20 THE IMPORTANCE OF VITAMIN ARetinyl palmitate (μg/g weight)figure 3: Pattern of retinyl ester concentration inthe pre- <strong>and</strong> post-natal rat lung (Masuyuma et al., 1997). 38The data show the 10-fold concentration of retinyl estersin the fetal lung, compared to the adult lung of the rat.The rapid decline prior to birth documents theimportance of retinyl ester hydrolysis to form retinol<strong>and</strong> subsequently retinoic acid. The latter controlslung maturation.6543Birth21015 17 19 21 1 3 5 7 AdultPrenatal Postnatalmight be a very small window during which the retinyl esters arestored in the lung shortly before they are needed. If, in the caseof early delivery, the stores are not adequately filled, this mighthave serious consequences for lung maturation. Retinoic acidreceptor (RAR) <strong>and</strong> RAR mRNA were detected in all samplesobtained from perinatal <strong>and</strong> adult rat lung, but only a trace ofRAR mRNA was detected in the fetuses on days 15, 17 <strong>and</strong> 19of gestation <strong>and</strong> in adults. After a maternal retinol deficiency of28 days, fetal body <strong>and</strong> lung weights were significantly lowerthan those of the controls; concentrations of retinyl palmitate<strong>and</strong> phosphatidylcholine (PC) in the lung after a maternal retinoldeficiency over 14, 21, or 28 days were significantly lowerthan those of controls. Expression of RAR mRNA in the groupwith 28-day retinol deficiency was lower than in controls. Thatof RAR mRNA was increased <strong>and</strong> that of RAR mRNA was notinfluenced by retinol deficiency. In the developing mouse embryo,RAR expression is spatially <strong>and</strong> temporally restricted invarious tissues, suggesting a role for RAR in morphogenesis. 39RAR is both a strong target for RA <strong>and</strong> also highly activated bytreatment with exogenous RA. 40 The rate of choline incorporationinto PC in fetal lung explants was significantly higher in thegroup treated with RA than in the controls. RA enhanced theeffect of epidermal growth factor on choline incorporation <strong>and</strong>prevented that of dexamethasone. Taken together, marginal deficiencyresults in the altered expression of nuclear receptors ofvitamin A, with impaired maturation as a consequence.The influence of vitamin A supply for the post-nataldevelopment of the lung in preterm infantsAn adequate vitamin A intake during pregnancy is of great importancefor the formation of retinyl ester stores in the developinglung. These stores are the basis for RA formation during lungmaturation <strong>and</strong> postnatal function, with long-term benefits asabove. 18 However, in the case of early delivery or very low birthweight, an insufficient vitamin A supply during pregnancy mighthave serious consequences.A disease observed recurrently in connection with vitamin Asupply is bronchopulmonary dysplasia (BPD). The pathogenesisof BPD certainly depends on a multitude of factors. Some of theobserved morphological changes are strongly reminiscent ofvitamin A deficiency in humans <strong>and</strong> animals. Of particular noteis the focal loss of ciliated cells with keratinizing metaplasia <strong>and</strong>necrosis of the bronchial mucosa, as well as an increase in mucoussecreting cells. 41Focal keratinizing metaplasia, such as may occur after vitaminA deficiency, especially strengthens the assumption of animpairment of differentiation on the level of gene expression.Since vitamin A regulates the expression of different cytokeratins<strong>and</strong> therefore influences terminal differentiation, it seemsobvious to assume the existence of common mechanisms. Consequently,premature neonates are dependent on a sufficientsupply of vitamin A to ensure adequate lung maturation. Theearlier a child is born before its due date, the lower its serumretinol levels. 31Retinol serum levels in neonatesIt was shown repeatedly that serum retinol level <strong>and</strong> RBP leveldepends on birth weight <strong>and</strong> is significantly lower in prematureinfants with low birth weight, compared to similar-aged neonateswith higher birth weight. 30 In addition, mothers from lowincome groups had lower levels of serum vitamin A <strong>and</strong> a higherincidence of prematurity. 42 Significantly lower retinol levels canbe found in the liver of premature infants, in comparison to neonates.43 Plasma values lower than 0.70 μmol/L are not rare inthis case, <strong>and</strong> they should be taken as an indicator of a relativevitamin A deficit.Very low plasma vitamin A levels can be found recurrentlyin premature infants compared to term neonates. 44,45 This can,among other things, be attributed to the relative immaturity ofthe liver for the synthesis of retinol binding proteins. The neonateis almost exclusively dependent on the mother for its supply: thisincludes the lung retinyl esters which are either directly absorbedby the cells (from chylomicrons) or by esterification of retinolafter uptake into the cells. These lung retinyl ester stores can onlybe sufficiently filled if the mother guarantees an appropriate vitaminA supply, especially during late pregnancy.Reduced plasma levels during the first developmental months
SIGHT AND LIFE | VOL. 25 (1) | <strong>2011</strong> THE IMPORTANCE OF VITAMIN A 2121have a considerable influence on the total development of infants,as well as on their susceptibility to infections. In the caseof reduced retinol plasma levels, repeated infections are moreoften described, 3,46 <strong>and</strong> are counted among the main complicationsof a poor vitamin A supply in developing countries. Inaddition, the serum vitamin A level during infectious diseases,particularly of the respiratory tract, continues to drop. 47,48 Thiscan be explained on the one h<strong>and</strong> by an increased metabolicdem<strong>and</strong>, <strong>and</strong> on the other h<strong>and</strong> by renal elimination of retinol<strong>and</strong> of RBP during the process of acute infections. 49 If the retinylester stores of the lung are low at delivery, these storage sites arereplenished with difficulty, <strong>and</strong> as a consequence lung functionmay be impaired.Marginal vitamin A deficiency in developed countriesEven in developed countries with a wide variety of food containingpreformed vitamin A, low plasma levels (
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