FETAL LUNG MATURATION: PREVENTION OF RDS

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The object of the research proposed in this Program Project (Renewal) Grant Application is to define the molecular events involved in the differences of fetal type II pneumonocytes and thus provide a rational basis for the treatment and prevention of respiratory distress syndrome (RDS). The goal of Project 1 is to define the relationship between glycogen metabolism and the synthesis of surfactant glycerophospholipids. The synthesis of platelet-activating factor and its role in glycogenolysis will be investigated. The role of the cytidylate charge and surfactant apoproteins in the regulation of surfactant glycerophospholipid metabolism will be investigated. The mechanisms that govern the putative regulatory enzymes of surfactant glycerophospholipid synthesis will be determined. The goal of Project 2 is to define the molecular mechanisms that mediate the developmental expression of the gene encoding the major surfactant apoprotein (SP-35) and the hormonal regulation thereof. Changes in the transcriptional activity of the gene during fetal lung development as well as the effect of hormones on mRNAs synthesis and half- life will be evaluated. Genomic regions involved in developmental and hormonal regulation of the SP-35 gene will be identified and DNA binding proteins that interact with these regions will be isolated and characterized. The SP-35 cDNA will be expressed in eukaryotic cells to learn more concerning its function. The goal of Project 3 is to determine the role of the adrenergic system in developing fetal lung. The effects of alpha and beta agonists, cyclic AMP analogs, and phosphodiesterase inhibitors on the levels of SP-35 and its mRNA will be defined. The effects of various hormones on cyclic AMP levels in fetal lung tissue will be determined. Control and treated fetal lung explants will be evaluated by light and electron microscopy. Surfactant apoproteins and glycerophospholipids will be quantitated in lung lavage obtained from low birth weight infants treated with theophylline. The goal of Project 4 is to define the developmental expression and immunocytochemical localization of the low molecular weight, hydrophobic surfactant apoproteins in fetal lung. The effects of insulin and other regulatory factors on their synthesis and accumulation in fetal lung tissue will be evaluated. The morphological effects of insulin on fetal lung will be described. The concentration of surfactant apoproteins in amniotic fluids obtained from diabetic and nondiabetic pregnancies will be determined. The goal of Project 5 is to determine the mechanism whereby prolonged intrauterine "stress" alters fetal lung maturation in chronically instrumented fetal and pregnant sheep. The effects of estradiol-17 beta, arginine vasopressin, ritodine as well as prolonged placental hypoperfusion on the plasma levels of stress hormones and tracheal fluid surfactant components will be evaluated during the last 30 days of gastation. We will obtain umbilical cord blood samples at the time of birth from human pregnancies at risk of prolonged feta "stress" and correlate changes in stress hormones with the occurrance of RDS. Databases of 28,000 mother-infant pairs and 1,400 infants, is less than 1500 gm birth weight, will be utilized to determine whether infants with prolonged intrauterine stress have altered pulmonary function.