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

Pediatr Res. 2007 Jun;61(6):716-21. doi: 10.1203/pdr.0b013e3180534219.


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

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Disease Models, Animal
  • Enterocolitis, Necrotizing / drug therapy*
  • Enterocolitis, Necrotizing / pathology
  • Intestinal Mucosa / metabolism
  • Intestines / drug effects
  • Intestines / pathology
  • NF-kappa B / antagonists & inhibitors*
  • Nitric Oxide Synthase Type II / analysis
  • Nitric Oxide Synthase Type II / metabolism
  • Peptides / therapeutic use*
  • Rats
  • Rats, Sprague-Dawley


  • NF-kappa B
  • Peptides
  • Nitric Oxide Synthase Type II