THE ROLE OF PAF IN NEONATAL-NECROTIZING ENTEROCOLITIS

点击翻译按钮获取中文摘要

Necrotizing enterocolitis (NEC) is a common gastrointestinal disease of premature infants without clearly defined etiology or treatment. Current theory suggests that many factors including hypoxia, bacterial colonization, feeding, and prematurity contribute to the development of disease, but the final common pathway associating the risk factors with the intestinal pathology remains unclear. Our previous studies have shown that the inflammatory mediator platelet activating factor (PAF) may be involved in the pathogenesis of bowel necrosis. The overall emphasis of this proposal is to investigate the importance of PAF and altered PAF metabolism in this disease, and to delineate specific mechanisms involved in the pathogenesis. We hypothesize that local intestinal PAF metabolism is altered in neonatal NEC, that PAF dysregulation leads to apoptosis of intestinal epithelium, disruption of tight junctional integrity, mucosal permeability, and activation of the secondary inflammatory cascade, and that this modulation is critical for the development of the disease. Therefore the specific aims of this proposal are: l) To elucidate the mechanisms of altered PAF metabolism and biological activity in the developing and injured intestine, and 2) To investigate the mechanisms of PAF-induced mucosal damage, and to delineate the underlying role of PAF-induced mucosal damage in NEC pathogenesis. To accomplish our goals, we have developed a neonatal rat model of NEC that mimics the human condition, and will study the effects of altered PAF metabolism on the development of intestinal nectosis, and on pathophysiologic events preceding the evolution of bowel injury. in addition, to identify the cellular and molecular level regulation of epithelial cell damage, we will use various tissue culture models of the intestinal epithelium. To elucidate specific mechanisms resulting in altered PAF regulation in the intestinal microenvironment we will evaluate if activation of local PAF production, decreased PAF degradation, or altered PAF- receptor expression and function results from typical NEC risk factors (formula feeding and asphyxia) or change during developmental maturation. in addition, we will evaluate the effect of altered PAF regulation on apoptosis and mucosal penneability, and clarify the roles of these factors in the initiation of NEC and the signal transduction mechanisms that lead to these events following PAF receptor activation. Results from these experiments should clarify key mechanisms linking the risk factors of NEC with the pathologic outcome, and may provide new strategies for the prevention of NEC in premature newborns.