NEUROPEPTIDES IN LUNG DEVELOPMENT AND INJURY

我们的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。 在患有BPD的人类婴儿中，含有BLP的肺神经内分泌细胞（PNEC）数量增加。肺BLP和BLP受体mRNA水平通常在小管期达到峰值，在肺泡形成期间下降至低水平。 早产儿过多的BLP可增强BPD，介导支气管周围和间质纤维化，反应性气道疾病，并抑制肺泡化。 我们在2种不同的BPD狒狒模型中观察到出生后约48- 72小时尿BLP水平增加，BLP水平与随后的慢性肺病的严重程度相关。出生后用抗BLP单克隆抗体2A 11治疗在两种模型中保护免受BPD。我们将使用三个目的来解决我们的总体假设：目的1：确定2A 11在体内预防早产狒狒急性和慢性肺病的药理学机制和临床有用性。 假设1：2A 11在早期BPD期间通过阻断BLP的促炎作用发挥作用。 我们将在125 d/PRN模型中比较2A 11与不相关的鼠IgG对照MOPC 21。我们还将评估BLP受体拮抗剂。目的2：使用简化的体外肺泡化系统分析BLP和2A 11作用的细胞和药理学机制。假设2：（a）在囊状期早期BLP异常升高抑制肺泡化。(b)在此过程中BLP的关键靶细胞是间充质细胞，其改变介质的产生以变得抗血管生成。我们将表征由BLP诱导的成纤维细胞来源的能够调节肺泡化的mRNA。 目的3：与其他U10研究者合作，探讨BLP和/或PNEC作为其他BPD相关变化的介导者的作用。 假设三：BLP由氧化损伤诱导，并作为近端细胞因子，促进急性和慢性炎症与间质纤维化。 有效的抗氧化治疗应减少BLP分泌，从而改善临床结局。在资源允许的情况下，将考虑使用抗氧化剂和2A 11进行联合治疗。 这些方法将有助于阐明BPD的潜在病理生理学。拟议的调查将促进合理的改善治疗的基础上全面了解疾病的机制。

Our overall hypothesis is that bombesin-like peptide (BLP) is an early mediator of lung injury in bronchopulmonary dysplasia (BPD). Increased numbers of pulmonary neuroendocrine cells (PNECs) containing BLP occur in human infants with BPD. Pulmonary BLP and BLP receptor mRNA levels normally peak during the canalicular period, declining to low levels during alveolarization. Excessive BLP in preterm infants could potentiate BPD, mediating peribronchiolar and interstitial fibrosis, reactive airways disease, and inhibiting alveolarization. We observe increased urine BLP levels approximately 48-72h after birth in 2 distinct baboon models of BPD, with BLP levels correlating with severity of subsequent chronic lung disease. Postnatal treatment with anti-BLP monoclonal antibody 2A11 protects against BPD in both models. We will address our overall hypothesis using three Aims: AIM 1: To determine the pharmacological mechanisms and clinical usefulness of 2A11 for preventing acute and chronic lung disease in preterm baboons in vivo. Hypothesis number 1: 2A11 functions by blocking pro-inflammatory effects of BLP during early BPD. We will compare 2A11 to an irrelevant murine IgG control, MOPC21, in the 125d/PRN model. We will also evaluate a BLP receptor antagonist. AIM 2: To analyze cellular and pharmacological mechanisms of BLP and 2A11 effects using simplified in vitro alveolarization systems. Hypotheses number 2: (a) Abnormally elevated BLP during the early saccular period inhibits alveolarization. (b) Key target cells for BLP during this process are mesenchymal cells, which alter production of mediators to become anti-angiogenic. We will characterize fibroblast-derived mRNAs induced by BLP that are able to modulate alveolarization. AIM 3: To explore the role of BLP and/or PNECs as mediators of other BPD-associated changes, in collaboration with other U10 investigators. Hypothesis number 3: BLP is induced by oxidant injury and acts as a proximal cytokine, promoting acute and chronic inflammation with interstitial fibrosis. Effective anti-oxidant therapy should decrease BLP secretion, leading to improved clinical outcomes. Combined modality treatment with anti-oxidants together with 2A11 will be considered as resources permit. These approaches will be instrumental in clarifying the underlying pathophysiology of BPD. The proposed investigations will facilitate rational improvements in therapeutics based on a comprehensive understanding of disease mechanisms.