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

描述（由申请人提供）：坏死性小肠结肠炎（NEC）是早产儿最常见的胃肠道疾病，在美国每年有3，000至4，000名婴儿患病。NEC的发生与多种因素有关，主要包括早产、肠道喂养、肠道缺氧/缺血和细菌定植。尽管有显著的发病率和死亡率，但NEC的病因和发病机制仍知之甚少。我们实验室最近的一篇论文已经证明了严重NEC样损伤的新生大鼠回肠中IL-18的显著内源性过量产生。在这个建议中，我们希望进一步阐明IL-18在NEC发病机制中的作用。 除了回肠中的病理学效应之外，严重NEC损伤通常随后是多系统器官衰竭，包括肝衰竭。肝功能障碍通常与合成功能丧失、肝细胞坏死和炎性介质（如TNF-α）释放相关。我们最近证实，在我们的新生大鼠模型中，库普弗细胞（KC）（肝巨噬细胞）中TNF-α的上调与回肠疾病的严重程度相关。此外，我们已经表明，当KC被抑制时，NEC动物肠腔内容物中TNF-α的增加被减弱，并且KC的抑制与肠损伤的减少有关。 该建议的中心假设是，IL-18和TNF-α的过度产生在新生大鼠NEC的发展和进展中起重要作用。我们关注IL-18和TNF-α，因为我们相信这些细胞因子最有可能在疾病发病机制中发挥重要作用。我们将用以下两个具体目的来检验中心假设：1）确定促炎性IL- 18是否对NEC的发展至关重要，和2）确定新生大鼠肝脏中促炎性TNF-α的产生和释放的伴随改变是否加剧新生NEC的发展。 NEC的独特和高度相关的大鼠实验模型将用于完成拟议的研究。 这些研究的结果应澄清IL-18和/或TNF-α是否对新生大鼠模型中NEC损伤的发展和进展至关重要。从这些研究中获得的数据将用于确定在临床试验中进行抗IL-18或抗TNF-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.