We propose to elucidate the molecular events in fetal lung which are involved in the biosynthesis of dipalmitoylphosphatidylcholine (DP-PC) and phosphatidylglycerol (PG). The role of phosphatidate phosphohydrolase (PAPase), cholinephosphotransferase, and CTP:phosphocholine cytidylyl transferase in the regulation of cytidine monophosphate (CMP) formation and the mechanisms for palmitate enrichment of phosphatidylcholine (PC) to form DP-PC will be investigated. We envision that CMP levels in the fetal lung may regulate the formation of phosphatidylinositol (PI) and PG. Increased availability of CMP leads to increased cytidine diphosphate diglyceride (CDP-DG) formation from CMP and PI, leading to increased phosphatidylglycerolphosphate (PGP) formation. We believe that PAPase catalyzes both the conversion of phosphatidic acid to sn-1,2-diglycerides and of PGP to PG. Hence, the mechanism controlling the activity of PAPase in the type II pneumocyte is of major importance in the synthesis of PC, PI, and PG. The participation of the SER, Golgi apparatus, and lysosomes in lamellar body formation will be investigated. The role of estrogen, cortisol, insulin, and prolactin in the biochemical maturation of the type II pneumocyte and the events involved in the expression of estrogen and prolactin receptors will be given special attention. The release of lamellar bodies from the type II pneumocyte will be studied. The hormonal events in the human fetus which are related to lung maturation will be studied by determining the relationship of umbilical cord plasma levels of prolactin, cortisol, and estrogen to the L/S ratio, and incidence of RDS. We are especially interested in evaluating the hormonal milieu of newborns who may have experienced, as fetuses, accelerated or delayed lung maturation and to ascertain how maternal complications may alter the hormonal milieu of the fetus and the timetable of fetal lung maturation. The findings of such studies will be fundamental to the understanding of the biochemical basis of lung maturation and are essential to the formulation of a rational treatment paradigm to accelerate lung maturation in human fetuses.
Showing the most recent 10 out of 71 publications
