Gastrin-Releasing Peptide and Bronchopulmonary Dysplasia

胃泌素释放肽与支气管肺发育不良

• 批准号: 8187308
• 负责人: CHARLES Michael COTTEN
• 金额: $ 47.85万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8187308
• 关键词: 8-hydroxy-2' -deoxyguanosine; Adult; Age; Allantoin; Animal Model; Animals; Antioxidants; Biological; Biological Markers; Birth; Birth Weight; Bronchopulmonary Dysplasia; Childhood; Chronic; Chronic lung disease; Clinical; Data; Development; Environmental Exposure; Epidemiologic Studies; F2-Isoprostanes; Gastrin releasing peptide; Gestational Age; Histologic; Hyperoxia; Individual Differences; Infant; Integration Host Factors; Intervention; Life; Lung; Lung Inflammation; Lung diseases; Mediating; Mediator of activation protein; Messenger RNA; Modeling; Morbidity - disease rate; Neuroendocrine Cell; Neuropeptides; Organ; Outcome; Oxidative Stress; Papio; Pathogenesis; Pathology; Perinatal; Play; Predisposition; Premature Infant; Prevalence; Production; Proteins; Pulmonary function tests; Reactive Oxygen Species; Recruitment Activity; Risk; Risk Factors; Role; Sampling; Severities; Structure of parenchyma of lung; Testing; Translating; Urine; base; disorder risk; improved; insight; lung injury; postnatal; premature; prenatal; respiratory; response; therapeutic target; urinary

DESCRIPTION (provided by applicant): We have strong evidence that Gastrin-Releasing Peptide (GRP), a neuropeptide produced by pulmonary neuroendocrine cells, mediates lung inflammation and remodeling in BPD. In two baboon models of BPD and in premature human infants, we demonstrated that GRP levels are elevated in urine shortly after birth only in animals or infants that develop BPD, but long before there are clinical or pathological manifestations of BPD. The increase in urine GRP in BPD infants correlates with histologic evidence of increased numbers of GRP- positive neuroendocrine cells in the lungs of infants with BPD. Importantly, high GRP levels during the early postnatal period are associated with an increased risk of long-term chronic lung disease. In the premature baboon hyperoxia-induced lung injury model that mimics current BPD pathology, blockade of GRP early in the postnatal period results in amelioration of later lung disease. GRP is upregulated by hyperoxia suggesting that it may be a central downstream regulator for the development of BPD and subsequent lung disease. Based on our preliminary data, we propose the following hypothesis: In BPD infants, poor respiratory outcomes in the first year of life are directly related to sustained, elevated GRP levels. Postnatal GRP levels fail to decrease to normal adult levels due to an increased production of reactive oxygen species (ROS) that reflect the interaction between environmental exposures and host factors. Our Specific Aims are: Aim 1: To determine whether increased urinary GRP levels in the early postnatal period, at 36 weeks post-menstrual age, and post-discharge positively correlate with increased severity of lung disease during the first year of life. Aim 2: To determine whether reactive oxygen species (indicated by elevated urinary F2-isoprostane metabolites, 8-hydroxy-2'-deoxyguanosine, allantoin) directly correlate with increased GRP. PUBLIC HEALTH RELEVANCE: Bronchopulmonary dysplasia (BPD) among preterm infants is the major cause of chronic lung disease in infants. Our project will test whether increased production of gastrin-releasing peptide, a protein made in the lungs of premature infants, increases the prevalence and severity of chronic lung disease during childhood.

描述（由申请人提供）：我们有强有力的证据表明，胃蛋白释放肽（GRP）是由肺神经内分泌细胞产生的神经肽，可介导BPD中的肺部炎症和重塑。在BPD的两种狒狒模型和早产婴儿中，我们证明了仅在出生后不久出生后尿液中的GRP水平升高，但在患有BPD的动物或婴儿中，尿液的水平升高，但早在BPD的临床或病理表现之前很久。 BPD婴儿尿液GRP的增加与BPD婴儿肺中GRP-阳性神经内分泌细胞数量增加的组织学证据相关。重要的是，产后早期的GRP水平高与长期慢性肺部疾病的风险增加有关。在早产狒狒高氧引起的肺损伤模型中，模仿当前的BPD病理学，在产后期初对GRP的封锁导致后来的肺部疾病改善。 GRP被高氧上调，表明它可能是BPD发展和随后肺部疾病的中心下游调节剂。根据我们的初步数据，我们提出了以下假设：在BPD婴儿中，生命第一年的呼吸不良结果与持续的，升高的GRP水平直接相关。由于反映环境暴露与宿主因素之间相互作用的活性氧（ROS）的产生增加，产后GRP水平无法降低到正常的成人水平。我们的具体目的是：目标1：确定产后早期，月经后36周的尿中GRP水平是否升高，并在生命的第一年中与肺部疾病的严重程度增加正相关。 目的2：确定活性氧（用尿液F2-异丙烷代谢产物，8-羟基-2'-脱氧鸟苷，Allantoin，Allantoin表示）是否与GRP直接相关。 公共卫生相关性：早产儿中的支气管肺发育不良（BPD）是婴儿慢性肺部疾病的主要原因。我们的项目将测试增加胃蛋白释放肽的产生是早产婴儿肺部生产的蛋白质，会增加儿童期慢性肺部疾病的患病率和严重程度。