Vitamin A is a micronutrient necessary for maintenance of normal epithelial differentiation and function, including the tracheobronchial epithelium. In work supported by past SCOR funding, we have demonstrated that premature, very low birth weight (VLBW) neonates are vitamin A deficient at birth, that this nutritional deficiency contributes to the pathogenesis of bronchopulmonary dysplasia (BPD), and that vitamin A supplementation from early postnatal life reduces both the incidence and morbidity of BPD. We hypothesize that the observed vitamin A deficiency in this high-risk population of neonates predisposes them to abnormal tissue repair of the conducting airways, and perhaps pulmonary parenchyma, following acute and chronic forms of lung injury. The mechanism by which vitamin A promotes normal epithelial repair as well as how vitamin A is metabolized, both broadly and at the cellular level, remain poorly understood. The overall objective of this project is to understand the role of retinol (vitamin A) and its metabolite, retinoic acid, in normal pulmonary epithelial cell differentiation during tissue repair and following both acute and chronic lung injury. In an effort to transfer knowledge obtained in the laboratory to practical clinical application at the nursery bedside, this project will have two interrelated subprojects. The Basic Science portion of this project (Subproject A) consists of a series of experiments designed to further our understanding of how retinol and retinoic acid promote normal tracheobronchial and pulmonary epithelial differentiation at the cellular level. Therefore, we propose to identify specific cells targeted for retinoid action in the tracheobronchial tree and lung as well as identify specific retinoic acid responsive genes that contribute to pulmonary cell growth and differentiation. To further our understanding of the mechanism of action of retinoids, we propose to determine whether the influence of retinoids is at the level of gene transcription. The Clinical portion of this project (Subproject B) consists of a series of studies designed to characterize further vitamin A metabolism in VLBW neonates and to examine further the beneficial effects of retinol supplementation in promotion of normal epithelial repair in these infants. Therefore, we propose to determine the total body pool size or reserve of vitamin A in infants of varying gestational ages (including VLBW neonates). We also propose to characterize further a functional, clinically applicable test of vitamin A status in VLBW infants at risk for BPD as well as use this test to optimize vitamin A nutrition during early postnatal life. Finally, we propose to study the vitamin A status of older infants with chronic BPD to determine whether these infants remain relatively vitamin A deficient despite early supplementation. The long-term goal of this project is to increase our knowledge of how retinoids promote normal epithelial differentiation from a basic understanding at the cellular level to practical application in the intensive care nursery.
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