THE ROLE OF PAF IN NEONATAL-NECROTIZING ENTEROCOLITIS

PAF 在新生儿坏死性小肠结肠炎中的作用

• 批准号: 6521184
• 负责人: MICHAEL S CAPLAN
• 金额: $ 27万
• 依托单位: NORTHSHORE UNIVERSITY HEALTHSYSTEM
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-01 至 2004-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6521184
• 关键词: apoptosis; colitis; cytokine receptors; disease /disorder model; intestinal mucosa; laboratory rat; membrane permeability; necrosis; newborn animals; platelet activating factor; receptor expression

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.

坏死性小肠结肠炎（NEC）是没有明确定义的病因或治疗的早产婴儿的常见胃肠道疾病。目前的理论表明，许多因素包括缺氧，细菌定殖，喂养和早产有助于疾病的发展，但是将风险因素与肠道病理相关的最终共同途径尚不清楚。我们先前的研究表明，炎症介质血小板激活因子（PAF）可能与肠坏死的发病机理有关。该提议的总体重点是研究PAF和PAF代谢在该疾病中的重要性，并描述发病机理中涉及的特定机制。我们假设在新生儿NEC中改变了局部肠道PAF代谢，PAF失调会导致肠上皮上皮细胞的凋亡，紧密连接性完整性的破坏，粘膜渗透率的破坏以及次生炎症级联的激活以及这种调节对疾病的发展至关重要。因此，该提案的具体目的是：l）阐明发育中和受伤的肠道中PAF代谢和生物学活性改变的机制，以及2）研究PAF诱导的粘膜损伤的机制，并描述NEC病原体中PAF诱导的粘膜损害的潜在作用。为了实现我们的目标，我们开发了一种模仿人类状况的NEC的新生大鼠模型，并将研究改变PAF代谢对肠道损伤进化之前的病理生理事件的改变的影响。此外，为了确定上皮细胞损伤的细胞和分子水平调节，我们将使用肠上皮的各种组织培养模型。为了阐明导致肠道微环境中PAF调节改变的特定机制，我们将评估局部PAF产生的激活，降低PAF降解或PAF受体表达和功能是否改变了典型的NEC危险因素（公式喂养和沥青喂养）或在发育成熟过程中的变化导致的。此外，我们将评估PAF调节改变对凋亡和粘膜分解性的影响，并阐明这些因素在NEC启动中的作用以及导致PAF受体激活后这些事件的信号转导机制。这些实验的结果应阐明将NEC的危险因素与病理学结果联系起来的关键机制，并可能为预防早产新生儿中NEC的新策略提供新的策略。