Chymase inhibitor TY-51469 in therapy of inflammatorybowel disease

摘要

AIM: To investigate the effect of chymase inhibitor TY-51469 in the therapy of inflammatory bowel disease and the underlying mechanism. METHODS: Seventy-five healthy Sprague-Dawley rats were randomly assigned to one of the three groups(control group, model group and TY-51469 experiment group) and each group had twenty-five rats. The rats of the model group and experiment group were subjected to treatment with 3.5% dextran sulfate sodium(DSS) 10 mg/kg to induce colitis. The control group and model group were subjected to intraperitoneal injection of saline, while the experiment group was subjected to intraperitoneal injection of 10 mg/kg TY-51469 each day. Five rats of each group were sacrificed on 0, 7, 14, 21 and 28 d, respectively. The degree of inflammation was assessed by histopathological scoring; flow cytometry was performed to detect the proportion of CD4+CD25+ Tregs in peripheral blood; colon tissues of rats were collected to measure m RNA and protein expression by PCR, Western blot and immunohistochemistry; serum levels of interleukin(IL)-10, transforming growth factor(TGF)-β1 and IL-17A were detected by ELISA. RESULTS: The rats in the experiment group and model group had significantly more severe colitis than the ones in the control group(P 0.05). After treatment with TY-51469, the rats in the experiment group had significantly less severe colitis compared with the model group on 7, 14, 21 and 28 d(P < 0.05). The proportion of CD4+CD25+ Tregs was lower in the model group and experiment group than in the control group; the experiment group had a significantly higher proportion of CD4+CD25+ Tregs than that in the model group(P < 0.05). The model group and experiment group demonstrated lower expression of Foxp3 than the control group; the experiment group had higher Foxp3 expression than the model group(P < 0.05). Cytokines IL-10, TGF-β1 and IL-17 A were lower in the model group and experiment group than in the control group; the experiment group had higher expression than the model group(P < 0.05). CONCLUSION: After treatment with chymase inhibitor TY-51469, the experiment group demonstrated more significantly reduced intestinal inflammation and higher expression of immune tolerance related cytokines(IL-10, TGF-β1, IL-17A) and Foxp3 which is specifically expressed in Tregs compared with the model group. Therefore, chymase inhibitor TY-51469 might ameliorate the progression of DSS-induced colitis possibly by increasing the expression of Tregs and cytokines.