Neuropeptides and chronic lung disease in newborns

（申请人的摘要）总体假设是蛙皮素样肽 (BLP)是支气管肺发育不良（BPD）肺损伤的早期介质。 患有BPD的人类婴儿的肺神经内分泌数量增加 细胞（PNEC）含有BLP。BLP升高可介导BPD肺损伤， 包括间质纤维化和反应性气道疾病。新数据 表明早产儿在出生后第2-5天尿BLP水平升高， 年龄的人患BPD的风险增加10倍，即使在所有其他因素正常化的情况下， 变量包括早产。尿BLP水平升高也会在短期内发生 出生后，在2个狒狒模型的BPD，其中BLP水平与 随后的慢性肺病（CLD）的严重程度。产后治疗， 抗BLP单克隆抗体2A 11在两种模型中都保护BPD。的 研究人员建议使用三个具体的假设来解决整个假设， 目标。在目标#1和#2中，他们将测试高氧新生儿 小鼠提供了有效的CLD模型，其与 人BPD。研究人员将确定BLP如何导致肺损伤 在小鼠模型中，以及肺内BLP是否触发特异性 促炎级联反应也是高氧CLD的特征。的 研究者将描述随时间推移的组织病理学变化，分析 PNEC、肥大细胞、嗜酸性粒细胞、纤维化和肺泡化，以及 尿BLP和血清类胰蛋白酶水平的动力学。他们将评估BLP阻塞 抗体（2A 11）作为小鼠模型中CLD的预防剂，和 评估哪些BLP受体可能参与介导高氧CLD 使用GRP-R、BRS-3和/或NMB-R缺陷的小鼠。#30033;的目标，将？ 与其他SCOR合作，探索BLP作为CLD调解人的作用 investigators.研究人员将分析与以下因素相关的临床因素： 早产儿尿BLP升高，并估计肥大细胞的相对数量 细胞和嗜酸性粒细胞与CLD婴儿的BLP水平相比。 最后，他们将比较基因改变的高氧CLD患者的病程， 血红素氧合酶-1，CRH， 多配体聚糖，或一组促炎分子，包括CCR 3，CXCR 3， NK-1 R和CD 10/NEP 24.11。这些研究将有助于阐明细胞和 BLP可能有助于病理生理学的分子机制 BPD，并促进新的预防性治疗的发展， 婴儿处于危险之中。

(Applicant's Abstract) The overall hypothesis is that bombesin-like peptide (BLP) is an early mediator of lung injury in bronchopulmonary dysplasia (BPD). Human infants with BPD have increased numbers of pulmonary neuroendocrine cells (PNECs) containing BLP. Elevated BLP could mediate lung injury in BPD, including interstitial fibrosis and reactive airways disease. The new data indicate that premature infants with elevated urine BLP levels at days 2-5 of age have a 10-fold increased risk of BPD, even when normalized for all other variables including prematurity. Elevated urine BLP levels also occur shortly after birth in 2 baboon models of BPD, in which BLP levels correlate with severity of subsequent chronic lung disease (CLD). Postnatal therapy with anti-BLP monoclonal antibody 2A11 protects against BPD in both models. The investigators propose to address the overall hypothesis using three Specific Aims. In Aims #1 and #2, they will test the hypotheses that hyperoxic newborn mice provide a valid model of CLD with similarity to specific features of human BPD. The investigators will determine how BLP contributes to lung injury in the murine model, and whether intratracheal BLP triggers specific pro-inflammatory cascades that also characterize hyperoxic CLD. The investigators will characterize histopathological changes over time, analyzing PNECs, mast cells, eosinophils, fibrosis, and alveolarization, and the kinetics of urine BLP and serum tryptase levels. They will assess BLP blocking antibody (2A11) as a prophylactic agent for CLD in the mouse model and evaluate which BLP receptors might be involved in mediating hyperoxic CLD using mice deficient in GRP-R, BRS-3, and/or NMB-R. In Aim #3, they will explore the role of BLP as a mediator of CLD in collaboration with other SCOR investigators. The investigators will analyze clinical factors associated with elevated urine BLP in premature infants, and estimate relative numbers of mast cells and eosinophils as compared to BLP levels in human infants with CLD. Finally, they will compare the course of hyperoxic CLD in genetically altered newborn mice with over-expression and/or deficiency of heme oxygenase-1, CRH, syndecans, or a panel of pro-inflammatory molecules including CCR3, CXCR3, NK-1R, and CDl0/NEP 24.11. These studies will help to clarify cellular and molecular mechanisms by which BLP could contribute to the pathophysiology of BPD, and facilitate the development of novel prophylactic treatments for infants at risk.