Transgenic expression of group V, but not group X, secreted phospholipase A2 in mice leads to neonatal lethality because of lung dysfunction
Transgenic expression of group V, but not group X, secreted phospholipase A2 in mice leads to neonatal lethality because of lung dysfunction
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DOI：
10.1074/jbc.m607975200
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发表时间：
2006-11-24
影响因子：
4.8
通讯作者：
Murakami, Makoto
中科院分区：
文献类型：
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作者：
Ohtsuki, Mitsuhiro;Taketomi, Yoshitaka;Murakami, Makoto
为了阐明分泌型磷脂酶A（2）（sPLA（2））酶在体内的功能，我们产生了V组sPLA（2）（sPLA（2）-V）和X组sPLA（2）（sPLA（2）X）的转基因（Tg）小鼠，它们在体外对磷脂酰胆碱有效地起作用。我们发现sPLA（2）-V Tg小鼠在新生期因呼吸衰竭而死亡。sPLA（2）-V Tg小鼠的肺表现为肺不张，肺泡壁增厚，空气间隙狭窄，伴有巨噬细胞浸润，类花生酸水平仅发生适度变化。sPLA（2）-V Tg小鼠的这种严重肺缺陷可归因于肺表面活性剂磷脂、磷脂酰胆碱和磷脂酰甘油的显著减少。鉴于sPLA（2）-V在严重炎症的人肺中的表达大大升高，我们目前的结果提出了一种有趣的可能性，即这种同工酶可能有助于经常在呼吸窘迫综合征患者的肺中观察到的持续的表面活性剂水解。相比之下，sPLA（2）-X Tg新生儿显示呼吸道轻微异常，肺泡结构和表面活性剂成分正常。这一意想不到的结果可能是因为sPLA（2）-X蛋白在大多数组织中作为无活性的酶原存在。在sPLA（2）-X Tg小鼠的炎性肉芽组织中检测到sPLA（2）-X的活性形式。这些结果表明，sPLA（2）-X在生理条件下大部分保持无活性，并且其蛋白水解激活发生在炎症或其他尚未鉴定的体内环境中。
In an effort to elucidate the functions of secreted phospholipase A(2) (sPLA(2)) enzymes in vivo, we generated transgenic (Tg) mice for group V sPLA(2) (sPLA(2)-V) and group X sPLA(2) ( sPLA(2)X), which act potently on phosphatidylcholine in vitro. We found that sPLA(2)-V Tg mice died in the neonatal period because of respiratory failure. The lungs of sPLA(2)-V Tg mice exhibited atelectasis with thickened alveolar walls and narrow air spaces, accompanied by infiltration of macrophages and only modest changes in eicosanoid levels. This severe pulmonary defect in sPLA(2)-V Tg mice was attributable to marked reduction of the lung surfactant phospholipids, phosphatidylcholine and phosphatidylglycerol. Given that the expression of sPLA(2)-V is greatly elevated in human lungs with severe inflammation, our present results raise the intriguing possibility that this isozyme may contribute to ongoing surfactant hydrolysis often observed in the lungs of patients with respiratory distress syndrome. In contrast, sPLA(2)-X Tg neonates displayed minimal abnormality of the respiratory tract with normal alveolar architecture and surfactant composition. This unexpected result was likely because sPLA(2)-X protein existed as an inactive zymogen in most tissues. The active form of sPLA(2)-X was detected in tissues with inflammatory granulation in sPLA(2)-X Tg mice. These results suggest that sPLA(2)-X mostly remains inactive under physiological conditions and that its proteolytic activation occurs during inflammation or other as yet unidentified circumstances in vivo.