PATHOGENESIS OF NEONATAL NECROTIZING ENTEROCOLITIS

描述(改编自调查员的摘要和/或目标)： 第一个奖项申请的总体目标是测试 假设细菌在体内的定植和黏附模式 肠道在决定新生儿是否患上NEC方面起着重要作用。这个 拟议的工作是以下观察结果的延伸 申请人：1)地方性NEC不能归因于单一的 致病因子，2)分离的大肠杆菌(E.coli)菌株 NEC病例和控制措施高度遵守 体外和体内的肠上皮细胞也会引起细胞损伤， 3)阻断了细菌引起的黏附和细胞损伤。 通过与来自对照的选定肠球菌菌株混合感染 而来自NEC病例的肠球菌则没有这种作用。在这 应用，建议研究以确定什么机制是 对大肠杆菌测试菌株与肠道的粘附性负责 上皮细胞。针对大肠杆菌AS表面特异性黏附的抗血清 以及该菌株的非粘附性同源突变株将被用于 定义允许细菌黏附到 肠道细胞与不同环境因素的影响 与NEC有关的细菌粘附性。另一系列实验 将试图确定对照婴儿的肠球菌是如何阻止 大肠埃希菌对肠上皮细胞的粘附性。的第三个组成部分 这个项目的重点是宿主对细菌--上皮细胞的反应 粘连，特别注意肿瘤坏死的变化 贴壁细菌所产生的肿瘤坏死因子(TNF)。最后，研究将是 以确定是否有抗炎药，如 超氧化物歧化酶、米索前列醇和地塞米松可减弱 细菌附着引起的组织坏死。

DESCRIPTION (adapted from investigator's abstract and/or aims): The overall objective of this FIRST award application is to test the hypothesis that patterns of bacterial colonization and adherence in the bowel play a role in determining whether newborns develop NEC. The proposed work represents an extension of the following observations by the applicant: 1) endemic NEC cannot be attributed to a single infectious agent, 2) Escherichia coli (E. coli) strains isolated from NEC cases and controls that exhibit a high degree of adherence to intestinal epithelia in-vitro and in-vivo also cause cell injury, and 3) the adherence and cell injury elicited by these bacteria are blocked by co-infection with selected strains of Enterococci from control infants while Enterococci from NEC cases had no such effect. In this application, studies are proposed to determine what mechanisms are responsible for the adherence of the E. coli test strain to intestinal epithelia. Antisera directed against specific adhesions on E. coli as well as non-adherent isogeneic mutants of the strain will be used to define the adhesion molecule that allows for bacterial adherence to intestinal cells and the influence of different environmental factors relevant to NEC on bacterial adherence. Another series of experiments will attempt to determine how Enterococci from control infants block the adherence of E. coli to intestinal epithelia. The third component of this project will focus on host responses to bacteria-epithelial cell adhesion, with particular attention devoted to changes in tumor necrosis factor (TNF) elicited by adherent bacteria. Finally, studies will be performed to determine whether anti-inflammatory agents such as superoxide dismutase (SOD), misoprostol, and dexamethasone attenuate the tissue necrosis caused by adherent bacteria.