Elevation of retinyl ester level in the lungs of rats following repeated intraperitoneal injections of retinoic acid or retinoyl glucuronide

Barua, Arun B.; McGowan, Stephen E.; Ivanoff, Kristi D; Goswami, Bhabesh C.; Olson, James A.

doi:10.1016/j.pupt.2003.12.001

Cited by 6 publications

(4 citation statements)

References 27 publications

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“…Indeed, kinetic studies carried out in adult rats have indicated a regulatory role of RA on the metabolism of retinol (47), as the fractional uptake of [ 3 H]retinol from plasma into the lungs was increased in rats fed RA in the diet, as was the VA content of the lungs. Similarly, lung RE was higher in adult rats treated with a water-soluble metabolite of RA, retinoyl-b-glucuronide, or RA for 12 days (48). However, to our knowledge, an oral supplement of VA combined with RA has not been studied previously.…”

Section: Discussionmentioning

confidence: 87%

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

Ross

Ambalavanan

Zolfaghari

et al. 2006

Journal of Lipid Research

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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...

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Section: Discussionmentioning

confidence: 87%

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

Ross

Ambalavanan

Zolfaghari

et al. 2006

Journal of Lipid Research

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“…In those neonates given VARA, the concentration of RE in the lungs was increased synergistically, several times more than by the same amount of VA alone. Other studies in adult rats treated by repeated intraperitoneal doses of RA (21) or fed a high level of RA in the diet (22) have also shown that RA increases the storage of VA in the lungs. However, in our studies, the RA dose was much lower and the effect of VARA on lung RE was apparent after the first dose (20).…”

Section: Introductionmentioning

confidence: 85%

The Components of VARA, a Nutrient-Metabolite Combination of Vitamin A and Retinoic Acid, Act Efficiently Together and Separately to Increase Retinyl Esters in the Lungs of Neonatal Rats

Ross¹,

Li²,

Wu³

2006

The Journal of Nutrition

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Retinoic acid (RA), produced from vitamin A (VA, retinol), is required for normal lung development and postnatal lung maturation. The concentration of retinyl ester (RE), the major storage form of retinol, decreases in the lungs in the perinatal period. Previously, we tested VARA, a nutrient-metabolite combination of VA and RA (10:1 molar ratio), on lung RE formation in postnatal rats and showed that the components of VARA acted synergistically to increase lung RE, as compared with the effects of equal amounts of VA and RA given alone. In this study, we first determined the equivalency of orally administered VARA in comparison to a standard oral supplement of VA, with respect to lung and liver RE storage. In a dose-dilution study, VARA was 4 times as effective as the standard dose of VA (VARA-25% did not differ from VA-100%). The synergistic effect of VARA was selective for the lungs, compared with the liver, in which VA and VARA had equal effects. Secondly, we tested whether the 2 components of VARA must be coadministered to exert their synergistic effect on lung RE content. RA and VA and were administered separately and together as VARA. Although RA alone had no effect on lung RE in this 24-h experiment, RA synergized with VA administered either 12 h before RA or 12 h after RA, as well as when coadministered as VARA. We infer that VA and RA are both limiting for lung RE formation in neonates. Given the importance of bioactive retinoids in cell differentiation and lung development, assuring an adequate lung RE content postnatally could be of benefit for lung maturation.

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“…High recoveries were achieved for RA and a new internal standard, at-4,4-dimethyl-RA, was used. Barua et al (2004) extracted ROH, RA, and RE from rat lung tissue after daily intraperitoneal injections of RA or retinoyl -glucuronide. Chopped tissue ground with anhydrous sodium sulfate to remove water was extracted with 2 volumes (w/v) 2-propanol/dichloromethane (1:1 v/v), filtered, and the solid residue further extracted three to four times with dichloromethane.…”

Section: Extractionmentioning

confidence: 99%

“…Chopped tissue ground with anhydrous sodium sulfate to remove water was extracted with 2 volumes (w/v) 2-propanol/dichloromethane (1:1 v/v), filtered, and the solid residue further extracted three to four times with dichloromethane. The pooled extracts were dried by vacuum and dissolved in 500 L 2-propanol/dichloromethane (1:1 v/v) before chromatographic analysis (Barua et al, 2004). McCaffery et al (2002) extracted RA and ROH from rat liver homogenate with a mixture of ethanol/2-propanol (2:1 v/v; 1 mL/100 mg wet tissue), while RA was extracted from retina isolated from mice (embryonic day 13-15) using hexane-dioxane-2-propanol 25:5:0.5 (v/v/v).…”

Section: Extractionmentioning

confidence: 99%

Methods for detecting and identifying retinoids in tissue

Gundersen

2006

J. Neurobiol.

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Methods for retinoid analysis in tissue include direct spectrophotometry or fluorometry and retinoid responsive reporter constructs in the form of cell reporter assays or transgenic reporter animals, but chromatographic methods dominate and posses several superior features in quantitative analysis. The multitude of extraction protocols used can coarsely be divided into manual liquid-liquid extraction protocols and semi-or fully automated solid phase extraction-based protocols.Liquid chromatographic separation in reversed phase dominates although normal phase is also used. Detection is mainly performed with UV detectors although electrochemical and fluorescence detection is also used. Mass spectrometry in combination with LC is more often used in retinoid analysis and is likely to dominate in the future.

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Elevation of retinyl ester level in the lungs of rats following repeated intraperitoneal injections of retinoic acid or retinoyl glucuronide

Cited by 6 publications

References 27 publications

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

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

The Components of VARA, a Nutrient-Metabolite Combination of Vitamin A and Retinoic Acid, Act Efficiently Together and Separately to Increase Retinyl Esters in the Lungs of Neonatal Rats

Methods for detecting and identifying retinoids in tissue

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