title: Silencing hyperoxia-induced C/EBPα in neonatal mice improves lung architecture via enhanced proliferation of alveolar epithelial cells.
abstract: Postnatal lung development requires proliferation and differentiation of specific cell types at precise times to promote proper alveolar formation. Hyperoxic exposure can disrupt alveolarization by inhibiting cell growth; however, it is not fully understood how this is mediated. The transcription factor CCAAT/enhancer binding protein-α (C/EBPα) is highly expressed in the lung and plays a role in cell proliferation and differentiation in many tissues. After 72 h of hyperoxia, C/EBPα expression was significantly enhanced in the lungs of newborn mice. The increased C/EBPα protein was predominantly located in alveolar type II cells. Silencing of C/EBPα with a transpulmonary injection of C/EBPα small interfering RNA (siRNA) prior to hyperoxic exposure reduced expression of markers of type I cell and differentiation typically observed after hyperoxia but did not rescue the altered lung morphology at 72 h. Nevertheless, when C/EBPα hyperoxia-exposed siRNA-injected mice were allowed to recover for 2 wk in room air, lung epithelial cell proliferation was increased and lung morphology was restored compared with hyperoxia-exposed control siRNA-injected mice. These data suggest that C/EBPα is an important regulator of postnatal alveolar epithelial cell proliferation and differentiation during injury and repair.
authors.affiliation: Division of Neonatology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Guang
authors.initials: G
authors.lastname: Yang
authors.forename: Maurice D
authors.initials: MD
authors.lastname: Hinson
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Bordner
authors.forename: Qing S
authors.initials: QS
authors.lastname: Lin
authors.forename: Amal P
authors.initials: AP
authors.lastname: Fernando
authors.forename: Ping
authors.initials: P
authors.lastname: La
authors.forename: Clyde J
authors.initials: CJ
authors.lastname: Wright
authors.forename: Phyllis A
authors.initials: PA
authors.lastname: Dennery
mesh_terms: D000818:Animals; D000831:Animals, Newborn / Q000033:anatomy & histology / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000037:antagonists & inhibitors; D004847:Epithelial Cells / Q000145:classification / Q000378:metabolism / Q000473:pathology; D005260:Female; D020868:Gene Silencing; D018496:Hyperoxia / Q000378:metabolism* / Q000473:pathology; D007267:Injections; D008168:Lung / Q000098:blood supply / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000378:metabolism / Q000473:pathology*; D034741:RNA, Small Interfering / Q000008:administration & dosage; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: D015415:Biomarkers; D022763:CCAAT-Enhancer-Binding Protein-alpha; D050759:Cyclin-Dependent Kinase Inhibitor p21; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D018809:Proliferating Cell Nuclear Antigen; D034741:RNA, Small Interfering