慢溃宁抑制和逆转溃疡性结肠炎不典型增生的临床和实验研究
摘要
溃疡性结肠炎是发生于黏膜或黏膜下层的非特异性炎症,临床以腹痛、腹泻、黏液脓血便为主要特征。病程迁延难愈,被认为是世界难治病之一。随着炎症的进展,溃疡性结肠炎发生癌变的危险累计率增高,有学者统计溃疡性结肠炎10年、20年、30年患者发生结直肠癌累积危险性2%,8%,18%,每人每年发病率为5%,患有溃疡性结肠炎导致死亡的人数占总体患者的15%。因此预防、抑制和逆转溃疡性结肠炎癌变有其重要的临床价值。在临床目前多采用美沙拉嗪等药物来防治其癌变。
溃疡性结肠炎属于祖国医学的“泄泻”、“肠游”、“滞下”、“痢疾”、“肠风”、“脏毒”等范畴,其中又以“泄泻”、“痢疾”论述为多。但溃疡性结肠炎癌变因其发病的时间长,且反复发作,因此更像祖国医学的“休息痢”。中医治疗溃结及其癌变方法很多,针灸,中药栓剂,中药加灌肠,单独灌肠,中药与西药结合等。中医在治疗疾病方面其副作用小,价格低廉,疗效确切,利用中医药治疗溃结癌变有其广阔的发展前景。
灌肠法有其独特的优势,能够直达病所,直接在局部发挥作用,而且50-70%的药物可以消除首过效应,药物的可利用率较高。直肠具有吸收功能,因此药物能够在局部被重吸收,发挥其疗效。
本课题首先经过大量的文献研究,进行了临床观察,然后进行实验设计,从临床和实验研究两方面研究慢溃宁的作用机制与临床疗效,为中医药预防抑制和逆转溃疡性结肠炎癌变提供了新的思路。
目的：
实验研究：通过随机对照研究,确定小鼠溃疡性结肠炎不典型增生模型的建立,并在此基础上观察慢溃宁颗粒对AOM/DSS诱导的小鼠不典型增生的预防抑制作用,并行免疫组化观察p53及COX-2在各组中小鼠结肠黏膜的表达,为利用免疫指标预防UC癌变提供了一定的理论基础。
临床研究：通过观察东直门医院的临床及住院病人,观察慢溃宁灌肠剂对溃疡性结肠炎不典型增生的临床观察,从而为利用中医中药治疗溃结及其癌变提供了更为广阔的临床思路。
方法：
实验研究：
实验一：小鼠模型的建立方法：全部小鼠分成4组,每组15只,即正常对照组、AOM组、DSS组、AOM/DSS组,每组小鼠15只。AOM/DSS组、AOM组按10mg/kg的剂量经腹腔注射浓度为1mg/ml的AOM溶液,每只注射0.2ml。AOM/DSS组、DSS组小鼠给予3%的DSS溶液连续自然饮用2周,AOM组、空白对照组小鼠自然饮用蒸馏水；2周后持续常规饮用蒸馏水1周,如此重复3次,共9周。观察：小鼠的一般情况,结肠的大体形态损伤,结肠组织学损伤,光镜下观察结肠病理形态学变化。
实验二：6周龄Balb/c小鼠,随机分为6组,每组20只。分为正常组、模型空白组、中药低剂量组、中药中剂量组、中药高剂量组及美沙拉嗪组。在应用AOM/DSS造模的同时给予中药慢馈宁和美沙拉嗪等药物,连续给药6周,正常组及模型组给予生理盐水。观察小鼠一般情况,疾病活动度指数评分,结肠的大体形态损伤评分,结肠组织学损伤评分,光镜观察结肠病理形态学变化,并进一步应用免疫组化方法对每组20张石蜡切片行免疫组化,观察每组中p53及COX-2在结肠组织中的表达情况。
临床研究：采用随机对照的临床试验方法,将纳入的40例患者,分为治疗组和对照组各20例,治疗组给予慢溃宁灌肠剂灌肠,慢溃宁灌肠剂临睡前1次,每次50m1。对照组给予美沙拉嗪缓释灌肠液灌肠。观察其中医证候积分,经治疗后内镜分级比较,总疗效比较,两组患者治疗前后ESR、CRP比较及免疫组化NF-kB及COX-2在结肠黏膜的表达情况。
结果：
实验研究结果：
实验一：AOM与正常组结肠黏膜大体正常,而DSS组在6周后未见到不典型增生,而AOM/DSS组可见大量的不典型增生。9周后DSS组可见少量的低级别不典型增生,而AOM/DSS组大部分可见高级别异型增生,有的甚至可见到腺瘤及癌变。
实验二：造模后小鼠出现腹泻,黏液脓血便,喜扎堆,食量减少等。但经过给药后情况慢慢的改善。在DAI评分方面西药组、中药中剂量组、中药高剂量组三组症状无明显差异,p0.05。在形态学积分及组织病理学积分方面,西药组与中药中、高剂量组无统计学差异,并优于低剂量组。通过病理学观察,可见西药组及中药中、高剂量组可见不典型增生的数量明显较模型组减少,但仍伴不同程度的炎症,说明在预防其不典型增生方面有其一定的效果。免疫组化结果显示：p53及COX-2在模型组的表达最多,正常组很少表达。用药组的表达比模型组明显减少,在四组药物预防过程中,美沙拉嗪组及中药中高剂量组三者表达均比中药低剂量组表达亦少。美沙拉嗪组与中药中、高剂量组三组表达未见明显的统计学差异。
临床观察结果：治疗组与对照组相比：在证候积分及证候疗效方面,治疗组优于对照组；治疗后两组患者结肠黏膜病变情况,经Ridit分析,u=-2.326,P=0.057>0.05,差异无统计学意义。两组病例总疗效比较经X2检验,无统计学差异。两组患者治疗前后ESR、CRP比较,有统计学差异。但两者治疗后,CRP具有统计学差异,治疗组优于对照组；两组均有不良反应发生,两组间不良反应发生率差异无统计学意义(x2=0.54,p>0.05)。两组免疫组化结果显示NF-kB及COX2在治疗前均有高表达,经治疗后有所下降,但是治疗组下降更明显。
结论：
实验研究：通过实验一发现AOM/DSS联合应用可以缩短造模的时间,诱导成不典型增生的时间可缩短为6周,二个循环。实验二利用中药慢溃宁颗粒与西药美沙拉嗪两者进行对比及观察p53及COX-2在结肠中的表达方面,说明两者均可预防和抑制UC向不典型增生转变。
临床研究：慢溃宁灌肠剂可明显预防和抑制UC向不典型增生转变。
Ulcerative colitis is non-specific inflammation which occurs at the mucosa or submucosa. Its clinical manifestations are abdominal pain, diarrhea, blood and pus stool as the main features. The course of UC is long. It is difficult to cure, so it is considered as one of the diseases which is difficult to treat. With the progress of the inflammation, the risk of UC cancerous cumulative rate is increasing. Someone counted the risk of cancer cumulative which was2%,8%,18%in10years,20years and30years. The disease incidence is5%per person and4%per year. The mortality rate of the ulcerative colitis is15%in the overall patients. Therefore there is important clinical value in preventing, inhibiting, reversing the UC carcinogenesis. Now we use mesalazine to prevent cancer, but the side effects of drugs are great.
Ulcerative colitis is called diarrhea, dysentery in Chinese medicine. The pathogenesis of UC is long and over and over again. There are many methods in treating UC and UC to cancer, such as acupuncture, the plug of chinese medicine.There is much advantage in treating UC with Chinese medicine, small side-effect,cheapness and effectiveness. There is broad prospects for the development of Chinese medicine in treating UCCRC.
Enema has its unique advantages to patients.It can work directly to disease location, and50-70%of the drug can eliminate the first-pass effect. It can fully take advantage of drug efficacy. The rectal has good function of absorption, so mang drugs can be absorbed again. Enema can play important role in absorption. This topic was through research about literature firstly, then clinical observation, experimental studies finally. We studied the mechanism and clinical efficacy of the Chinese medicine by clinical and experimental research.It provided new idea in preventing and reversing UCCRC in Chinese medicine.
Objective
Experimental rearch:
Experimental studies:We made use of randomized controlled study to determine the the mice model of the dysplasia and the time of forming dysplasia. Then on this basis of the experimental One, we observed the Chinese medicine Mankuining granule preventing the dysplasia of the UC in mice though AOM/DSS. We also studied the expression of the p53and COX-2in6groups of the colonic mucosa.
Clinical rearch; Observed the Mankuining enema to the dysplasia of UC patients in the clinical research and safety, It can provide the clinical basis in Traditional Chinese Medicine inhibiting and reversing ulcerative colitis carcinogenesis.
Method
Experimental research:
Experiment One:The method of the mice model:All mice were divided into four groups: the normal group, the AOM group, the DSS group and the AOM+DSS group. Each group has15mice. The A/D group and AOM group were given the AOM solution with dose of AOM1mg/ml by intraperitoneal injection.Each mouse was given0.2ml. After one week, AOM/DSS group and DSS group were given3%DSS in2weeks. AOM group and the normal group were given to the distilled water and so for a loop.Then maintaining3cycles. Then observe the general situation, the morphology score, the histologic injury and Pathomorphological changes.
Experiment Two:6-week-old Balb/c mice were randomly divided into six groups, including the normal group, the blank model group, the Chinese medicine of low-dose group, the middle group,the high dose group and the mesalazine group. The mice model was given AOM/DSS solution,at the same time the mice were given the drugs.The normal group and the blank model group were given the saline in6weeks. Then observe the general situation, the DAI scores, the gross morphology scores. the histologic injury scores and pathomorphological changes. Then observe the expression of the p53and COX-2in6groups of the colonic mucosa in Immunohis tochemistry.
Clinical research:We used a randomized controlled clinical trial methods. The40patients were divided into two groups, the treatment group and the control group. Each group has20patients. The treatment group was given the Chinese medicine and the Mankuining enema. The Mankuining enema was given50ml once before sleep. The control group was daily given mesalamine enema. Observe the TCM syndrome score after treatment, the endoscopy comparison, the comparison of total effect and the ESR, CRP comparison before and after treatment and the expression of the NF-Kb and COX-2colonic mucosa in Immunohistochemistry.
Results
Experimental research results:
Experimental One:The colonic mucosa of AOM and the normal group is normal.The DSS group was not seen dysplasia in the colonic mucosa after6weeks and a little after9weeks.The group AOM/DSS could be seen much low-grade-dysplasia in the mucosa after6weeks and high-grade-dysplasia after9weeks,some were even seen adenoma and cancer.
Experiment Two:After the mice model, the mice were diarrhea, pus and blood stool, hi get together and poor appetite. But after3weeks the situation would be improved after given the medicine. Chinese herbal medicine was no significant difference between with the middle and high-dose group and the western medicine group, Western medicine group and middle dose group is better than the low-dose group. The pathological results show that the inflammation did not progress to dysplasia with the prevention of the medicine. Immunohistochemical results:The expression of p53and COX-2is the most in the model group and with little or no expression in the normal group. The expression of the drug group was significantly little compared with the model group. Mesalazine group and Chinese medicine in the middle and high-dose group expressed less than those in Chinese medicine low-dose group. There was no significant difference among mesalazine group and Chinese medicine in the middle and high-dose group.
Cl inical Observation Results:After treatment, the two group in the colonic mucosa lesions were not statistically significant difference by Ridit analysis, u=-2.326, P=0.057>0.05. Symptom scores were significantly improved in the two groups after treatment, but comparing the two groups there was no significant difference (P>0.05). The total effect of the two groups was compared by χ2test, still no statistically significant difference. There was significant difference before and after treatment in ESR, CRP,but no significant difference between the two groups. Both groups had incidence of adverse reactions,and there was no significant difference between the two groupss (χ2=0.54, P>0.05).
Conclusion:
Experimental studies:By the dug AOM and DSS combination, the model of dysplasia could short the time to six weeks, two-cycle. The Chinese medicine had the same effective with mesalazine to prevent and suppress UC to dysplasia and inhibit p53and COX-2expression in the colon.
In the cilinal research the Mankuining enema can significantly in suppressing UC to dysplasia.
溃疡性结肠炎属于祖国医学的“泄泻”、“肠游”、“滞下”、“痢疾”、“肠风”、“脏毒”等范畴,其中又以“泄泻”、“痢疾”论述为多。但溃疡性结肠炎癌变因其发病的时间长,且反复发作,因此更像祖国医学的“休息痢”。中医治疗溃结及其癌变方法很多,针灸,中药栓剂,中药加灌肠,单独灌肠,中药与西药结合等。中医在治疗疾病方面其副作用小,价格低廉,疗效确切,利用中医药治疗溃结癌变有其广阔的发展前景。
灌肠法有其独特的优势,能够直达病所,直接在局部发挥作用,而且50-70%的药物可以消除首过效应,药物的可利用率较高。直肠具有吸收功能,因此药物能够在局部被重吸收,发挥其疗效。
本课题首先经过大量的文献研究,进行了临床观察,然后进行实验设计,从临床和实验研究两方面研究慢溃宁的作用机制与临床疗效,为中医药预防抑制和逆转溃疡性结肠炎癌变提供了新的思路。
目的：
实验研究：通过随机对照研究,确定小鼠溃疡性结肠炎不典型增生模型的建立,并在此基础上观察慢溃宁颗粒对AOM/DSS诱导的小鼠不典型增生的预防抑制作用,并行免疫组化观察p53及COX-2在各组中小鼠结肠黏膜的表达,为利用免疫指标预防UC癌变提供了一定的理论基础。
临床研究：通过观察东直门医院的临床及住院病人,观察慢溃宁灌肠剂对溃疡性结肠炎不典型增生的临床观察,从而为利用中医中药治疗溃结及其癌变提供了更为广阔的临床思路。
方法：
实验研究：
实验一：小鼠模型的建立方法：全部小鼠分成4组,每组15只,即正常对照组、AOM组、DSS组、AOM/DSS组,每组小鼠15只。AOM/DSS组、AOM组按10mg/kg的剂量经腹腔注射浓度为1mg/ml的AOM溶液,每只注射0.2ml。AOM/DSS组、DSS组小鼠给予3%的DSS溶液连续自然饮用2周,AOM组、空白对照组小鼠自然饮用蒸馏水；2周后持续常规饮用蒸馏水1周,如此重复3次,共9周。观察：小鼠的一般情况,结肠的大体形态损伤,结肠组织学损伤,光镜下观察结肠病理形态学变化。
实验二：6周龄Balb/c小鼠,随机分为6组,每组20只。分为正常组、模型空白组、中药低剂量组、中药中剂量组、中药高剂量组及美沙拉嗪组。在应用AOM/DSS造模的同时给予中药慢馈宁和美沙拉嗪等药物,连续给药6周,正常组及模型组给予生理盐水。观察小鼠一般情况,疾病活动度指数评分,结肠的大体形态损伤评分,结肠组织学损伤评分,光镜观察结肠病理形态学变化,并进一步应用免疫组化方法对每组20张石蜡切片行免疫组化,观察每组中p53及COX-2在结肠组织中的表达情况。
临床研究：采用随机对照的临床试验方法,将纳入的40例患者,分为治疗组和对照组各20例,治疗组给予慢溃宁灌肠剂灌肠,慢溃宁灌肠剂临睡前1次,每次50m1。对照组给予美沙拉嗪缓释灌肠液灌肠。观察其中医证候积分,经治疗后内镜分级比较,总疗效比较,两组患者治疗前后ESR、CRP比较及免疫组化NF-kB及COX-2在结肠黏膜的表达情况。
结果：
实验研究结果：
实验一：AOM与正常组结肠黏膜大体正常,而DSS组在6周后未见到不典型增生,而AOM/DSS组可见大量的不典型增生。9周后DSS组可见少量的低级别不典型增生,而AOM/DSS组大部分可见高级别异型增生,有的甚至可见到腺瘤及癌变。
实验二：造模后小鼠出现腹泻,黏液脓血便,喜扎堆,食量减少等。但经过给药后情况慢慢的改善。在DAI评分方面西药组、中药中剂量组、中药高剂量组三组症状无明显差异,p0.05。在形态学积分及组织病理学积分方面,西药组与中药中、高剂量组无统计学差异,并优于低剂量组。通过病理学观察,可见西药组及中药中、高剂量组可见不典型增生的数量明显较模型组减少,但仍伴不同程度的炎症,说明在预防其不典型增生方面有其一定的效果。免疫组化结果显示：p53及COX-2在模型组的表达最多,正常组很少表达。用药组的表达比模型组明显减少,在四组药物预防过程中,美沙拉嗪组及中药中高剂量组三者表达均比中药低剂量组表达亦少。美沙拉嗪组与中药中、高剂量组三组表达未见明显的统计学差异。
临床观察结果：治疗组与对照组相比：在证候积分及证候疗效方面,治疗组优于对照组；治疗后两组患者结肠黏膜病变情况,经Ridit分析,u=-2.326,P=0.057>0.05,差异无统计学意义。两组病例总疗效比较经X2检验,无统计学差异。两组患者治疗前后ESR、CRP比较,有统计学差异。但两者治疗后,CRP具有统计学差异,治疗组优于对照组；两组均有不良反应发生,两组间不良反应发生率差异无统计学意义(x2=0.54,p>0.05)。两组免疫组化结果显示NF-kB及COX2在治疗前均有高表达,经治疗后有所下降,但是治疗组下降更明显。
结论：
实验研究：通过实验一发现AOM/DSS联合应用可以缩短造模的时间,诱导成不典型增生的时间可缩短为6周,二个循环。实验二利用中药慢溃宁颗粒与西药美沙拉嗪两者进行对比及观察p53及COX-2在结肠中的表达方面,说明两者均可预防和抑制UC向不典型增生转变。
临床研究：慢溃宁灌肠剂可明显预防和抑制UC向不典型增生转变。
Ulcerative colitis is non-specific inflammation which occurs at the mucosa or submucosa. Its clinical manifestations are abdominal pain, diarrhea, blood and pus stool as the main features. The course of UC is long. It is difficult to cure, so it is considered as one of the diseases which is difficult to treat. With the progress of the inflammation, the risk of UC cancerous cumulative rate is increasing. Someone counted the risk of cancer cumulative which was2%,8%,18%in10years,20years and30years. The disease incidence is5%per person and4%per year. The mortality rate of the ulcerative colitis is15%in the overall patients. Therefore there is important clinical value in preventing, inhibiting, reversing the UC carcinogenesis. Now we use mesalazine to prevent cancer, but the side effects of drugs are great.
Ulcerative colitis is called diarrhea, dysentery in Chinese medicine. The pathogenesis of UC is long and over and over again. There are many methods in treating UC and UC to cancer, such as acupuncture, the plug of chinese medicine.There is much advantage in treating UC with Chinese medicine, small side-effect,cheapness and effectiveness. There is broad prospects for the development of Chinese medicine in treating UCCRC.
Enema has its unique advantages to patients.It can work directly to disease location, and50-70%of the drug can eliminate the first-pass effect. It can fully take advantage of drug efficacy. The rectal has good function of absorption, so mang drugs can be absorbed again. Enema can play important role in absorption. This topic was through research about literature firstly, then clinical observation, experimental studies finally. We studied the mechanism and clinical efficacy of the Chinese medicine by clinical and experimental research.It provided new idea in preventing and reversing UCCRC in Chinese medicine.
Objective
Experimental rearch:
Experimental studies:We made use of randomized controlled study to determine the the mice model of the dysplasia and the time of forming dysplasia. Then on this basis of the experimental One, we observed the Chinese medicine Mankuining granule preventing the dysplasia of the UC in mice though AOM/DSS. We also studied the expression of the p53and COX-2in6groups of the colonic mucosa.
Clinical rearch; Observed the Mankuining enema to the dysplasia of UC patients in the clinical research and safety, It can provide the clinical basis in Traditional Chinese Medicine inhibiting and reversing ulcerative colitis carcinogenesis.
Method
Experimental research:
Experiment One:The method of the mice model:All mice were divided into four groups: the normal group, the AOM group, the DSS group and the AOM+DSS group. Each group has15mice. The A/D group and AOM group were given the AOM solution with dose of AOM1mg/ml by intraperitoneal injection.Each mouse was given0.2ml. After one week, AOM/DSS group and DSS group were given3%DSS in2weeks. AOM group and the normal group were given to the distilled water and so for a loop.Then maintaining3cycles. Then observe the general situation, the morphology score, the histologic injury and Pathomorphological changes.
Experiment Two:6-week-old Balb/c mice were randomly divided into six groups, including the normal group, the blank model group, the Chinese medicine of low-dose group, the middle group,the high dose group and the mesalazine group. The mice model was given AOM/DSS solution,at the same time the mice were given the drugs.The normal group and the blank model group were given the saline in6weeks. Then observe the general situation, the DAI scores, the gross morphology scores. the histologic injury scores and pathomorphological changes. Then observe the expression of the p53and COX-2in6groups of the colonic mucosa in Immunohis tochemistry.
Clinical research:We used a randomized controlled clinical trial methods. The40patients were divided into two groups, the treatment group and the control group. Each group has20patients. The treatment group was given the Chinese medicine and the Mankuining enema. The Mankuining enema was given50ml once before sleep. The control group was daily given mesalamine enema. Observe the TCM syndrome score after treatment, the endoscopy comparison, the comparison of total effect and the ESR, CRP comparison before and after treatment and the expression of the NF-Kb and COX-2colonic mucosa in Immunohistochemistry.
Results
Experimental research results:
Experimental One:The colonic mucosa of AOM and the normal group is normal.The DSS group was not seen dysplasia in the colonic mucosa after6weeks and a little after9weeks.The group AOM/DSS could be seen much low-grade-dysplasia in the mucosa after6weeks and high-grade-dysplasia after9weeks,some were even seen adenoma and cancer.
Experiment Two:After the mice model, the mice were diarrhea, pus and blood stool, hi get together and poor appetite. But after3weeks the situation would be improved after given the medicine. Chinese herbal medicine was no significant difference between with the middle and high-dose group and the western medicine group, Western medicine group and middle dose group is better than the low-dose group. The pathological results show that the inflammation did not progress to dysplasia with the prevention of the medicine. Immunohistochemical results:The expression of p53and COX-2is the most in the model group and with little or no expression in the normal group. The expression of the drug group was significantly little compared with the model group. Mesalazine group and Chinese medicine in the middle and high-dose group expressed less than those in Chinese medicine low-dose group. There was no significant difference among mesalazine group and Chinese medicine in the middle and high-dose group.
Cl inical Observation Results:After treatment, the two group in the colonic mucosa lesions were not statistically significant difference by Ridit analysis, u=-2.326, P=0.057>0.05. Symptom scores were significantly improved in the two groups after treatment, but comparing the two groups there was no significant difference (P>0.05). The total effect of the two groups was compared by χ2test, still no statistically significant difference. There was significant difference before and after treatment in ESR, CRP,but no significant difference between the two groups. Both groups had incidence of adverse reactions,and there was no significant difference between the two groupss (χ2=0.54, P>0.05).
Conclusion:
Experimental studies:By the dug AOM and DSS combination, the model of dysplasia could short the time to six weeks, two-cycle. The Chinese medicine had the same effective with mesalazine to prevent and suppress UC to dysplasia and inhibit p53and COX-2expression in the colon.
In the cilinal research the Mankuining enema can significantly in suppressing UC to dysplasia.
引文
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