Rough and rocky road to the retinoid revolution.

Some of us who were born in the middle of Europe between World Wars I and II had to face quite a few unusual challenges that we all met in different ways. I was born and raised in Prague, Czechoslovakia, a country at the time of my birth that was governed by a Western style of democracy, which was later destroyed by the occupation by Nazi Germany and subsequently by the takeover by the equally cruel Communists. Life required special means of adaptation to the changing living conditions and a great deal of luck to survive.

Vitamin A status and postnatal dexamethasone treatment in bronchopulmonary dysplasia.

Objective: Vitamin A (retinol) plays an important role in epithelial regeneration during recovery from lung injury in bronchopulmonary dysplasia (BPD). Dexamethasone is used in the postnatal treatment of very low birth weight (VLBW) neonates with BPD. To test the hypothesis that the vitamin A status is critical for the beneficial pulmonary response to dexamethasone, we performed a prospective cohort study in which we characterized the changes in plasma concentrations of vitamin A and retinol-binding protein (RBP) in response to dexamethasone, and correlated these changes with the pulmonary outcome.

European Consensus Statement on Lung Cancer: risk factors and prevention. Lung Cancer Panel.

This article is based on discussions of the lung cancer panel at the Hohenheim Consensus Meeting organized by the World Health Organization and the German Ministry of Health in November 1996. Panel members were international experts in the field of diet and cancer who discussed specific questions relating to lung cancer risk factors and prevention.

Safety aspects of vitamin A administration.

Objective: To review longstanding experience in the safe use of vitamin A as therapeutic agent in prematurely born human neonates and more recently with young children infected with the respiratory syncytial virus (RSV).

Design: The studies reviewed were designed to intervene with vitamin A in the form of retinyl palmitate in human neonates and infants showing low levels of retinol in the blood.

Setting: Vanderbilt University School of Medicine.

Retinoids in lung development.

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.

Regulation of metabolism by retinoic acid and its nuclear receptors.

It is now well established that the pleiotropic effects of vitamin A-with the exception of the vision process-are mediated by its acid derivatives. Although all-trans retinoic acid has been known for some time to be an essential regulator for many important biological processes, critical roles for other acid derivatives have more recently emerged. The acid isoforms affect a large diversity of biological systems, including embryonal cells, lymphoid cells, and nerve and muscle cells, as well as essential developmental programs.

Safety and pharmacokinetics of vitamin A therapy for infants with respiratory syncytial virus infections.

Infants with respiratory syncytial virus infection have low serum vitamin A levels. We treated 21 respiratory syncytial virus-infected children with 12,500 to 25,000 IU of oral vitamin A. Vitamin A levels were normalized at 6 h, and none of the children experienced vitamin A toxicity or exacerbation of respiratory illness.

Vitamin A status and airway infection in mechanically ventilated very-low-birth-weight neonates.

Vitamin A (retinol) plays an important role in immunity. Respiratory and enteral infections in children are associated with low serum vitamin A concentrations that improve during recovery. To test the hypothesis that airway infection in very-low-birth-weight (VLBW) neonates likewise may be associated with a change in vitamin A status, we examined 20 VLBW neonates (selection criteria: birth weight 700-1300 g, gestational age 26-30 weeks, need for supplemental oxygen and mechanical ventilation for > 72 hr after birth) who were enrolled in the control group of a randomized clinical trial of vitamin A supplementation reported earlier.

Mainstream and sidestream cigarette smoke exposure increases retinol in guinea pig lungs.

We have studied in guinea pigs the effects of cigarette smoke exposure on vitamin A (retinol) levels in plasma, lung, lung lavage, and liver. Smoke was generated from 1R3F cigarettes in a smoke exposure instrument designed by University of Kentucky Tobacco and Health Research Institute. Three-week-old male guinea pigs were exposed to mainstream, sidestream, or sham smoke, generated twice daily from three cigarettes for 6 weeks.

Sequential evaluation of plasma retinol-binding protein response to vitamin A administration in very-low-birth-weight neonates.

Vitamin A (retinol) deficiency is associated with impaired healing from lung injury in very-low-birth-weight (VLBW) neonates susceptible to bronchopulmonary dysplasia (BPD). Vitamin A supplementation from birth may ameliorate this adverse outcome. We hypothesized that plasma retinol-binding protein (RBP) response to vitamin A administration, which provides a dynamic measure to vitamin A status, might be useful for early recognition of vitamin A deficiency in VLBW neonates at risk for BPD.

Intramuscular versus enteral vitamin A supplementation in very low birth weight neonates.

We conducted a randomized trial in very low birth weight neonates (n = 51) to determine whether vitamin A supplementation by enteral administration would increase plasma vitamin A concentrations to the same degree as by intramuscular administration. Mean plasma vitamin A concentrations were significantly higher in the intramuscular-administration group than in the enteral-administration group by postnatal day 7; this effect persisted throughout the remainder of the trial. At the dosage used in this trial, vitamin A supplementation by the enteral route is not as effective as that by the intramuscular route in very low birth weight neonates.

Depletion of retinyl esters in the lungs coincides with lung prenatal morphological maturation.

Close to birth rat fetuses have lungs which are depleted in retinyl esters. Glucocorticoids administered to pregnant rats accelerate this process. We have investigated changes in fetal lung levels of retinol and retinyl palmitate and accompanying morphological changes after administration of dexamethasone to pregnant rats on day 18 of pregnancy.

Serum vitamin A levels in respiratory syncytial virus infection.

Respiratory syncytial virus causes worldwide epidemics of respiratory disease. Of 23 children infected with respiratory syncytial virus, 65% had low serum concentrations of vitamin A during acute illness; these low values were associated with more severe illness. Vitamin A supplementation may have a role in the management of infection with respiratory syncytial virus.

Effect of maternal dexamethasone treatment on fetal lung vitamin A stores in the perinatal rat.

Vitamin A (retinol) is essential for normal differentiation of developing respiratory epithelium. Significant vitamin A storage occurs in the fetal lung near term (gestational day 21) in the perinatal rat, and the developing lung may be dependent on these local vitamin A stores during growth and differentiation. The growth and differentiation of fetal lungs can be enhanced by maternal treatment with glucocorticosteroids.

A retinoic acid response element from the rat CRBPI promoter is activated by an RAR/RXR heterodimer.

The expression of the rat cellular retinol binding protein I (rCRBPI) can be upregulated in vivo by retinoic acid (RA). Here we have analyzed the rCRBPI promoter region and compared it to the corresponding mouse sequence. We find that the CRBPI 5' flanking region has been highly conserved between rat and mouse, including a RA response element (RARE) approximately 1 kb upstream of the start of transcription.

The lungs and vitamin A.

Evidence is reviewed supporting the view that vitamin A (retinol) and its metabolite, retinoic acid, called natural retinoids, are major factors involved in differentiation and in maturation of the lungs. This conclusion is based on morphological observation that lack of this dietary micronutrient causes keratinizing squamous metaplasia of the bronchopulmonary tree that can be reversed by refeeding the animal with retinol. In addition to these observations suggesting an indirect participation of retinol and/or retinoic acid in the differentiation of this organ, more direct evidence is presented that this vitamin is involved in pulmonary gene expression.

Effect of retinoids on nuclear retinoic acid receptors mRNA in adipose tissue of retinol-deficient rats.

In this study, we examined effects of retinol deficiency and three retinoids, all-trans-retinoic acid, 13-cis-retinoic acid, and etretin, the aromatic derivative of retinoic acid on nuclear retinoic acid receptor isoforms alpha, beta, and gamma mRNA in rat adipose tissue. Retinol deficiency caused an almost 50% decrease in isoform beta mRNA levels of adipose tissue, whereas little change occurred in the abundance of alpha and gamma isoforms transcripts in this tissue. Intragastric administration of all-trans-retinoic acid to retinol-deficient rats increased the adipose tissue retinoic acid receptor isoforms beta and gamma mRNA levels sixfold and twofold, respectively, in 4 h as compared to adipose tissue of retinol-deficient rats that were administered cottonseed oil.

Differential effects of all-trans and 13-cis-retinoic acid on mRNA levels of nuclear retinoic acid receptors in rat lung and liver.

The effects of three retinoids, all-trans-retinoic acid (all-trans-RA), 13-cis-RA, and etretin were examined on mRNA abundance of nuclear retinoic acid receptors (RAR-alpha, beta, and gamma) in lung and liver of retinol deficient and chow fed rats. All-trans-RA increased lung RAR-beta mRNA levels 5 or 11-fold in chow fed and retinol deficient rats, respectively. Similarly to lung, liver RAR-beta mRNA levels were 3-fold higher in retinol deficient rats fed all-trans-RA than the rats fed cottonseed oil.

Retinoic acid affects the expression of nuclear retinoic acid receptors in tissues of retinol-deficient rats.

The multitude of biological effects of the vitamin A metabolite, retinoic acid, are mediated by nuclear retinoic acid receptors (RARs), which are members of the steroid/thyroid hormone receptor superfamily. RAR-alpha, -beta, and -gamma are encoded by three genes from which multiple isoforms can be generated. Recent studies suggest that the expression of at least some RAR isoforms can be regulated by retinoic acid in certain cell lines.

Opposing effects of retinoic acid and dexamethasone on cellular retinol-binding protein ribonucleic acid levels in the rat.

Cellular retinol-binding protein (CRBP) is a potential mediator of vitamin A action. To determine whether retinoic acid and dexamethasone administration, alone and in combination, influence CRBP gene expression, adult female vitamin A-sufficient Sprague-Dawley rats randomly received 1) all-trans retinoic acid (100 micrograms) by intragastric intubation, 2) dexamethasone (2 micrograms/g BW) by ip injection, or 3) both all-trans retinoic acid and dexamethasone in the same doses. Control animals received either cottonseed oil by intragastric intubation or saline by ip injection.