Inhibition of nuclear factor-κB ameliorates bowel injury and prolongs survival in a neonatal rat model of necrotizing enterocolitis
Inhibition of nuclear factor-κB ameliorates bowel injury and prolongs survival in a neonatal rat model of necrotizing enterocolitis
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DOI：
10.1203/pdr.0b013e3180534219
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发表时间：
2007-06-01
影响因子：
3.6
通讯作者：
Caplan, Michael S.
中科院分区：
文献类型：
--
作者：
De Plaen, Isabelle G.;Liu, Shirley X. L.;Caplan, Michael S.
坏死性小肠结肠炎（NEC）是早产儿发病和死亡的主要原因。NEC与血浆和组织中受转录因子核因子-κ B（NF-κ B）调节的促炎细胞因子水平升高相关。然而，NF-κ B B是否介导新生儿NEC的损伤仍不清楚。因此，我们研究了NF-κ B B的活化状态围产期在小肠和新生大鼠模型的NEC。我们发现，肠道NF-κ B在出生时被强烈激活，在母鼠喂养的新生大鼠中，在一天内下调。相反，在应激动物中，NF-κ B在第1天和第2天都保持强烈活化，并且这伴随着第2天内源性NF-κ B抑制蛋白I κ B α和I κ B β水平的显著降低。为了确定NF-κ B活性升高在NEC肠损伤中的重要性，我们给予NEMO结合域（NBD）肽，该肽选择性抑制关键的上游I κ B激酶（IKK）。在该模型中，NBD而不是对照肽降低了死亡率和肠损伤，支持NEC中肠损伤由NF-κ B活性升高引起的假设。因此，我们的研究结果使我们得出结论，选择性NF-κ B抑制代表了NEC的一个有前途的治疗策略。
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-kappa B (NF-kappa B). It remains unknown, however, whether NF-kappa B mediates injury in neonatal NEC. We therefore examined the activation status of NF-kappa B perinatally in the small intestine and in a neonatal rat model of NEC. We found that intestinal NF-KB is strongly activated at birth and, in dam-fed newborn rats, is down-regulated within a day. In contrast, NF-kappa B 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-kappa B inhibitor protein I kappa B alpha and I kappa B beta at d 2. To determine the importance of elevated NF-kappa B activity in intestinal injury in NEC, we administered the NEMO-binding domain (NBD) peptide that selectively inhibits the critical upstream I kappa B 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-kappa B activity. Our findings therefore lead us to conclude that selective NF-kappa B inhibition represents a promising therapeutic strategy for NEC.