Many human premature infants develop bronchopulmonary dysplasia (BPD), and some studies suggest a relationship between premature retinol levels and the incidence or severity of BPD. However, accurate assessment or evaluation of a possible """"""""conditional vitamin A deficiency"""""""" in this patient population has not been accomplished. Vitamin A is essential for normal epithelial cell growth and differentiation. In lung, vitamin A deficiency is characterized by a loss of cilia and the development of squamous metaplasia in the respiratory tract which are similar to changes found in BPD. The overall objective here is to clarify the role of vitamin A in the pathogenesis and repair of BPD. First, we will assess the vitamin A (retinol) status of low birthweight (< 1500 grams) premature infants with an Intramuscular Relative Dose Response (IM-RDR) test. Optimal conditions will first be established in the vitamin-A-deficient rat model. Then, the IM-RDR will be used in premature infants of birthweight < 1500 grams to see if its estimate of the vitamin A status at day 0 and day 28 is predictive or unrelated to the chances of having BPD. The IM-RDR will be validated with liver biopsy samples when infant deaths occur. Serum retinol binding protein (RBP) levels will be done simultaneously with the IM-RDR. The IM-RDR (for retinol and RBP) will be compared in gestational age corrected populations without lung disease at day 28 to those with BPD. BPD will be diagnosed by established criteria. If the IM-RDR can be used to predict the chances of BPD, we will purpose a later study of BPD and vitamin A supplementation. Second, in the laboratory, we will study how vitamin A might relate to BPD on a biochemical level through its action on the alveolar Type II epithelial cell. This will be done by showing: (a) uptake and metabolism of retinol to retinoic acid; (b) presence of cellular- binding protein for retinol (CRBP); (c) presence of retinoic acid nuclear receptors (RARs), quantitation of expression. Other experiments will demonstrate biochemically that vitamin A contributes to the integrity of the differentiated state of type II epithelial cells in culture. These include: (a) synthesis of phospholipids in control and vitamin-A-deficient cells; (b) measurements of the status of Type II cell markers in cells of control and deficient animals, and the effect of vitamin A (retinoic acid). Finally, we will study the effects of oxygen on lung vitamin A.
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