PATHOGENESIS OF NEONATAL NECROTIZING ENTEROCOLITIS

点击翻译按钮获取中文摘要

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.