Therapeutic Potential of the Combination of Pentoxifylline and Vitamin-E in Inflammatory Bowel Disease: Inhibition of Intestinal Fibrosis.

Abstract

Background: Although intestinal fibrosis is a consequence of recurrent inflammation in Inflammatory bowel disease (IBD), alleviating inflammation alone does not prevent the progression of fibrosis, suggesting that the development of direct anti-fibrotic agents is necessary. This study aimed to evaluate the anti-fibrotic properties of combination treatment with pentoxifylline (PTX) and vitamin E (Vit-E) on human primary intestinal myofibroblasts (HIMFs) and the therapeutic potential of the combination therapy in murine models of IBD. Methods: HIMFs were pretreated with PTX, Vit-E, or both, and incubated with TGF-β1. We performed Western blot, qPCR, collagen staining, and immunofluorescence to estimate the anti-fibrotic effects of PTX and Vit-E. The cytotoxicity of these was investigated through MTT assay. To induce murine models of IBD for in vivo study, C57BL/6 mice were treated with repeated cycles of dextran sulfate sodium (DSS), developing chronic colitis. We examined whether the combined PTX and Vit-E treatment would effectively ameliorate colonic fibrosis in vivo. Results: We found that the co-treatment with PTX and Vit-E suppressed TGF-β1-induced expression of fibrogenic markers, with decreased expression of pERK, pSmad2, and pJNK, more than either treatment alone in HIMFs. Neither PTX nor Vit-E showed any significant cytotoxicity in given concentrations. Consistently with the in vitro results, the co-administration with PTX and Vit-E effectively attenuated colonic fibrosis with recovery from thickening and shortening of colon in murine models of IBD. Conclusions: These findings demonstrated that the combination of PTX and Vit-E exhibits significant anti-fibrotic effects in both HIMFs and in vivo IBD models, providing a promising therapy for IBD.