The overall goal of this project is to elucidate the control of surfactant phospholipid synthesis and to determine how hormones influence this process during fetal lung development. Such information is essential for development of rational therapeutic approaches to prevention and/or control of the respiratory distress syndrome (RDS) in premature newborn humans. Although considerable progress has been made in combating RDS, it is still a major cause of morbidity and mortality among premature infants. A major focus in this application will be on the mechanisms of regulation of choline-phosphate cytidylyltransferase (CYT) - the enzyme which catalyzes the rate-limiting step in phosphatidylcholine synthesis. There is evidence that CYT activity is increased when phosphatidylcholine synthesis is increased by estrogen, glucocorticoids and thyroid hormone in fetal lung. There is also evidence that the catalytic activity rather than the amount of the enzyme is increased. We will determine whether such increase in CYT activity is mediated by phospholipids, fatty acids, intracellular translocation or dephosphorylation/phosphorylation. We will examine effects of estrogen in the fetal rabbit and those of glucocorticoids and thyroid hormone in the fetal rat. In addition, we will examine regulation of phospholipid synthesis and CYT activity in adult rat type II cells under conditions of altered phospholipid synthesis in response to cyclic AMP and phosphodiesterase inhibitors, other drugs which influence phospholipid synthesis and altered cultural conditions. We will determine how phospholipids in the culture medium stimulate phosphatidylcholine synthesis in type II cells, whether CYT activity is increased under these conditions, whether the effect is specifically on phosphatidylcholine or if other phospholipids are also affected and if other enzymes of phospholipid synthesis are stimulated. In addition to these studies, we will determine if the hormones influence rate-regulatory enzymes in the glycolytic pathway and in fatty acid synthesis. We will explore the possibility that estromedins in the circulation mediate the stimulatory effect of estrogen on fetal lung maturation. In this largely biochemical study we will use lungs from intact fetal rabbits and rats after maternal hormone administration, fetal rabbit and rat lung explants in organ culture and type II pneumocytes from the adult rat in primary culture.
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