Retinoids in lung development

Abstract

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.

Alveolarization in Retinoic Acid Receptor-β–Deficient Mice

“…The distance from one wall of the marked airspace to the opposite wall was measured using a ruler in the same orientation as the horizontal portion of the cross on the transparent grid. This dimension is the point-sampled intercept (1) and was used to calculate the volume of the individual airspaces using the formula l 3 /3. An average of 34 alveoli and 19 alveolar ducts or sacs were measured per animal.…”

“…Retinoids regulate the development of the conducting airways and the gas-exchange portion of the lung (1). The major biologically active retinoid, all-trans retinoic acid, is a metabolite of retinol (vitamin A) (2).…”

“…The major biologically active retinoid, all-trans retinoic acid, is a metabolite of retinol (vitamin A) (2). Retinol can be stored within lung tissue esterified to fatty acids, where it can be released by retinyl ester hydrolases and then be converted to all-trans retinoic acid (1). All-trans retinoic acid binds with high affinity to retinoic acid receptors (RARs), which exist in three isoforms, ␣, ␤, and ␥ (3).…”

Effects of Retinoic Acid on Airspace Development and Lung Collagen in Hyperoxia-Exposed Newborn Rats

“…In a subsequent study, Massaro and Massaro (14) demonstrated that the inhibition of alveolarization produced by dexamethasone treatment of newborn rats could be attenuated by the administration of retinoic acid. In addition to antagonizing some actions of dexamethasone, retinoic acid has been shown to play a role in lung development (15)(16)(17)(18), and retinoids appear to participate in lung repair after hyperoxic injury (19,20).…”

Sp1 up-regulates cAMP-response-element-binding protein expression during retinoic acid-induced mucous differentiation of normal human bronchial epithelial cells

“…Retinoic acid (RA) exerts a profound effect on vertebrate development, cellular differentiation, and homeostasis [1][2][3][4]. In addition, RA plays a pivotal role in the induction and maintenance of mucociliary differentiation of airway epithelial cells [5][6][7][8][9][10].…”