Conditional deletion of Abca3 in alveolar type II cells alters surfactant homeostasis in newborn and adult mice
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(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.
Abca3, gene regulation, surfactant, lipids
Besnard, Valerie
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Matsuzaki, Yohei
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Clark, Jean Clark
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Xu, Yan
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Wert, Susan E.
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Ikegami, Machiko
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Stahlman, Mildred T.
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Weaver, Timothy E.
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Hunt, Alan N.
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Postle, Anthony D.
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Whitsett, Jeffrey A.
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26 February 2010
Besnard, Valerie
39b843ae-0b82-440e-8bfc-191cf6d8619c
Matsuzaki, Yohei
4a392224-46f1-459e-99d5-fd08918dfb32
Clark, Jean Clark
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Xu, Yan
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Wert, Susan E.
cdc863a5-5f42-47fd-af49-fb1e10dab174
Ikegami, Machiko
24da55aa-037b-4900-b817-691033d39ffc
Stahlman, Mildred T.
58cc1067-a244-4e7f-8124-60e8bc92b93a
Weaver, Timothy E.
bdf793ed-fa17-46cc-98b2-9362edd7415b
Hunt, Alan N.
95a3e223-da96-40e7-b47d-27dce014e305
Postle, Anthony D.
0fa17988-b4a0-4cdc-819a-9ae15c5dad66
Whitsett, Jeffrey A.
84fb8fc3-212e-4741-8934-d4083cd6549b
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).
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(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.
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Published date: 26 February 2010
Keywords:
Abca3, gene regulation, surfactant, lipids
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Local EPrints ID: 49342
URI: http://eprints.soton.ac.uk/id/eprint/49342
ISSN: 1040-0605
PURE UUID: 772831fd-9c64-465d-b246-d9cc4d9fb907
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Date deposited: 08 Mar 2010
Last modified: 16 Mar 2024 02:48
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Author:
Valerie Besnard
Author:
Yohei Matsuzaki
Author:
Jean Clark Clark
Author:
Yan Xu
Author:
Susan E. Wert
Author:
Machiko Ikegami
Author:
Mildred T. Stahlman
Author:
Timothy E. Weaver
Author:
Alan N. Hunt
Author:
Jeffrey A. Whitsett
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