慢性应激对小鼠溃疡性结肠炎的影响

目的观察慢性束缚应激对葡聚糖酸钠(DSS)诱导的小鼠溃疡性结肠炎(UC)的影响。方法64只BALB/C小鼠分为6组,单纯应激组、正常对照组各16只,应激 2DSS组、应激 4DSS组、2DSS组、4DSS组各8只。采用自制的束缚笼对应激组小鼠建立慢性心理应激动物模型。采用小鼠自由饮用DSS溶液的方法建立UC模型。每日观察各组疾病活动指数(DAI)。并在实验结束后测量结肠组织损伤评分(HS)、髓过氧化物酶(MPO)活性。HS评分通过在光镜下观察结肠组织学改变得出。并用分光光度法测定结肠组织中MPO的活性。结果单纯应激组小鼠体重增长较正常对照组缓慢(P<0.05)。4DSS组小鼠DAI评分、HS评分及结肠组织MPO活性均较正常对照组增高(P<0.05)。应激 4DSS组上述指标较正常对照组变化更显著,与4DSS组比较亦增高(P<0.05)。2DSS组上述指标与正常对照组相比无明显区别(P>0.05)。应激 2DSS组上述指标较正常对照组增高(P<0.05)。结论慢性束缚应激可以使小鼠发生UC的易感性增加并加重DSS结肠炎的病理损伤。     

Protective Effect of Lafutidine, a Novel Histamine H2-Receptor Antagonist, on Dextran Sulfate Sodium-Induced Colonic Inflammation Through Capsaicin-Sensitive Afferent Neurons in Rats

Lafutidine, a histamine H2-receptor antagonist, exhibits gastric mucosal protective action mediated by capsaicin-sensitive afferent neurons, in addition to a potent antisecretory effect. In this study we examined the effect of lafutidine on dextran sulfate Na (DSS)-induced ulcerative colitis in rats, in relation to capsaicin-sensitive afferent neurons. Experimental colitis was induced in rats by daily treatment with 3% DSS in drinking water for 7 days. Lafutidine, capsaicin, and cimetidine were administered per os twice daily for 6 days. The ulceration area, colon length, and myeloperoxidase (MPO) activity were measured on day 7 after the onset of DSS treatment. DSS caused severe mucosal lesions in the colon, accompanied by an increase in MPO activity as well as a decrease in body weight gain and colon length. Daily administration of lafutidine dose-dependently reduced the severity of DSS-induced colitis and significantly mitigated changes in the colon length and MPO activity. The effects of lafutidine were mimicked by daily administration of capsaicin but not cimetidine and were totally abolished by chemical ablation of capsaicin-sensitive afferent neurons. In contrast, desensitization of afferent neurons significantly worsened the colonic inflammation induced by DSS. It was also found that both lafutidine and capsaicin increased the secretion of mucus in the colonic mucosa. These results suggest that lafutidine is effective against the ulcerative colitis induced by DSS through capsaicin-sensitive afferent neurons. This action might be attributable at least partly to the enhancement of colonic mucus secretion.     

Basic fibroblast growth factor enema improves experimental colitis in rats

BACKGROUND/AIMS: Growth factors have a potential role in gastrointestinal mucosal repair. Although basic fibroblast growth factor (bFGF) is known to contribute to wound healing, however, the role of bFGF in the treatment of inflammatory bowel disease has not been established. The aim of this study is to investigate the therapeutic effects of intracolonic bFGF administration on both the clinical symptoms and histological mucosal repair in an experimental model of colitis in rats. METHODOLOGY: Acute colitis was induced with 5% dextran sulfate sodium (DSS) given for one week in drinking water. The rats were treated daily with recombinant human bFGF enema (400 microg/kg/day) or vehicle once daily from day 1 to day 7. Clinical score (stool consistency, weight loss and hemoccult/gross rectal bleeding), colon length and histological score of mucosal injury in colonic tissue samples were analyzed. RESULTS: Administration of bFGF enema significantly reduced clinical score (p < 0.01) and histological score (p < 0.01). No specific side effect of bFGF was noted. CONCLUSIONS: These results suggest that bFGF enema is clinically safe and useful in the treatment of inflammatory bowel disease. BFGF enema may contribute as a novel therapy of IBD.     

Polaprezinc (N-(3-aminopropionyl)-L-histidinato zinc) ameliorates dextran sulfate sodium-induced colitis in mice

OBJECTIVE: Polaprezinc (N-(3-Aminopropionyl)-L-histidinato zinc), an anti-ulcer drug, has been reported to have an anti-inflammatory action in several inflammatory diseases. The aim of this study was to investigate the effect of polaprezinc on dextran sulfate (DSS)-induced colitis in mice. MATERIAL AND METHODS: Mice with colitis induced by DSS were intrarectally treated with polaprezinc (15 mg/kg) or zinc sulfate (7.5 mg/kg) every day after the administration of DSS for 7 days. Disease activity index (DAI) and histological tissue damage were assessed. Levels of myeloperoxidase (MPO) activity, tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma in the colon were measured. Expression of heat shock protein (HSP) 25 and HSP70 in the colon was analyzed by Western blot analysis. RESULTS: DAI and histological scores were remarkably reduced in polaprezinc-treated mice with DSS-induced colitis. Polaprezinc suppressed the increase of MPO activity and the production of TNF-alpha and IFN-gamma in the colon tissues of mice with DSS-induced colitis. Expression of HSP25 and HSP70 was remarkably up-regulated in the colon tissues of polaprezinc-treated mice during DSS treatment. CONCLUSIONS: Polaprezinc suppresses DSS-induced colitis in mice, partly through inhibition of production of pro-inflammatory cytokine, suppression of neutrophils accumulation and cytoprotection by overexpression of HSPs. Polaprezinc could be useful in the treatment of inflammatory bowel diseases.     

Effect of Scutellariae Radix extract on experimental dextran-sulfate sodium-induced colitis in rats

AIM： To investigate the effect of Scutellariae Radix extract （SRE） on ulcerative colitis （UC） in rats induced by dextran-sulfate sodium （DSS）. METHODS： Colitis was induced in male Sprague-Dawley （SD） rats （170-180 g） by 4% dextran sulfate sodium （DSS, wt/v, MW 54000） in drinking water for 8 d. The treated rats received 4% DSS and SRE orally （100 mg/kg per day）. Control rats received either tap water or SRE only. Macroscopic assessment which included body weight changes, fecal occult blood and stool consistency were determined daily. At the appointed time, the rats were sacrificed and the entire colons were removed. The colon length and the myeloperoxidase （MPO） activity were measured. The severity of colitis was graded by morphological and histological assessments. The ion transport activity of the colonic mucosa was assessed by electrophysiological technique. RESULTS： Rats treated with oral administration of 4% DSS regularly developed clinical and macroscopic signs of colitis. Treatment with SRE relieved the symptoms, including the reduction in body weight, shortening 2nd ulceration of the colon. Administration of SRE also significantly reduced the histological damage induced by DSS. Moreover, the Isc responses of the colonic mucosa to forskolin, were suppressed after the induction of colitis. The stimulated ion transport activity of DSS-rats treated with SRE displayed significant improvement in the secretory responsiveness. CONCLUSION： SRE was effective in treating acute DSS- induced ulcerative colitis, as gauged by reduced clinical disease, improved macroscopic and histological damage scores, and enhanced recovery of normal colonic secretory function.     

The Role of Zinc and Metallothionein in the Dextran Sulfate Sodium-Induced Colitis Mouse Model

Zinc (Zn) and its binding protein metallothionien (MT) have been proposed to suppress the disease activity in ulcerative colitis. To determine the role of Zn and MT in the dextran sulfate sodium (DSS)-induced model of colitis in mice, a DSS dose-response study was conducted in male C57BL/6 wild-type (MT+/+) and MT-null (MT−/−) mice by supplementing 2%, 3%, and 4% DSS in the drinking water for 6 days. In the intervention study, colitis was induced with 2% DSS, Zn (24 mg/ml as ZnO) was gavaged (0.1 ml) daily, concurrent with DSS administration, and the disease activity index (DAI) was scored daily. Histology, MT levels, and myeloperoxidase (MPO) activity were determined. DAI was increased (P<0.05) by 16% and 21% with 3% and 4% concentrations of DSS, respectively, compared to 2%, evident after 5 days of DSS administration. MPO activity was increased in MT+/+ compared to MT−/− mice and those receiving DSS. Zn administration had a 50% (P<0.05) lower DAI compared to DSS alone. Zn partially prevented the distal colon of MT+/+ by 47% from DSS-induced damage compared to MT−/− mice. MT did not prevent DSS-induced colitis and Zn was partially effective in amelioration of DSS-induced colitis.     

Dietary inulin improves distal colitis induced by dextran sodium sulfate in the rat

OBJECTIVES: Inulin stimulates intracolonic generation of butyrate and growth of lactic acid bacteria. This study investigated whether inulin protects against colitis. METHODS: Rats with dextran sodium sulfate colitis received inulin either orally (1% in drinking water, or 400 mg/day) or by enema. Matched groups received vehicle. In addition, fecal water obtained from inulin-fed rats was administered by enema to rats with colitis and compared with fecal water from control rats. Finally, rats with colitis received daily enemas of either butyrate (at 40 or 80 mmol/L) or vehicle. Inflammation was assessed by eicosanoid asssay in rectal dialysates and MPO activity in colonic tissue. Mucosal lesions were blindly scored by microscopic examination. Luminal pH was measured from cecum to rectum by a surface microelectrode. RESULTS: Oral inulin prevented inflammation, as evidenced by lower lesion scores (p < 0.05), decreased release of mediators (p < 0.05), and lower tissue MPO (p < 0.05) as compared with controls. Inulin induced acidic environment (pH <7.0) from cecum to left colon and increased counts of lactobacilli. Fecal water from inulin-fed rats also reduced scores (p < 0.05) and inflammation (p < 0.05). However, inulin or butyrate enemas had no effect. CONCLUSIONS: Oral inulin reduces the severity of dextran sodium sulfate colitis. The effect seems to be mediated by modification of the intracolonic milieu.     

Kefir treatment ameliorates dextran sulfate sodium-induced colitis in rats

AIM: To investigate the preventive effect of kefir on colitis induced with dextran sulfate sodium(DSS) in rats.METHODS: Twenty-four male Wistar-albino rats were randomized into four groups: normal control,kefircontrol,colitis,and kefir-colitis groups. Rats in the normal and kefir-control groups were administered tap water as drinking water for 14 d. Rats in the colitis and kefir-colitis groups were administered a 3% DSS solution as drinking water for 8-14 d to induce colitis. Rats in the kefir-control and kefir-colitis groups were administered 5 m L kefir once a day for 14 d while rats in the normal control and colitis group were administered an identical volume of the placebo(skim milk) using an orogastric feeding tube. Clinical colitis was evaluated with reference to the disease activity index(DAI),based on daily weight loss,stool consistency,and presence of bleeding in feces. Rats were sacrificed on the 15 th day,blood specimens were collected,and colon tissues were rapidly removed. Levels of myeloperoxidase(MPO),tumor necrosisfactor(TNF)-α,interleukin(IL)-10,malondialdehyde,and inducible nitric oxide synthase(i NOS) were measured in colon tissue.RESULTS: The DAI was lower in the kefir-colitis group than in the colitis group(on the 3rd and 5th days of colitis induction; P 0.01). The DAI was also significantly higher in the colitis group between days 2 and 6 of colitis induction when compared to the normal control and kefir-control groups. The DAI was statistically higher only on the 6th day in the kefircolitis group when compared to that in the normal control groups. Increased colon weight and decreased colon length were observed in colitis-induced rats. Mean colon length in the colitis group was significantly shorter than that of the kefir-control group. Kefir treatment significantly decreased histologic colitis scores(P 0.05). MPO activity in the colitis group was significantly higher than in the kefir-control group(P 0.05). Kefir treatment significantly reduced the DSS colitis-induced TNF-α increase(P 0.01). No statistically significant differences were observed among groups for IL-10 and MDA levels. Colon tissue i NOS levels in the colitis group were significantly higher than those in the control and kefir-colitis groups(P 0.05).CONCLUSION: Kefir reduces the clinical DAI and histologic colitis scores in a DSS-induced colitis model,possibly via reduction of MPO,TNF-α,and i NOS levels.     

A recombinant cystatin from Ascaris lumbricoides attenuates inflammation of DSS‐induced colitis

Helminthiasis may ameliorate inflammatory diseases, such as inflammatory bowel disease and asthma. Information about immunomodulators from Ascaris lumbricoides is scarce, but could be important considering the co‐evolutionary relationships between helminths and humans. We evaluated the immunomodulatory effects of a recombinant cystatin from A. lumbricoides on an acute model of dextran sodium sulphate (DSS)‐induced colitis in mice. From an A. lumbricoides cDNA library, we obtained a recombinant cystatin (rAl‐CPI). Protease activity inhibition was demonstrated on cathepsin B and papain. Immunomodulatory effects were evaluated at two intraperitoneal doses (0.5 and 0.25 μg/G) on mice with DSS‐induced colitis. Body weight, colon length, Disease Activity Index (DAI), histological inflammation score, myeloperoxidase (MPO) activity, gene expression of cytokines and cytokines levels in colon tissue were analysed. Treatment with rAl‐CPI significantly reduced DAI, MPO activity and inflammation score without toxic effects. Also, IL‐10 and TGF‐B gene overexpression was observed in rAl‐CPI‐treated group compared to DSS‐exposed control and healthy mice. Furthermore, a reduction in IL‐6 and TNF‐A expression was found, and this was confirmed by the levels of these cytokines in colonic tissue. In conclusion, rAl‐CPI reduces inflammation in a mouse model of DSS‐induced colitis, probably by increasing the expression of anti‐inflammatory cytokines and reducing pro‐inflammatory ones.     

瑞巴匹特预防葡聚糖硫酸酯钠诱发的小鼠结肠炎疗效观察及作用机制初探

目的近年氧自由基在溃疡性结肠炎(UC)发病过程中作用受到关注,一种新型的黏膜保护剂瑞巴匹特被认为具有清除氧自由基的作用,有望成为治疗溃疡性结肠炎的新药物。本文观察瑞巴匹特灌肠和灌胃治疗葡聚糖硫酸酯钠(DSS)诱发的小鼠结肠炎效果并探讨可能的作用机制。方法 3%DSS予8周龄雄性BALB/c小鼠自由饮用7 d制成小鼠结肠炎模型。予DSS前5 d开始瑞巴匹特(45 mg/kg/d)灌肠或灌胃治疗直到造模结束,处死小鼠取结肠组织,测量小鼠体重、结肠长度,进行大体和病理评分,分光光度法测定髓过氧化物酶、丙二醛含量,免疫组化法测定核因子κB(NFκB)表达水平,RT-PCR法测定过氧化物酶体增殖体激活受体γ(PPARγ)mRNA表达。结果与安慰剂对照组比较,瑞巴匹特灌肠和灌胃治疗组小鼠大体和病理评分显著改善,髓过氧化物酶活性、丙二醛含量、NFκB活性明显降低,PPARγmRNA的表达显著升高。结论瑞巴匹特可有效预防DSS诱发的小鼠结肠炎,其抑制炎症作用至少部分与清除氧自由基,从而维持局部PPARγ表达和抑制NFκB活性有关。     

康复新液对小鼠嗯唑酮结肠炎的疗效及其机制初探

我国溃疡性结肠炎的发病率不断升高,现有治疗尚存在不足,需寻找新的治疗方法和药物。目的：观察康复新液对小鼠嗯唑酮（OXZ）结肠炎的疗效,初步探讨其治疗机制。方法：将60只小鼠随机分为空白对照组、模型组、康复新液组、高浓度康复新液组、激素组,以OXZ灌肠诱导结肠炎模型。分别于灌肠后第3、8、13d处死小鼠。行疾病活动指数（DAI）、结肠大体评分和组织学评分,以ELISA法检测结肠组织髓过氧化物酶（MPO）、白细胞介素4（IL4）、干扰素．1（IFN-1）、肿瘤坏死因子．Or．（TNF—d）、NF—KB含量。结果：灌肠后第3、13d,与空白对照组相比,模型组DAI、结肠大体评分、组织学评分、MPO、IL-4、TNF-d、NF—KB含量均明显升高（P〈0．05）,IFN．1含量无明显差异。灌肠后第8、13d,给予康复新液和高浓度康复新液治疗后,上述指标均明显改善（P〈0．05）,IFN-y含量无明显差异。灌肠后第8d,激素组仅大体评分和IL-4含量明显降低（P〈0．05）。结论：康复新液灌肠可使OXZ诱导的小鼠结肠炎症明显减轻,其作用可能与抑制肠道异常炎症反应、调节细胞因子水平、抑制NF—KB转录有关。     

复方黄柏液对大鼠TNBS结肠炎的治疗机制探讨

背景：临床上采用复方黄柏液保留灌肠辅助治疗溃疡性结肠炎（UC）疗效满意,但其作用机制尚不清楚。目的：探讨复方黄柏液对三硝基苯磺酸（TNBS）诱发的大鼠结肠炎模型炎症损伤的治疗作用及其可能机制。方法：40只成年雌性Sprague-Dawley大鼠随机分成四组,正常对照组不予处理,其余三组以TNBS／乙醇溶液灌肠制作结肠炎模型后．分别予0．9％NaCl溶液1ml、5-氨基水杨酸（5-ASA）200mg／kg和复方黄柏液1ml灌肠,连续14d。治疗后评估大鼠疾病活动指数（DAI）以及结肠大体、组织学损伤情况;检测结肠组织髓过氧化物酶（MPO）活性和白三烯B4（LTB4）含量;心脏采血,流式细胞术检测中性粒细胞凋亡率。结果：与正常对照组相比,TNBS模型组DAI、结肠大体和组织学评分、结肠组织MPO活性和LTB。含量均显著升高,血中性粒细胞凋亡率显著降低（P〈0．01）;5-ASA治疗组和复方黄柏液治疗组上述指标均较TNBS模型组显著改善（P〈0．01）,两组间差异则无统计学意义。结论：复方黄柏液灌肠对大鼠TNBS结肠炎具有明显治疗作用,促进中性粒细胞凋亡、清除结肠局部损伤因子（MPO、LTB。）可能为其作用机制之一。     

Urinary 8-Hydroxydeoxyguanosine Excretion as a Non-Invasive Marker of Neutrophil Activation in Animal Models of Inflammatory Bowel Disease

Background: Because free radicals contribute to ulcerative colitis and Crohn's disease, assessing oxidative load in vivo could provide a surrogate marker of inflammation and disease status. Methods: Electrochemical high-performance liquid chromatography was used to study urinary excretion of 8-hydroxydeoxyguanosine (8-OH-dGUA), formed by reaction of hydroxyl radicals with native DNA, in 2,4,6-trinitrobenzene-sulfonic acid (TNBS) and dextran sulfate (DSS) rat models of bowel inflammation. Bowel myeloperoxidase (MPO) and histopathology were also assessed. Results: TNBS enema (75 mg/kg in 50% ethanol) and oral DSS (6% via drinking water) both yielded an inflammatory response reflected by increases in bowel MPO that were significantly correlated with tissue injury. In both models urinary 8-OH-dGUA excretion was significantly correlated with bowel MPO activity and epithelial injury and remained at control levels when neutrophils (PMN) were eliminated, whereas epithelial injury and crypt erosion persisted despite neutropenia. Conclusions: Urinary 8-OH-dGUA excretion directly reflects PMN activation in vivo, thereby providing a non-invasive surrogate marker for inflammation in these models which is more indicative of PMN activation than either MPO activity, which does not distinguish inactive from active MPO, or epithelial status, which is independent of PMN activation in both models.     

DSS、TNBS、OXZ诱导结肠炎动物模型的对比

目的 对比研究DSS、TNBS、OXZ诱导的结肠炎动物模型.方法 本研究选取了一般状态、DAI评分和组织学损伤评分几个方面来评价.结果 DSS组大鼠造模安全性较高,在整个实验过程中无大鼠出现死亡,而TNBS组及OXZ组均有2只大鼠出现死亡,DSS组大鼠DAI评分升高较快,于实验第7天时各模型组DAI评分差异无统计学意义,TNBS组组织学损伤最重,但各造模组之间差异无统计学意义.结论 三种造模方法均可以成功诱导大鼠实验性结肠炎模型,各造模组DAI评分和组织学损伤没有显著的差异.DSS造模方法具有较高的安全性.     

Modulation of the Effect of Dextran Sulfate Sodium-Induced Acute Colitis by the Administration of Different Probiotic Strains of Lactobacillus and Bifidobacterium

The pathogenic mechanism of inflammatory bowel diseases is not fully understood but colonic microflora including Lactobacillus and Bifidobacterium species may affect the induction of colonic inflammation. In this study the relative efficacy of different probiotic organisms in the prevention of colitis was compared in an induced rat colitis model. Three Lactobacillus strains and two Bifidobacterium strains were fed to Sprague-Dawley rats for 7 days prior to offering the rats 5% dextran sulfate sodium (DSS) in their drinking water to induce colitis and the administration of the probiotics continued for 7 days with the DSS. Colitis severity was assessed daily using a disease activity index (DAI). Samples were collected 7 days after colitis induction for intestinal bacterial flora and bacterial translocation. The DAI decreased significantly on days 4, 5, 6, and 7 in the Lactobacillus plantarum DSM 9843, Bifidobacterium sp. 3B1, and Bifidobacterium infantis DSM 15158 groups compared to the colitis control. It decreased significantly on days 5, 6, and 7 in the Bifidobacterium infantis DSM 15158 group compared to the Lactobacillus paracaesi DSM 13434 and Lactobacillus gasseri 5B3 groups. It also decreased significantly on day 7 in the L. plantarum DSM 9843 group compared to the L. gasseri 5B3 group. Bacterial translocation to the mesenteric lymph nodes decreased significantly in all treatment groups compared to the colitis control. Enterobacteriaceae bacterial translocation to the liver decreased in all treatment groups compared to the colitis control. Administration of certain strains of Lactobacillus and Bifidobacterium significantly improves the DAI and reduces bacterial translocation, and L. plantarum DSM 9843, Bifidobacterium sp. 3B1, and Bifidobacterium infantis DSM 15158 seem to have the best effect.     

Butyrate enema therapy stimulates mucosal repair in experimental colitis in the rat.

BACKGROUND--The short chain fatty acid (SCFA) butyrate provides energy for colonocytes, stimulates colonic fluid and electrolyte absorption and is recognised as an effective treatment for multiple types of colitis. AIM--To examine the impact of butyrate enema therapy on the clinical course, severity of inflammation, and SCFA stimulated Na+ absorption in a chronic experimental colitis. METHODS--Distal colitis was induced in rats with a trinitrobenzenesulphonic acid (TNBS) enema. Five days after induction, rats were divided into groups to receive: no treatment, saline enemas, or 100 mM Na-butyrate enemas daily. On day 24, colonic damage score and tissue myeloperoxidase (MPO) activity were evaluated. Colon was mounted in Ussing chambers and Na+ transport and electrical activities were measured during a basal period and after stimulation with 25 mM butyrate. RESULTS--In the untreated and the saline enema treated TNBS groups, diarrhoea and extensive colonic damage were seen, associated with increased tissue MPO activities and absent butyrate stimulated Na+ absorption. In contrast, in the butyrate enema treated TNBS group, diarrhoea ceased, colonic damage score improved, and tissue MPO activity as well as butyrate stimulated Na+ absorption recovered to control values. CONCLUSION--Butyrate enema therapy stimulated colonic repair, as evidenced by clinical recovery, decreased inflammation, and restoration of SCFA stimulated electrolyte absorption.     

Preventive efficacy of butyrate enemas and oral administration of Clostridium butyricum M588 in dextran sodium sulfate-induced colitis in rats

Butyrate enemas have been reported to be effective in ulcerative colitis. However, long-term use is difficult because of the troublesome procedure and the unpleasant smell. We therefore investigated the effects of the oral administration of Clostridium butyricum M588 (CBM588), an enterobacterium producing butyrate, in dextran sodium sulfate (DSS)-induced colitis in rats. First, we confirmed the effects of pre-treatment with a butyrate enema on DSS colitis. We then studied the efficacy of oral administration of CBM588 which was started 1 week prior to the induction of DSS colitis. In the CBM588 group, the ulcer index and myeloperoxidase (MPO) activity in the distal colon were significantly lower than in the control group. Proliferating cell nuclear antigen (PCNA) immuno-positive cells were increased around the ulcer in the CBM588 group. In regard to the contents of the cecum and colon, the proportions of Lactobacillus and Eubacterium were increased in the cecum in the CBM588 group. Further, there were significant increases of n-butyrate, propionate, and acetate concentrations in the cecum in the CBM588 group. These results indicated that the oral administration of CBM588 alleviated DSS-induced colitis, and may be useful instead of butyrate enema. Received: August 10, 1999 / Accepted: November 26, 1999     

Rebamipide enema is effective for treatment of experimental dextran sulfate sodium induced colitis in rats

We investigated therapeutic efficacy of rebamipide using dextran sulfate sodium (DSS) induced colitis model in rats. Three percent DSS solution was given to rats for 9 days. After that, we evaluated the drug efficacy on colitis sustained with continuous drinking of 1% DSS. Twice-daily treatment with 0.3% or 1% rebamipide for 14 days significantly ameliorated the stool abnormality in the colitis model, preferentially suppressed hematochezia. The colonic mucosal lesion, determined by Alcian blue staining on day 24, was significantly reduced by rebamipide enema in a dose-dependent manner. Either rebamipide or 5-aminosalycilic acid (5-ASA) enema treated once daily significantly ameliorated colitis. The minimum effective dose of rebamipide was 0.3% in once-daily treatment, and that of 5-ASA was 10%. In a mechanistic study, the epithelial cell sheet formation of the T84 colon cancer cell was measured as an increase in generation of trans-epithelial electrical resistance in vitro. Rebamipide accelerated the increase, while 5-ASA conversely suppressed it. These results suggest that rebamipide enema is effective for treatment of experimental ulcerative colitis (UC).     

葡聚糖硫酸钠自由饮用与定量灌胃诱导小鼠急性结肠炎模型的比较研究

背景：自由饮用葡聚糖硫酸钠（DSS）诱导的鼠类急性结肠炎模型均一性欠佳,动物死亡率较高。目的：评估2%DSS自由饮用或定量灌胃诱导的小鼠急性结肠炎模型模拟人类溃疡性结肠炎（UC）的效果和均一性。方法：予ICR小鼠2%DSS自由饮用或定量灌胃建立急性结肠炎模型,检测并比较正常对照组和两组模型小鼠的症状出现时间和频率、疾病活动指数（DAI）、DSS消耗量、死亡率、结肠长度、结肠损伤大体评分（MACD）、结肠组织病理学表现以及外周血白细胞计数和分类。结果：两组模型小鼠均出现类似人类UC的症状和组织病理学改变,结肠显著短缩,DAI、MACD以及外周血白细胞计数和中性粒细胞百分比显著高于正常对照组。与DSS自由饮用组相比,DSS定量灌胃组小鼠症状出现时间更为一致,症状出现率显著增高,动物死亡率和DSS消耗量显著减低。结论：2%DSS定量灌胃诱导的小鼠急性结肠炎模型能较稳定地模拟人类UC,均一性高,动物死亡率低。     

Rebamipide Enema is Effective for Treatment of Experimental Dextran Sulfate Sodium Induced Colitis in Rats

We investigated therapeutic efficacy of rebamipide using dextran sulfate sodium (DSS) induced colitis model in rats. Three percent DSS solution was given to rats for 9 days. After that, we evaluated the drug efficacy on colitis sustained with continuous drinking of 1% DSS. Twice-daily treatment with 0.3% or 1% rebamipide for 14 days significantly ameliorated the stool abnormality in the colitis model, preferentially suppressed hematochezia. The colonic mucosal lesion, determined by Alcian blue staining on day 24, was significantly reduced by rebamipide enema in a dose-dependent manner. Either rebamipide or 5-aminosalycilic acid (5-ASA) enema treated once daily significantly ameliorated colitis. The minimum effective dose of rebamipide was 0.3% in once-daily treatment, and that of 5-ASA was 10%. In a mechanistic study, the epithelial cell sheet formation of the T84 colon cancer cell was measured as an increase in generation of trans-epithelial electrical resistance in vitro. Rebamipide accelerated the increase, while 5-ASA conversely suppressed it. These results suggest that rebamipide enema is effective for treatment of experimental ulcerative colitis (UC).