We have strong evidence that Gastrin-Releasing Peptide (GRP), a neuropeptide produced by pulmonary neuroendocrine cells, mediates lung inflammation and remodeling in BPD. In two baboon models of BPD and in premature human infants, we demonstrated that GRP levels are elevated in urine shortly after birth only in animals or infants that develop BPD, but long before there are clinical or pathological manifestations of BPD. The increase in urine GRP in BPD infants correlates with histologic evidence of increased numbers of GRP- positive neuroendocrine cells in the lungs of infants with BPD. Importantly, high GRP levels during the early postnatal period are associated with an increased risk of long-term chronic lung disease. In the premature baboon hyperoxia-induced lung injury model that mimics current BPD pathology, blockade of GRP early in the postnatal period results in amelioration of later lung disease. GRP is upregulated by hyperoxia suggesting that it may be a central downstream regulator for the development of BPD and subsequent lung disease. Based on our preliminary data, we propose the following hypothesis: In BPD infants, poor respiratory outcomes in the first year of life are directly related to sustained, elevated GRP levels. Postnatal GRP levels fail to decrease to normal adult levels due to an increased production of reactive oxygen species (ROS) that reflect the interaction between environmental exposures and host factors.
Our Specific Aims are:
Aim 1 : To determine whether increased urinary GRP levels in the early postnatal period, at 36 weeks post-menstrual age, and post-discharge positively correlate with increased severity of lung disease during the first year of life.
Aim 2 : To determine whether reactive oxygen species (indicated by elevated urinary F2-isoprostane metabolites, 8-hydroxy-2'-deoxyguanosine, allantoin) directly correlate with increased GRP.
Bronchopulmonary dysplasia (BPD) among preterm infants is the major cause of chronic lung disease in infants. Our project will test whether increased production of gastrin-releasing peptide, a protein made in the lungs of premature infants, increases the prevalence and severity of chronic lung disease during childhood.
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