Inhibition of nuclear factor-kappaB 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-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.
De Plaen
Isabelle G
IG
Department of Pediatrics, Children's Memorial Hospital, Northwestern University Medical School, Chicago, Illinois 60614, USA. isabelledp@northwestern.edu
Liu
Shirley X L
SX
Tian
Runlan
R
Neequaye
Isaac
I
May
Michael J
MJ
Han
Xin-Bing
XB
Hsueh
Wei
W
Jilling
Tamas
T
Lu
Jing
J
Caplan
Michael S
MS
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
D016328:NF-kappa B; D010455:Peptides; D052247:Nitric Oxide Synthase Type II