Analysis of intestinal fibrosis in chronic colitis in mice induced by dextran sulfate sodium

Abstract

Fibrogenic mesenchymal cells including fibroblasts and myofibroblasts play a key role in intestinal fibrosis, however, their precise role is largely unknown. To investigate their role in intestinal fibrosis, we analyzed the lesions of chronic colitis in C57BL/6 (B6) mice induced by dextran sulfate sodium (DSS). B6 mice exposed to single cycle administration of DSS for 5 days developed acute colitis that progressed to severe chronic inflammation with dense infiltrates of mononuclear cells, irregular epithelial structure, thickening of colonic wall, and persistent deposits of collagen. Increased mRNA expressions of proinflammatory cytokines are correlated with extensive cellular infiltration, and the mRNA expressions of collagen 1, transforming growth factor (TGF)-β, and matrix metalloproteinases were also enhanced in the colon. In the colon of chronic DSS colitis, fibroblasts (vimentin(+), α-smooth muscle actin (α-SMA)(-)) were increased in both mucosal and submucosal layers, while myofibroblasts (vimentin(+), α-SMA(+)) were increased in mucosal but not in submucosal layers. Primary mouse subcutaneous fibroblast cultures experiments revealed that exogenously added TGF-β 1 substantially augmented the expressions of both vimentin and α-SMA proteins with increased production of collagen. In conclusion, profibrogenic mesenchymal cells play an important role in the development of intestinal fibrosis in this chronic DSS-induced colitis model.

Animal models of chemically induced intestinal inflammation: Predictivity and ethical issues

“…Enhanced expression of TGFβ as well as several extracellular matrix-related proteins was detected along with an increased level of extracellular matrix deposition (Lund & Zuniga, 2001;Suzuki et al, 2011). However, in the DSS model, as compared to other fibrosis models, a lower extracellular matrix deposition is observed, probably due to an increased metalloproteinase expression along with other pro-fibrotic factors.…”

“…Moreover, proliferation of myofibroblasts and cellular phenotype in the submucosal layer are quite different from the TNBS model. A possible explanation could be that increased TGFβ expression is not enough to completely change the cell phenotype, transforming fibroblasts into mature myofibroblasts, which are important contributors to fibrogenesis (Suzuki et al, 2011). Although the effective resemblance with human chronic inflammation has been questioned, the DSS model can undoubtedly address several mechanisms occurring in wound healing.…”

New endoscopic approach of anti-fibrotic therapy for inflammatory bowel disease

“…This is a new endoscopic submucosal injection possessing pancolonic delivery. We also established animal model that can bring insights into the pathogenesis of intestinal fibrosis (30) and demonstrated the therapeutic effect of STNM01 in view of anti-fibrosis as well as MH (25). As the balance between MH and fibrosis would contribute to disease outcome in tissue remodeling in IBD, we have investigated both endoscopic MH and histological fibrosis in animal and patients and shown endoscopy would be a feasible tool to predict the anti-fibrotic efficacy.…”

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]. …”