Multiple dosings wtih acidic retinoids increase retinol stores and expression of retinoid homeostatic genes in the lung of neonatal rats

Abstract

Previously we have shown that vitamin A (VA) combined with acidic retinoids synergistically increases retinol uptake and retinyl ester (RE) formation in neonatal rat lung, concomitant with the expression of several retinoid homeostatic genes: LRAT (lecithin:retinol acyltransferase), CYP26B1 (a cytochrome P450), and Stra6 (stimulated by retinoic acid gene 6). In the present study we compared the response to VA alone or combined with retinoic acid (RA) or a analog, Am580, in two timing protocols: single early dosing (d 4) vs. multiple dosings throughout the period of lung septation (d 4, 7, 11, 14). Multiple dosing resulted in a higher, cumulative increase in lung RE content for all treatments: vehicle<RA≅VA<Am580<VARA<VAAm580. However, most of the retinoid homeostatic genes were up‐regulated by acidic retinoids to the same extent after a single vs. multiple dosings. Lung functional gene, surfactant protein‐A (SPA1) mRNA remained nearly constant with both treatment and timing. In conclusion, multiple treatments of VA and acidic retinoids in combination during the septation period greatly increased neonatal lung RE content in a synergistic and cumulative manner. Repeated but transient induction of retinoid homeostatic genes by acidic retinoids at the time of each dosing may explain the observed cumulative synergistic enhancement of RE formation.Support: NIH CA90214.Grant Funding Source: NIH CA90214