title: Hyperoxia impairs alveolar formation and induces senescence through decreased histone deacetylase activity and up-regulation of p21 in neonatal mouse lung.
abstract: Alveolar development comprises the transition of lung architecture from saccules to gas-exchange units during late gestation and early postnatal development. Exposure to hyperoxia disrupts developmental signaling pathways and causes alveolar hypoplasia as seen in bronchopulmonary dysplasia affecting preterm human newborns. Expanding literature suggests that epigenetic changes caused by environmental triggers during development may lead to heritable changes in gene expression. Given recent data on altered histone deacetylase (HDAC) activity in lungs of humans and animal models with airspace enlargement/emphysema, we hypothesized that alveolar hypoplasia from hyperoxia exposure in neonatal mice is a consequence of cell cycle arrest and reduced HDAC activity and up-regulation of the cyclin-dependent kinase inhibitor, p21. We exposed newborn mice to hyperoxia and compared lung morphologic and epigenetic changes to room air controls. Furthermore, we pretreated a subgroup of animals with the macrolide antibiotic azithromycin (AZM), known to possess antiinflammatory properties. Our results showed that hyperoxia exposure resulted in alveolar hypoplasia and was associated with decreased HDAC1 and HDAC2 and increased p53 and p21 expression. Furthermore, AZM did not confer protection against hyperoxia-induced alveolar changes. These findings suggest that alveolar hypoplasia caused by hyperoxia is mediated by epigenetic changes affecting cell cycle regulation/senescence during lung development.
authors.affiliation: Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA. vlondhe@mednet.ucla.edu
authors.forename: Vedang A
authors.initials: VA
authors.lastname: Londhe
authors.forename: Isaac K
authors.initials: IK
authors.lastname: Sundar
authors.forename: Benjamin
authors.initials: B
authors.lastname: Lopez
authors.forename: Tiffany M
authors.initials: TM
authors.lastname: Maisonet
authors.forename: Yang
authors.initials: Y
authors.lastname: Yu
authors.forename: Zubair H
authors.initials: ZH
authors.lastname: Aghai
authors.forename: Irfan
authors.initials: I
authors.lastname: Rahman
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D017963:Azithromycin / Q000494:pharmacology; D001997:Bronchopulmonary Dysplasia / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D004195:Disease Models, Animal; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D056284:Histone Deacetylase 1 / Q000378:metabolism*; D056464:Histone Deacetylase 2 / Q000378:metabolism*; D006801:Humans; D018496:Hyperoxia / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D007231:Infant, Newborn; D051379:Mice; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000201:enzymology* / Q000254:growth & development / Q000473:pathology; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000893:Anti-Inflammatory Agents; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016159:Tumor Suppressor Protein p53; D017963:Azithromycin; C484389:Hdac1 protein, mouse; C533424:Hdac2 protein, mouse; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2