Sight and Life Magazine 1/2011

24 THE IMPORTANCE OF VITAMIN Afigure 7a: Schematic model of retinyl ester storage in the neonatal rat lung following VARA 67AA Lung RE on postnatal (P) days 4 and 8 in newborn rats treatedLog ₁₀ RE + retinol, nmol/g lung2.62.42.22.01.81.61.41.21.00.80.60.40.20c,d(1.6)b(5.5)P4a(45.7)d(1.0)c(2.8)P8b(6.8)with VARA, vitamin A or oil. Newborn rats (n = 7/group) were treatedon days 1, 2 and 3 with oil (control), vitamin A alone, or VARA, andlung RE was determined on P4 (n = 4/group) and P8 (n = 3/group).Data are the mean SD and were analyzed by 2-way ANOVA afterlog ₁₀ transformation (as illustrated), and the least squares meanstest. Values shown in parentheses are the anti-logs of the log ₁₀ means.(Adapted from Ross and Ambavalanan, 2007) 67B Lung and liver retinyl ester in 8-day-old rats treated with oil(control), VARA, dexamethasone (Dex), or Dex and VARA. (1) A LungRE + retinol concentration. (2) B Liver RE + retinol concentration.(3) C Plasma total retinol. For each treatment, n = 3 pools/groupwere analyzed by HPLC; each pool contained equal portions of tissueControlVitamin A aloneVARAAge: 0.0001Treatment: 0.0001Age*Trt: 0.003a > b > c > d, p < 0.003from 2 identically treated neonates. The results were analyzed bytwo-way ANOVA; different letters above groups indicate significantdifferences by the least squares means test. (Adapted from Ross andAmbalavanan, 2007) 67leads to higher plasma concentrations of retinyl palmitate and,subsequently, to higher uptake of the retinyl esters into tissues.However, the fact that more cases of retinopathy and necrotizingcolitis occurred in the once-per-week dose group, comparedwith the 10,000 IU three times per week group, may be the consequenceof the solubilzer polysorbate. Hale and co-workers 57evaluated the effect of the solubilizer (polysorbate 80) in neonatalpigs. The authors speculate that “rapid intravenous injectionof vitamin E emulsions produces massive accumulation inphagocytic cells of the spleen and to a lesser extent liver andlung, possibly leading to increased susceptibility to sepsis and/or abnormal pulmonary function.” The intravenously suppliedvitamin E (E-Ferol) led to deaths in 38 cases in 1984 in the USand was consequently stopped. Because a mixture of polysorbate80 and polysorbate 20 is used as a carrier in E-Ferol, thesecomponents were also tested and were found to be responsiblefor the suppression, especially the polysorbate 80.Improving lung retinyl ester storesRoss and co-workers documented a way to improve vitamin Asupply to the lung via administration of preformed vitamin A(VA) and RA (VARA) in a ratio of 10:1. 58 Based on their data, Rossand co-workers created a model of how and why retinyl esterstores are formed following delivery of preformed vitamin A plusRA. RA induces CYP26 and LRAT to save the cell from high andpotentially toxic concentrations. 59 As a consequence, the suppliedpreformed vitamin A entering the cell via the Stra6 receptoris stored as retinyl esters and the RA is detoxified; 6 h later,normal RA and ROH levels document the homoeostatic controlof the cell. (Figure 6)Ross and co-workers’ data also demonstrate that an isolatedsupply with RA might exert a short-term effect on lung maturation,but that, in the long term, the surplus of RA is detoxifiedand, consequently, without efficacy. In further experiments,James and co-workers showed that the synergistic effect of VARAon lung retinyl ester content was blunted in mice exposed tohyperoxia. 60 Regardless of the mechanism by which RA exerttheir effects, a sufficient content of retinyl esters or an increasefollowing the VARA application is essential for this benefit. Thecombination of VA and RA has the therapeutic potential of reducingBPD to a greater extent than VA or RA supplementationalone. (Figure 7)This data also clearly demonstrates that the usual approachto supply the lung of the newborn with vitamin A (intramuscularly)might be not very successful and explains the moderateand sometimes conflicting results. The proposed mechanismalso shows that delivery of RA alone might be counterproductive,and might lead to an up-regulation of the detoxifying enzymes(CYP26) and, in parallel, to an increased expression of CRABP,which may reduce RA action. The intramuscular supply in extremelylow birth weight infants with vitamin A might be also oflimited success, if it is not ensured that the liver can transport