Sequential targeted deficiency of SP-A and -D leads to progressive alveolar lipoproteinosis and emphysema
Sequential targeted deficiency of SP-A and -D leads to progressive alveolar lipoproteinosis and emphysema
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DOI：
10.1152/ajplung.00118.2002
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发表时间：
2002-11-01
影响因子：
4.9
通讯作者：
Poulain, FR
中科院分区：
文献类型：
--
作者：
Hawgood, S;Ochs, M;Poulain, FR
表面活性蛋白-A和-D(SP-A和SP-D)是集合素蛋白家族的成员。单独缺乏SP-A和SP-D的小鼠有不同的表型。两者都改变了对微生物挑战的炎症反应。为了进一步研究SP-A和SP-D在体内的功能，我们通过对G-418的分级抗性顺序靶向胚胎干细胞中紧密连锁的基因来培育这两种蛋白缺失的小鼠。在24周龄期间，支气管肺泡灌洗液中磷脂、蛋白质和巨噬细胞的含量逐渐增加。来自双缺陷小鼠的巨噬细胞表达高水平的基质金属蛋白酶-12，并发展成强烈但斑块状的肺部炎症。体视学分析显示单位体积的肺泡间隔组织明显增大和减少，与肺气肿相一致。这些变化在性质上类似于SP-D缺陷小鼠的肺部病理。这些双缺陷小鼠将有助于剖析SP-A和SP-D在宿主防御中潜在的功能重叠。
Surfactant proteins-A and -D (SP-A and SP-D) are members of the collectin protein family. Mice singly deficient in SP-A and SP-D have distinct phenotypes. Both have altered inflammatory responses to microbial challenges. To further investigate the functions of SP-A and SP-D in vivo, we developed mice deficient in both proteins by sequentially targeting the closely linked genes in embryonic stem cells using graded resistance to G-418. There is a progressive increase in bronchoalveolar lavage phospholipid, protein, and macrophage content through 24 wk of age. The macrophages from doubly deficient mice express high levels of the matrix metalloproteinase MMP-12 and develop intense but patchy lung inflammation. Stereological analysis demonstrates significant air space enlargement and reduction in alveolar septal tissue per unit volume, consistent with emphysema. These changes qualitatively resemble the lung pathology seen in SP-D-deficient mice. These doubly deficient mice will be useful in dissecting the potential overlap in function between SP-A and SP-D in host defense.