Vitamin A for prevention of bronchopulmonary dysplasia in extremely low birth weight infants : data on a water-soluble, nano-encapsuled retynil palmitate monopreparatino in the preterm lamb model

Abstract

Vitamin A, a fat soluble vitamin and transcription factor, and its active metabolite, retinoic acid, is essential for human health due to its effects on growth, maintenance and regeneration of many cells and tissues, including the lung tissue. The availability of vitamin A is crucial for embryonic lung development, maturation and function of the respiratory system including the development of the respiratory epithelium, alveologenesis and septation of alveoli. It is known that pregnant women are often at high risk for vitamin A deficiency, that vitamin A levels in women are directly proportional to cord blood vitamin A levels and that preterm infants suffer from vitamin A deficiency. Vitamin A deficiency is associated with the development of bronchopulmonary dysplasia, a developmental disorder of lung maturation and function, as well as long-term respiratory morbidity in this cohort. Indeed, the pathogenesis of bronchopulmonary dysplasia and morphological changes associated with vitamin A deficiency are similar in nature. The prevention of bronchopulmonary dysplasia in at-risk infants is an important aspect of early neonatal care since the condition affects a large number of survivors of preterm birth. It is characterized by chronic inflammation, impaired alveolarization and vascularization, which result in chronic lung damage with significant short- and long-term mortality and morbidity. Additional vitamin A supplementation in preterm neonates, in particular in infants with an extremely low birth weight, has been shown to prevent bronchopulmonary dysplasia and to improve long-term pulmonary outcome. However, the best method of its administration remains unclear. Currently, vitamin A is supplemented in the neonatal cohort for nutritive reasons using lipidsoluble intravenous multivitamin preparations, lipid-soluble intramuscular monopreparations or lipid-soluble oral solutions. However, when considering additional vitamin A supplementation for the prevention of bronchopulmonary dysplasia, there is still no consensus with regard to the optimal supplementation regime, since the best substrate, method and dose of administration remains to be established. The aim of my research project was the evaluation of a new substance, a nano-encapsuled, water- and fat-soluble retinyl ester monopreparation, originally used as a commercially available nutritional supplement, for its potential use in the neonatal population. The substance was applied in a well-established animal model of preterm birth and the feasibility of using the intravenous and endotracheal route of administration was explored. Vitamin A distribution in serum, lung and liver tissue was measured, and I studied the induction of the mRNA of three retinoid homeostatic genes, STRA6, LRAT and CYP26B1, as markers for changes in expression of early vitamin A homeostatic genes. Significant increases in retinol and retinyl palmitate levels in serum, lung and liver after intravenous and endotracheal administration were found, and I was able to show changes in the expression of mRNA of the tested retinoid homeostatic genes, demonstrating a very early vitamin A effect through cellular responses on a molecular level. The data positively supports the feasibility of using the tested nano-encapsuled, watersoluble vitamin A monopreparation for vitamin A supplementation in the preterm neonatal cohort using either the intravenous or endotracheal route. Further studies are warranted to assess practicalities with regard to the mode of application and to explore this substances’ kinetics and safety profile, interactions with other medications, short- and long-term effects and its long-term influence on bronchopulmonary dysplasia in the preterm neonatal population.