Milk Fat Globule-EGF Factor 8 Is a Critical Protein for Healing of Dextran Sodium Sulfate-Induced Acute Colitis in Mice

Ashish Chogle,Pauline M Chou,Jeffrey B Brown,Heng-Fu Bu,Xiao-Di Tan,Xiao Wang

doi:10.2119/molmed.2010.00074

Ashish Chogle, Pauline M Chou + Show 4 more

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https://doi.org/10.2119/molmed.2010.00074

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Abstract

Milk fat globule-EGF factor 8 (MFG-E8) has been shown to play an important role in maintaining the integrity of the intestinal mucosa and to accelerate healing of the mucosa in septic mice. Herein, we (a) analyzed the expression of MFG-E8 in the gut of wild-type (WT) C57BL/6 (MFG-E8(+/+)) mice with and without dextran sulfate sodium (DSS)-induced colitis, (b) characterized the pathological changes in intestinal mucosa of MFG-E8(+/+) and MFG-E8(-/-) mice with DSS-induced colitis and (c) examined the therapeutic role of MFG-E8 in inflammatory bowel disease by using DSS-induced colitis model. Our data documented that there was an increase in colonic and rectal MFG-E8 expression in MFG-E8(+/+) mice during the development of DSS colitis. MFG-E8 levels in both tissues decreased to below baseline during the recovery phase in mice with colitis. Changes in MFG-E8 gene expression correlated to the levels of inflammatory response and crypt-epithelial injury in both colonic and rectal mucosa in MFG-E8(+/+) mice. MFG-E8(-/-)mice developed more severe crypt-epithelial injury than MFG-E8(+/+) mice during exposure to DSS with delayed healing of intestinal epithelium during the recovery phase of DSS colitis. Administration of MFG-E8 during the recovery phase ameliorated colitis and promoted mucosal repair in both MFG-E8(-/-) and MFG-E8(+/+) mice, indicating that lack of MFG-E8 causes increased susceptibility to colitis and delayed mucosal healing. These data suggest that MGF-E8 is an essential protective factor for gut epithelial homeostasis, and exogenous administration of MFG-E8 may represent a novel therapeutic target in inflammatory bowel disease.

Highlights

Inflammatory bowel disease (IBD) is a term used to describe inflammatory conditions of the large and small intestine including Crohn’s disease and ulcerative colitis
By assessing the clinical colitis score, we revealed that dextran sulfate sodium (DSS)-treated mice became worse on day 7 but started improving once DSS feeds were stopped in both strains (Figure 1)
There is no significant difference in comparison of WT and Milk fat globule–EGF factor 8 (MFG-E8) deficient mice to their clinical colitis scores

Summary

Introduction

Inflammatory bowel disease (IBD) is a term used to describe inflammatory conditions of the large and small intestine including Crohn’s disease and ulcerative colitis. IBD could be considered to be an imbalance between proinflammatory and antiinflammatory mediators in the bowel mucosa [1]. Dysfunctions of the intestinal immune system and cross-reactivity against host epithelial cells have been implicated as major inflammatory mechanisms in IBD [2]. A number of peptides expressed in the intestine including ghrelin, galanin, melatonin, vasoactive intestinal peptide and adrenomedullin have been shown to have an antiinflammatory effect in IBD research models [3,4,5,6,7,8,9,10,11,12,13]

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