Retinoic Acid Combined with Vitamin A Synergizes to Increase Retinyl Ester Storage in the Lungs of Newborn and Dexamethasone-Treated Neonatal Rats

Abstract

Background: Retinyl esters (REs), the major storage form of vitamin A (retinol), provide substrates for the production of bioactive retinoids, including retinoic acid (RA), which are known to promote lung development and maturation. We previously showed that the nutrient-metabolite combination VARA (molar ratio 10 vitamin A to 1 RA), synergistically increased REs in the lungs of 1-week-old rats, compared to vitamin A or RA alone. Objectives: To test the hypotheses, first, that VARA is more effective in increasing lung RE than is vitamin A in newborn rats prior to alveolarization, and, second, that the effect of VARA is maintained during concurrent treatment with the glucocorticoid, dexamethasone (Dex). Methods: Newborn rats were treated with VARA, vitamin A alone, or oil (C) on postnatal days (P) 1–3, and RE in the lungs was quantified on P4, and again on P8 to assess retention. Additionally, neonatal rats were treated on P5–7 with VARA with and without Dex, and the lung and liver REs were quantified on P8. Results and Conclusions: Lung RE was nearly 8-fold higher in VARA compared to vitamin A-treated rats on P4 (p < 0.01) and 2.5-fold higher on P8. In neonates co-treated with Dex and VARA on P5–7, the elevation in lung RE on P8 by VARA was not antagonized by Dex, although Dex reduced growth. Lung morphology and development were not significantly altered. The VARA combination may significantly increase lung RE content even during concurrent Dex therapy. Because lung retinoids are important for lung maturation and repair, increasing lung RE may possibly have clinical benefit.

Direct and indirect vitamin A supplementation strategies result in different plasma and tissue retinol kinetics in neonatal rats

“…For liver and lung tissues, a measured portion of the extract was taken for analysis of radioactivity by LSC and a portion was used for saponification and analysis of total retinol by UPLC. Previous studies have shown that, in liver and lung ( 18 , 19 , 21 ), >90% of total retinol is esterified and thus the values reported here for total retinol in these tissues represent mostly retinyl esters. For other tissues, all of the extract was evaporated to dryness and analyzed for 3 H radioactivity by LSC.…”

Retinoid Homeostatic Gene Expression in Liver, Lung and Kidney: Ontogeny and Response to Vitamin A-Retinoic Acid (VARA) Supplementation from Birth to Adult Age

“…The neonatal ages of observation were selected to represent the pre-, early, and mid-septation stages of postnatal lung development. As shown in Fig 1A , on the day of dosing (P1, P4, P7, P10 and 2 months), each pup received a single oral dose delivered directly into the mouth via a small micropipette, as previously described [ 4 – 6 ]. The volume of each dose was ~0.4 μL/g body wt adjusted after weighing.…”

Differential and Isomer-Specific Modulation of Vitamin A Transport and the Catalytic Activities of the RBP Receptor by Retinoids

“…It was discovered recently that vitamin A and all- trans -retinoic acid synergistically increase retinol uptake and retinyl ester storage in neonatal rat lung (James et al 2010; Ross and Ambalavanan 2007; Ross and Li 2007; Wu and Ross 2010) and antibody production by the spleen (Tan et al 2012). In addition to the ability of retinoic acid to stimulate STRA6 expression, the ability of exogenous retinoic acid to stimulate STRA6’s activity may contribute to enhanced retinoid uptake.…”