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© 2007 American Society for Nutrition J. Nutr. 137:2371-2376, November 2007

Nutrient Physiology, Metabolism, and Nutrient-Nutrient Interactions

Retinol Combined with Retinoic Acid Increases Retinol Uptake and Esterification in the Lungs of Young Adult Rats when Delivered by the Intramuscular as well as Oral Routes1,2

A. Catharine Ross3,4,* and Nan-qian Li3

3 Department of Nutritional Sciences and 4 Huck Institute for the Life Sciences, The Pennsylvania State University, University Park, PA 16802

* To whom correspondence should be addressed. E-mail: acr6{at}psu.edu.


   ABSTRACT
TOP
 ABSTRACT
Introduction
 Materials and Methods
 Results and Discussion
 LITERATURE CITED
 
The lungs require an adequate supply of vitamin A for normal embryonic development, postnatal maturation, and maintenance and repair during adult life. We have previously shown that a nutrient-metabolite combination of vitamin A admixed with a small proportion (10%) of retinoic acid (RA), referred to as VARA, acts synergistically to increase lung retinyl ester (RE) concentration in neonatal rats. A series of studies was designed to test whether VARA increases RE in adult lungs, and whether VARA is more effective than vitamin A when given by the i.m. route. Orally administered VARA increased RE in the lungs of vitamin A–marginal adult rats more than either vitamin A or RA alone (P < 0.05). In vitamin A–deficient young adult rats, lung RE was increased by VARA when administered by the i.m. route. When a tracer of 3H-retinol was added to the placebo (oil), vitamin A, and VARA doses, total 3H and 3H-RE increased in the lungs more with VARA than vitamin A alone, for oral and i.m. dosing. Nevertheless, when VARA and vitamin A were given by the oral route, they were more effective in increasing RE in the liver. Plasma retinol was increased similarly in vitamin A–deficient rats after administration of VARA and vitamin A, by either the oral or the i.m. route. Overall, VARA can increase retinol uptake and esterification in adult lungs when delivered intramuscularly as well as orally.


   Introduction
TOP
 ABSTRACT
 Introduction
Materials and Methods
 Results and Discussion
 LITERATURE CITED
 
Retinoic acid (RA)5 produced by the oxidative metabolism of vitamin A (retinol) is critical for normal lung morphogenesis (1–3). Retinoids continue to play an essential role in the postnatal period, when the structure of the lungs of newborn humans and certain other mammals, including rats and mice, undergoes further development. Specifically, beginning in the last fetal period in humans and the early postnatal period in rats and mice, the lung alveoli undergo septation, which results in a significant increase of the gas exchange surface area, and capillary remodeling (1,4). Several studies have provided evidence that the daily administration of all-trans-RA during the postnatal period of alveolarization can promote septation in rats and mice (2,5,6), whereas RA also has promoted tissue repair and regeneration in adult animal models of acute and chronic lung injury (7–10). Understanding what types of vitamin A supplementation are optimal for premature and term infants has important implications for clinical practice (11).

Although RA and some analogs have shown beneficial effects on lung development, it seems likely that the generation of retinoids in situ, from stored vitamin A, might be equally or more effective. It is possible that endogenously generated retinoids would comprise an appropriate physiological mixture of compounds, and that tissue storage of vitamin A could obviate the need for frequent dosing with RA, which has a short half-life in vivo (12). Retinyl esters (RE) are the major storage form of vitamin A in nearly all tissues. Evidence has accumulated from animal studies, cell culture studies, and the analysis of clinical samples to support the idea that when factors involved in cellular RE storage are limited or aberrant, cell transformation is likely (13–16). The RE content of most tissues, including the lungs and liver, is low at birth. In babies, low plasma retinol is associated with increased risk of bronchopulmonary dysplasia (BPD), and, conversely, vitamin A supplementation may improve the outcome in babies who develop BPD (11,17–19). Vitamin A deficiency in adult rats was shown to be associated with injury of the lung parenchyma (20). Overall, several lines of evidence converge to suggest that an adequate supply of vitamin A in the lungs in the postnatal period and in adults may be beneficial in reducing the risk of developing perinatal lung disease and/or promoting recovery after injury to the adult lung.

We have shown previously that an oral supplement of vitamin A admixed with a small proportion (10%) of RA, referred to as VARA, causes a synergistic increase in RE in the lungs of neonatal rats, as compared with the increases produced by the same amounts of retinol and RA given alone (21). The synergistic effect of VARA in neonates was both strong, equaling >5 times the increase produced by RA or vitamin A alone (21,22), and rapid, with a significant increase by 6 h after oral administration of VARA (21). The synergy between vitamin A and RA does not require coadministration, because RA administered either 12 h before or after vitamin A and still result in increased lung RE to a level greater than that after treatment with an equal amount of vitamin A given alone (22).

In practice, vitamin A is sometimes administered intramuscularly (i.m.) to infants or adults requiring parental nutrition or having bowel disease or other complications that preclude oral feeding (23,24). Bauernfiend et al. (25) reviewed studies showing that vitamin A given i.m. increased in plasma retinol within 1 d, whereas liver vitamin A storage increased more slowly before reaching a plateau ~1 wk after i.m. dosing. It has not, however, been tested whether RA, when delivered with vitamin A as a component of VARA, is effective in increasing RE in the lungs of adults, or whether VARA is also effective when given by the i.m. route. In the present series of experiments, we set out to determine whether VARA 1) increases RE concentration synergistically in the lungs of adult rats; 2) is effective in increasing lung RE concentration when given by the i.m. route; and 3) promotes the uptake and metabolism of newly absorbed or newly released 3H-retinol, used as a tracer, into the lungs of adult rats. We conducted these studies in young adult rats fed either a vitamin A–marginal or vitamin A–deficient diet after weaning to produce conditions of low vitamin A status, similar to the situation of children and adults most likely to be treated with vitamin A.


   Materials and Methods
TOP
 ABSTRACT
 Introduction
 Materials and Methods
Results and Discussion
 LITERATURE CITED
 
    Animals and experimental designs. Animal protocols were approved by the Animal Use and Care Committee of the Pennsylvania State University. The diets, designated vitamin A–deficient, marginal, and adequate, were modifications of the AIN-93G diet (purchased in pelleted form from Research Diets), formulated to contain 0, 0.3, and 4 mg/kg retinol, as retinyl palmitate, respectively. Female rats, 5–7 d old and nursed by vitamin A–adequate Sprague-Dawley dams (Charles River Breeding Laboratory) were fed the vitamin A–deficient diet or marginal diet (26) and their pups were weaned at 21 d of age to either the same diet as their dam, or the vitamin A–adequate diet, as indicated. Studies were conducted when the young adult rats were 7-wk old.

Each rat received vitamin A 10 nmol/g body weight (BW) and/or RA at 2 nmol/g BW. VARA was the exact combination and thus contained 10% RA as compared with vitamin A (21). In Experiments 1 and 2, doses were delivered orally, 0.4 µL/g BW, prepared in canola oil as the vehicle (21,22). Experiment 1 had 5 groups of rats: a vitamin A–adequate group for comparison of tissue retinol levels to the vitamin A–marginal placebo (oil) group, and rats treated orally with vitamin A, RA, or VARA daily for 3 d. These groups were compared with the placebo group and each other (see Statistics). Experiment 2 had 4 groups of rats, a vitamin A–adequate reference group treated with oil that was compared with the placebo group of vitamin A–marginal rats, and vitamin A–marginal rats treated with vitamin A and VARA. In this experiment, the RA component of VARA was given 6 h before the vitamin A component (referred to as a split dose) and the study ended 24 h after treatment with vitamin A. In Experiment 3, 3 groups of vitamin A–deficient rats were treated with oil, VA, or VARA, prepared exactly as for oral delivery but delivered i.m. Each dose was loaded into a 1-mL syringe just before delivery, air was eliminated, the volume was adjusted based on BW, and the dose was then injected into the right hind leg muscle through a 22 or 23 gauge needle. Rats were held on the arm of one investigator while another investigator made the injection, as by using this procedure the rats did not struggle and each dose was delivered quantitatively. Experiment 4 comprised 6 groups of vitamin A–deficient rats, 2 of which received only oil as vehicle, either orally or i.m., and 4 of which received vitamin A or VARA, either orally or i.m. This experiment also included a reference group of rats fed vitamin A–diet that were repleted to a state of vitamin A adequacy with 2 doses of 340 µg of retinol given orally 14 and 7 d before the end of the experiment. The test doses all contained a tracer of 3H-retinol (1.64 TBq/mmol, containing 1 g/L {alpha}-tocopherol from Perkin-Elmer), which was first mixed with oleic oil, 50 nmol/dose as carrier, dissolved in a small volume of canola oil, and distributed equally into each of the treatment doses, so that they all contained the same amount of 3H-retinol per volume. Rats received 0.4 µL/g BW either orally or i.m. The pipette tips used for oral dosing were extracted so that the amount of 3H-retinol present in the oral dose could be corrected for each rat, according to the amount of 3H-retinol that was left behind. The same dose preparations were used for the i.m. injections; these were delivered completely and thus there was no need for correction.

    Lipid extraction and total retinol and retinyl esters. Tissues were collected as described previously (26,27). In the first study, RE and retinol were resolved into individual peaks by HPLC and quantified separately (21). From the results of the first study, it was apparent that, despite quantitative differences, there were no discernible qualitative differences in either the proportion of RE (> 90%) vs. unesterified retinol, or the pattern of individual RE (palmitate/oleate > stearate > minor peaks) (21), and, therefore, we discontinued quantifying RE and retinol separately and instead determined total retinol after saponification, using trimethylmethoxyphenyl-retinol as an internal standard (28).

    Statistics. The effect of the diet (vitamin A–deficient or marginal vs. vitamin A–adequate or repleted) before treatment was analyzed in Experiments 1, 2, and 3 by unpaired t test. Treatment effects in each study were compared by 1-way ANOVA, followed by Fisher's protected least significant difference test or least squares means test. When variances were unequal, data were subjected to transformation (log10) before analysis. The relationship of 3H-RE and tissue total retinol was analyzed by linear regression analysis. Differences with P < 0.05 were considered significant.


   Results and Discussion
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results and Discussion
LITERATURE CITED
 
    VARA, more than vitamin A alone, increases lung retinyl esters and total retinol when administered orally to vitamin A–marginal young adult rats. Vitamin A concentrations in the lungs of vitamin A–marginal young adult rats equaled ~2.5 nmol/g tissue (Fig. 1A), slightly higher than the ~1 nmol/g concentration for the newborn/neonatal offspring of vitamin A–adequate mothers, as reported previously (21), and about half that of the vitamin A–adequate young adult reference group (P = 0.036, t test, Fig. 1A). After treatment with RA, vitamin A, or VARA for 3 consecutive d, lung RE + retinol (~95% RE) increased (P < 0.05 for all groups vs. oil). The increase in lung RE with VARA, as compared with vitamin A and RA given individually, was additive (Fig. 1A). The pattern of lung RE (palmitate/oleate > stearate > > unesterified retinol) was similar for each group (data not shown).


Figure 1
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  		FIGURE 1  Total retinol (RE plus retinol) concentrations in the lungs (A) and liver (B) of young adult vitamin A–marginal rats treated for 3 d with oil, RA, vitamin A, and VARA (Expt. 1). Values are means ± SE, n = 4 or 5. *Vitamin A–marginal oil group differs from the vitamin A–adequate reference group, P < 0.05 (t test). For the vitamin A–marginal rats, means without a common letter differ, P < 0.05.

 
In the liver of rats fed the vitamin A–marginal diet, the concentration of RE + retinol was below the value of 70 nmol/g liver, which is used as an indicator of low or inadequate vitamin A reserves in humans (29), and significantly less than the sum of RE + retinol in the liver of vitamin A–adequate rats (P = 0.005). Liver RE was unaffected by treatment with RA alone and was increased to the same level by vitamin A and VARA (Fig. 1B), similar to previous findings in neonatal rats (21,30). Differences among groups for unesterified retinol mirrored those for RE (not shown).

Experiment 2 tested the response to vitamin A vs. VARA given orally in a 24-h single-dose study in vitamin A–marginal young adult rats. To determine whether providing RA before vitamin A would "prime" the lungs to respond better to vitamin A, the VARA components were split with the RA component delivered 6 h before the vitamin A component. Lung total retinol increased significantly after vitamin A alone, equal to the level in the reference group fed the vitamin A–adequate diet continuously. The increase was greater with VARA (P < 0.005, Fig. 2A). For liver total retinol, effects of vitamin A and the split dose of VARA did not differ (Fig. 2B). Plasma retinol did not differ among any of the groups (data not shown).


Figure 2
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  		FIGURE 2  Total retinol in the lungs (A) and liver (B) of young adult rats of marginal vitamin A status treated for 24 h with oral doses of vitamin A or a split dose of VARA, in which the RA component was delivered 6 h before the vitamin A component (Expt. 2). A vitamin A (VA)–adequate (ad.) reference group was fed the vitamin A–adequate diet continuously from weaning. Values are means ± SE, n = 4. *Vitamin A–marginal oil group differs from the vitamin A–Ad. reference group, P = 0.049 (A) and P = 0.0001 (B). For the vitamin A–marginal rats, means without a common letter differ, P < 0.005 (A) and P < 0.0001 (B).

 
    VARA increases total retinol in lungs when delivered by the intramuscular route. Experiment 3 tested the response to vitamin A or VARA given by the i.m. route to vitamin A–deficient young adult rats. Biochemical vitamin A deficiency was confirmed by the very low lung, liver, and plasma total retinol levels before treatment (Fig. 3A–C), as compared with rats in the vitamin A–repleted group (all P < 0.005), but the rats did not exhibit physical signs of deficiency or slowing of growth. Whereas vitamin A-i.m. increased lung total retinol concentration (Fig. 3A), VARA-i.m. increased it twice as much, to a level 10 times that in the oil group (Fig. 3A). Total retinol in liver (Fig. 3B) and plasma (Fig. 3C) did not differ between the vitamin A- and VARA-treated groups.


Figure 3
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  		FIGURE 3  Total retinol in the lungs (A), liver (B), and plasma (C) of young adult vitamin A–deficient rats treated with vitamin A or VARA i.m. for 12 h (Expt. 3). Values are means ± SE, n = 4 or 5. *Vitamin A–deficient placebo group differs from the vitamin A–repleted reference group, P = 0.049 (A) and P = 0.0001 (B and C). For the vitamin A–deficient rats, means without a common letter differ, P < 0.01 (A) and P = 0.0001 (B and C).

 
    VARA increases newly absorbed 3H-retinol in the lungs, whether delivered by the oral or the intramuscular route. To confirm these results, and to determine whether the uptake and metabolism of newly absorbed retinol from the intestine or mobilized from the muscle is stimulated when 10% of RA is admixed with vitamin A, we compared treatments with vehicle alone (oral or i.m., which were similar and therefore were combined) to treatments with vitamin A and VARA, given either orally or i.m, in vitamin A–deficient rats. A reference group of vitamin A–repleted rats was also included. All groups received the same 3H-retinol tracer dose. Growth was not affected by the vitamin A–deficient diet (Table 1), but relative liver weight was slightly lower in the vitamin A–deficient placebo group. There was no evidence of fatty liver in these vitamin A–deficient rats, in contrast to a report for mice (31). Relative liver weight returned to values similar to the control group after treatment with vitamin A or VARA and correlated with the increase in plasma retinol (R2 = 0.37, P < 0.0004).


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  		TABLE 1 Characteristics of vitamin A–deficient, retinol-repleted, and vitamin A– and VARA-treated rats, and lung and liver 3H-RE 12 h after oral and i.m. dosing (Expt. 4)1

 
For the oral doses, the percentage of lipid-soluble 3H in the lungs increased in the order VARA-oral > vitamin A-oral > oil (all P < 0.05; Fig. 4A). Lipid-soluble 3H was also higher in the VARA-i.m. group than in the oil group, although it was not significantly elevated by VA-i.m. alone (VARA-i.m. > VA-i.m. = oil, P < 0.05). Combining the results for both routes of administration, RA doubled the 3H-retinol and its metabolites present in the lungs of young adult rats (P = 0.02). 3H-Retinyl ester increased in direct proportion to total retinol mass (Fig. 4B, R2 = 0.711, P < 0.0001), indicating that the tracer used to monitor the uptake, esterification, and accumulation of newly absorbed retinol in the lungs mirrored the increase in vitamin A mass. Overall, for both routes of delivery, lung total retinol was approximately doubled in groups treated with RA (mean ± SE, 30.7 ± 5.9 nmol/g) compared with untreated rats (13.6 ± 3.7 nmol/g, P = 0.017).


Figure 4
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  		FIGURE 4  Lipid-soluble total 3H and 3H- RE in the lungs (A,C) and liver (B,D) of rats 12 h after vitamin A and VARA, administered by either the oral or i.m. route (Expt. 4). Oil represents both oral and i.m. treatments, which did not differ and so were combined. In A and C, values are means ± SE, n = 4 or 5, except oil, n = 4. Means without a common letter differ, P <0.05. Correlations between 3H-RE and total retinol concentration in lung (B) and liver (D) are shown.

 
The recovery of 3H in the organic phase in the liver was low in the vitamin A–deficient oil group (Fig. 4C). The higher fractional uptake of 3H from the oral doses is likely to reflect the transport of newly absorbed vitamin A from the intestines by chylomicrons and the rapid clearance of most chylomicron remnants from plasma into the liver (32). In contrast, the lower fractional uptake of 3H from the i.m doses is likely to reflect the slower adsorption of 3H-retinol by retinol-binding protein (RBP). 3H-Retinol from the depot site of injection could potentially be bound by apo-RBP that was synthesized within muscle tissue (33) or by circulating apo-RBP during its transit through the extravascular tissue space (34). In the liver, unlike the lungs, RA had no discernable effect on 3H-retinol uptake and metabolism, but 3H-RE increased in direct proportion to total retinol (Fig. 4D, R2 = 0.77, P < 0.0001), indicating that the uptake and esterification of the newly administered 3H-retinol used as tracer closely resembled the increase in vitamin A mass in the liver over the 12-h period of this study. For both 3H-RE and total retinol, the increase was greater when vitamin A was delivered orally rather than intramuscularly.

The percentage of lipid-soluble 3H in the form of 3H-RE was low in both the lungs and liver in the vitamin A–deficient oil group (Table 1), which may reflect the very low lecithin:retinol acyltransferase (LRAT) gene expression and enzyme activity in vitamin A–deficient animals (35,36). Twelve hours after treatment with vitamin A or VARA by either the oral or i.m. route, 3H-RE was similar to or greater than in vitamin A–repleted rats (Table 1). Although esterification increased quickly, the percentage of 3H-retinol as 3H-RE was less than is typical for the percentage of total retinol present as RE in the steady state, >90% in lung and >95% in liver; this suggests that the esterification of the 3H-retinol dose was still incomplete at 12 h.

In conclusion, this study provides evidence that admixing a small proportion of RA (10%) into an amount of retinol similar to that used therapeutically promotes the uptake of retinol into the lungs, whether the dose is delivered by the oral or i.m. route. Thus intestinal absorption and metabolism of retinol and/or RA do not appear to be essential for VARA to increase RE and retinol in the lungs. Nonetheless, vitamin A and VARA administered orally were considerably more effective in reaching the lungs in our short-term studies than the same quantities of vitamin A and VARA given i.m. However, the oral doses were more effective in increasing liver vitamin A reserves, while plasma retinol was increased to ~1 µmol/L, regardless of the route of administration. We would predict that in situations in which the synthesis of RBP may be compromised, such as during inflammation or due to a nutritional deficiency of protein and/or energy, the uptake of retinol administered by the i.m. route could be even less efficient than in the present study, because inflammation and protein-calorie malnutrition are known to reduce the synthesis and plasma levels of RBP and retinol (37–39). On the other hand, the oral route may have an added advantage of providing retinoids directly to the intestinal epithelium, where they may have a beneficial effect on intestinal barrier functions (40) and gut-associated lymphoid cells (41). However, because VARA-i.m. increased lung RE compared with the placebo treatment, whereas vitamin A-i.m. did not, VARA could offer an advantage over vitamin A alone for delivering retinol to the lungs, when the enteral delivery of vitamin A is not possible.


   ACKNOWLEDGMENTS
 
We thank Dr. Sandhya Sankaranarayanan, Dr. Quiyan Chen, and Lili Wu for their helpful assistance with dose administration and tissue collection.


   FOOTNOTES
 
1 Supported by NIH CA-90214 and funds from the Dorothy Foehr Huck chair. Back

2 Author disclosures: A. C. Ross and N. Li, no conflicts of interest. Back

5 Abbreviations used: BPD, bronchopulmonary dysplasia; BW, body weight; RA, retinoic acid; RBP, retinol-binding protein; RE, retinyl ester; VA, vitamin A; VARA, a combination of vitamin A and RA, 10:1 molar ratio. Back

Manuscript received 6 June 2007. Initial review completed 4 July 2007. Revision accepted 23 July 2007.


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 Results and Discussion
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