Conditional deletion of Abca3 in alveolar type II cells alters surfactant homeostasis in newborn and adult mice.
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.
Besnard
Valérie
V
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.
Matsuzaki
Yohei
Y
Clark
Jean
J
Xu
Yan
Y
Wert
Susan E
SE
Ikegami
Machiko
M
Stahlman
Mildred T
MT
Weaver
Timothy E
TE
Hunt
Alan N
AN
Postle
Anthony D
AD
Whitsett
Jeffrey A
JA
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
D018528:ATP-Binding Cassette Transporters; C512026:Abca3 protein, mouse; D037661:Pulmonary Surfactant-Associated Proteins; D012333:RNA, Messenger