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 #
5R01HL085103-04
Application #
8307418
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Lin, Sara
Project Start
2009-07-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
4
Fiscal Year
2012
Total Cost
$407,991
Indirect Cost
$160,491
Name
Yale University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Bhandari, Vineet (2014) Postnatal inflammation in the pathogenesis of bronchopulmonary dysplasia. Birth Defects Res A Clin Mol Teratol 100:189-201
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
Ghelfi, Elisa; Yu, Chen-Wei; Elmasri, Harun et al. (2013) Fatty acid binding protein 4 regulates VEGF-induced airway angiogenesis and inflammation in a transgenic mouse model: implications for asthma. Am J Pathol 182:1425-33
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
Sun, Huanxing; Choo-Wing, Rayman; Sureshbabu, Angara et al. (2013) A critical regulatory role for macrophage migration inhibitory factor in hyperoxia-induced injury in the developing murine lung. PLoS One 8:e60560
Bhandari, Vineet; Choo-Wing, Rayman; Harijith, Anantha et al. (2012) Increased hyperoxia-induced lung injury in nitric oxide synthase 2 null mice is mediated via angiopoietin 2. Am J Respir Cell Mol Biol 46:668-76
Harijith, Anantha; Choo-Wing, Rayman; Cataltepe, Sule et al. (2011) A role for matrix metalloproteinase 9 in IFNýý-mediated injury in developing lungs: relevance to bronchopulmonary dysplasia. Am J Respir Cell Mol Biol 44:621-30
Bhandari, Vineet (2010) Hyperoxia-derived lung damage in preterm infants. Semin Fetal Neonatal Med 15:223-9