Journal
PLOS ONE
Volume 6, Issue 9, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0025058
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Categories
Funding
- Canadian Institute for Health Research (CIHR)
- Canadian Association of Gastroenterology-AstraZeneca-CIHR
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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-alpha expression (70-80-fold) and tissue protein (50-fold) were increased, whereas IL-1 beta 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 TGF beta) and mucin genes (15-18 fold for Muc2 and Muc3) concomitant with depletion of goblet cell and adherent mucin. Remarkably, treatment with TNF-alpha neutralizing antibody markedly altered DSS injury with reduced DAI, restoration of the adherent and goblet cell mucin and IL-1 beta and mucin gene expression. We conclude that early onset colitis is dependent on TNF-alpha 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.
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