Abstract
Neonatal necrotizing enterocolitis (NEC) is a devastating gastrointestinal disease of preterm infants. Increased intestinal epithelium permeability is an early event in NEC pathogenesis. Autophagy and apoptosis are induced by multiple stress pathways which may impact the intestinal barrier, and they have been associated with pathogenesis of diverse gastrointestinal diseases including inflammatory bowel disease. Using both in vitro and in vivo models, this study investigates autophagy and apoptosis under experimental NEC stresses. Furthermore this study evaluates the effect of erythropoietin (Epo), a component of breast milk previously shown to decrease the incidence of NEC and to preserve intestinal barrier function, on intestinal autophagy and apoptosis. It was found that autophagy and apoptosis are both rapidly up regulated in NEC in vivo as indicated by increased expression of the autophagy markers Beclin 1 and LC3II, and by evidence of apoptosis by TUNEL and cleaved caspase-3 staining. In the rat NEC experimental model, autophagy preceded the onset of apoptosis in intestine. In vitro studies suggested that Epo supplementation significantly decreased both autophagy and apoptosis via the Akt/mTOR signaling pathway and the MAPK/ERK pathway respectively. These results suggest that Epo protects intestinal epithelium from excessive autophagy and apoptosis in experimental NEC.
Highlights
Neonatal necrotizing enterocolitis (NEC) is a devastating gastrointestinal disease, and a leading cause of morbidity and mortality in premature infants
Neither Beclin 1-positive staining nor LC3-positive staining was observed in intestinal tissue sections from NEC diseased pups in the absence of primary antibody indicating that the staining was not a nonspecific stain from the secondary antibody
We find that autophagy and apoptosis are both up regulated in experimental NEC
Summary
Neonatal necrotizing enterocolitis (NEC) is a devastating gastrointestinal disease, and a leading cause of morbidity and mortality in premature infants. Autophagy is an evolutionarily conserved homeostatic process which occurs in all cells at low basal levels for protein and organelle turnover. During nutrient starvation or trophic growth factor withdrawal, autophagy is up regulated to supply cells with metabolites as survival fuel. Autophagy is generally regarded as a cytoprotective process. Autophagy has been reported to occur in the intestinal epithelium of neonatal piglets in early postnatal life [9], and to be activated in the intestinal epithelium of NEC patients and in the ileum of experimental NEC rats [10]. The connection between activation of autophagy and induction of NEC is still poorly understood
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