Bronchopulmonary dysplasia (BPD) often complicates prolonged mechanical ventilation after premature birth. Defining the mechanisms that cause BPD and developing a safe, effective treatment strategy are the ultimate objectives of this project. To study the pathogenesis of BPD and to test various therapeutic interventions, we developed a preterm lamb model that mimics the clinical and pathological findings of this disease. The underlying hypothesis is that early postnatal inflammation of the immature lung exposed to prolonged, repetitive stretch with 02-enriched gas leads to oxidant and protease induced lung injury that can be inhibited or prevented by early and continuous postnatal delivery of inhaled nitric oxide (iNO), the response to which may be enhanced by antenatal steroid treatment. The proposal has 3 specific aims: (i) to compare immediate vs delayed (7d) postnatal delivery of continuous, low-dose iNO (and the relevant control, no iNO) in chronically ventilated preterm lambs; (ii) to determine if antenatal steroid treatment will modify the response to immediate or delayed iNO; and (iii) to determine if iNO will inhibit lung inflammation and thereby facilitate postnatal adaptation of the pulmonary circulation and respiratory tract, leading to improved respiratory gas exchange. This project complements the clinical trial of iNO in preterm infants with respiratory failure. Serial specimens of bronchial secretions, lung lavage fluid and lung lymph will allow assessment of inflammation in evolving BPD. The research plan includes physiological, biochemical, histological and molecular techniques to define mechanisms underlying abnormalities in the lung circulation (persistent elevation of vascular resistance, edema from increased vascular filtration pressure, loss of the pulmonary vasodilator response to iNO, increased arterial smooth muscle, reduced numbers of microvessels and less capillary surface density, decreased expression of endothelial nitric oxide synthase and soluble guanylate cyclase); respiratory tract (increased expiratory resistance, proliferation of bronchiolar smooth muscle, reduced numbers of alveoli); and lung interstitium (increased lung tropoelastin expression and disordered elastin accumulation) that characterize the lamb model of BPD. Collaborative studies with other SCOR projects that focus on surfactant proteins and function (I), vascular endothelial growth factor and its receptors (II), inflammatory mediators (III), and mitogens that influence smooth muscle proliferation and connective tissue elements (IV) will provide new insight on mechanisms of lung dysfunction and dysplasia in BPD and the impact of iNO and antenatal steroids on these abnormalities.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
2P50HL056401-06
Application #
6507864
Study Section
Special Emphasis Panel (ZHL1)
Project Start
1996-09-01
Project End
2006-07-31
Budget Start
Budget End
Support Year
6
Fiscal Year
2001
Total Cost
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Hamvas, Aaron; Deterding, Robin; Balch, William E et al. (2014) Diffuse lung disease in children: summary of a scientific conference. Pediatr Pulmonol 49:400-9
Merrill, J D; Ballard, P L; Courtney, S E et al. (2011) Pilot trial of late booster doses of surfactant for ventilated premature infants. J Perinatol 31:599-606
Posencheg, M A; Gow, A J; Truog, W E et al. (2010) Inhaled nitric oxide in premature infants: effect on tracheal aspirate and plasma nitric oxide metabolites. J Perinatol 30:275-80
Albertine, Kurt H; Dahl, Mar Janna; Gonzales, Linda W et al. (2010) Chronic lung disease in preterm lambs: effect of daily vitamin A treatment on alveolarization. Am J Physiol Lung Cell Mol Physiol 299:L59-72
Hibbs, Anna Maria; Black, Dennis; Palermo, Lisa et al. (2010) Accounting for multiple births in neonatal and perinatal trials: systematic review and case study. J Pediatr 156:202-8
Walsh, Michele C; Hibbs, Anna Maria; Martin, Camilia R et al. (2010) Two-year neurodevelopmental outcomes of ventilated preterm infants treated with inhaled nitric oxide. J Pediatr 156:556-61.e1
Zupancic, John A F; Hibbs, Anna Maria; Palermo, Lisa et al. (2009) Economic evaluation of inhaled nitric oxide in preterm infants undergoing mechanical ventilation. Pediatrics 124:1325-32
Kolla, Venkatadri; Gonzales, Linda W; Bailey, Nicole A et al. (2009) Carcinoembryonic cell adhesion molecule 6 in human lung: regulated expression of a multifunctional type II cell protein. Am J Physiol Lung Cell Mol Physiol 296:L1019-30
Hibbs, Anna Maria; Walsh, Michele C; Martin, Richard J et al. (2008) One-year respiratory outcomes of preterm infants enrolled in the Nitric Oxide (to prevent) Chronic Lung Disease trial. J Pediatr 153:525-9
Reyburn, Brent; Li, Marlana; Metcalfe, Drew B et al. (2008) Nasal ventilation alters mesenchymal cell turnover and improves alveolarization in preterm lambs. Am J Respir Crit Care Med 178:407-18

Showing the most recent 10 out of 94 publications