791.
44.Wang AL,Li Z,Yuan M,et al.Sinomenine inhibits activation of rat retinal mi -croglia induced by advanced glycation end products[J].Int Immunopharmacol,2007,7(12):1552-1558.
45.方勇飞,王勇,周新,等.青藤碱对佐剂性关节炎大鼠滑膜细胞核因子κB信号转导的影响及其机制[J].中国临床康复,2005,9(7):204-205.
46.Medina C,Videla S,Radomski A,et al.Increased activity and expression of mat -rix metalloproteinase-9 in a rat model of distal colitis[J].Am J Physiol Gastr -ointest Liver Physiol,2003,284(1):116-122.
47.Stallmach A,Chan CC,Ecker K-W,et al.Comparable expression of matrix meta -lloproteinases 1 and 2 in pouchitis and ulcerative colitis[J].Gut,2000,47(3):415-422.
48.Gao Q,Meijer MJ,Kubben FJ,et al.Expression of matrix metalloproteinases -2 and -9 in intestinal tissue of patients with inflammatory bowel diseases[J].Dig Liver Dis,2005,37(8):584-592.
49.Piril(a|¨) E,Ramamurthy NS,Sorsa T,et al.Gelatinase A(MMP-2),collagenase-2(MMP-8),and laminin-5 gamma2-chain expression in murine inflammatory bo -wel disease(ulcerative colitis)[J].Dig Dis Sci,2003,48(1):93-98.
50.杨汝春,王永钧,林京莲,等.青藤碱对白介素1β诱导的肾小管上皮细胞骨架变化和明胶酶活性的影响[J].中华肾脏病杂志,2006,22(8):499-502.
51.Von Lampe B,Barthel B,Coupland SE,et al.Differential expression of matrix metalloproteinases and their tissue inhibitors in colon mucosa of patients with inflammatory bowel disease[J].Gut,2000,47(1):63-73.
52.Medina C,Santana A,Paz MC,et al.Matrix metalloproteinase-9 modulates intes -tinal injury in rats with transmural colitis[J].J Leukoc Biol,2006,79(5):954-962.
53.Zhou H,Wong YF,Wang J,et al.Sinomenine ameliorates arthritis via MMPs,TIMPs,and cytokines in rats[J].Biochem Biophys Res Commun,2008,376(2):352-357.
54.Waetzig GH,Seegert D,Rosenstiel P,et al.p38 mitogen-activated protein kinase is activated and linked to TNF-alpha signaling in inflammatory bowel disease[J]. J Immunol,2002,168(10):5342-5351.
55.Hollenbach E,Neumann M,Vieth M,et al.Inhibition of p38MAP kinase-and RI -CK/NF-kappaB-signaling suppresses inflammatory bowel disease[J].FASEB J,2004,18(13):1550-1552.
56.王峻,郭德玉.TNF-α对胃癌细胞MMP-2和MMP-9表达的诱导作用[J].世界华人消化杂志,2007,15(11):1208-1212.
57.Han YP,Tuan TL,Wu H,et al.TNF-alpha stimulates activation of pro-MMP-2in human skin through NF-(kappa)B mediated induction of MT1-MMP[J].J Ce -ll Sci,2001,114(pt 1):131-139.
58.朱军华,陶凯雄,王国斌.TNF-α对肝癌细胞VEGF和MMP-9表达的影响[J].中国普外基础与临床杂志,2005,12(4):384-389.
59.Lee CW,Lin CC,Lin WN,et al.TNF-alpha induces MMP-9 expression via ac.-tivation of Src/EGFR,PDGFR/PI3K/AKt cascade and promotion of NF-kappa B/p300 binding in human tracheal smooth muscle cells[J].Am J Physiol Lung Cell Mol Physiol,2007,292(3):L799-L812.
60.Meijer MJ,Mieremet-Ooms MA,van Duijn W,et al.Effect of the anti-tumor necrosis factor-alpha antibody infliximab on the ex vivo mucosal matrix meta -lloproteinase-proteolytic phenotype in inflammatory bowel disease[J].Inflamm Bowel Dis,2007,13(2):200-210.
61.Gao Q,Meijer MJ,Schl(u|¨)ter UG,et al.Infliximab treatment influences the serolo -gical expression of matrix metalloproteinase(MMP)-2 and -9 in Crohn's disease [J].Inflamm Bowel Dis,2007,13(6):693-702.
62.Lin CC,Tseng HW,Hsieh HL,et al.Tumor necrosis factor-alpha induces MM -P-9 expression via p42/p44 MAPK,JNK,and nuclear factor-kappaB in A549 ce -lls[J].Toxicol Appl Pharmacol,2008,229(3):386-398.
63.Wiehler S,Cuvelier SL,Chakrabarti S,et al.p38 MAP kinase regulates rapid ma -trix metalloproteinase-9 release from eosinophils[J].Biochem Biophys Res Co -mmun,2004,315(2):463-470.
1 Ishiguro Y.Mucosal proinflammatory cytokine production correlates with endoscopic activity of ulcerative colitis[J].J Gastroenterol,1999,34(1):66-74.
2 贾百灵,侯晓华.溃疡性结肠炎患者血清白细胞介素1β检测[J].郑州大学学报(医学版),2004,39(2):306-308.
3 张文俊,许国铭,李兆申,等.血清白细胞介素1β与溃疡性结肠炎的关系[J].第二军医大学学报,2002,23(12):1345-1346.
4 Zou K,Liu S,Xie X,et al.Clinical significance and assessment of cytokines in various stages of ulcerative colitis[J].J Tongji Med Univ,2001,21(4):308-309.
5 Yamamoto T,Maruyama Y,Umegae S,et al.Mucosal inflammation in the terminal ileum of ulcerative colitis patients:endoscopic findings and cytokine profiles[J]. Dig Liver Dis,2008,40(4):253-259.
6 Wedrychowicz A,Stopyrowa J,Fyderek K,et al.Stool interleukin 1beta and interleukin 1 receptor antagonist concentrations in children with active ulcerative colitis and during recovery[J].Eur J Pediatr,2003,162(7-8):541-542.
7 Evgenikos N,Bartolo DC,Hamer-Hodges DW,et al.Assessment of ileoanal pouch inflammation by interleukin-1 beta and interleukin-8 concentration in the gut lumen[J].Dis Colon Rectum,2002,45(2):249-255.
8 Sawa Y,Oshitani N,Adachi K,et al.Comprehensive analysis of intestinal cyto -kine messenger RNA profile by real-time quantitative polymerase chain reaction in patients with inflammatory bowel disease[J].Int J Mol Med,2003,11(2):175-179.
9 Arai F,Takahashi T,Furukawa K,et al.Mucosal expression of interleukin-6 and interleukin-8 messenger RNA in ulcerative colitis and in Crohn's disease[J].Dig Dis Sci,1998,43(9):2071-2079.
10 Ashwood P,Harvey R,Verjee T,et al.FunctionaL interactions between mucosal IL-1,IL-1ra and TGF-β beta 1 in ulcerative colitis[J].Inflamm res,2004,53(2):53-59.
11 Witkin SS,Gerber S,Ledger WJ.Influence of interleukin-1 receptor antagonist gene polymorphism on disease[J].Clin Infect Dis,2002,34(2):204-209.
12 Dinarello CA.Biologic basis for interleukin-1 in disease[J].Blood,1996,87(6):2095-2147.
13 杨幼林,刘芳,李宝杰,等.IL-1β和IL-1Ra基因单核苷酸多态性同溃疡性结肠炎的相关性[J].胃肠病学和肝病学杂志,2007,16(4):377-340.
14 薛惠平,倪培华,吴洁敏,等.炎症性肠病IL-1β基因多态性及连锁不平衡研究[J].上海交通大学学报(医学版),2006,26(8):912-915.
15 Balding J,Livingstone WJ,Conrov J,et al.Inflammatory bowel disease:the role of inflammatory cytokine gene polymorphisms[J].Mediators Inflamm,2004,13(3): 181-187.
16 彭仲生,胡品津,崔毅,等.溃疡性结肠炎的IL-1β、IL-1RA、LMP2基因多态性研究[J].中国免疫学杂志,2002,18(12):852-855.
17 Cao W,Vrees MD,Potenti FM,et al.Interleukin 1beta-induced production of H2O2 contributes to reduced sigmoid colonic circular smooth muscle contractility in ulcerative colitis[J].J Pharmacol Exp Ther,2004,311(1):60-70.
18 Cao W,Fiocchi C,Pricolo VE.Production of IL-1beta,hydrogen peroxide,and nitric oxide by colonic mucosa decreases sigmoid smooth muscle contractility in ulcerative colitis[J].Am J Physiol cell Physiol,2005,289(6):C1408-C1416.
19 Malo MS,Biswas S,Abedrapo MA,et al.The pro-inflammatory cytokines,IL-1beta and TNF-alpha,inhibit intestinal alkaline phosphatase gene expression[J].DNA Cell Biol,2006,5(12):684-695.
20 贾百灵,侯晓华.溃疡性结肠炎患者血清TNF-α的变化[J].第四军医大学学报,2004,25(9):849-850.
21 Murch SH,Braegger CP,Walker-Smith JA,et al.Location of tumour necrosis factor alpha by immunohistochemistry in chronic inflammatory bowel disease[J].Gut,1993,34(12):1705-1709.
22 Whittall T,Wang Y,Kelly CG,et al.Tumor necrosis factor-alpha production stimulated by heat shock protein 70 and its inhibition in circulating dendritic cells and cells eluted from mucosal tissues in Crohn's disease[J].Clin Exp Immunol,2006,143(3):550-559.
23 Zhou YH,Yu JP,Liu YF,et al.Effects of Ginkgo biloba extract on inflammatory mediators(SOD,MDA,TNF-alpha,NF-kappaBp65,IL-6) in TNBS-induced colitis in rats[J].Mediators Inflamm.,2006,2006(5):92642.
24 Noguchi M,Hiwatashi N,Liu Z,et al.Secretion imbalance between tumour necrosis factor and its inhibitor in inflammatory bowel disease[J].Gut,1998,43(2):203-209.
25 Saiki T,Mitsuvama K,Tovonaga A,et al.Detection of pro-and anti-inflammatory cytokines in stools of patient with inflammatory bowel[J].Scand J Gastroenterol,1998,33(6):616-622.
26 Hadziselimovic F,Emmons LR,Gallati H,et al.Soluble tumour necrosis factor receptors p55、p75 in the urine monitor disease activity and the efficacy of treatment of inflammatory bowel disease[J].Gut,1995,37(2):260-263.
27 崔静,刘占举,唐芙爱.炎症性肠病患者血清肿瘤坏死因子和白介素8检测[J].郑州大学学报(医学版),2006,41(5):825-827.
28 Wang YD,Mao JW.Expression of matrix metalloproteinase-1 and tumor necrosis factor-alpha in ulcerative colitis[J].World J Gastroenterol,2007,13(44):5926-5932.
29 Baena A,Leung JY,Sullivan AD,et al.TNF-alpha promoter single nucleotide polymorphisms are markers of human ancestry[J].Genes Immun,2002,3(8):482-487.
30 Koss K,Satsangi J,Fanning GC,et al.Cytokine(TNF alpha,LT alpha and IL-10)polymorphisms in inflammatory bowel diseases and normal controls:differential effects on production and allele frequencies[J].Genes Immun,2000,1(3):185-190.
31 Gonzalez S,Rodrigo L,Martinez-Borra J,et al.TNF-alpha-308A promoter poly -morphism is associated with enhanced TNF-alpha production and inflammatory activity in Crohn's patients with fistulizing disease[J].Am J Gastroenterol,2003,98(5):1101-1106.
32 Linderson Y,Bresso F,Buentke E,et al.Functional interaction of CARD15/NOD2and Crohn's disease-associated TNF alpha polymorphisms[J].Int J Colorectal Dis,2005,20(4):305-311.
33 宋瑛,吴开春,张沥,等.肿瘤坏死因子基因多态性与炎症性肠病的相关性分析[J].中华消化杂志 2005,25(4):202-206.
34 曹倩,高敏,周刚,等.肿瘤坏死因子基因多态性与溃疡性结肠炎相关性研究 [J].中华消化杂志,2006,26(7):460-463.
35 Cucchiara S,Latiano A,Palmieri O,et al.Polymorphisms of tumor necrosis factor-alpha but not MDR1 influence response to medical therapy in pediatriconset inflammatory bowel disease[J].J Pediatr Gastroenterol Nutr,2007,44(2):171-179.
36 项利鹃,陈春晓.肿瘤坏死因子α基因多态性与炎症性肠病的关系[J].浙江医学,2006,28(4):261-263.
37 Zipperlen K,Peddle L,Melay B,et al.Association of TNF-alpha polymorphisms in Crohn disease[J].Hum Immunol,2005,66(1):56-59.
38 袁岸龙,夏冰,侯炜,等.肿瘤坏死因子-α基因多态性与炎症性肠病的相关性研究[J].中华消化杂志,2004,24(4):243-244.
39 Yamamoto-Furusho JK,Uscanga LF,Vargas-Alarcon G,et al.Polymorphisms in the promoter region of tumor necrosis factor alpha(TNF-alpha)and the HLA-DRB1locus in Mexican Mestizo patients with ulcerative colitis[J].Immunol Lett,2004,95(1):31-35.
40 Louis E,Peeters M,Franchimont D,et al.Tumor necrosis factor(TNF)gene poly -morphism in Crohn's disease(CD):influence on disease behaviour?[J].Clin Exp Immunol,2000,119(1):64-68.
41 Araujo F,Pereira AC,Mota GF,et al.The influence of tumor necrosis factor-308and C-reactive protein G1059C gene variants on serum concentration of C-reactive protein:evidence for an age-dependent association[J].Clin Chim Acta,2004,349(1-2):129-134.
42 Jeanmonod P,von K(a|¨)nel R,Maly FE,et al.Elevated plasma C-reactive protein in chronically distressed subjects who carry the A allel of the TNF-alpha-308G/A polymorphism[J].Psychosom Med,2004,66(4):501-506.
43 Vatay A,Bene L,Kovacs A,et al.Relationship between the tumor necrosis factor alpha polymorphism and the serum C-reactive protein levels in inflammatory bowel disease[J].Immunogenetics,2003,55(4):247-252.
44 Mittal RD,Manchanda PK,Bid HK,et al.Analysis of polymorphisms of tumor necrosis factor-alpha and polymorphic xenobiotic metabolizing enzymes in infla -mmatory bowel disease:Study from northern India[J].J Gastroenterol Hepatol,2007,22(6):920-924.
45 Meijer MJ,Mieremet-Ooms MA,van Hogezand RA,et al.Role of matrix metall -oproteinase,tissue inhibitor of metalloproteinase and tumor necrosis factor-alpha single nucleotide gene polymorphisms in inflammatory bowel disease[J].World J Gastroenterol,2007,13(21):2960-2966.
46 Wang F,Graham WV,Wang Y,et al.Interferon-gamma and tumor necrosis factor-alpha synergize to induce intestinal epithelial barrier dysfunction by up-regulating myosin light chain kinase expression[J].Am J Pathol,2005,166(2):409-419.
47 崔巍,刘冬妍,马力,等.TNF-α对肠上皮细胞紧密连接蛋白表达的作用[J].世界华人消化杂志,2007,15(16):1788-1793.
48 Szlosarek PW,Balkwill FR.Tumour necrosis factor alpha:a potential target for the therapy of solid tumours[J].Lancet Oncol,2003,4(9):567-573.
49 Ebert EC.Tumor necrosis factor-αenhances intraepithelial lymphocyte proliferatio -n and migration[J].J Gut,1998,42(5):650-665.
50 Medina C,Videla S,Radomski A,et al.Increased activity and expression of matri -x metalloproteinase-9 in a rat model of distal colitis[J].Am J Physiol Gastrointest Liver Physiol,2003,284(1):116-122.
51 McKaig BC,McWilliams D,Watson SA,et al.Expression and regulation of tissue inhibitor of metalloproteinase-1 and matrix metalloproteinases by intestinal myofi -broblasts in inflammatory bowel disease[J].Am J Pathol,2003,162(4):1355-1360.
52 Von Lampe B,Barthel B,Coupland SE,et al.Differential expression of matrix metalloproteinases and their tissue inhibitors in colon mucosa of patients with inflammatory bowel disease[J].Gut,2000,47(1):63-73.
53 Heuschkel RB,MacDonald TT,Monteleone G,et al.Imbalance of stromelysin-1and TIMP-1 in the mucosal lesion of children with inflammatory bowel disease[J].Gut,2000,47(1):57-62.
54 Matsuno K,Adachi Y,Yamamoto H,et al.The expression of matrix metallopro -teinase matrilysin indicates the degree of inflammation in ulcerative colitis[J].J Gastroenterol,2003,38(4):348-354.
55 缪应雷,欧阳钦,段丽平,等.基质金属蛋白酶-1、基质金属蛋白酶-2和基质金属蛋白酶-3在溃疡性结肠炎患者肠黏膜的表达[J].临床内科杂志,2005,22(10):682-684.
56 Newell KJ,Matrisian LM,Driman DK.Matrilysin(matrix metalloproteinase-7)expression in ulcerative colitis-related tumorigenesis[J].Mol Carcinog,2002,34(2):59-63.
57 Piril(a|¨).E,Ramamurthy NS,Sorsa T,et al.Gelatinase A(MMP-2),collagenase-2(MMP-8),and laminin gamma2-chain expression in murine inflammatory bowel disease(ulcerative colitis)[J].Dig Dis Sci,2003,48(1):93-98.
58 张文俊,许国铭,李兆申,等.基质金属蛋白酶3和9在溃疡性结肠炎中表达的研究[J].中华消化杂志,2003,23(3):187-188.
59 陈锡美,刘文滨,陈文骏,等.溃疡性结肠炎患者基质金属蛋白酶-2,9和抑制因子-1,2的表达及其意义[J].临床内科杂志,2003,20(7):384-386.
60 Gao Q,Meijer MJ,Kubben FJ,et al.Expression of matrix metalloproteinases-2and -9 in intestinal tissue of patients with inflammatory bowel diseases[J].Dig Liver Dis,2005,37(8):584-592.
61 Medina C,Santana A,Paz MC,et al.Matrix metalloproteinase-9 modulates intestinal injury in rats with transmural colitis[J].J Leukoc Biol,2006,79(5):954-962.
62 Brinkman BM, Telliez JB, Schievella AR, et al. Engagement of tumor necrosis factor(TNF)receptor 1 leads to ATF-2 and P38 mitogen-activated protein kinase-dependent TNF-alpha gene expression[J]. J Biol Chem, 1999, 274(43): 30882-308806.
63 Hoffmeyer A, Grosse-wilde A, Flory E, et al. Differene mitogen-activated protein kinase signaling pathways cooperate to regulate tumor necrosis factor alpha gene expression in T lymphocytes[J]. J Biol Chem, 1999,274(7):4319-4327.
64 Waetzig GH, Seegert D, Rosenstiel P, et al. p38 mitogen-activated protein kinase is activated and linked to TNF-alpha signaling in inflammatory bowel disease[J]. J Immunol, 2002,168(10):5342-5351.
65 Hollenbach E, Neumann M, Vieth M, et al. Inhibition of p38MAP kinase- and RICK/NF-kappaB-signaling suppresses inflammatory bowel disease[J]. FASEB J, 2004,18(13):1550-1552.
66 Rutault K, Hazzalin CA, Mahadevan LC. Combinations of ERK and P38MAPK inhibitors ablate tumor necrosis factor-alpha(TNF-alpha) mRNA induction: Evidence for selective destabilization of TNF-alpha transcripts[J]. J Biol Chem, 2001,276(9):6666-6674.