Abstract
The sequential events and the inflammatory mediators that characterize disease onset and progression of ulcerative colitis (UC) are not well known. In this study, we evaluated the early pathologic events in the pathogenesis of colonic ulcers in rats treated with dextran sodium sulfate (DSS). Following a lag phase, day 5 of DSS treatment was found clinically most critical as disease activity index (DAI) exhibited an exponential rise with severe weight loss and rectal bleeding. Surprisingly, on days 1-2, colonic TNF-α expression (70-80-fold) and tissue protein (50-fold) were increased, whereas IL-1β only increased on days 7-9 (60-90-fold). Days 3-6 of DSS treatment were characterized by a prominent down regulation in the expression of regulatory cytokines (40-fold for IL-10 and TGFβ) and mucin genes (15-18 fold for Muc2 and Muc3) concomitant with depletion of goblet cell and adherent mucin. Remarkably, treatment with TNF-α neutralizing antibody markedly altered DSS injury with reduced DAI, restoration of the adherent and goblet cell mucin and IL-1β and mucin gene expression. We conclude that early onset colitis is dependent on TNF-α that preceded depletion of adherent and goblet cell mucin prior to epithelial cell damage and these biomarkers can be used as therapeutic targets for UC.
Highlights
Inflammatory bowel disease (IBD), an umbrella term that includes Crohn’s disease and ulcerative colitis (UC), are chronic relapsing inflammatory disorders of the gut that are believed to occur in genetically predisposed individuals due to exposure of unknown environmental and microbial agents [1]
Disease Activity Index (DAI) and Tissue damage DAI is a cumulative index of body weight loss, rectal bleeding and stool malformation and is considered as the best measure of clinical activity of colitis [6]
The ulcerated areas in the TNF-a neutralizing antibody treated group on day 9 seem restricted to the surface epithelium (Fig. 9F) with well-organized crypts with mucin filled goblet cells. These data suggest that neutralizing TNF-a markedly affected mucin release, mucus depletion and crypt inflammation to restrict the mucosal damaging effects of Dextran Sodium Sulphate (DSS). This is the first comprehensive study to quantify the salient features of early onset and acute progressive events in the pathogenesis of DSS induced colitis
Summary
Inflammatory bowel disease (IBD), an umbrella term that includes Crohn’s disease and ulcerative colitis (UC), are chronic relapsing inflammatory disorders of the gut that are believed to occur in genetically predisposed individuals due to exposure of unknown environmental and microbial agents [1]. Loss of mucosal tolerance is due to an uncontrolled inflammatory cascade resulting from a number of mutual and probably sequential events involving both immune (gut associated lymphoid tissues, GALT and professional antigen presenting cells, APC) and non-immune cells/molecules (epithelial cells of gut and resident microflora) [1,2]. Studies to unravel the pathogenesis of UC have been focused on various mucosal models of inflammation that closely resembles human colitis. One of the most comprehensively illustrated models of experimental colitis is Dextran Sodium Sulphate (DSS) induced colitis which mimics the clinical and histological features of human UC as the colonic lesions exhibits high homogeneity and reproducibility [3]. Acute and chronic colitis induced by DSS has been used to study changes in metabolically labeled and tissue mucin content [4] and/or changes in epithelial permeability, MPO and pro-inflammatory cytokines [4]
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