Retinoids and abnormal alveolar development

Abstract

Extremely preterm infants are at high risk for a form of chronic lung disease called bronchopulmonary dysplasia (BPD), which is characterized by impaired alveolar development. Exposure to hyperoxia and deficiency of vitamin A (VA) contribute to the development of BPD in preterm infants. Randomized controlled trials indicate VA supplementation decreases BPD and/or death. However, 25% of preterm infants continue to remain VA deficient despite supplementation, probably due to impairment in VA transport, VA is stored in the liver as retinyl esters which are transported to the lung and irreversibly metabolized into all-trans-retinoic acid (ATRA), the active metabolite. A combination of VA and ATRA increases lung retinyl esters more than either VA or ATRA alone in neonatal rats. We hypothesized that this increase in lung retinyl ester content would reduce hyperoxia-induced lung inflammation and improve lung development. In order to test our hypothesis, we developed models of short and longer-term hyperoxia exposure in newborn C57Bl/6J mice that were administered either vehicle, VA, ATRA, or 10:1 molar combination of VA and ATRA (VARA). Animals exposed to 4 days of hyperoxia had increased lung retinoids with VARA more so than by either VA or ATRA alone. VARA attenuated the hyperoxia-induced increases in macrophage inflammatory protein (MIP)-2α, suggesting that VARA may influence pro-inflammatory mediators. The 4 day exposure did not lead to observable differences in alveolar development among groups. Newborn mice that were administered VARA and exposed to 14 days of hyperoxia had increased lung retinoids accompanied by improved alveolar development and lung function. Furthermore, VARA attenuated hyperoxia-induced increases in DNA damage, protein oxidation, and specific pro-inflammatory mediators including MIP-2α Taken together, these findings demonstrate that VARA is effective in improving lung VA content during short and longer-term hyperoxia exposures and that increased lung VA improves hyperoxia-induced impaired alveolar development and lung function, possibly through modulation of oxidative stress and pro-inflammatory pathways.