Advances in perinatal care, including antenatal steroids, surfactant therapy and improved ventilator strategies, have markedly increased survival of extremely low birth weight infants. However, bronchopulmonary dysplasia (BPD), the chronic lung disease that follows premature birth, remains a major cause of perinatal morbidity and mortality. BPD is a major public health problem, occurring in over 10,000 new cases per year in the USA and causing prolonged hospitalizations, recurrent respiratory exacerbations, impaired lung function into adulthood, exercise intolerance, and pulmonary hypertension in survivors. BPD is characterized by abnormal lung structure due to an arrest of vascular and alveolar growth, but mechanisms contributing to the pathogenesis and optimal treatment of BPD remain poorly understood. Vascular endothelial growth factor (VEGF) is a potent mitogen and critical survival and maintenance factor for lung vascular endothelium. VEGF and its down-stream mediator, nitric oxide (NO), are essential for lung angiogenesis during early embryogenesis, but less is known about its roles and mechanisms of its effects later during development and in the setting of neonatal lung disease. Our past studies have shown that disruption of VEGF - NO signaling causes dysmorphic lung vascular growth and decreased alveolarization in experimental and clinical BPD. Inhibition of angiogenesis impairs alveolarization during lung development, and treatment with VEGF or inhaled NO (iNO) enhances endothelial survival, vascular growth and lung structure in diverse animal models of BPD. However, randomized clinical trials have failed to demonstrate that iNO therapy consistently prevents BPD in human preterm infants, as summarized in a recent NICHD Consensus Conference. Although several issues related to patient selection and study design may account for variability between studies, the failure of iNO therapy to consistently prevent BPD further highlights the importance of developing alternate strategies to preserve endothelial function and angiogenesis in premature infants. Since VEGF treatment improves vascular and alveolar growth in experimental BPD yet has no direct effects on airway epithelium, we hypothesize that in addition to NO activation, VEGF-induced enhancement of lung structure may be mediated through non-NO dependent pathways, and that these pathways may mediate critical epithelial-mesenchymal interactions that are essential for improving lung vascular and alveolar growth in BPD. Based on strong preliminary data, we further hypothesize that the effects of VEGF on lung structure are dependent upon stimulation of hepatocyte growth factor and enhanced retinoic acid production by vascular endothelium (""""""""angiocrine factors""""""""). In this renewal, we propose a series of integrative studies that incorporate physiologic, cell and molecular approaches towards understanding BPD.

Public Health Relevance

Broncho-pulmonary dysplasia (BPD), the chronic lung disease that follows premature birth, is a major public health problem that is associated with significant mortality and morbidity. Despite improvements in perinatal care, BPD persists as a major complication, occurring in nearly 10,000 infants per year in the USA alone. This project proposes to determine mechanisms through which vascular and alveolar growth are impaired in experimental models of BPD, which may lead to the development of new therapeutic strategies for its prevention or treatment.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL068702-09A1
Application #
8372775
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Lin, Sara
Project Start
2001-06-20
Project End
2016-07-31
Budget Start
2012-09-01
Budget End
2013-07-31
Support Year
9
Fiscal Year
2012
Total Cost
$420,655
Indirect Cost
$97,759
Name
University of Colorado Denver
Department
Pediatrics
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Yun, Eun Jun; Lorizio, Walter; Seedorf, Gregory et al. (2016) VEGF and endothelium-derived retinoic acid regulate lung vascular and alveolar development. Am J Physiol Lung Cell Mol Physiol 310:L287-98
Seedorf, Gregory; Metoxen, Alexander J; Rock, Robert et al. (2016) Hepatocyte growth factor as a downstream mediator of vascular endothelial growth factor-dependent preservation of growth in the developing lung. Am J Physiol Lung Cell Mol Physiol 310:L1098-110
Gien, Jason; Kinsella, John; Thrasher, Jodi et al. (2016) Retrospective Analysis of an Interdisciplinary Ventilator Care Program Intervention on Survival of Infants with Ventilator-Dependent Bronchopulmonary Dysplasia. Am J Perinatol :
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
Galambos, Csaba; Sims-Lucas, Sunder; Ali, Noorjahan et al. (2015) Intrapulmonary vascular shunt pathways in alveolar capillary dysplasia with misalignment of pulmonary veins. Thorax 70:84-5
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
Mandell, Erica; Seedorf, Gregory J; Ryan, Sharon et al. (2015) Antenatal endotoxin disrupts lung vitamin D receptor and 25-hydroxyvitamin D 1α-hydroxylase expression in the developing rat. Am J Physiol Lung Cell Mol Physiol 309:L1018-26
Baker, Christopher D; Abman, Steven H (2015) Impaired pulmonary vascular development in bronchopulmonary dysplasia. Neonatology 107:344-51
Mandell, Erica; Powers, Kyle N; Harral, Julie W et al. (2015) Intrauterine endotoxin-induced impairs pulmonary vascular function and right ventricular performance in infant rats and improvement with early vitamin D therapy. Am J Physiol Lung Cell Mol Physiol 309:L1438-46

Showing the most recent 10 out of 63 publications