VARA attenuates hyperoxia-induced impaired alveolar development and lung function in newborn mice

Abstract

James ML, Ross AC, Nicola T, Steele C, Ambalavanan N. VARA attenuates hyperoxia-induced impaired alveolar development and lung function in newborn mice. Am J Physiol Lung Cell Mol Physiol 304: L803-L812, 2013. First published April 12, 2013 doi:10.1152/ajplung.00257.2012We have recently shown that a combination of vitamin A (VA) and retinoic acid (RA) in a 10:1 molar ratio (VARA) synergistically increases lung retinoid content in newborn rodents, more than either VA or RA alone in equimolar amounts. We hypothesized that the increase in lung retinoids would reduce oxidative stress and proinflammatory cytokines, resulting in attenuation of alveolar simplification and abnormal lung function in hyperoxia-exposed newborn mice. Newborn C57BL/6 mice were exposed to 85% O2 (hyperoxia) or air (normoxia) for 7 or 14 days from birth and given vehicle or VARA every other day. Lung retinol content was measured by HPLC, function was assessed by flexiVent, and development was evaluated by radial alveolar counts, mean linear intercept, and secondary septal crest density. Mediators of oxidative stress, inflammation, and alveolar development were evaluated in lung homogenates. We observed that VARA increased lung retinol stores and attenuated hyperoxia-induced alveolar simplification while increasing lung compliance and lowering resistance. VARA attenuated hyperoxiainduced increases in DNA damage and protein oxidation accompanied with a reduction in nuclear factor (erythroid-derived 2)-like 2 protein but did not alter malondialdehyde adducts, nitrotyrosine, or myeloperoxidase concentrations. Interferon-␥ and macrophage inflammatory protein-2␣ mRNA and protein increased with hyperoxia, and this increase was attenuated by VARA. Our study suggests that the VARA combination may be a potential therapeutic strategy in conditions characterized by VA deficiency and hyperoxia-induced lung injury during lung development, such as bronchopulmonary dysplasia in preterm infants. bronchopulmonary dysplasia; vitamin A; retinoic acid; 8-OH deoxyguanosine; nuclear factor (erythroid-derived 2)-like 2 protein; 10:1 molar combination of Vitamin A and all-trans retinoic acid BRONCHOPULMONARY DYSPLASIA (BPD) in preterm infants, a common cause of morbidity and mortality, is characterized by fewer and larger alveoli with loss of septation (alveolar simplification) and reduced microvascular development (2,8,15,27). The etiology of BPD is multifactorial and includes genetic predisposition, barotrauma, and volutrauma from mechanical ventilation, reactive oxygen species (ROS) production from prolonged oxygen use and high oxygen concentrations, and infections that lead to inflammation, damage, and attenuation of normal growth and repair of the developing neonatal lung (2).Extremely low birth weight (ELBW; birth wt Յ1,000 g) infants are at high risk for the development of BPD (3). Low plasma and tissue concentrations of vitamin A (VA; retinol) are often observed in ELBW infants and are associated with a higher incidence of BPD (43). Randomized controlled tri...

Hyperoxia promotes polarization of the immune response in ovalbumin‐induced airway inflammation, leading to a TH17 cell phenotype

“…We reasoned that hyperoxia could significantly alter the microenvironment of the inflammatory site and, consequently, induce increased IL-17 expression in lung tissue. This is consistent with the known effects of hyperoxia, including the induction of expression of IL-6 [106][107][108], Nrf2, MPO, IFN-g, IL-1a, IL-4, IL-5, IL-6, IL-13, IL-17, TNF-a, VEGF, MIP-2a, MIG, CCL2, LIF, KC (IP)-10 [109], and TGF-b [110][111][112][113][114][115]. In particular, IL-6 and TGF-b are precursor molecules (in mice) to polarization of naive TH cells into TH17.…”

Early Exposure to Hyperoxia or Hypoxia Adversely Impacts Cardiopulmonary Development

“…The specific role of oxidative stress in modulating airway reactivity was not assessed in our study. However, we have previously demonstrated increased oxidative stress in lung homogenates after neonatal hyperoxia exposure (41).…”

Integrated Genomic Analyses in Bronchopulmonary Dysplasia

“…Gene expression was evaluated at different points during alveolar septation and hyperoxia exposure, using samples from studies approved by the UAB Institutional Animal Care and Use Committee. 17 , 18 RNA was isolated from lung homogenates for real-time RT-PCR using specific primers. 19 …”