Of the four million babies born in the USA each year: 1 in 8 is born prematurely. Respiratory distress syndrome (RDS) and it's sequelae, contribute significantly to 1,140 of the 5,520 deaths each year due to complications of prematurity. Despite the significant strides that have been made in neonatal intensive care, the consequences of RDS have not been significantly altered. Since a cure for premature delivery has not been accomplished to date, investigators have focused on ways to enhance lung maturation. Vascular endothelial cell growth factor (VEGF) is an important regulator of vascular development and lung maturation. The effects of VEGF in the developing lung and the mechanisms of these effector responses, however, have no been described. To define the effects of VEGF we used a novel, inducible, overexpression transgenic system in which transgenes can be selectively targeted to the lung and activated in utero, in neonates or in adult animals. When VEGF was overexpressed in the adult respiratory tract, a complex phenotype was noted that included heightened bronchial and parenchymal angiogenesis, mononuclear inflammation, and an impressive survival advantage in the setting of 100% oxygen exposure. These alterations were associated with significant increase in total lung phospholipids and an increase in surfactant protein (SP)-B and C but not A or D. Interestingly, nitric oxide (NO)-dependent pathways were responsible for the vascular and survival effects but not the effects of VEGF on alveolar maturation. When VEGF was selectively expressed in the neonatal lung, enhanced lung maturation was also appreciated. In contrast to what was seen in the adult, however, VEGF expression was associated with enhanced hyperoxic acute lung injury (HALI). As a result of these findings we have generated the following hypotheses: 1) VEGF is a pivotal mediator of vascular and alveolar maturation in the murine lung. 2) VEGF, while enhancing lung maturation, simultaneously enhances respiratory susceptibility to HALI in the developing lung 3) The effects of VEGF are mediated by NO-dependent and -independent pathways with enhanced HALI being mediated by the former and enhanced lung maturation being mediated via the latter. If our hypotheses are correct: this would suggest that an optimal VEGF-based intervention to enhance lung maturation would be VEGF in combination with an NO inhibitor. To test these hypotheses, we propose to: 1) Define the effects of VEGF on vascular and alveolar development in the fetal and newborn (NB) lung. 2) Define the role(s) of NO, and understand the mechanism of the NO pathway in the pathogenesis of the vascular and alveolar effects of VEGF in the fetal and NB lung. 3) Characterize the effects of, and understand the mechanism(s) of antenatal VEGF activation and/or NO in the fetal lung exposed to hyperoxia. Project Narrative: Understanding the effects of VEGF augmentation in the developing lung as a method of lung maturation, and defining the contributions of the Nitric Oxide pathway in this process, can pave the way for appropriate therapeutic interventions in the human disease context of Respiratory Distress Syndrome.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL085103-02
Application #
7895712
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Lin, Sara
Project Start
2009-07-01
Project End
2011-06-30
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
2
Fiscal Year
2010
Total Cost
$413,750
Indirect Cost
Name
Yale University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Sureshbabu, Angara; Syed, Mansoor; Das, Pragnya et al. (2016) Inhibition of Regulatory-Associated Protein of Mechanistic Target of Rapamycin Prevents Hyperoxia-Induced Lung Injury by Enhancing Autophagy and Reducing Apoptosis in Neonatal Mice. Am J Respir Cell Mol Biol 55:722-735
Zhou, Kevin C; Huang, Brendan K; Gamm, Ute A et al. (2016) Erratum: Particle streak velocimetry-optical coherence tomography: a novel method for multidimensional imaging of microscale fluid flows: erratum. Biomed Opt Express 7:2360-1
Syed, Mansoor A; Choo-Wing, Rayman; Homer, Robert J et al. (2016) Role of Nitric Oxide Isoforms in Vascular and Alveolar Development and Lung Injury in Vascular Endothelial Growth Factor Overexpressing Neonatal Mice Lungs. PLoS One 11:e0147588
Sureshbabu, Angara; Syed, Mansoor A; Boddupalli, Chandra Sekhar et al. (2015) Conditional overexpression of TGF?1 promotes pulmonary inflammation, apoptosis and mortality via TGF?R2 in the developing mouse lung. Respir Res 16:4
Gamm, Ute A; Huang, Brendan K; Syed, Mansoor et al. (2015) Quantifying hyperoxia-mediated damage to mammalian respiratory cilia-driven fluid flow using particle tracking velocimetry optical coherence tomography. J Biomed Opt 20:80505
Huang, Brendan K; Gamm, Ute A; Bhandari, Vineet et al. (2015) Three-dimensional, three-vector-component velocimetry of cilia-driven fluid flow using correlation-based approaches in optical coherence tomography. Biomed Opt Express 6:3515-38
Bhandari, Vineet (2014) Postnatal inflammation in the pathogenesis of bronchopulmonary dysplasia. Birth Defects Res A Clin Mol Teratol 100:189-201
Berger, Jessica; Bhandari, Vineet (2014) Animal models of bronchopulmonary dysplasia. The term mouse models. Am J Physiol Lung Cell Mol Physiol 307:L936-47
Choo-Wing, Rayman; Syed, Mansoor A; Harijith, Anantha et al. (2013) Hyperoxia and interferon-?-induced injury in developing lungs occur via cyclooxygenase-2 and the endoplasmic reticulum stress-dependent pathway. Am J Respir Cell Mol Biol 48:749-57
Sun, Huanxing; Choo-Wing, Rayman; Fan, Juan et al. (2013) Small molecular modulation of macrophage migration inhibitory factor in the hyperoxia-induced mouse model of bronchopulmonary dysplasia. Respir Res 14:27

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