EGF IN NEONATAL NECROTIZING ENTEROCOLITIS

新生儿坏死性小肠结肠炎（NEC）是早产儿最常见的胃肠道（GI）疾病，其发病率和死亡率都很高，在美国每年有3000至4000名婴儿受到这种疾病的折磨。导致NEC发生的因素很多，主要有早产、肠内喂养、感染性病原体和/或肠道缺氧缺血。肠内喂养几乎总是NEC发生的先决条件。然而，NEC发病的确切机制尚不清楚。在人类中，对926名新生儿进行的多中心试验表明，与母乳喂养的婴儿相比，配方奶粉喂养的婴儿患NEC的几率要高6-10倍。在动物实验中，母乳也能预防NEC。这些发现激发了人们对牛奶中预防NEC的各种成分的研究。表皮生长因子（EGF）是治疗NEC最有前途的候选药物之一。许多哺乳动物的乳汁都含有高浓度的表皮生长因子。此外，母乳是哺乳期新生儿EGF的主要来源。相比之下，EGF在所有商业婴儿配方奶粉中都不存在。EGF促进胃肠道上皮损伤愈合。另一个与EGF密切相关的肽是转化生长因子- α (tgf - α)。tgf - α是EGF相关肽家族的一员，与EGF具有显著的氨基酸序列同源性，具有相似的生物学效应，并且与同一受体EGF-受体（EGF- r）具有高亲和力。EGF和tgf - α都存在于新生儿胃肠道中，它们对胃肠道上皮愈合过程的直接影响已得到证实。由于大多数哺乳动物的乳汁中不存在tgf - α，因此新生儿肠道中TGF-a的主要来源是肠道内源性产生和胰腺分泌。最近，我们已经证明乳源性EGF调节新生大鼠肠道tgf - α合成。我们的长期目标是了解乳源性生物活性物质在NEC发病机制中的作用。该提案的中心假设是EGF将阻止新生大鼠NEC的发展。乳鼠是研究NEC病因的最佳实验模型之一。我们的实验室有多年的人工饲养哺乳大鼠的经验，因此我们有很好的条件来追求这一假设。目前，还没有有效的治疗方法来预防NEC的发生。该建议的基本原理是，在开发坏死性小肠结肠炎的适当治疗之前，必须了解EGF在分子和细胞病理水平上对新生儿的影响。具体目的：我将验证乳源性EGF将阻止哺乳大鼠NEC发展的假设。特异性目的II将检验肠外给药EGF将预防NEC和促进NEC愈合的假设。特异性Aim III将验证外源性EGF治疗NEC会上调NEC乳鼠肠道中EGF受体和tgf - α的表达的假设。

Neonatal necrotizing enterocolitis (NEC) is the most common gastrointestinal (GI) disease of premature infants with excessive morbidity and mortality 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, infectious agents and/or intestinal hypoxia-ischemia Enteral feeding is nearly always a prerequisite for the development of NEC. However, the exact mechanism of NEC pathogenesis is poorly understood. In humans, multicenter trials with 926 neonates have shown that NEC is 6-10 times more common in formula-fed infants compared to those fed with human milk. In animal experiments, maternal milk also prevents NEC. These findings have stimulated the search for various components of milk that protects against NEC. Epidermal growth factor (EGF) is one of the most promising candidates for the treatment of NEC. Mammalian milk of many species contains high concentrations of EGF. Moreover, maternal milk is the major source of EGF for neonates during the suckling period. In contrast, EGF is absent in all commercial infant formulas. EGF accelerates healing of injured gastrointestinal epithelium. Another peptide closely related to EGF is transforming growth factor-alpha (TGF-alpha). TGF-alpha is a member of the family of EGF-related peptides, sharing with EGF significant amino acid sequence homology, similar biological effects, and high affinity to the same receptor - EGF- receptor (EGF-R). Both EGF and TGF-alpha are presented in the neonatal gastrointestinal tract and their direct effects on healing processes in the gastrointestinal epithelium are well established. Since TGF-alpha is absent in the milk of most mammals, the major source of intestinal TGF-a in neonates is intestinal endogenous production and pancreatic secretion. Recently, we have shown that milk-borne EGF modulates intestinal TGF-alpha synthesis in neonatal rats. Our long-term goal is to understand the role of milk-borne biologically active substances in the pathogenesis of NEC. The central hypothesis of this proposal is that EGF will prevent the development of NEC in newborn rats. One of the best experimental models to study the etiology of NEC are suckling rats. Our laboratory has many years of experience with artificial rearing of suckling rats and therefore we are well positioned to pursue this hypothesis. Currently, there is no efficient treatment to prevent the incidence of NEC. The rationale of this proposal is that the effect of EGF on neonates at the molecular and cellular pathology level must be understood before an adequate therapy of necrotizing enterocolitis can be developed Specific Aim I will test the hypothesis that milk-borne EGF will prevent the development of NEC in suckling rats. Specific Aim II will test the hypothesis that parenteral administration of EGF will prevent NEC and improve healing of NEC in suckling rats. Specific Aim III will test the hypothesis that the treatment of NEC with exogenous EGF will upregulate intestinal expression of EGF receptor and TGF-alpha in suckling rats with NEC.