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.
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.
|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|
|Mandell, Erica; Seedorf, Gregory; Gien, Jason et al. (2014) Vitamin D treatment improves survival and infant lung structure after intra-amniotic endotoxin exposure in rats: potential role for the prevention of bronchopulmonary dysplasia. Am J Physiol Lung Cell Mol Physiol 306:L420-8|
|Gien, Jason; Tseng, Nancy; Seedorf, Gregory et al. (2014) Peroxisome proliferator activated receptor-?-Rho-kinase interactions contribute to vascular remodeling after chronic intrauterine pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 306:L299-308|
|Wolf, David; Tseng, Nancy; Seedorf, Gregory et al. (2014) Endothelin-1 decreases endothelial PPARýý signaling and impairs angiogenesis after chronic intrauterine pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 306:L361-71|
|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|
|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|
|Tang, Jen-Ruey; Michaelis, Katherine A; Nozik-Grayck, Eva et al. (2013) The NF-ýýB inhibitory proteins IýýBýý and IýýBýý mediate disparate responses to inflammation in fetal pulmonary endothelial cells. J Immunol 190:2913-23|
|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|
|Gien, Jason; Tseng, Nancy; Seedorf, Gregory et al. (2013) Endothelin-1 impairs angiogenesis in vitro through Rho-kinase activation after chronic intrauterine pulmonary hypertension in fetal sheep. Pediatr Res 73:252-62|
|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|
Showing the most recent 10 out of 43 publications