Fisher J H, Sheftelyevich V, Ho Y S, Fligiel S, McCormack F X, Korfhagen T R, Whitsett J A, Ikegami M
Pulmonary/Critical Care Medicine, Denver Health Medical Center and University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.
Am J Physiol Lung Cell Mol Physiol. 2000 Feb;278(2):L365-73. doi: 10.1152/ajplung.2000.278.2.L365.
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.
表面活性蛋白（SP）D（SP-D）基因的靶向破坏导致了显著的肺类脂沉积症，其特征为肺泡肺磷脂增加，这表明SP-D在表面活性剂稳态中发挥了此前未被预料到的作用。在本研究中，我们测试了肺中SP-D的局部产生是否会影响SP-D缺陷型[SP-D(-/-)]和SP-D野生型[SP-D(+/+)]小鼠的表面活性剂含量。大鼠SP-D（rSP-D）在人SP-C启动子的控制下表达，从而产生了rSP-D、SP-D(+/+)转基因小鼠。与SP-D(+/+)亲代品系相比，rSP-D、SP-D(+/+)小鼠支气管肺泡灌洗液中的SP-D含量增加了30至50倍。SP-D浓度的增加并未改变肺形态、磷脂含量和表面活性蛋白mRNA。同样，SP-D转基因也未干扰内源性小鼠SP-D mRNA的产生。将rSP-D、SP-D(+/+)小鼠与SP-D(-/-)小鼠杂交，以评估SP-D在肺中的选择性表达是否可能纠正SP-D(-/-)小鼠的脂质稳态异常。SP-D在呼吸道上皮中的选择性表达对肺功能没有不利影响，可纠正表面活性剂磷脂含量并显著降低磷脂酰胆碱的掺入。SP-D调节表面活性剂脂质稳态，在局部发挥作用以抑制肺实质中表面活性剂磷脂的掺入，并维持肺泡中肺泡磷脂的含量。生物活性组织和肺泡SP-D的显著增加并未改变肺形态、巨噬细胞丰度或结构，也未改变表面活性剂的积聚。
