In the premature infant, the doctus arteriosus frequently remains open for many days or weeks after delivery. As many as 70% of newborns delivered prior to 28 weeks gestation will require some form of therapy to close their patient doctus. If left unclosed, a persistent patent doctus arteriosus is associated with significant morbidity: bronchopulmonary dysplasia (with its prolonged need for mechanical ventilation) and necrotizing enterocolitis. Numerous studies have shown that early closure of the doctus arteriosus decreases the severity of bronchopulmonary dysplasia and decreases the incidence of necrotizing enterocolitis. Although inhibitors of prostaglandin synthesis, like indomethacin,, induce doctus closure in 85% of preterm infants in whom they are used, doctus reopening occurs in 20-30% of treated infants. Recent studies demonstrate that the postnatal development of doctus wall hypoxia is an essential step in the anatomic remodeling (luminal endothelial proliferation, migration, and smooth muscle cell death) that leads to permanent closure. The studies proposed in this application will examine the mechanisms involved in early, spontaneous doctus closure in the full-term newborn and those involved in the delayed closure of the premature newborn. They will also examine the mechanisms involved in the high rate of doctus reopening after indomethacin-induced closure. They will use the premature baboon model of persistent patent doctus arteriosus, which is the only model that mimics the long-term events surrounding doctus patency in the preterm human. They will examine the hypothesis that vasoactive factors that alter doctus tone (e.g., prostaglandins, nitric oxide) also interact with an deregulate the growth factors and death factors involved in anatomic remodeling. They will examine mechanisms to increase doctus wall hypoxia in the preterm newborn. They will use immunohistochemical, Western, and Northern techniques to study changes in mRNA and protein expression; they will use assays of cell migration, proliferation, and cell death in isolated vessels, endothelial and smooth muscle cells in culture. They will characterize changes in receptor populations and test their findings in vivo. These studies should increase our understanding of what initiates and sustains the process of ductus closure after birth and why it does not occur in the preterm infant.
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