tranilast and Colitis

Topics: Administration, Oral; Animals; Anti-Infective Agents; Biological Availability; Colitis; Colon; Disease Models, Animal; Drug Carriers; Drug Compounding; Gastrointestinal Agents; Hydrogen-Ion Concentration; Intestinal Mucosa; Male; Micelles; Neutrophil Infiltration; ortho-Aminobenzoates; Particle Size; Peroxidase; Rats, Sprague-Dawley; Solubility; Technology, Pharmaceutical; Trinitrobenzenesulfonic Acid

The present study aimed to verify the efficacy of tranilast (TL) for treating inflammatory bowel disease (IBD) with the use of an experimental colitis model. The experimental colitis model was prepared by intrarectal instillation of 2,4,6-trinitrobenzenesulfonic acid (TNBS; 40mg/kg) dissolved in water containing 25% ethanol. The pharmacological effects of TL after repeated oral administration were evaluated by biomarker and histological analyses, and the pharmacokinetic behavior of TL was also examined after single oral administration. The intrarectal instillation of TNBS solution caused colitis, as evidenced by ca. 2.2-, 5-, and 3-fold increases in myeloperoxidase (MPO) activity, infiltrated cell numbers, and the thickness of the submucosa in the colon, respectively. However, orally-taken TL (10mg/kg, twice a day for 9days) led to a 92% reduction in the increase of the MPO level by TNBS enema, and cellular infiltration and thickened submucosa in the experimental colitis model tended to also be suppressed by repeated oral administration of TL. The oral bioavailability of TL in TNBS-treated rats was calculated to be as low as ca. 6.5%, and the poor oral absorption of TL may be a limitation of the treatment for IBD. TL could attenuate TNBS-induced colitis on the basis of the obtained results, and the anti-inflammatory effects would have clinical relevance to the therapeutic outcomes of TL in IBD patients. Although further improvement in the oral bioavailability of TL might be required for better pharmacological outcomes, TL would be an efficacious agent for treating IBD.

Topics: Animals; Anti-Inflammatory Agents; Colitis; Colon; Disease Models, Animal; Inflammatory Bowel Diseases; Intestinal Mucosa; Male; ortho-Aminobenzoates; Peroxidase; Protective Agents; Rats; Rats, Wistar; Trinitrobenzenesulfonic Acid

Mast cells in the gut play an important role in the innate and adaptive immune responses that are relevant to human inflammatory bowel disease. However, the contribution of mast cells to the development of inflammatory bowel disease is not well understood. This study aimed to determine the role of mast cells in oxazolone-induced colitis and to explore whether the mast cell membrane stabiliser tranilast could ameliorate colonic inflammation.. Wild-type rats and mast cell-deficient rats were sensitised and challenged with oxazolone, then treated with tranilast after challenge. Controls were treated with saline.. Mast cell-deficient rats presented a weak response to oxazolone, while wild-type rats showed severe ulcerative colitis after stimulation with oxazolone. The mast cell-deficient rats model had a significantly lower disease activity index score than wild-type rats model (1.8±1.64 vs. 8.3±0.58 respectively; P<0.01). Tranilast could reduce the secretion of cytokines, immunoglobulins and myeloperoxidase activity in tranilast treatment groups compared with the model group. The number of mast cells in the wild-type model was higher than in the other groups. There was no significant change in mast cell-deficient rats.. Mast cells play an important role in oxazolone-induced colitis. The mast cell membrane stabiliser tranilast can ameliorate oxazolone-induced colitis via a mast cell-dependent pathway.

Topics: Adjuvants, Immunologic; Animals; Colitis; Colon; Cytokines; Disease Models, Animal; Histamine H1 Antagonists; Inflammatory Bowel Diseases; Interleukin-13; Interleukin-33; Interleukin-6; Mast Cells; ortho-Aminobenzoates; Oxazolone; Rats

Mast cells play a key role in the pathophysiology of inflammatory bowel disease (IBD). Tranilast, a mast cell stabilizer, has been empirically used for IBD in Japan, but its precise role in the treatment of IBD is largely unknown. To investigate the role of tranilast for the treatment of IBD, tranilast was administered intrarectally to mice with dextran sulfate sodium (DSS)-induced colitis. Tranilast ameliorated DSS colitis clinically and pathologically, as demonstrated by decreased number and degranulation of mast cells in the colon. mRNA expression was increased for tumor necrosis factor-alpha, interferon-gamma and interleukin (IL)-6, and decreased for IL-10 in the colon of DSS colitis mice. In contrast, tranilast markedly decreased expression of mRNAs for the pro-inflammatory cytokines, and increased that of the anti-inflammatory cytokines. Moreover, tranilast increased heme oxygenase (HO)-1 expression on colonic epithelial cells as well as on colon-infiltrating cells of DSS colitis. In conclusion, tranilast ameliorated DSS colitis by regulating mast cell degranulation, decreasing inflammatory cytokines and increasing anti-inflammatory cytokines. Tranilast might exert these effects partly through enhanced HO-1 expression in the colon, suggesting a potential adjunctive therapy for IBD.

Topics: Administration, Rectal; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cell Degranulation; Colitis; Cytokines; Dextran Sulfate; Female; Fluorescent Antibody Technique; Gene Expression; Heme Oxygenase-1; Mast Cells; Mice; Mice, Inbred C57BL; ortho-Aminobenzoates; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Colitis; Crohn Disease; Female; Humans; ortho-Aminobenzoates