Conditional deletion of Abca3 in alveolar type II cells alters surfactant homeostasis in newborn and adult mice

Valérie Besnard, Yohei Matsuzaki, Jean Clark, Yan Xu, Susan E. Wert, Machiko Ikegami, Mildred T. Stahlman, Timothy E. Weaver, Alan N. Hunt, Anthony D. Postle, Jeffrey A. Whitsett

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37 Citations (Scopus)

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 Abca3Δ/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.

Original languageEnglish
Pages (from-to)L646-L659
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume298
Issue number5
DOIs
Publication statusPublished - 2010 May

Keywords

  • Compensation
  • Gene regulation
  • Lipids
  • Lung

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

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    Besnard, V., Matsuzaki, Y., Clark, J., Xu, Y., Wert, S. E., Ikegami, M., Stahlman, M. T., Weaver, T. E., Hunt, A. N., Postle, A. D., & Whitsett, J. 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(5), L646-L659. https://doi.org/10.1152/ajplung.00409.2009