Inhibition of nuclear factor-κB ameliorates bowel injury and prolongs survival in a neonatal rat model of necrotizing enterocolitis

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-kappa B (NF-kappa B). It remains unknown, however, whether NF-kappa B mediates injury in neonatal NEC. We therefore examined the activation status of NF-kappa B perinatally in the small intestine and in a neonatal rat model of NEC. We found that intestinal NF-KB is strongly activated at birth and, in dam-fed newborn rats, is down-regulated within a day. In contrast, NF-kappa B 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-kappa B inhibitor protein I kappa B alpha and I kappa B beta at d 2. To determine the importance of elevated NF-kappa B activity in intestinal injury in NEC, we administered the NEMO-binding domain (NBD) peptide that selectively inhibits the critical upstream I kappa B 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-kappa B activity. Our findings therefore lead us to conclude that selective NF-kappa B inhibition represents a promising therapeutic strategy for NEC.