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 #
5R01HL085703-03
Application #
7790625
Study Section
Special Emphasis Panel (ZRG1-RES-B (03))
Program Officer
Blaisdell, Carol J
Project Start
2008-04-01
Project End
2013-02-28
Budget Start
2010-03-01
Budget End
2011-02-28
Support Year
3
Fiscal Year
2010
Total Cost
$654,392
Indirect Cost
Name
University of Colorado Denver
Department
Pediatrics
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Morrow, Lindsey A; Wagner, Brandie D; Ingram, David A et al. (2017) Antenatal Determinants of Bronchopulmonary Dysplasia and Late Respiratory Disease in Preterm Infants. Am J Respir Crit Care Med 196:364-374
Gien, Jason; Kinsella, John; Thrasher, Jodi et al. (2017) Retrospective Analysis of an Interdisciplinary Ventilator Care Program Intervention on Survival of Infants with Ventilator-Dependent Bronchopulmonary Dysplasia. Am J Perinatol 34:155-163
Maron, Bradley A; Abman, Steven H (2017) Translational Advances in the Field of Pulmonary Hypertension. Focusing on Developmental Origins and Disease Inception for the Prevention of Pulmonary Hypertension. Am J Respir Crit Care Med 195:292-301
Carlton, Erin F; Sontag, Marci K; Younoszai, Adel et al. (2017) Reliability of Echocardiographic Indicators of Pulmonary Vascular Disease in Preterm Infants at Risk for Bronchopulmonary Dysplasia. J Pediatr 186:29-33
Lynch, Anne M; Wagner, Brandie D; Mandava, Naresh et al. (2016) The Relationship of Novel Plasma Proteins in the Early Neonatal Period With Retinopathy of Prematurity. Invest Ophthalmol Vis Sci 57:5076-5082
Galambos, Csaba; Sims-Lucas, Sunder; Abman, Steven H et al. (2016) Intrapulmonary Bronchopulmonary Anastomoses and Plexiform Lesions in Idiopathic Pulmonary Arterial Hypertension. Am J Respir Crit Care Med 193:574-6
Abman, Steven H (2016) New guidelines for managing pulmonary hypertension: what the pediatrician needs to know. Curr Opin Pediatr 28:597-606
Mourani, Peter M; Sontag, Marci K; Younoszai, Adel et al. (2015) Early pulmonary vascular disease in preterm infants at risk for bronchopulmonary dysplasia. Am J Respir Crit Care Med 191:87-95
Acker, Shannon N; Mandell, Erica W; Sims-Lucas, Sunder et al. (2015) Histologic identification of prominent intrapulmonary anastomotic vessels in severe congenital diaphragmatic hernia. J Pediatr 166:178-83
Di Maria, Michael V; Younoszai, Adel K; Sontag, Marci K et al. (2015) Maturational Changes in Diastolic Longitudinal Myocardial Velocity in Preterm Infants. J Am Soc Echocardiogr 28:1045-52

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