Pulmonary-specific expression of SP-D corrects pulmonary lipid accumulation in SP-D gene-targeted mice
Pulmonary-specific expression of SP-D corrects pulmonary lipid accumulation in SP-D gene-targeted mice
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DOI：
10.1152/ajplung.2000.278.2.l365
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发表时间：
2000-02-01
影响因子：
4.9
通讯作者：
Ikegami, M
中科院分区：
文献类型：
--
作者：
Fisher, JH;Sheftelyevich, V;Ikegami, M
有针对性地破坏表面活性蛋白（SP）D（SP-D）基因导致了显著的肺脂质沉积，其特征在于肺泡肺磷脂增加，表明SP-D在表面活性物质体内平衡中的先前意想不到的作用。在本研究中，我们测试了肺中SP-D的局部产生是否影响SP-D缺陷[SP-D（-/-）]和SP-D野生型[SP-D（+/+）]小鼠的表面活性剂含量。在人SP-C启动子的调控下表达大鼠SP-D（rSP-D），产生rSP-D、SP-D（+/+）转基因小鼠。与SP-D（+/+）亲本品系相比，rSP-D、SP-D（+/+）小鼠支气管肺泡灌洗液中的SP-D含量增加了30- 50倍。肺形态、磷脂含量和表面活性蛋白mRNA未因SP-D浓度增加而改变。同样，内源性小鼠SP-D mRNA的产生不受SP-D转基因的干扰。将rSP-D、SP-D（+/+）小鼠与SP-D（-/-）小鼠交配以评估SP-D的肺选择性表达是否可以纠正SP-D（-/-）小鼠中的脂质稳态异常。呼吸道上皮中SP-D的选择性表达对肺功能没有不良影响，纠正了表面活性剂磷脂含量，并显著降低了磷脂酰胆碱掺入。SP-D调节表面活性剂脂质体内平衡，局部发挥作用以抑制肺实质中的表面活性剂磷脂掺入并维持肺泡中的肺泡磷脂含量。生物活性组织和肺泡SP-D的显著增加不会改变肺形态、巨噬细胞丰度或结构或表面活性剂蓄积。
Targeted disruption of the surfactant protein (SP) D (SP-D) gene caused a marked pulmonary lipoidosis characterized by increased alveolar lung phospholipids, demonstrating a previously unexpected role for SP-D in surfactant homeostasis. In the present study, we tested whether the local production of SP-D in the lung influenced surfactant content in SP-D-deficient [SP-D(-/-)] and SP-D wild-type [SP-D(+/+)] mice. Rat SP-D (rSP-D) was expressed under control of the human SP-C promoter, producing rSP-D, SP-D(+/+) transgenic mice. SP-D content in bronchoalveolar lavage fluid was increased 30- to 50-fold in the rSP-D, SP-D(+/+) mice compared with the SP-D(+/+) parental strain. Lung morphology, phospholipid content, and surfactant protein mRNAs were unaltered by the increased concentration of SP-D. Likewise, the production of endogenous mouse SP-D mRNA was not perturbed by the SP-D transgene. rSP-D, SP-D(+/+) mice were bred to SP-D(-/-) mice to assess whether lung-selective expression of SP-D might correct lipid homeostasis abnormalities in the SP-D( -/-) mice. Selective expression of SP-D in the respiratory epithelium had no adverse effects on lung function, correcting surfactant phospholipid content and decreasing phosphatidylcholine incorporation significantly. SP-D regulates surfactant lipid homeostasis, functioning locally to inhibit surfactant phospholipid incorporation in the lung parenchyma and maintaining alveolar phospholipid content in the alveolus. Marked increases in biologically active tissue and alveolar SP-D do not alter lung morphology, macrophage abundance or structure, or surfactant accumulation.