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* = Presenting author

P098 Anti-fibrotic effects of a novel small compound that promotes the nuclear translocation of YB-1 in a mouse model of colorectal fibrosis

J. Imai*1, K. Hozumi2, Y. Inagaki3, T. Mine1

1Tokai university School of Medicine, Gastroenterology, Isehara, Japan, 2Tokai university School of Medicine, Immunology, Isehara, Japan, 3Tokai university School of Medicine, Regenerative Medicine, Isehara, Japan

Background

Intestinal fibrotic stricture is a major complication of inflammatory bowel disease. Despite its clinical importance, anti-fibrotic therapy has not been implemented. Approximately 40% of CD patients with ileal disease develop clinically apparent strictures. TGF-β is considered the major factor contributing to tissue fibrosis. Previously, we have shown that the administration of a small compound, HSc025, which promotes the nuclear translocation of YB-1 as a downstream effector of IFN-γ and antagonises TGF-β /Smad signalling, improved fibrosis in several murine tissues, such as lung, skin, and liver. In this study, we evaluated the anti-fibrotic effect of HSc025 on colorectal fibrosis in TNBS-induced murine chronic colitis.

Methods

Colonic inflammation was induced by intrarectal injection of a 2% solution of 2,4,6-trinitrobenzene sulfonic acid (TNBS) in 50% ethanol. The dose of TNBS solution was sequentially increased in the range of 0.4–1.6 mg by 8 weekly injections. Daily oral administration of HSc025 (3, 15 and 75 mg/kg) after the sixth injection of TNBS. Histological analysis of colonic fibrosis was evaluated by Sirius-red stain, and sircol collagen assay. The mRNA expression of the murine Col1A2 gene in the colon samples was assessed by real-time polymerase chain reaction (PCR) analysis. Colonic production of cytokines and in-vitro stimulation of TNBS-specific T-cells in draining lymph nodes was evaluated.

Results

Daily oral administration of HSc025 (3, 15 and 75 mg/kg) suppressed collagen production and decreased the severity of colorectal fibrosis in a dose-dependent manner. In addition, the local production of TGF-β was also decreased after HSc025 treatment, whereas that of IL-13 and TNF-α was not affected. HSc025 administration maintained the IFN-γ production levels, even at a late stage when it was lost without the drug treatment.

Conclusion

These results demonstrate that HSc025 could be a therapeutic candidate for intestinal fibrosis in inflammatory bowel disease by altering the local production of cytokines, as well as by direct suppressing collagen production.