Role of Transforming Growth Factor-beta in Neonatal Necrotizing Enterocolitis

描述(申请人提供)：坏死性小肠结肠炎(NEC)是一种获得性、危及生命的胃肠道疾病，影响5%-15%的出生体重低于1500克的新生儿，是这些患者的主要死亡原因。该病的特点是强烈的炎症反应、缺血性改变和坏死。尽管NEC的发病机制尚不清楚，但当粘膜损伤或通透性改变允许细菌移位到固有层，导致白细胞募集和组织破坏时，该疾病被认为是发生的。这种由细菌/细菌产物引起的不受限制的急性炎症模型与最近的观察结果不一致，即在成人中，由于基质细胞衍生因子(如转化生长因子-2)的作用，巨噬细胞等肠道细胞对细菌产物具有严重的“无能”。研究人员提供了初步数据，并提出了一个新的假设，即NEC几乎仅见于早产儿，因为由于转化生长因子-2的影响，粘膜对细菌产品的耐受性是发育调节的，因此在早产儿肠道中存在缺陷，并且增加转化生长因子-2的表达或生物活性可以预防/改善类似NEC的肠道损伤。这项应用旨在研究在发育中的肠道中增强转化生长因子-2活性的策略，以增强粘膜对细菌产品的耐受性。该研究有三个具体目的：1)确定特定细菌在新生儿肠粘膜的定植模式是否会影响肠道黏膜炎症通路的正常发育下调或影响对NEC样肠损伤的易感性；2)确定乳源性转化生长因子-22在预防NEC样肠损伤中的作用，以及新生儿肠内补充转化生长因子-22是否可以为预防NEC样肠损伤提供额外保护；以及3)确定在发育过程中上调生长因子-22的表达或激活是否可以保护发育中的肠道免受NEC样肠损伤的影响。该项目的长期目标是确定可以在未来的临床研究中测试的针对NEC的新的预防/治疗策略。公共卫生相关性：坏死性小肠结肠炎(NEC)是极早产儿发病率和死亡率的主要原因。在这一应用中，研究人员提出了一个新的假设，即NEC几乎只发生在早产儿中，因为这些婴儿对肠道细菌的正常耐受性尚未建立，并提出了三种不同的策略来纠正这一缺陷，这反过来可以帮助预防或治疗NEC。

DESCRIPTION (provided by applicant): Necrotizing enterocolitis (NEC) is an acquired, life-threatening gastrointestinal disease affecting 5-15% of neonates born weighing less than 1500 g and is a leading cause of death in these patients. The disease is characterized by an intense inflammatory response, ischemic changes, and necrosis. Although the etiopathogenesis of NEC is not well understood, the disease is believed to occur when mucosal injury or altered permeability allows bacterial translocation into the lamina propria, causing leukocyte recruitment and tissue destruction. This model of unrestricted acute inflammation due to bacteria/bacterial products is inconsistent with recent observations that in the adult, intestinal cells such as macrophages are profoundly `anergic' to bacterial products due to the effect of stromal cell-derived factors such as transforming growth factor (TGF)-2. The investigators present preliminary data and propose a novel hypothesis that NEC is seen almost exclusively in the premature infant because mucosal tolerance to bacterial products, which is due to the effects of TGF-2, is developmentally regulated and therefore deficient in the preterm intestine, and that augmentation of TGF-2 expression or bioactivity can prevent/ameliorate NEC-like intestinal injury. This application is designed to investigate strategies to augment TGF-2 activity in the developing intestine in order to enhance mucosal tolerance to bacterial products. There are three specific aims: 1) to determine whether specific patterns of bacterial colonization of the neonatal intestinal mucosa affect the normal developmental downregulation of inflammatory pathways in the intestinal mucosa or influence susceptibility to NEC-like intestinal injury; 2) to determine the role of milk-borne TGF-22 in protection against NEC-like intestinal injury, and whether enteral supplementation of TGF-22 in the neonate can provide additional protection against NEC-like intestinal injury; and 3) to determine whether pharmacological upregulation of TGF-22 expression or activation in the developing intestine can protect against NEC-like intestinal injury. The long-term goals of this project are to identify newer preventive/therapeutic strategies against NEC that can be tested in future clinical studies. PUBLIC HEALTH RELEVANCE: Necrotizing enterocolitis (NEC) is a major cause of morbidity and mortality in extremely premature infants. In this application, the investigators present a novel hypothesis that NEC occurs almost exclusively in premature infants because normal tolerance to gut bacteria is not yet established in these infants and propose three different strategies to correct this deficiency, which can, in turn, help prevent or treat NEC.