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

Isabelle G. De Plaen*, Shirley X.L. Liu, Runlan Tian, Isaac Neequaye, Michael J. May, Xin Bing Han, Wei Hsueh, Tamas Jilling, Jing Lu, Michael S. Caplan

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

63 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)716-721
Number of pages6
JournalPediatric research
Volume61
Issue number6
DOIs
StatePublished - Jun 2007

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health

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