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
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.
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.
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.
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.