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BPD的狒狒模型和早产儿中，我们证明了只有在BPD的动物或婴儿出生后不久尿液中GRP水平升高，但早在BPD的临床或病理表现出现之前。BPD婴儿尿液中GRP的增加与BPD婴儿肺部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，产后早期高GRP水平与长期慢性肺部疾病的风险增加有关。在模拟当前BPD病理的早产狒狒高氧诱导肺损伤模型中，在产后早期阻断GRP可改善后期肺部疾病。高氧可上调GRP，这表明它可能是BPD及随后肺部疾病发展的中心下游调节因子。基于我们的初步数据，我们提出以下假设：在BPD婴儿中，生命第一年的不良呼吸结果与持续升高的GRP水平直接相关。由于活性氧（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，产后GRP水平不能降低到正常的成人水平。我们的具体目的是：目的1：确定产后早期、经后36周和出院后尿GRP水平升高是否与出生后第一年肺部疾病严重程度增加呈正相关。目的2：确定活性氧（以尿f2 -异前列腺素代谢物、8-羟基-2′-脱氧鸟苷、尿囊素升高为指标）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.