title: Inhibition of nuclear factor-kappaB ameliorates bowel injury and prolongs survival in a neonatal rat model of necrotizing enterocolitis.
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-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.
authors.affiliation: Department of Pediatrics, Children's Memorial Hospital, Northwestern University Medical School, Chicago, Illinois 60614, USA. isabelledp@northwestern.edu
authors.forename: Isabelle G
authors.initials: IG
authors.lastname: De Plaen
authors.forename: Shirley X L
authors.initials: SX
authors.lastname: Liu
authors.forename: Runlan
authors.initials: R
authors.lastname: Tian
authors.forename: Isaac
authors.initials: I
authors.lastname: Neequaye
authors.forename: Michael J
authors.initials: MJ
authors.lastname: May
authors.forename: Xin-Bing
authors.initials: XB
authors.lastname: Han
authors.forename: Wei
authors.initials: W
authors.lastname: Hsueh
authors.forename: Tamas
authors.initials: T
authors.lastname: Jilling
authors.forename: Jing
authors.initials: J
authors.lastname: Lu
authors.forename: Michael S
authors.initials: MS
authors.lastname: Caplan
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D004195:Disease Models, Animal; D020345:Enterocolitis, Necrotizing / Q000188:drug therapy* / Q000473:pathology; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II / Q000032:analysis / Q000378:metabolism; D010455:Peptides / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D016328:NF-kappa B; D010455:Peptides; D052247:Nitric Oxide Synthase Type II