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Erythropoietin Protects Intestinal Epithelial Barrier Function and Lowers the Incidence of Experimental Neonatal Necrotizing Enterocolitis

The impermeant nature of the intestinal barrier is maintained by tight junctions (TJs) formed between adjacent intestinal epithelial cells. Disruption of TJs and loss of barrier function are associated with a number of gastrointestinal diseases, including neonatal necrotizing enterocolitis (NEC), th...

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Published in:The Journal of biological chemistry 2011-04, Vol.286 (14), p.12123-12132
Main Authors: Shiou, Sheng-Ru, Yu, Yueyue, Chen, Sangzi, Ciancio, Mae J., Petrof, Elaine O., Sun, Jun, Claud, Erika C.
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description The impermeant nature of the intestinal barrier is maintained by tight junctions (TJs) formed between adjacent intestinal epithelial cells. Disruption of TJs and loss of barrier function are associated with a number of gastrointestinal diseases, including neonatal necrotizing enterocolitis (NEC), the leading cause of death from gastrointestinal diseases in preterm infants. Human milk is protective against NEC, and the human milk factor erythropoietin (Epo) has been shown to protect endothelial cell-cell and blood-brain barriers. We hypothesized that Epo may also protect intestinal epithelial barriers, thereby lowering the incidence of NEC. Our data demonstrate that Epo protects enterocyte barrier function by supporting expression of the TJ protein ZO-1. As immaturity is a key factor in NEC, Epo regulation of ZO-1 in the human fetal immature H4 intestinal epithelial cell line was examined and demonstrated Epo-stimulated ZO-1 expression in a dose-dependent manner through the PI3K/Akt pathway. In a rat NEC model, oral administration of Epo lowered the incidence of NEC from 45 to 23% with statistical significance. In addition, Epo treatment protected intestinal barrier function and prevented loss of ZO-1 at the TJs in vivo. These effects were associated with elevated Akt phosphorylation in the intestine. This study reveals a novel role of Epo in the regulation of intestinal epithelial TJs and barrier function and suggests the possible use of enteral Epo as a therapeutic agent for gut diseases.
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subjects Akt PKB
Animals
Animals, Newborn
Cell Line, Tumor
Disease Models, Animal
Electric Impedance
Enterocolitis, Necrotizing - drug therapy
Enterocytes - cytology
Enterocytes - drug effects
Enterocytes - metabolism
Erythropoietin
Erythropoietin - pharmacology
Erythropoietin - therapeutic use
Fluorescent Antibody Technique
Gastrointestinal
Humans
Immunoblotting
Interferon
Intestinal Mucosa - cytology
Intestinal Mucosa - metabolism
Intestine
Intestines - cytology
Intestines - drug effects
Membrane Proteins - genetics
Membrane Proteins - metabolism
Molecular Bases of Disease
Necrotizing Enterocolitis
Phosphatidylinositol 3-Kinases - metabolism
Phosphoinositide-3 Kinase Inhibitors
Phosphoproteins - genetics
Phosphoproteins - metabolism
Proto-Oncogene Proteins c-akt - antagonists & inhibitors
Proto-Oncogene Proteins c-akt - metabolism
Rat
Rats
RNA Interference
T84
Tight Junction
Tight Junctions - drug effects
Tight Junctions - metabolism
ZO-1
Zonula Occludens-1 Protein
title Erythropoietin Protects Intestinal Epithelial Barrier Function and Lowers the Incidence of Experimental Neonatal Necrotizing Enterocolitis
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