Bronchopulmonary dysplasia (BPD) is a chronic lung disease of infancy that is the result of premature birth. Infants with BPD have abnormal lung structure that is characterized by reduced pulmonary vascular density and a dysmorphic vascular structure. This results in impaired gas exchange, exercise intolerance, pulmonary hypertension, an increased incidence of asthma and early mortality. The mechanisms that impair lung development are poorly understood and there are few therapeutic interventions in the treatment of BPD. Recently, circulating angiogenic or endothelial progenitor cells (EPC) have been identified and characterized. These EPCs are believed to play a role in the recovery of blood vessels after injury. The role of EPCs during normal lung vascular and alveolar growth is unknown. In addition, the role these cells play in the neonate during the recovery from lung injury is unknown. Our goal is to characterize the role of EPCs in lung growth and development and determine if these cells are able to play a role in lung vascular and alveolar growth during and in recovery after lung injury. We propose the following hypothesis that a reduction in the mobilization, engraftment and survival of non- resident lung endothelial precursor cells (EPCs), is a mechanism contributing to impaired lung vascular and alveolar growth during and after exposure to neonatal hyperoxia. In order to study this hypothesis we are proposing the following specific aims in a mouse model: 1) To determine the therapeutic role of exogenous EPCs in the maintenance of lung vascular and alveolar growth during exposure to, and in the recovery from, neonatal moderate hyperoxia. 2) To determine if non-resident lung bone marrow derived cells participate in the preservation of lung structure during moderate hyperoxia exposure of adult mice. 3) To study, in vitro, the mechanisms by which VEGF, Epo, NO and hyperoxia affect EPC growth and function. PROJECT NARRATIVE: We expect that the results of this study will provide a better understanding of the roles and mechanisms by which extrinsic (circulating) cells and intrinsic (resident lung) cells play in lung vascular and alveolar growth, especially during and in the recovery from neonatal lung injury. A better understanding of these mechanisms of neonatal lung injury and repair may lead to novel therapies in the treatment of BPD.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Lung Injury, Repair, and Remodeling Study Section (LIRR)
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Blaisdell, Carol J
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University of Colorado Denver
Schools of Medicine
United States
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Nijmeh, Hala; Balasubramaniam, Vivek; Burns, Nana et al. (2014) High proliferative potential endothelial colony-forming cells contribute to hypoxia-induced pulmonary artery vasa vasorum neovascularization. Am J Physiol Lung Cell Mol Physiol 306:L661-71
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
Baker, Christopher D; Balasubramaniam, Vivek; Mourani, Peter M et al. (2012) Cord blood angiogenic progenitor cells are decreased in bronchopulmonary dysplasia. Eur Respir J 40:1516-22
Kloxin, April M; Lewis, Katherine J R; DeForest, Cole A et al. (2012) Responsive culture platform to examine the influence of microenvironmental geometry on cell function in 3D. Integr Biol (Camb) 4:1540-9
Balasubramaniam, Vivek; Ryan, Sharon L; Seedorf, Gregory J et al. (2010) Bone marrow-derived angiogenic cells restore lung alveolar and vascular structure after neonatal hyperoxia in infant mice. Am J Physiol Lung Cell Mol Physiol 298:L315-23
Baker, Christopher D; Ryan, Sharon L; Ingram, David A et al. (2009) Endothelial colony-forming cells from preterm infants are increased and more susceptible to hyperoxia. Am J Respir Crit Care Med 180:454-61
Balasubramaniam, Vivek; Ingram, David A (2009) Endothelial progenitors in the risk of developing bronchopulmonary dysplasia: can we include endothelial progenitor cells in BPD risk assessment? Am J Respir Crit Care Med 180:488-90