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LPCAT1 regulates surfactant phospholipid synthesis and is required for transitioning to air breathing in mice
James P. Bridges, … , Robert J. Mason, John M. Shannon
James P. Bridges, … , Robert J. Mason, John M. Shannon
Published April 19, 2010
Citation Information: J Clin Invest. 2010;120(5):1736-1748. https://doi.org/10.1172/JCI38061.
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Research Article Pulmonology Article has an altmetric score of 3

LPCAT1 regulates surfactant phospholipid synthesis and is required for transitioning to air breathing in mice

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Abstract

Respiratory distress syndrome (RDS), which is the leading cause of death in premature infants, is caused by surfactant deficiency. The most critical and abundant phospholipid in pulmonary surfactant is saturated phosphatidylcholine (SatPC), which is synthesized in alveolar type II cells de novo or by the deacylation-reacylation of existing phosphatidylcholine species. We recently cloned and partially characterized a mouse enzyme with characteristics of a lung lysophosphatidylcholine acyltransferase (LPCAT1) that we predicted would be involved in surfactant synthesis. Here, we describe our studies investigating whether LPCAT1 is required for pulmonary surfactant homeostasis. To address this issue, we generated mice bearing a hypomorphic allele of Lpcat1 (referred to herein as Lpcat1GT/GT mice) using a genetrap strategy. Newborn Lpcat1GT/GT mice showed varying perinatal mortality from respiratory failure, with affected animals demonstrating hallmarks of respiratory distress such as atelectasis and hyaline membranes. Lpcat1 mRNA levels were reduced in newborn Lpcat1GT/GT mice and directly correlated with SatPC content, LPCAT1 activity, and survival. Surfactant isolated from dead Lpcat1GT/GT mice failed to reduce minimum surface tension to wild-type levels. Collectively, these data demonstrate that full LPCAT1 activity is required to achieve the levels of SatPC essential for the transition to air breathing.

Authors

James P. Bridges, Machiko Ikegami, Lauren L. Brilli, Xueni Chen, Robert J. Mason, John M. Shannon

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Figure 5

Lung SatPC content is decreased in E18.5 Lpcat1GT/GT mice.

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Lung SatPC content is decreased in E18.5 Lpcat1GT/GT mice.
   
(A) Measu...
(A) Measurement of lung tissue SatPC content in E18.5 mice demonstrates that Lpcat1GT/GT lungs contain significantly less SatPC. Data represent n = 5 per genotype and are normalized to tissue weight. *P < 0.01 versus Lpcat1+/+ and Lpcat1GT/+. (B) qPCR analysis of Abca3, Sftpb, and Sftpc from lung tissue of E18.5 mice shows that expression of these genes is unchanged. Data represent n = 5 for each genotype and are normalized to Actb. (C) Immunoblot analysis of lung homogenate from E18.5 mice using antisera directed against the C terminus of LPCAT1 (Mr ~60 kDa), pro-SFTPC (Mr ~21 kDa), the mature peptide of SFTPC (Mr ~4 kDa), or the mature peptide of SFTPB (Mr ~16 kDa, nonreduced). The blot for mature SFTPB was stripped and reprobed with α-ACTIN as a loading control. Note the lack of LPCAT1 immunoreactivity in Lpcat1GT/GT mice (arrow) and no change in pro-SFTPC, mature SFTPC, or mature SFTPB protein. (D) Immunohistochemical analysis of pro-SFTPC, mature SFTPB, LPCAT1, and ABCA3 in lung sections from Lpcat1GT/GT and Lpcat1+/+ mice confirms the results in C. Scale bars: 50 μm.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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