| Objective: Ulcerative colitis associated intestinal mucosa dysplasia is one kind disease of colorectal mucosa dysplasia, whose colorectal mucosa pathology shows epithelial and glandular deviation from normal differentiation, and the morphology and function also show a atypia performance after the repeated stimulation of inflammation. Now ulcerative colitis associated intestinal mucosa hyperplasia has clear as one of the precancerous lesion of colorectal cancer, which can make the canceration rate of UC increased significantly. Meanwhile, it plays the most important role in the UC carcinogenesis process, and currently the more specific preventive drug for ulcerative colitis associated intestinal mucosa dysplasia is mesalazine. The traditional notions find that the occurrence of inflammation, hyperplasia and tumors is related to the high expression of cyclooxygenase cox-2. Celecoxib has interference effect on the happening of inflammation, hyperplasia and tumors as a kind of cox-2 inhibitor. However, UC associated CRC and CRC differ in some place, and celecoxib via oral may lead to the liver and kidney dysfunction、cardiovascular adverse events, especially in elderly patients. Thus, this experiment focuses on exploring the prevention and treatment effects of the different concentrations of celecoxib by coloclysis on the process of Ulcerative colitis associated early carcinogenesis and to analyze the possible mechanism.Methods:Sixty C57BL/6 male mice which were 4 to 5 weeks old were randomly divided into six groups, each group had 10 mice. This groups were labeled as the high dose of celecoxib group(A),the middle dose of celecoxib group(B), the low dose of celecoxib group(C), mesalazine group(D), model group(E), Blank group(F). Experiment started after a week of adaptive feeding. Except the blank group(F), other groups of mice used Azoxymethane/Dextran sulfate sodium(AOM/DSS) combined technique to establish the experimental mouse model, and the specific steps were that the mice were given small dose of azoxymethane AOM(10 mg/kg) by a single of intraperitoneal injection. After a week, 2% dextran sodium sulfate DSS was drinked 7 days, and normal water was drinked 14 days. Modeling of five days, the mice of Group A were given the 1.5 mg/ml high dose of celecoxib via coloclysis, the mice of Group B were given the 1.0 mg/ml middle dose of celecoxib via coloclysis, the mice of Group C were given the 0.5 mg/ml low dose of celecoxib via coloclysis, the mice of Group D were given the 60g:4g dose of mesalazine via coloclysis, the mice of Group E were given the same dose of 0.9% sodium chloride injection via coloclysis, and the mice were clystered at a dose of 0.1ml/10 g every time and once a day. The mice were sacrificed at 4 weeks of the experiment, the changes of colon tissue were observed with naked eyes, and the differents of colon pathological and the results of immunohistochemistry COX-2, CDX-2, BCL-2 expression were assayed under microscope. The levels of serum cytokines were detected by the Elisa boxes. Meanwhile, the generally change of mice in each groups were observated in the experimental process, such as hair color, weight, mental.Results: Compared with group E, Group A and B were similar to Group F by the visual observation, the colon surfaces of which were smoother and the vascular textures of which were clear and the stools of which were forming. But in group C and D, the colon surfaces were less smooth and the stools were relatively forming; By HE staining, we could observe that the mucosas of group A and B were more complete,and the glands of group A and B were neater. Meanwhile, the colorectal epithelial mucosa of group C was with superficial ulcer, which of group D was causally with lymphocyte infiltration, and which of group E was mainly chronic inflammation associated with light to moderate hyperplasia by HE staining; Compared with the control group F, the serum cytokines IL-6 and TNF-α levels were significantly increased in the model group E, the difference was statistically significant(P<0.05). And compared with the model group E, the serum cytokines IL-6 and TNF-α levels of the treated groups were significantly reduced, and among them, the TNF-α levels of group A and B changed obviously than that of other treated groups, the difference was statistically significant(P<0.05); Compared with the control group F, the immunohistochemistry results showed that the COX-2 and BCL-2 level scores were increased significantly in the model group E, while the CDX-2 level score of which was significantly lower, the difference was statistically significant(P<0.05). And the COX-2 and BCL-2 level scores of the treated groups were significantly lower than that of the model group E, but compared with the model group E, the CDX-2 level scores of which were significantly higher. Among this treated groups, the COX-2 level scores of the treated group A and B were significantly lower than that of the treated group C and D, the difference was statistically significant(P<0.05), and the BCL-2 level scores of the treated group treatment group A, B, D were lower than the score of group C, the difference was statistically significant(P<0.05). However, the difference was not statistically significant among the CDX-2 level scores of the treated group A, B, C, D(P>0.05).Conclusion:Celecoxib by coloclysis has the effects of prevention and treatment in ulcerative colitis associated intestinal mucosa dysplasia, and the effects of middle and high dose of celecoxib by coloclysis are more obvious, and the mechanism may be related to a down-regulation in the expression of COX-2, BCL-2, and reducting the production of inflammatory factors IL-6, TNF-α, meanwhile, it may also be one of its preventive mechanism that celecoxib can improve the expression of CDX-2 in the colorectal tissue. |
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