title: Chymase inhibitor TY-51469 in therapy of inflammatory bowel disease.
abstract: OBJECTIVE
  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).
  
  
  CONCLUSIONS
  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.
authors: 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.
authors: Wei-Xin
authors: WX
authors: Liu
authors: 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.
authors: Ying
authors: Y
authors: Wang
authors: 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.
authors: Li-Xuan
authors: LX
authors: Sang
authors: 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.
authors: Shen
authors: S
authors: Zhang
authors: 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.
authors: Ting
authors: T
authors: Wang
authors: 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.
authors: Feng
authors: F
authors: Zhou
authors: 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.
authors: Shou-Zhi
authors: SZ
authors: Gu
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D053818:Chymases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003092:Colitis / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D003106:Colon / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D018836:Inflammation Mediators / Q000097:blood; D016753:Interleukin-10 / Q000097:blood; D020381:Interleukin-17 / Q000097:blood; D017207:Rats, Sprague-Dawley; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D012720:Severity of Illness Index; D013449:Sulfonamides / Q000494:pharmacology*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D013876:Thiophenes / Q000494:pharmacology*; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000097:blood
chemical_list: D000893:Anti-Inflammatory Agents; D051858:Forkhead Transcription Factors; C500522:Foxp3 protein, rat; C515934:Il17a protein, rat; D018836:Inflammation Mediators; D020381:Interleukin-17; D015842:Serine Proteinase Inhibitors; D013449:Sulfonamides; C524344:TY 51469; C508962:Tgfb1 protein, rat; D013876:Thiophenes; D053773:Transforming Growth Factor beta1; D016753:Interleukin-10; D016264:Dextran Sulfate; D053818:Chymases
keywords: Chymase inhibitor; Cytokines; Inflammatory bowel disease; Rats; Tregs