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，发病率和死亡率过高，每年困扰美国3000至4000名婴儿。NEC的发展受多种因素的影响，主要包括早产、肠道喂养、感染性因素和/或肠道缺氧--缺血肠道喂养几乎总是NEC发展的先决条件。然而，NEC的确切发病机制尚不清楚。在人类身上，对926名新生儿进行的多中心试验表明，配方奶喂养的婴儿中NEC的发病率是母乳喂养婴儿的6-10倍。在动物实验中，母乳也可以预防NEC。这些发现刺激了人们对牛奶中防止NEC的各种成分的研究。表皮生长因子(EGF)是治疗NEC最有前景的候选药物之一。许多种类的哺乳动物的牛奶中都含有高浓度的EGF。此外，母乳是新生儿哺乳期表皮生长因子的主要来源。相比之下，EGF在所有商业婴儿配方奶粉中都不存在。EGF可促进受损胃肠上皮的愈合。另一种与EGF密切相关的多肽是转化生长因子-α(TGF-α)。转化生长因子-α是EGF相关多肽家族的一员，与EGF具有显著的氨基酸序列同源性、相似的生物学效应以及与同一受体--EGF-受体(EGF-R)的高亲和力。表皮生长因子和转化生长因子-α都存在于新生儿的胃肠道中，它们对胃肠道上皮愈合过程的直接作用已经得到证实。由于大多数哺乳动物的乳汁中不存在转化生长因子-α，新生儿肠道转化生长因子-α的主要来源是肠道内源性产物和胰腺分泌。最近，我们发现乳源性EGF对新生大鼠肠道转化生长因子-α的合成有调节作用。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。这一建议的中心假设是，EGF将阻止新生大鼠NEC的发展。乳鼠是研究NEC病因学的最佳实验模型之一。我们的实验室在人工饲养哺乳大鼠方面有多年的经验，因此我们处于有利地位来研究这一假说。目前，还没有有效的治疗方法来预防NEC的发生。这一建议的基本原理是，必须在分子和细胞病理水平上了解EGF对新生儿的影响，然后才能开发出适当的坏死性小肠结肠炎的治疗方法。《特定目的II》将验证这样一种假说，即非肠道注射EGF可以预防乳鼠NEC并促进NEC的愈合。特定目的III将验证外源性EGF治疗NEC将上调NEC乳鼠肠道EGF受体和转化生长因子-α表达的假说。

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.