Gastrin-Releasing Peptide and Bronchopulmonary Dysplasia

描述(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，我们证明只有在BPD发生的动物或婴儿出生后不久，尿中GRP水平才会升高，但BPD的临床或病理表现出现很长时间之前。BPD患儿尿GRP的升高与BPD患儿肺内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。在模仿目前BPD病理的早产儿高氧诱导的肺损伤模型中，在出生后早期阻断GRP可以改善后来的肺部疾病。GRP被高氧上调，提示它可能是BPD和随后的肺部疾病发生的中心下游调节因子。基于我们的初步数据，我们提出了以下假设：在BPD婴儿中，出生一年的不良呼吸结果与持续升高的GRP水平直接相关。由于反映环境暴露和宿主因素之间相互作用的活性氧物种(ROS)的产生增加，出生后GRP水平未能下降到正常成人水平。我们的具体目标是：目标1：确定出生后早期、月经后36周和出院后尿GRP水平升高是否与出生一年内肺部疾病严重程度的增加呈正相关。目的：探讨尿液中F2-异前列腺素代谢物、8-羟基-2‘-脱氧鸟苷、尿囊素升高所指示的活性氧是否与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.