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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 7

Analysis of surfactant-associated proteins in newborn Lpcat1GT/GT mice.

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Analysis of surfactant-associated proteins in newborn Lpcat1GT/GT mice.
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(A–F). H&E-stained lung tissue sections from newborn Lpcat1GT/GT mice that succumbed from RDS, showing areas of atelectasis and hemorrhaging (C, arrow) compared with less-affected areas in the same lung (C, arrowhead) and lungs of asymptomatic Lpcat1GT/GT (B) and wild-type littermates (A). (D–F) High-power magnifications of areas boxed in A–C. ABCA3 protein levels were assessed by immunostaining (G–I). Scale bars: 500 μm (A–C), 100 μm (D–F), 50 μm (G–I). (J) qPCR analysis of Abca3, Sftpb, and Sftpc from lung tissue of newborn mice. Data represent n = 5 for each genotype and were normalized to Actb. (K) Immunoblot analysis of lung homogenate from newborn mice using antisera directed against 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. (L–O) Representative transmission electron micrograph of lung tissue from a newborn Lpcat1GT/GT RDS mouse and a Lpcat1+/+ littermate control. Note the numerous lamellar bodies in alveolar type II cells (arrowheads, L and M) and abundant luminal surfactant and tubular myelin structures (arrows, N and O) in both genotypes. Scale bars: 2 μm (L–O).

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

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