Basic Study
Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Feb 7, 2016; 22(5): 1826-1833
Published online Feb 7, 2016. doi: 10.3748/wjg.v22.i5.1826
Chymase inhibitor TY-51469 in therapy of inflammatory bowel disease
Wei-Xin Liu, Ying Wang, Li-Xuan Sang, Shen Zhang, Ting Wang, Feng Zhou, Shou-Zhi Gu
Wei-Xin Liu, Ying Wang, Shen Zhang, Ting Wang, Feng Zhou, Department of Gastroenterology, First Affiliated Hospital, China Medical University, Shenyang 110001, Liaoning Province, China
Li-Xuan Sang, Department of Cadre Ward II, First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
Shou-Zhi Gu, Department of Anatomy, Seirei Christopher College, Hamamatsu 4338558, Japan
Author contributions: Liu WX and Gu SZ designed the research; Sang LX, Zhang S, Wang Y and Zhou F performed the research; Liu WX and Wang T analyzed the data; Liu WX and Wang Y wrote the paper.
Supported by Science and Technology Project of Liaoning Province, No. 2013225303; and Science and Technology Project of Shenyang City, No. F13-316-1-40.
Institutional review board statement: This study was approved by the Institute Research Medical Ethics Committee of the First Affiliated Hospital of China Medical University.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of China Medical University.
Conflict-of-interest statement: All of the authors declare that there is no conflict of interest.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Wei-Xin Liu, Professor, Department of Gastroenterology, First Affiliated Hospital, China Medical University, No. 155 North Nanjing Street, Heping District, Shenyang 110001, Liaoning Province, China. weixinliu@yahoo.com
Telephone: +86-24-83282863 Fax: +86-24-83282863
Received: March 15, 2015
Peer-review started: March 15, 2015
First decision: April 13, 2015
Revised: June 10, 2015
Accepted: August 25, 2015
Article in press: August 25, 2015
Published online: February 7, 2016
Abstract

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 mRNA 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) before treatment on day 0; no significant difference was observed between the experiment group and model 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-17A 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.

Keywords: Chymase inhibitor, Tregs, Inflammatory bowel disease, Cytokines, Rats

Core tip: Until now, little is known of the role of chymase inhibitor in the immune system and no investigation has been performed in inflammatory bowel disease (IBD). In the present study, we built a Sprague-Dawley rat model of colitis induced with dextran sulfate sodium (DSS) and treated the model rats with chymase inhibitor TY-51469. The changes of Tregs were further detected to investigate the effect of chymase inhibitor TY-51469 on IBD and to explore the underlying mechanism. The results indicated that chymase inhibitor TY-51469 might ameliorate the progression of DSS-induced colitis possibly by increasing the expression of Tregs and cytokines.