title: Conditional deletion of Abca3 in alveolar type II cells alters surfactant homeostasis in newborn and adult mice.
abstract: ATP-binding cassette A3 (ABCA3) is a lipid transport protein required for synthesis and storage of pulmonary surfactant in type II cells in the alveoli. Abca3 was conditionally deleted in respiratory epithelial cells (Abca3(Δ/Δ)) in vivo. The majority of mice in which Abca3 was deleted in alveolar type II cells died shortly after birth from respiratory distress related to surfactant deficiency. Approximately 30% of the Abca3(Δ/Δ) mice survived after birth. Surviving Abca3(Δ/Δ) mice developed emphysema in the absence of significant pulmonary inflammation. Staining of lung tissue and mRNA isolated from alveolar type II cells demonstrated that ∼50% of alveolar type II cells lacked ABCA3. Phospholipid content and composition were altered in lung tissue, lamellar bodies, and bronchoalveolar lavage fluid from adult Abca3(Δ/Δ) mice. In adult Abca3(Δ/Δ) mice, cells lacking ABCA3 had decreased expression of mRNAs associated with lipid synthesis and transport. FOXA2 and CCAAT enhancer-binding protein-α, transcription factors known to regulate genes regulating lung lipid metabolism, were markedly decreased in cells lacking ABCA3. Deletion of Abca3 disrupted surfactant lipid synthesis in a cell-autonomous manner. Compensatory surfactant synthesis was initiated in ABCA3-sufficient type II cells, indicating that surfactant homeostasis is a highly regulated process that includes sensing and coregulation among alveolar type II cells.
authors.affiliation: The Perinatal Institute and Section of Neonatology, Perinatal and Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, Department of Pediatrics and University of Cincinnati College of Medicine, Ohio.
authors.forename: Valérie
authors.initials: V
authors.lastname: Besnard
authors.forename: Yohei
authors.initials: Y
authors.lastname: Matsuzaki
authors.forename: Jean
authors.initials: J
authors.lastname: Clark
authors.forename: Yan
authors.initials: Y
authors.lastname: Xu
authors.forename: Susan E
authors.initials: SE
authors.lastname: Wert
authors.forename: Machiko
authors.initials: M
authors.lastname: Ikegami
authors.forename: Mildred T
authors.initials: MT
authors.lastname: Stahlman
authors.forename: Timothy E
authors.initials: TE
authors.lastname: Weaver
authors.forename: Alan N
authors.initials: AN
authors.lastname: Hunt
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Postle
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Whitsett
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D056809:Alveolar Epithelial Cells / Q000378:metabolism* / Q000648:ultrastructure; D000818:Animals; D000831:Animals, Newborn; D001483:Base Sequence; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D006706:Homeostasis; D006801:Humans; D007231:Infant, Newborn; D050356:Lipid Metabolism; D051379:Mice; D046529:Microscopy, Electron, Transmission; D011247:Pregnancy; D011656:Pulmonary Emphysema / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D037661:Pulmonary Surfactant-Associated Proteins / Q000172:deficiency / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012127:Respiratory Distress Syndrome, Newborn / Q000209:etiology
chemical_list: D018528:ATP-Binding Cassette Transporters; C512026:Abca3 protein, mouse; D037661:Pulmonary Surfactant-Associated Proteins; D012333:RNA, Messenger