J. Lipid Res.
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A more recent version of this article appeared on March 1, 2007

Papers In Press, published online ahead of print December 1, 2006
J. Lipid Res., doi:10.1194/jlr.M600449-JLR200
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Submitted on October 10, 2006
Revised on November 28, 2006
Accepted on December 1, 2006

ABCA3 inactivation in mice causes respiratory failure, loss of pulmonary surfactant and depletion of lung phosphatidylglycerol

Michael L. Fitzgerald, Ramnik Xavier, Kathleen J. Haley, Ruth Welti, Julie L. Goss, Cari E. Brown, Debbie Z. Zhuang, Susan A. Bell, Naifang Lu, Mary Mckee, Brian Seed, and Mason W. Freeman

Lipid Metabolism/CCIB, Mass General Hospital/Harvard Medical, Boston, MA 02114

Corresponding Author: freeman{at}molbio.mgh.harvard.edu

The highly branched mammalian lung relies on surfactant, a mixture of phospholipids, cholesterol and hydrophobic proteins, to reduce intra-alveolar surface tension and prevent lung collapse. Human mutations in the ABCA3 transporter have been associated with childhood respiratory disease of variable severity and onset. Here we report the generation of Abca3 null mice, which became lethargic, cyanotic and died within an hour of birth. Tissue blots found ABCA3 expression was highest in lung but was also detectable in other tissues including the kidney. Gross development of kidney and lung was normal in neonatal Abca3-/- pups, but the mice failed to inflate their lungs, leading to death from atelectatic respiratory failure. Ultrastructural analysis of the Abca3-/- lungs revealed an absence of surfactant from the alveolar space and a profound loss of mature lamellar bodies, the intracellular storage organelle for surfactant. Mass spectrometry measurement of over 300 phospholipids in lung tissue taken from Abca3-/- mice showed a dramatic reduction of phosphatidylglycerol levels, as well as selective reductions in phosphatidylcholine species containing short acyl chains. These results establish a requirement of ABCA3 for lamellar body formation and pulmonary surfactant secretion and suggest a unique and critical role for the transporter in the metabolism of pulmonary phosphatidylglycerol. They also demonstrate the utility of the Abca3 null mouse as a model for a devastating human disease.


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