NEUROPEPTIDES IN LUNG DEVELOPMENT AND INJURY

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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.