Dextran sulfate sodium administered orally is depolymerized in the stomach and induces cell cycle arrest plus apoptosis in the colon in early mouse colitis

Oncol Rep. 2012 Nov;28(5):1597-605. doi: 10.3892/or.2012.1969. Epub 2012 Aug 10.

Abstract

The mechanisms responsible for human inflammatory bowel disease remain poorly understood. The pathogenic factors for dextran sulfate sodium (DSS)-induced colitis, one of the experimental animal colitis models, also remain unknown. Furthermore, detailed studies on DSS metabolism in the gut lumen have not been reported. Therefore, we investigated DSS metabolism in the mouse gut lumen and report the mechanisms which induce colitis. DSS was labeled with 2-aminopyridine (pyridylamino-DSS, PA-DSS). PA-DSS was administered orally to male BALB/cA Jcl mice. The metabolites and histological findings were observed using HPLC and light or fluorescence microscopy. PA-DSS with Mr 5000 was depolymerized rapidly in the gastric lumen, and the depolymerized PA-DSS was absorbed in the small intestine. Therefore, the majority of the PA-DSS in the cecal contents returned to Mr 5000 PA-DSS, escaping absorption in the small intestine. Mr 5000 DSS induced severe colitis, and immunostaining using an anti-mouse Ki-67 antibody and the TUNEL assay showed that DSS arrested the cell cycle at the G0 phase and induced apoptosis of the colonic epithelium. Mr 2500 PA-DSS, however, induced these same effects weakly. During these processes, we observed that the epithelial cells can depolymerize DSS themselves. An in vitro study using Caco-2 cells also showed similar effects. Mr 5000 DSS was depolymerized in the gut lumen and epithelial cells. Therefore, the molecular mass distribution of the DSS differed between each part in the lumen. As an early stage event, DSS induced colitis through cell cycle arrest and apoptosis according to its molecular mass.

MeSH terms

  • Administration, Oral
  • Aminopyridines
  • Animals
  • Apoptosis*
  • Caco-2 Cells
  • Cell Cycle Checkpoints*
  • Cell Line, Tumor
  • Colitis / chemically induced
  • Colitis / pathology*
  • Colon / metabolism
  • Colon / pathology
  • Dextran Sulfate / administration & dosage*
  • Dextran Sulfate / chemistry
  • Dextran Sulfate / metabolism*
  • Disease Models, Animal
  • Humans
  • Inflammatory Bowel Diseases / etiology
  • Intestinal Mucosa / pathology*
  • Male
  • Mice
  • Mice, Inbred BALB C

Substances

  • Aminopyridines
  • Dextran Sulfate
  • alpha-aminopyridine