title: VARA attenuates hyperoxia-induced impaired alveolar development and lung function in newborn mice.
abstract: We 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 hyperoxia-induced 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-γ and macrophage inflammatory protein-2α 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.
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35249, USA.
authors.forename: Masheika L
authors.initials: ML
authors.lastname: James
authors.forename: A Catharine
authors.initials: AC
authors.lastname: Ross
authors.forename: Teodora
authors.initials: T
authors.lastname: Nicola
authors.forename: Chad
authors.initials: C
authors.lastname: Steele
authors.forename: Namasivayam
authors.initials: N
authors.lastname: Ambalavanan
mesh_terms: D000818:Animals; D000831:Animals, Newborn / Q000254:growth & development*; D005260:Female; D018496:Hyperoxia / Q000503:physiopathology*; D018836:Inflammation Mediators / Q000378:metabolism; D008168:Lung / Q000254:growth & development*; D008170:Lung Compliance / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000096:biosynthesis; D011650:Pulmonary Alveoli / Q000254:growth & development*; D012333:RNA, Messenger / Q000378:metabolism; D019063:Tenascin / Q000096:biosynthesis; D014212:Tretinoin / Q000008:administration & dosage* / Q000627:therapeutic use; D014801:Vitamin A / Q000008:administration & dosage* / Q000378:metabolism* / Q000627:therapeutic use; D014802:Vitamin A Deficiency / Q000378:metabolism
chemical_list: D018836:Inflammation Mediators; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D019063:Tenascin; C075278:platelet-derived growth factor A; D014801:Vitamin A; D014212:Tretinoin
keywords: 10:1 molar combination of Vitamin A and all-trans retinoic acid; 8-OH deoxyguanosine; bronchopulmonary dysplasia; nuclear factor (erythroid-derived 2)-like 2 protein; retinoic acid; vitamin A