Conditional deletion of Abca3 in alveolar type II cells alters surfactant homeostasis in newborn and adult mice
Besnard, Valerie, Matsuzaki, Yohei, Clark, Jean Clark, Xu, Yan, Wert, Susan E., Ikegami, Machiko, Stahlman, Mildred T., Weaver, Timothy E., Hunt, Alan N., Postle, Anthony D. and Whitsett, Jeffrey A. (2010) Conditional deletion of Abca3 in alveolar type II cells alters surfactant homeostasis in newborn and adult mice. American Journal of Physiology: Lung Cellular and Molecular Physiology, 298, (2) (doi:10.1152/ajplung.00409.2009).
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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(Delta/Delta)) 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(Delta/Delta) mice survived after birth. Surviving Abca3(Delta/Delta) mice developed emphysema in the absence of significant pulmonary inflammation. Staining of lung tissue and mRNA isolated from alveolar type II cells demonstrated that approximately 50% of alveolar type II cells lacked ABCA3. Phospholipid content and composition were altered in lung tissue, lamellar bodies and BALF from adult Abca3(Delta/Delta) mice. In adult Abca3(Delta/Delta) mice, cells lacking ABCA3 had decreased expression of mRNAs associated with lipid synthesis and transport. FOXA2 and C/EBPalpha, 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 co-regulation among alveolar type II cells.
|Digital Object Identifier (DOI):||doi:10.1152/ajplung.00409.2009|
|Keywords:||Abca3, gene regulation, surfactant, lipids|
|Subjects:||R Medicine > RC Internal medicine
Q Science > QP Physiology
R Medicine > RJ Pediatrics > RJ101 Child Health. Child health services
|Divisions:||University Structure - Pre August 2011 > School of Medicine > Infection, Inflammation and Repair
|Date Deposited:||08 Mar 2010|
|Last Modified:||31 Mar 2016 12:26|
|RDF:||RDF+N-Triples, RDF+N3, RDF+XML, Browse.|
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