Neuropeptides and chronic lung disease in newborns

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(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.