Role of IL-18 and TNF-a in Necrotizing Enterocolitis

描述(申请人提供)：坏死性小肠结肠炎(NEC)是早产儿最常见的胃肠道疾病，每年在美国有3,000至4,000名婴儿患病。许多因素参与了NEC的发展，主要是早产、肠道喂养、肠道缺氧/缺血和细菌定植。尽管NEC的发病率和死亡率很高，但其病因和发病机制尚不清楚。我们实验室最近的一篇论文表明，患有严重NEC样损伤的新生大鼠回肠内存在戏剧性的内源性IL-18过量产生。在这项建议中，我们希望进一步阐明IL-18在NEC发病机制中的作用。 除了回肠的病理影响外，严重的NEC损伤通常伴随着多系统器官衰竭，包括肝功能衰竭。肝功能障碍通常与合成功能丧失、肝细胞坏死和炎性介质的释放有关，如肿瘤坏死因子-α。我们最近在我们的新生大鼠模型中证明了驻留在肝脏的巨噬细胞库普弗细胞(KC)中肿瘤坏死因子-α的上调与回肠疾病的严重程度相关。此外，我们还发现，当KC被抑制时，NEC动物肠腔内容物中增加的肿瘤坏死因子-α被减弱，并且KC的抑制与肠道损伤的减少有关。 这一建议的中心假设是IL-18和肿瘤坏死因子-α的过度产生在新生大鼠NEC的发生和发展中起着重要作用。我们将重点放在IL-18和TNF-α上，因为我们认为这些细胞因子在疾病发病机制中最有可能发挥重要作用。我们将通过以下两个具体目标来检验中心假说：1)确定促炎因子IL-18是否对NEC的发育至关重要；2)确定新生大鼠肝脏中促炎因子-α的产生和释放的伴随变化是否加剧了新生NEC的发育。 将使用独特且高度相关的NEC大鼠实验模型来完成拟议的研究。这些研究的结果应该澄清IL-18和/或肿瘤坏死因子-α是否在新生大鼠模型中NEC损伤的发生和发展中起关键作用。从这些研究中获得的数据将被用于确定在临床试验中进行抗IL-18或抗肿瘤坏死因子-α治疗的可行性。

DESCRIPTION (provided by applicant): Necrotizing enterocolitis (NEC) is the most common gastrointestinal disease of premature infants that afflicts 3,000 to 4,000 babies in the United States each year. Many factors contribute to the development of NEC, mainly prematurity, enteral feeding, intestinal hypoxia/ischemia, and bacterial colonization. Despite significant morbidity and mortality, the etiology and pathogenesis of NEC is poorly understood. A recent paper from our laboratory has demonstrated a dramatic endogenous overproduction of IL-18 in the ileum of neonatal rats with severe NEC-like injury. In this proposal, we want to further clarify the role of IL-18 during NEC pathogenesis. In addition to pathologic effects in the ileum, severe NEC injury is often followed by multisystem organ failure including hepatic failure. Hepatic dysfunction is frequently associated with loss of synthetic functions, hepatocellular necrosis, and release of inflammatory mediators, such as TNF-alpha. We recently demonstrated upregulation of TNF-alpha in Kupffer cells (KC), the resident hepatic macrophage, is correlated with ileal disease severity in our neonatal rat model. In addition, we have shown increased TNF-alpha in the luminal intestinal contents of animals with NEC is attenuated when KC are inhibited, and inhibition of KC is associated with decreased intestinal damage. The central hypothesis of this proposal is that overproduction of IL-18 and TNF-alpha play an essential role in the development and progression of NEC in newborn rats. We have focused on IL-18 and TNF-alpha because we believe these cytokines are the most likely to play a significant role in disease pathogenesis. We will test the central hypothesis with the following two specific aims: 1) determine if proinflammatory IL- 18 is essential for the development of NEC and 2) determine if the development of neonatal NEC is exacerbated by concomitant alterations in production and release of pro-inflammatory TNF-alpha in neonatal rat liver. The unique and highly relevant rat experimental model of NEC will be used to complete proposed research. Results from these studies should clarify if IL-18 and/or TNF-alpha are crucial for the development and progression NEC injury in the neonatal rat model. Data obtained from these studies will be used to determine the feasibility of pursuing anti-IL-18 or anti-TNF-alpha treatment in clinical trials.