Necrotizing enterocolitis (NEC) is a major cause of morbidity and death in premature infants. NEC is associated with increased levels of pro-inflammatory cytokines in plasma and tissues that are regulated by the transcription factor nuclear factor-κB (NF-κB). It remains unknown, however, whether NF-κB mediates injury in neonatal NEC. We therefore examined the activation status of NF-κB perinatally in the small intestine and in a neonatal rat model of NEC. We found that intestinal NF-κB is strongly activated at birth and, in dam-fed newborn rats, is down-regulated within a day. In contrast, NF-κB remains strongly activated at both d 1 and d 2 in stressed animals, and this is accompanied by a significant decrease in the levels of the endogenous NF-κB inhibitor protein IκBα and IκBβ at d 2. To determine the importance of elevated NF-κB activity in intestinal injury in NEC, we administered the NEMO-binding domain (NBD) peptide that selectively inhibits the critical upstream IκB kinase (IKK). NBD but not a control peptide decreased mortality and bowel injury in this model, supporting the hypothesis that bowel injury in NEC results from elevated NF-κB activity. Our findings therefore lead us to conclude that selective NF-κB inhibition represents a promising therapeutic strategy for NEC. © International Pediatrics Research Foundation, Inc. 2007. All Rights Reserved.
