“FINAL ACCEPTED VERSION” G-00467-2004.R1 Title: “Acute colitis induced by dextran sulphate sodium progresses into chronicity in C57BL/6 but not in BALB/c mice – correlation between symptoms and inflammation”

Exposure to dextran sulphate sodium (DSS) induces acute colitis, which is normally resolved after DSS removal. To study chronicity, mice are typically subjected to 3-5 cycles of weekly DSS-exposures, each followed by resting period of 1-2 weeks. Herein, we describe a novel and convenient way of inducing chronic, progressive colitis by a single exposure to DSS. C57BL/6 mice exposed to DSS for 5 days, developed acute colitis that progressed into severe chronic inflammation. The plasma haptoglobin levels remained high during the chronic phase, showing that the inflammation was active. Surprisingly, the mice regained their original weight along with the progression of colitis and the only apparent symptom was loose feces. Histopathological changes 4 weeks after DSS removal were dense infiltrates of mononuclear cells, irregular epithelial structure and persistent deposits of collagen. A progressive production of the cytokines IL-1β, IL-12p70 and IL-17 correlated to the extensive cellular infiltration, whereas high IFN-γ production was mainly found late in the chronic phase. Similar to C57BL/6, BALB/c mice exposed to five days of DSS developed acute colitis as previously described. The acute colitis was accompanied by elevated plasma levels of haptoglobin and increased colonic levels of IL-1α/β, IL-6, IL-18 and G-CSF. However, soon after DSS-removal BALB/c mice recovered and were symptom-free within two weeks and completely recovered 4 weeks after DSS removal in terms of histopathology, haptoglobin levels and local cytokine production. In summary, these data stress the effect of genetic background on the outcome of DSS-provocation. We believe that the current protocol to induce chronic colitis in C57BL/6 offers a robust model for validating future therapies for treatment of inflammatory bowel disease.