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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Infectious Diseases, Reproductive Health, Asthma and Pulmonary Conditions Study Section (IRAP)
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Blaisdell, Carol J
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Duke University
Schools of Medicine
United States
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Blaisdell, Carol J; Troendle, James; Zajicek, Anne et al. (2018) Acute Responses to Diuretic Therapy in Extremely Low Gestational Age Newborns: Results from the Prematurity and Respiratory Outcomes Program Cohort Study. J Pediatr 197:42-47.e1
Hamvas, Aaron; Feng, Rui; Bi, Yingtao et al. (2018) Exome sequencing identifies gene variants and networks associated with extreme respiratory outcomes following preterm birth. BMC Genet 19:94
Keller, Roberta L; Feng, Rui; DeMauro, Sara B et al. (2017) Bronchopulmonary Dysplasia and Perinatal Characteristics Predict 1-Year Respiratory Outcomes in Newborns Born at Extremely Low Gestational Age: A Prospective Cohort Study. J Pediatr 187:89-97.e3
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Edwards, Laura; DeMeo, Stephen; Hornik, Chi D et al. (2016) Gabapentin Use in the Neonatal Intensive Care Unit. J Pediatr 169:310-2
Ahlfeld, Shawn K; Davis, Stephanie D; Kelley, Katherine J et al. (2016) Early Elevation of Plasma Periostin Is Associated with Chronic Ventilator-Dependent Bronchopulmonary Dysplasia. Am J Respir Crit Care Med 194:1430-1433
Maitre, Nathalie L; Ballard, Roberta A; Ellenberg, Jonas H et al. (2015) Respiratory consequences of prematurity: evolution of a diagnosis and development of a comprehensive approach. J Perinatol 35:313-321
Pryhuber, Gloria S; Maitre, Nathalie L; Ballard, Roberta A et al. (2015) Prematurity and respiratory outcomes program (PROP): study protocol of a prospective multicenter study of respiratory outcomes of preterm infants in the United States. BMC Pediatr 15:37
Poindexter, Brenda B; Feng, Rui; Schmidt, Barbara et al. (2015) Comparisons and Limitations of Current Definitions of Bronchopulmonary Dysplasia for the Prematurity and Respiratory Outcomes Program. Ann Am Thorac Soc 12:1822-30

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