De Plaen Isabelle G, Liu Shirley X L, Tian Runlan, Neequaye Isaac, May Michael J, Han Xin-Bing, Hsueh Wei, Jilling Tamas, Lu Jing, Caplan Michael S
Department of Pediatrics, Children's Memorial Hospital, Northwestern University Medical School, Chicago, Illinois 60614, USA.
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.
坏死性小肠结肠炎（NEC）是早产儿发病和死亡的主要原因。NEC与血浆和组织中促炎细胞因子水平升高有关，这些细胞因子受转录因子核因子-κB（NF-κB）调控。然而，NF-κB是否介导新生儿NEC损伤仍不清楚。因此，我们在围产期检测了小肠和NEC新生大鼠模型中NF-κB的激活状态。我们发现，肠道NF-κB在出生时强烈激活，在母乳喂养的新生大鼠中，一天内就会下调。相比之下，在应激动物中，NF-κB在第1天和第2天仍强烈激活，并且在第2天内源性NF-κB抑制蛋白IκBα和IκBβ水平显著降低。为了确定NEC中NF-κB活性升高在肠道损伤中的重要性，我们给予了选择性抑制关键上游IκB激酶（IKK）的NEMO结合域（NBD）肽。在此模型中，NBD肽而非对照肽降低了死亡率和肠道损伤，支持了NEC肠道损伤是由NF-κB活性升高所致的假说。因此，我们的研究结果使我们得出结论，选择性抑制NF-κB是一种有前景的NEC治疗策略。
