Bronchopulmonary dysplasia (BPD) is the chronic lung disease that follows mechanical ventilation and oxygen therapy for respiratory failure in premature newborns. Characterized by dysmorphic lung vascular growth and decreased alveolarization, BPD is a complex disease with interactions between genetic and environmental factors contributing to its pathobiology. Clinical studies strongly support a genetic basis for BPD, but genetic risk factors that contribute to the pathogenesis or severity of BPD are unknown. Over the past several years, our lab and others have implicated a critical role for impaired angiogenesis in the pathogenesis of BPD. Vascular endothelial growth factor (VEGF) is a potent endothelial cell mitogen and survival factor that stimulates lung angiogenesis and maintains vascular function. VEGF stimulates angiogenesis through upregulation of endothelial nitric oxide synthase (eNOS), which increases nitric oxide (NO) production. Experimental models of BPD in several species have shown that impaired VEGF signaling, decreased eNOS gene expression, and decreased NO bioavailability due to high oxidant stress increase susceptibility of the developing lung for pulmonary hypertension, impaired angiogenesis and reduced alveolarization. Clinically, reduced lung VEGF expression has been found in infants dying with BPD and pulmonary vascular disease. Inhaled NO therapy enhances alveolar and vascular growth and lowers pulmonary vascular resistance in animal models of BPD, further suggesting that reduced NO production or bioavailability may contribute to chronic lung disease in premature newborns. Additional laboratory studies have further demonstrated critical interactions between VEGF-NO signaling and other angiogenic molecules, including the angiopoietin-Tie 2 system, endothelin-1, and prostacyclin, and circulating endothelial progenitor cells (EPCs) in lung growth and structure. Based on these findings, we hypothesize that early pulmonary vascular disease contributes to the incidence and severity of BPD, and that genetic variations that impair the VEGF-NO pathways and angiogenic signaling, including circulating EPCs, increase the susceptibility of premature newborns for the development of BPD. In these studies, we will carefully characterize the clinical phenotype and subtypes of BPD through precise determination of oxygen requirement, early morbidities and serial echocardiograms. Using the quantitative phenotype, we will employ a combined population based and family based association test (involving the collection of DNA from mother, father, and affected child trios), utilizing DNA from subjects enrolled into a prospective study of premature newborns at the University of Colorado and Indiana University who are at high risk for developing BPD. Project Narrative: Bronchopulmonary dysplasia (BPD) is the chronic lung disease that follows mechanical ventilation and oxygen therapy for respiratory failure in premature newborns. Characterized by dysmorphic lung vascular growth and decreased alveolarization, BPD is a complex disease with interactions between genetic and environmental factors contributing to its pathobiology. Clinical studies strongly support a genetic basis for BPD, but genetic risk factors that contribute to the pathogenesis or severity of BPD are unknown. Over the past several years, our lab and others have implicated a critical role for impaired angiogenesis in the pathogenesis of BPD. Vascular endothelial growth factor (VEGF) is a potent endothelial cell mitogen and survival factor that stimulates lung angiogenesis and maintains vascular function. VEGF stimulates angiogenesis through upregulation of endothelial nitric oxide synthase (eNOS), which increases nitric oxide (NO) production. Experimental models of BPD in several species have shown that impaired VEGF signaling, decreased eNOS gene expression, and decreased NO bioavailability due to high oxidant stress increase susceptibility of the developing lung for pulmonary hypertension, impaired angiogenesis and reduced alveolarization. Clinically, reduced lung VEGF expression has been found in infants dying with BPD and pulmonary vascular disease. Inhaled NO therapy enhances alveolar and vascular growth and lowers pulmonary vascular resistance in animal models of BPD, further suggesting that reduced NO production or bioavailability may contribute to chronic lung disease in premature newborns. Additional laboratory studies have further demonstrated critical interactions between VEGF-NO signaling and other angiogenic molecules, including the angiopoietin-Tie 2 system, endothelin-1, and prostacyclin, and circulating endothelial progenitor cells (EPCs) in lung growth and structure. Based on these findings, we hypothesize that early pulmonary vascular disease contributes to the incidence and severity of BPD, and that genetic variations that impair the VEGF-NO pathways and angiogenic signaling, including circulating EPCs, increase the susceptibility of premature newborns for the development of BPD. In these studies, we will carefully characterize the clinical phenotype and subtypes of BPD through precise determination of oxygen requirement, early morbidities and serial echocardiograms. Using the quantitative phenotype, we will employ a combined population based and family based association test (involving the collection of DNA from mother, father, and affected child trios), utilizing DNA from subjects enrolled into a prospective study of premature newborns at the University of Colorado and Indiana University who are at high risk for developing BPD.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL085703-05
Application #
8242049
Study Section
Special Emphasis Panel (ZRG1-RES-B (03))
Program Officer
Blaisdell, Carol J
Project Start
2008-04-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2012
Total Cost
$634,578
Indirect Cost
$112,621
Name
University of Colorado Denver
Department
Pediatrics
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Abman, Steven H; Conway, Simon J (2014) Developmental determinants and changing patterns of respiratory outcomes after preterm birth. Birth Defects Res A Clin Mol Teratol 100:127-33
Galambos, Csaba; Sims-Lucas, Sunder; Abman, Steven H (2014) Three-dimensional reconstruction identifies misaligned pulmonary veins as intrapulmonary shunt vessels in alveolar capillary dysplasia. J Pediatr 164:192-5
Mourani, Peter M; Kinsella, John P; Clermont, Gilles et al. (2014) Intensive care unit readmission during childhood after preterm birth with respiratory failure. J Pediatr 164:749-755.e3
Gadhia, Monika M; Cutter, Gary R; Abman, Steven H et al. (2014) Effects of early inhaled nitric oxide therapy and vitamin A supplementation on the risk for bronchopulmonary dysplasia in premature newborns with respiratory failure. J Pediatr 164:744-8
Mourani, Peter M; Abman, Steven H (2013) Pulmonary vascular disease in bronchopulmonary dysplasia: pulmonary hypertension and beyond. Curr Opin Pediatr 25:329-37
Galambos, Csaba; Sims-Lucas, Sunder; Abman, Steven H (2013) Histologic evidence of intrapulmonary anastomoses by three-dimensional reconstruction in severe bronchopulmonary dysplasia. Ann Am Thorac Soc 10:474-81
Baker, Christopher D; Black, Claudine P; Ryan, Sharon L et al. (2013) Cord blood endothelial colony-forming cells from newborns with congenital diaphragmatic hernia. J Pediatr 163:905-7
Delaney, Cassidy; Gien, Jason; Roe, Gates et al. (2013) Serotonin contributes to high pulmonary vascular tone in a sheep model of persistent pulmonary hypertension of the newborn. Am J Physiol Lung Cell Mol Physiol 304:L894-901
Baker, Christopher D; Seedorf, Gregory J; Wisniewski, Benjamin L et al. (2013) Endothelial colony-forming cell conditioned media promote angiogenesis in vitro and prevent pulmonary hypertension in experimental bronchopulmonary dysplasia. Am J Physiol Lung Cell Mol Physiol 305:L73-81
Mourani, Peter M; Harris, J Kirk; Sontag, Marci K et al. (2011) Molecular identification of bacteria in tracheal aspirate fluid from mechanically ventilated preterm infants. PLoS One 6:e25959

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