CLINICOPATHOLOGICAL STUDY OF DEXTRAN SULFATE SODIUM EXPERIMENTAL MURINE COLITIS

BACKGROUND: We undertook this study in order to fully characterize the clinical and histopathology features of the dextran sulfate sodium (D SS) model of experimental murine colitis and to discover the earliest histopathologic changes that lead to colitis. EXPERIMENTAL DESIGN: Acu te colitis was induced in Swiss-Webster mice by 7 days of oral DSS wit h animals sacrificed daily. Chronic colitis was induced by: (a) 7 days of oral DSS followed by 7 days of H2O (for 1, 2, and 3 cycles) and (b ) 7 days of oral DSS followed by 14 and 21 days of H2O. In each experi mental group, the entire colons were examined histologically and corre lated with clinical symptoms. RESULTS: Acute clinical symptoms (diarrh ea and/or grossly bloody stool) were associated with the presence of e rosions and inflammation. More importantly, the earliest histologic ch anges which predated clinical colitis was loss of the basal one-third of the crypt (day 3), which progressed with time to loss of the entire crypt resulting in erosions on day 5. The earliest changes were very focal and not associated with inflammation. Inflammation was a seconda ry phenomena and only became significant after erosions appeared. Anim als treated with only 7 days of DSS followed by 14 and 21 days of H2O developed a chronic colitis with the following histologic features: ar eas of activity (erosions and inflammation), inactivity, crypt distort ion, florid epithelial proliferation and possible dysplasia. These cha nges were similar to animals given 3 cycles of DSS. The clinical disea se activity index correlated significantly with pathologic changes in both the acute and chronic phases of the disease. CONCLUSIONS: The mec hanism of DSS colitis is presently unknown. However, the finding of cr ypt loss without proceeding or accompanying inflammation suggests that the initial insult is at the level of the epithelial cell with inflam mation being a secondary phenomena. This may be a good model to study how early mucosal changes lead to inflammation and the biology of the colonic enterocyte. Chronic colitis induced after only 7 days of DSS m ay serve as a useful model to study the effects of pharmacologic agent s in human inflammatory disease and mechanisms of perpetuation of infl ammation. Finally, we believe that this model has the potential to stu dy the dysplasia cancer sequence in inflammatory disease.