NEUROPEPTIDES IN LUNG DEVELOPMENT AND INJURY

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 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。BPD患儿肺内含有BLP的神经内分泌细胞(PNECs)数量增加。肺BLP和BLP受体的mRNA水平通常在肺小管期达到峰值，在肺泡化过程中下降到低水平。早产儿过多的BLP可加重BPD，介导细支气管周围和间质纤维化，反应性呼吸道疾病，并抑制肺泡化。我们观察到两种不同的BPD狒狒模型出生后大约48-72小时尿BLP水平升高，BLP水平与随后慢性肺部疾病的严重程度相关。出生后用抗BLP单抗2A11对两种模型的BPD均有保护作用。我们将通过三个目标来解决我们的总体假设：目标1：确定2A11在活体内预防早产儿急性和慢性肺部疾病的药理机制和临床用途。假设1：2A11在BPD早期通过阻断BLP的促炎作用发挥作用。我们还将评估BLP受体拮抗剂。目的：利用简化的体外肺泡化系统分析BLP和2A11作用的细胞和药理机制。假设2：(A)球囊早期异常升高的BLP抑制肺泡化。(B)在这一过程中，BLP的关键靶细胞是间充质细胞，它会改变介质的产生，从而成为抗血管生成的细胞。我们将鉴定BLP包含的能够调节肺泡化的成纤维细胞来源的mRNAs。目的3：与其他U10研究人员合作，探讨BLP和/或PNEC作为其他BPD相关变化的中介细胞的作用。假设3：BLP由氧化损伤诱导，作为近端细胞因子，促进急性和慢性炎症和间质纤维化。有效的抗氧化剂治疗应该减少BLP的分泌，从而改善临床结果。在资源允许的情况下，将考虑使用抗氧化剂和2A11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。拟议的调查将有助于在全面了解疾病机制的基础上合理改进治疗方法。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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 peribrochiolar 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 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 included 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 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 improvement in therapeutics based on comprehensive understanding of disease mechanisms.