ABCA3 inactivation in mice causes respiratory failure, loss of pulmonary surfactant, and depletion of lung phosphatidylglycerol
ABCA3 inactivation in mice causes respiratory failure, loss of pulmonary surfactant, and depletion of lung phosphatidylglycerol
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DOI：
10.1194/jlr.m600449-jlr200
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发表时间：
2007-03-01
影响因子：
6.5
通讯作者：
Freeman, Mason W.
中科院分区：
文献类型：
--
作者：
Fitzgerald, Michael L.;Xavier, Ramnik;Freeman, Mason W.
高度分支的哺乳动物肺依赖于表面活性剂，磷脂，胆固醇和疏水蛋白的混合物，以降低肺泡内表面张力并防止肺萎陷。ABCA 3转运蛋白的人类突变与不同严重程度和发作的儿童呼吸道疾病相关。在这里，我们报告了Abca 3基因缺失小鼠的产生，这些小鼠变得嗜睡和发绀，并在出生后1小时内死亡。组织印迹发现ABCA 3在肺中表达最高，但在其他组织中也可检测到，包括肾脏。新生Abca 3（-/-）幼仔的肾脏和肺的总体发育正常，但小鼠未能使其肺膨胀，导致因肺不张呼吸衰竭而死亡。Abca 3-/-肺的超微结构分析显示，肺泡腔中没有表面活性剂，成熟板层体（表面活性剂的细胞内储存细胞器）严重丢失。对取自Abca 3（-/-）小鼠的肺组织中> 300种磷脂的质谱测量显示磷脂酰甘油（PG）水平的显著降低以及含有短酰基链的磷脂酰胆碱种类的选择性降低。这些结果建立了板层体形成和肺表面活性物质分泌的ABCA 3的要求，并建议一个独特的和关键的作用，在肺PG的代谢转运。他们还证明了实用程序的Abca 3空小鼠作为一个模型，一个毁灭性的人类疾病。
The highly branched mammalian lung relies on surfactant, a mixture of phospholipids, cholesterol, and hydrophobic proteins, to reduce intraalveolar 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 and cyanotic and died within 1 h 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 > 300 phospholipids in lung tissue taken from Abca3(-/-) mice showed a dramatic reduction of phosphatidylglycerol (PG) 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 PG. They also demonstrate the utility of the Abca3 null mouse as a model for a devastating human disease.