Irsogladine maleate ameliorates inflammation and fibrosis in mice with chronic colitis induced by dextran sulfate sodium

Abstract

Intestinal fibrosis is a common and severe complication of inflammatory bowel disease (IBD), especially Crohn's disease (CD). To investigate the therapeutic approach to intestinal fibrosis, we have developed a mouse model of intestinal fibrosis by administering dextran sulfate sodium (DSS) and examining the effects of irsogladine maleate (IM) [2,4-diamino-6-(2,5-dichlorophenyl)-s-triazine maleate], which has been widely used as an antiulcer drug for gastric mucosa in Japan, on DDS-induced chronic colitis. In this experimental colitis lesion, several pathognomonic changes were found: increased deposition of collagen, increased number of profibrogenic mesenchymal cells such as fibroblasts (vimentin(+), α-SMA(-)) and myofibroblasts (vimentin(+), α-SMA(+)) in both mucosa and submucosa of the colon with infiltrating inflammatory cells, and increased mRNA expressions of collagen type I, transforming growth factor (TGF)-β, matrix metalloproteinase (MMP)-2, and tissue inhibitor of matrix metalloproteinase (TIMP)-1. When IM was administered intrarectally to this colitis, all these pathological changes were significantly decreased or suppressed, suggesting a potential adjunctive therapy for intestinal fibrosis. IM could consequently reduce fibrosis in DSS colitis by direct or indirect effect on profibrogenic factors or fibroblasts. Therefore, the precise effect of IM on intestinal fibrosis should be investigated further.

Hepatocyte Growth Factor Facilitates Esophageal Mucosal Repair and Inhibits the Submucosal Fibrosis in a Rat Model of Esophageal Ulcer

“…The blockade of TGF-β signaling, either at the extracellular or intracellular level, is a strategy for preventing fibrosis [45]. ECM degradation is mediated by MMPs (a marker of fibrosis) and TIMPs [46]. MMPs and TIMPs are central to the ECM turnover and actively regulate inflammation and remodeling [45].…”

“…Besides, the activity of MMPs was controlled by transcriptional regulation, proenzyme activation by TIMPs [47]. Yamaguchi reported that the mRNA expression levels of TGF-β1, MMP-2 and TIMP-1 were markedly increased in chronic dextran sulfate sodium-induced colitis in comparison to control mice [46]. Ding reported that homocysteine promoted intestinal fibrosis in a rat model of trinitrobenzene sulfonic acid (TNBS)-induced colitis and homocysteine increased the mRNA expression of TGF-β1, MMP-2, -9 and TIMP-1 in the colonic tissue of rats with TNBS/ethanol-induced colitis.…”

Irsogladine Maleate Prevents Colitis in Interleukin-10 Gene-Deficient Mice by Reducing Interleukin-12 and -23 Production

“…Since 1984, various mechanisms of action of IM to protect the mucosa in the gastrointestinal tract were reported, 14) including a few articles referring to anti-inflammatory effects in colitis. Among these reports, Yamaguchi et al showed that IM prevented fibrosis in a dioctyl sodium sulfosuccinate (DSS)-induced colitis model through suppressing the production of proinflammatory cytokines, 15) and Kamei et al reported that one of the mechanisms underlying amelioration of experimental colitis by IM may be correlated with secretion of mucus preventing bacterial invasion by disrupting mucosal integrity induced with indomethacin.…”

“…[12][13][14] Several recent reports have indicated that IM has antiinflammatory and protective effects in areas of the gastrointestinal mucosae other than the stomach. 15,16) The administration of IM by enema was shown to improve chronic experimental colitis induced by dextran sulfate sodium, suggesting that topical IM therapy could downregulate cytokine production.…”

New Therapeutic Avenues for Treatment of Fibrosis: Can We Learn from Other Diseases?

“…Animal models of fibrosis have been recently summarized and reviewed by Pizarro and colleagues [36,37]. In most of the animal models, fibrosis is either induced by chemicals such as dextran sodium sulfate [38,39,40] or 2,4,6- trinitrobenzenesulfonic acid [41,42,43,44,45,46,47,48], or by bacterial cell wall products such as peptidoglycan [49,50]. …”