Vitamin A combined with retinoic acid increases retinol uptake and lung retinyl ester formation in a synergistic manner in neonatal rats

Abstract

Vitamin A (VA) is stored in tissues predominantly as retinyl esters (REs), which provide substrate for the production of bioactive retinoids. Retinoic acid (RA), a principal metabolite, has been shown to induce postnatal lung development. To better understand lung RE storage, we compared VA (given as retinyl palmitate), RA, and a nutrient-metabolite combination, VARA, given orally on postnatal days 5-7, for their ability to increase lung RE in neonatal rats. VARA increased lung RE significantly [z14, 2.4, 2.1, and ,1 nmol/g for VARA, VA, RA, and control (C), respectively; P , 0.001]; the increase by VARA was more than additive compared with the effects of VA and RA alone. Lung histology and morphometry were unchanged. In a 6 h metabolic study, providing [ In conclusion, VARA, a 10:1 nutrientmetabolite combination, increased lung RE significantly compared with VA alone and could be a promising therapeutic option for enhancing the delivery of VA to the lungs.-Ross, A. C., N. Ambalavanan, R. Zolfaghari, and N-q. Li. Vitamin A combined with retinoic acid increases retinol uptake and lung retinyl ester formation in a synergistic manner in neonatal rats. Retinyl esters (REs) are the most abundant form of vitamin A (VA) in most tissues (1). The hydrolysis of RE generates retinol, which, through oxidative metabolism, yields retinoic acid (RA) (2), a retinoid hormone capable of activating nuclear retinoid receptors and thereby inducing or repressing the transcription of many genes (3-5). Among its many physiological actions, RA regulates cell proliferation, differentiation, and cell-cell interactions (6). For the lungs, retinoids are essential for normal morphogenesis in the fetal period, for maturation and remodeling in the perinatal and postnatal periods, and for maintenance of the fully matured lungs (7-10). In humans, the lungs undergo septation of the thick-walled air saccules in the perinatal period, beginning at approximately week 28 of gestation, with a 2-to 4-fold increase in the gas exchange surface area by weeks 30-40 (7, 11, 12). In rats and mice, septation and the formation of pulmonary alveoli occur mainly in the first 2 weeks of postnatal life (7,10,(12)(13)(14). Whereas a deficiency of dietary VA for 6 weeks resulted in an increased size of rat lung airspaces and reduced elastin in the parenchyma (15), the administration of RA to neonatal rats from postnatal day 3 to 14 increased the septation of the lungs (16,17). RA also attenuated the oxygen-induced inhibition of alveolarization in rats reared during the period of septation in a hyperoxic environment (18). Retinol has shown promise in reducing pulmonary dysfunction in a lamb model of preterm lung injury (19) and in clinical studies of preterm human infants susceptible to bronchopulmonary dysplasia (20)(21)(22)(23)(24)(25).The neonatal rodent is a useful model in which to study the biochemical and morphological development of the lungs in the perinatal period. Previous studies have characterized the ontogeny of RE storage in the lungs and liver...

Vitamin A Supplementation Transiently Increases Retinol Concentrations in Extrahepatic Organs of Neonatal Rats Raised under Vitamin A–Marginal Conditions

“…This observation was similar to findings in neonatal piglets, in which the liver ranked as the highest in terms of retinol concentration, followed by the kidneys and lungs, irrespective of VA treatment (23). However, kinetic studies in rats supplemented with VARA have shown a dramatic stimulatory effect of supplementation on the uptake and retention of retinyl esters by the lungs and intestine (14,36), consistent with the previously demonstrated role of retinoic acid in upregulating genes responsible for VA storage (37)(38)(39). Based on these results, we speculate that VA alone may not be as effective as VARA in promoting extrahepatic retinol deposition, although future kinetic analyses of our data are needed to confirm this hypothesis.…”

Acidic retinoids synergize with vitamin A to enhance retinol uptake and STRA6, LRAT, and CYP26B1 expression in neonatal lung

“…In experiment 1 (3 day study, n = 4/group) 5 day old neonates were treated once a day for 3 days with oil (control), VA alone, RA, 9-cis -RA, both isomers mixed in a 1:1 ratio, or VA combined with each the same acidic retinoids. Twenty-four hours after the last treatment, neonates were euthanized and tissues collected ( 12 ). In experiments 2 and 3 (acute studies lasting 6 and 12 h), 6-7 day old pups were treated with oil (control), VA alone, RA alone, Am580 alone, VA combined with RA (VARA), or with Am580 (VAAm).…”

“…As RA is not reduced to retinol in vivo and thus is not a substrate for tissue RE synthesis, the increase in RE in the lungs implies that RA plays a regulatory role in this organ, in some manner facilitating RE formation. The synergistic effect of VARA was selective for the lungs, as RE formation in the liver did not differ between VARA and an equal dose of VA only ( 12,17 ). In a metabolic study using [ 3 H]retinol to trace the uptake of newly absorbed retinol, we found that RA served to direct more of the [ 3 H]retinol tracer and, thus, the oral VA supplement, into the neonatal lung ( 12 ).…”

Retinoic Acid Fails to Reverse Oligohydramnios-Induced Pulmonary Hypoplasia in Fetal Rats

“…The administration of ATRA to pregnant rats results in the rapid transfer across the placenta to the fetuses (27). Lung retinyl ester was increased in neonatal rats treated with ATRA and retinyl ester storage granules were increased by exogenous ATRA in cultured lipid interstitial cells (28,29). RA exerts its effects through nuclear retinoic acid receptors, which are present in the fetal rat lung (30).…”