The Applicants hypothesize that glucocorticoids given to pregnant women to stimulate antenatal fetal lung maturation and postnatally to treat bronchopulmonary dysplasia (BPD), may interfere with vitamin A metabolism. They think vitamin A is essential for control of lung development and for pulmonary repair.
The specific aims are to clarify: 1) the biochemical mechanism for glucocorticoid-induced changes in synthesis and endogenous levels of retinoic acid; 2) the interaction of vitamin A/dexamethasone on surfactant development; 3) the effect of modulation of cellular retinoic acid binding protein and retinoic acid receptor genes on functional markers of the surfactant system; and 4) the effect of transfection to increase cellular retinoic acid binding protein and retinoic acid receptors on surfactant markers, and the effects of dexamethasone on those same markers. These experiments will be performed in vitro in type II pneumocytes and in fetal lung explants from vitamin A-deficient rat pups. To study the cellular retinoic acid binding protein and retinoic acid receptor, studies will be performed in isolated lung cells using surfactant markers, studying the effect of dexamethasone on surfactant markers, and what happens to those markers following transfection to increase cellular retinoic acid binding protein and retinoic acid receptors. The study is significant because of the potential to clarify vitamin A's role in pulmonary development, which the investigators believe is essential for developing novel therapies to use in lung development and in the repair of lung injury.
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