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The "retinoid revolution" has had considerable impact on research activity in the field of lung development. Postnatal lungs are very sensitive to dietary retinol (R) deprivation. The trachea and the bronchopulmonary tree in R-deficient animals show a striking change in morphology. The columnar epithelium undergoes keratinizing metaplasia, which is reversed when R is supplied. The fetal lung develops postnatally to become one of the most complex organs, characterized by 40 different cell types. The fetal lungs can accumulate retinyl esters. Before birth an unknown signal causes the lowering of these esters, which may be the source of retinoic acid (RA). The administration of glucocorticoids speeds up this process, which in turn is followed by acceleration of lung maturation, ending postnatally. It is not clear what role, if any, the cellular retinoid binding proteins play in this phenomenon. Fetal lung branching leading to the development of the alveolar tree is accelerated by RA, and so is the expression of some fetal genes coding for surfactant proteins and the enzymes that produce their lipid components. It is not clear whether RA influences the development of pulmonary epithelium by interacting directly with the epithelial cells or whether its effects require interaction with other cels like mesenchymal cells. Nuclear RA receptors are intimately involved in lung development. Despite the wealth of evidence on the effect of retinoids on lung development, the application of vitamin A to clinical work has been limited to prematurely delivered infants who have immature lungs. Here attempts are made, by improving their R status, to aid in the development and healing of lungs injured by oxygen therapy.

ABSTRACT. We prospectively assessed and compared the vitamin A status of two groups of preterm neonates (~1 5 0 0 g birth weight, <32 wk gestation), one who developed clinical and radiographic evidence of bronchopulmonary dysplasia (BPD) (n = lo), and the other (control) who developed no significant lung disease (n = 8). The infants with BPD in this study required prolonged mechanical ventilation and supplemental Oz therapy, and had a higher incidence of cardiorespiratory complications when compared to controls. Their mean plasma vitamin A concentrations were significantly lower than those of controls at four sampling times in the 1st postnatal month. In contrast to the controls, infants with BPD showed a substantial decline in their plasma vitamin A concentrations from the initial values, and a high percentage of individual values of plasma vitamin A concentration in these infants were

Retinoic acid may be the natural morphogen used to generate digit pattern in the chick limb bud. It has been proposed that retinoic acid acts by binding to a cellular retinoic acid-binding protein (CRABP) and then entering the nucleus to alter the pattern of gene activity. High-affinity receptors that bind both retinoic acid and DNA and are analogous to the steroid receptors have been identified. But the concentration of endogenous retinoic acid in the limb and the binding coefficient of the nuclear receptors indicate that they are saturated throughout the limb. Here we investigate the CRABP distribution in the developing chick limb bud. We find CRABP in the area of intense morphogenetic activity at the tip, with a differential distribution across the anteroposterior axis, the high point being at the anterior margin. Retinoic acid also forms a concentration gradient across the limb bud, but is highest on the posterior side. We propose that CRABP could be reducing the effective concentration of retinoic acid reaching the nucleus to a level appropriate for the differential regulation of gene transcription, providing a spatially modulated morphogenetic gradient of information for digit formation.

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