Dextran sodium sulfate (DSS) induces necrotizing enterocolitis-like lesions in neonatal mice

Abstract

BackgroundNecrotizing enterocolitis (NEC) is an inflammatory bowel disease of preterm human newborns with yet unresolved etiology. An established neonatal murine model for NEC employs oral administration of lipopolysaccharides (LPS) combined with hypoxia/hypothermia. In adult mice, feeding dextran sodium sulfate (DSS) represents a well-established model for experimental inflammatory bowel disease. Here we investigated the effect of DSS administration on the neonatal murine intestine in comparison with the established NEC model.Methods3-day-old C57BL/6J mice were either fed formula containing DSS or LPS. LPS treated animals were additionally stressed by hypoxia/hypothermia twice daily. After 72 h, mice were euthanized, their intestinal tissue harvested and analyzed by histology, qRT-PCR and flow cytometry. For comparison, adult C57BL/6J mice were fed with DSS for 8 days and examined likewise. Untreated, age matched animals served as controls.ResultsAdult mice treated with DSS exhibited colonic inflammation with significantly increased Cxcl2 mRNA expression. In contrast, tissue inflammation in neonatal mice treated with DSS or LPS plus hypoxia/hypothermia was present in colon and small intestine as well. Comparative analysis of neonatal mice revealed a significantly increased lesion size and intestinal Cxcl2 mRNA expression after DSS exposure. Whereas LPS administration mainly induced local neutrophil recruitment, DSS treated animals displayed increased monocytes/macrophages infiltration.ConclusionsOur study demonstrates the potential of DSS to induce NEC-like lesions accompanied by a significant humoral and cellular immune response in the small and large intestine of neonatal mice. The new model therefore represents a good alternative to LPS plus hypoxia/hypothermia administration requiring no additional physical stress.

Necrotizing Enterocolitis: State of the Art in Translating Experimental Research to the Bedside

“…71 Sangild et al showed that with a single stress factor alone, formula feeding of a human infant formula, 57% of piglets presented with clinical and histopathological signs of NEC, while piglets fed colostrum had a reduction in severity of NEC as well as in the adverse effects of feeding. 65 Of note in their study was the demonstration that NEC-like intestinal inflammation occurred after oral colostrum eating, without exposure to hypoxic or hypothermic insults. 65 Their group has also validated this model of NEC induction by confirming release of IL-6.…”

“…65 Of note in their study was the demonstration that NEC-like intestinal inflammation occurred after oral colostrum eating, without exposure to hypoxic or hypothermic insults. 65 Their group has also validated this model of NEC induction by confirming release of IL-6. 72 Other investigators have used the newborn piglet model to show the role of reactive oxygen species in NEC, 73 gastric intramural pH monitoring in NEC, 74 attenuation of T cell-mediated mucosal immunity in NEC, 75 and the role of PAF in NEC.…”

“…Aside from the standard NEC induction protocols described above, other stress factors have also been used by investigators to induce NEC in mouse pups. Ginzel et al 65 have shown that dextran sodium sulfate (DSS), which has been prevalently used to model inflammatory bowel disease and colitis, 66 is sufficient to induce NEC in neonatal mice along with formula feeding. In this model, Ginzel et al confirmed that pups receiving DSS had NEC-like lesions, tissue inflammation, and increased monocyte/macrophage infiltration.…”

“…In this model, Ginzel et al confirmed that pups receiving DSS had NEC-like lesions, tissue inflammation, and increased monocyte/macrophage infiltration. 65 Another model of NEC induction in mouse pups involves the elimination of Paneth cells. These cells reside at the bottom of intestinal crypts and are the key effectors of innate mucosal defense via production of antimicrobial peptides.…”

RNA Purity, Real-Time PCR Sensitivity, and Colon Segment Influence mRNA Relative Expression in Murine Dextran Sodium Sulfate Experimental Colitis

“…3 Acute and chronic inflammation, colonic adenocarcinoma, and necrotizing enterocolitis models have been reported by variations on dosing, inclusion of azomethane, and animal age, respectively. 4 In addition, the effectiveness of the DSS model depends on the strain and colony of mice used, as well as the DSS MW. As DSS is a polysaccharide, its MW can vary according to the number of monosaccharides attached, modifying its pharmacokinetics.…”