In many infants with BPD abnormal pulmonary microvascular development and pulmonary artery (PA) structural remodeling are observed. The latter process includes abnormal muscularization of resistance PA in the lung periphery, as well as medial hypertrophy, adventitial thickening and fibrosis in more proximal PA. The causes of abnormal pulmonary vascular development and structural remodeling in BPD are poorly understood. It has long been assumed that the expanded population of cells in the thickened PA originates via proliferation of resident lung fibroblasts and smooth muscle cells (SMC), as well as via differentiation of resident lung fibroblasts into myofibroblasts. However, new experimental evidence suggests a non-resident source for tissue mesenchymal cells (fibroblasts, myofibroblasts, SMC). Among different types of mesenchymal progenitors, a subpopulation of circulating leukocytes, termed fibrocytes, has been proposed as a major contributor to the structural tissue remodeling and fibrosis in healing wounds, bleomycin-induced lung injury, and asthma. We have recently demonstrated the robust PA accumulation of fibrocytes in chronic hypoxic neonatal pulmonary hypertension and showed that these circulating cells are crucial for the pulmonary vascular structural remodeling seen in that setting. Our preliminary data suggest that circulating fibrocytes also contribute to the vascular remodeling observed in neonatal rats and mice exposed to hyperoxia (animal models of BPD). Preliminary data support a role for oxidant imbalances and endothelin in the recruitment of fibrocytes to the lung. We therefore propose to test the overall hypothesis that, in the setting of hyperoxia-induced lung injury, circulating fibrocytes are recruited to the lung where they act as progenitors of mesenchymal cells, and contribute significantly to pulmonary vascular remodeling and pulmonary hypertension, and that EC-SOD and ET-1 play critical roles in this process. We will determine the mechanisms involved in the recruitment of fibrocytes to the lung and lung vasculature and their contribution to remodeling using both pharmacologic strategies and genetic models to manipulate expression of molecules potentially involved in fibrocyte recruitment and differentiation. These experiments will result in a better understanding of vascular changes in BPD and, ultimately in the development of selective therapeutic strategies to decrease the recruitment of circulating mesenchymal progenitors to the hyperoxic lung in human infants with BPD.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
5P50HL084923-05
Application #
8214145
Study Section
Special Emphasis Panel (ZHL1)
Project Start
2011-01-01
Project End
2012-12-31
Budget Start
2011-01-01
Budget End
2012-12-31
Support Year
5
Fiscal Year
2011
Total Cost
$64,849
Indirect Cost
Name
University of Colorado Denver
Department
Type
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
Vorhies, Erika E; Ivy, David Dunbar (2014) Drug treatment of pulmonary hypertension in children. Paediatr Drugs 16:43-65
Nicolarsen, Jeremy; Ivy, Dunbar (2014) Progress in the diagnosis and management of pulmonary hypertension in children. Curr Opin Pediatr 26:527-35
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
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; Dorfm├╝ller, 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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