In contrast to lung branching morphogenesis, studies of the mechanisms that regulate lung vascular development and that link capillary growth with alveolarization are relatively recent and limited in scope. Lack of information regarding lung vascular growth and its connection with alveolar growth is unfortunate, because developmental abnormalities of the pulmonary circulation contribute to the pathogenesis of several important neonatal cardiopulmonary disorders including pulmonary hypertension in the newborn. Further, there is growing recognition that the importance of understanding basic mechanisms of lung vascular growth in the context of human disease may be best highlighted in the setting of bronchopulmonary dysplasia (BPD). BPD is a significant health care problem associated with acute and long-term pulmonary consequences. Recent data from animal and clinical studies suggest that impaired vascular growth may contribute to abnormalities of lung architecture, especially decreased alveolarization, and thus play a critical role in the pathogenesis of BPD. However, little is known about the mechanisms of pulmonary vascular injury in the immature lung, the impact of this injury on growth and development of the lung, or its contribution to the pathogenesis of BPD and pulmonary hypertension. The overall goal of this proposal is to generate clinical and basic information that will provide insight into the mechanisms contributing to the pulmonary vascular abnormalities that characterize BPD, to evaluate currently available therapies aimed at reducing lung injury and restoring vascular and lung growth and to examine in animal models new approaches aimed at ameliorating perinatal lung injury and restoring vascular and lung growth. Three clinical and two basic projects are proposed. The clinical projects will evaluate the impact of inhaled nitric oxide (iNO) on BPD, the role of specific genetic factors in predisposing infants to BPD, and the development of improved techniques to assess the presence of pulmonary hypertension and the responses to therapy in infants with pulmonary hypertension. Two basic projects will dissect the mechanisms contributing to lung vascular remodeling in murine, rodent, and ovine models and evaluate the effects of novel pharmacologic agents on lung vascular disease in these models. The long-term goal is to utilize information derived from these models to develop new and improved therapies for the infant with BPD.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
5P50HL084923-05
Application #
8016059
Study Section
Special Emphasis Panel (ZHL1-CSR-S (M1))
Program Officer
Moore, Timothy M
Project Start
2007-01-12
Project End
2012-12-31
Budget Start
2011-01-01
Budget End
2012-12-31
Support Year
5
Fiscal Year
2011
Total Cost
$453,946
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
Li, Min; Riddle, Suzette; Zhang, Hui et al. (2016) Metabolic Reprogramming Regulates the Proliferative and Inflammatory Phenotype of Adventitial Fibroblasts in Pulmonary Hypertension Through the Transcriptional Corepressor C-Terminal Binding Protein-1. Circulation 134:1105-1121
Kinsella, John P; Cutter, Gary R; Steinhorn, Robin H et al. (2014) Noninvasive inhaled nitric oxide does not prevent bronchopulmonary dysplasia in premature newborns. J Pediatr 165:1104-1108.e1
Nicolarsen, Jeremy; Ivy, Dunbar (2014) Progress in the diagnosis and management of pulmonary hypertension in children. Curr Opin Pediatr 26:527-35
Vorhies, Erika E; Ivy, David Dunbar (2014) Drug treatment of pulmonary hypertension in children. Paediatr Drugs 16:43-65
Jone, Pei-Ni; Hinzman, Julie; Wagner, Brandie D et al. (2014) Right ventricular to left ventricular diameter ratio at end-systole in evaluating outcomes in children with pulmonary hypertension. J Am Soc Echocardiogr 27:172-8
Takatsuki, Shinichi; Rosenzweig, Erika B; Zuckerman, Warren et al. (2013) Clinical safety, pharmacokinetics, and efficacy of ambrisentan therapy in children with pulmonary arterial hypertension. Pediatr Pulmonol 48:27-34
Takatsuki, Shinichi; Parker, Donna K; Doran, Aimee K et al. (2013) Acute pulmonary vasodilator testing with inhaled treprostinil in children with pulmonary arterial hypertension. Pediatr Cardiol 34:1006-12
Tuder, Rubin M; Archer, Stephen L; Dorfmüller, Peter et al. (2013) Relevant issues in the pathology and pathobiology of pulmonary hypertension. J Am Coll Cardiol 62:D4-12
Su, Zhenbi; Tan, Wei; Shandas, Robin et al. (2013) Influence of distal resistance and proximal stiffness on hemodynamics and RV afterload in progression and treatments of pulmonary hypertension: a computational study with validation using animal models. Comput Math Methods Med 2013:618326
Wagner, Brandie D; Takatsuki, Shinichi; Accurso, Frank J et al. (2013) Evaluation of circulating proteins and hemodynamics towards predicting mortality in children with pulmonary arterial hypertension. PLoS One 8:e80235

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