In the premature infant, the ductus arteriosus frequently remains open for many days after birth. As many as 70% of newborns delivered prior to 28 weeks gestation will require some form of therapy to close their patent ductus. If left unclosed, a persistent patent ductus arteriosus (PDA) is associated with significant morbidity: increased severity of bronchopulmonary dysplasia, a prolonged need for mechanical ventilation, and an increased incidence of necrotizing enterocolitis. Although inhibitors of prostaglandin synthesis, like indomethacin, induce ductus closure in 85% of preterm infants in whom they are used, ductus reopening occurs in 20-30% of treated infants. Recent studies demonstrate that the postnatal development of ductus wall hypoxia initiates the anatomic changes that prevent the ductus from reopening after birth. During permanent closure of the preterm ductus, luminal endothelial cells proliferate, adhere to each other, and plug up the constricted luminal space. The mechanisms that induce these changes in the endothelium are currently unknown. Recently it has been observed that the postnatal changes in the luminal endothelium are closely associated with inflammatory changes in the ductus wall. The studies proposed in this application will determine how a persistent patent ductus arteriosus alters lung function in the preterm newborn by examining its effects on lung edema, lung morphology and lung surfactant. They will determine the role of inflammation in ductus remodeling and permanent ductus closure. They will determine the role of endothelial adhesion molecules (like VE-cadherin) in endothelial plug formation. And they will determine the role of Vascular Endothelial Growth Factor (VEGF) on the inflammatory changes and the reorganization of VE cadherin that occur during ductus remodeling. They will use Real Time PCR, in situ hybridization, and immunohistochemistry to study changes in mRNA and protein expression in vivo and in vitro. They will use isolated ductus arteriosus in organ culture to study the role of hypoxia on the expression of proinflammatory factors in the tissue. They will use ductus luminal endothelial cells and assays of cell adhesion to study the role of endothelial adhesion molecules on endothelial plug formation in vitro. These studies should increase our understanding of how the patent ductus arteriosus alters pulmonary function in the preterm infant and what produces its permanent closure.
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