Pulmonary epithelial cell expression of GM-CSF corrects the alveolar proteinosis in GM-CSF-deficient mice
Pulmonary epithelial cell expression of GM-CSF corrects the alveolar proteinosis in GM-CSF-deficient mice
复制标题
DOI：
10.1172/jci118461
复制
发表时间：
1996-02-01
影响因子：
15.9
通讯作者：
Whitsett, JA
中科院分区：
文献类型：
--
作者：
Huffman, JA;Hull, WM;Whitsett, JA
粒细胞-巨噬细胞集落刺激因子（GM-CSF）基因通过同源重组突变导致小鼠肺泡蛋白沉积症。为了进一步辨别GM-CSF在表面活性剂体内平衡中的作用，将GM-CSF的合成导向GM-CSF无效突变小鼠（GM-/-）的呼吸上皮，所述GM-/-小鼠具有在来自人表面活性剂蛋白-C（SP-C）基因的启动子的控制下表达GM-CSF的嵌合基因。将携带SP-C-GM-CSF构建体的转基因小鼠（SP-C-GM+）与GM-/-小鼠交配，导致双转基因GM-/-、SP-C-GM+小鼠中肺泡蛋白沉积症的完全纠正。在肺外未发现转基因的影响。双转基因小鼠支气管肺泡灌洗液中GM-CSF明显升高。在GM-/-、SP-C-GM+小鼠中，支气管肺泡灌洗液中的表面活性蛋白-A和-B以及磷脂正常化，在GM-CSF缺乏和-充满小鼠的肺中，SP-A、-B和-C mRNA不变。转基因小鼠呼吸道上皮细胞中GM-CSF的表达恢复了GM-/-小鼠表面活性物质的稳态。从这些发现，我们得出结论，GM-CSF调节清除或catalysts，而不是表面活性剂蛋白质和脂质的合成。
Mutation of the granulocyte-macrophage colony-stimulating factor (GM-CSF) gene by homologous recombination caused alveolar proteinosis in mice. To further discern the role of GM-CSF in surfactant homeostasis, the synthesis of GRM-CSF was directed to the respiratory epithelium of GM-CSF-null mutant mice (GM-/-)with a chimeric gene expressing GM-CSF under the control of the promoter from the human surfactant protein-C (SP-C) gene. Transgenic mice bearing the SP-C-GM-CSF construct (SP-C-GM+) were bred to GM-/- mice resulting in complete correction of alveolar proteinosis in bitransgenic GM-/-, SP-C-GM+ mice. No effects of the transgene were found outside the lung. GM-CSF was increased in bronchoalveolar lavage fluid of the bitransgenic mice. Surfactant proteins-A and -B and phospholipid in bronchoalveolar lavage fluid were normalized in the GM-/-, SP-C-GM+ mice, SP-A, -B, and -C mRNAs were unaltered in lungs from GM-CSF-deficient and -replete mice. Expression of GM-CSF in respiratory epithelial cells of transgenic mice restores surfactant homeostasis in GM-/- mice. From these findings, we conclude that GM-CSF regulates the clearance or catabolism rather than synthesis of surfactant proteins and lipids.