Gastrin-Releasing Peptide and Bronchopulmonary Dysplasia

描述（由申请人提供）：我们有强有力的证据表明，胃泌素释放肽（GRP），一种由肺神经内分泌细胞产生的神经肽，介导BPD的肺部炎症和重塑。在两个狒狒模型的BPD和人类早产儿，我们证明，GRP水平升高，出生后不久，只有在动物或婴儿发展BPD，但早在有临床或病理表现的BPD。BPD婴儿尿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，出生后早期的高GRP水平与长期慢性肺部疾病的风险增加有关。在模仿当前BPD病理学的早产狒狒高氧诱导的肺损伤模型中，在出生后早期阻断GRP导致后期肺部疾病的改善。GRP被高氧上调，这表明它可能是BPD和随后的肺部疾病发展的中心下游调节因子。根据我们的初步数据，我们提出以下假设：在BPD婴儿中，生命第一年的呼吸不良结果与持续升高的GRP水平直接相关。出生后GRP水平未能降低到正常成人水平，这是由于反应性氧（ROS）的产生增加，反映了环境暴露和宿主因素之间的相互作用。我们的具体目标是：目标1：确定出生后早期、月经后36周龄和出院后尿GRP水平升高是否与出生后第一年肺部疾病严重程度升高呈正相关。 目标二：确定活性氧（由尿F2-异前列烷代谢物、8-羟基-2 '-脱氧鸟苷、尿囊素升高指示）是否与GRP升高直接相关。

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.