Alteration of the pulmonary surfactant system in full-term infants with hereditary ABCA3 deficiency
Alteration of the pulmonary surfactant system in full-term infants with hereditary ABCA3 deficiency
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DOI：
10.1164/rccm.200509-1535oc
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发表时间：
2006-09-01
影响因子：
24.7
通讯作者：
Schmitz, Gerd
中科院分区：
文献类型：
--
作者：
Brasch, Frank;Schimanski, Sven;Schmitz, Gerd
原理：已知ABCA 3突变会导致致命的表面活性物质缺乏症。目的：我们研究了ABCA 3蛋白的表达在足月新生儿不明原因呼吸窘迫综合征（URDS）以及ABCA 3突变的相关性表面活性物质homeostasis.Methods：肺组织的婴儿URDS进行了分析ABCA 3在II型肺细胞的表达。对ABCA 3基因的编码外显子进行测序。表面活性物质蛋白的表达进行了研究，免疫组化，免疫电镜，和Western blotting.Results：ABCA 3蛋白的表达被发现大大减少或不存在10的14个婴儿URDS。直接测序揭示了不同的ABCA 3突变聚集在ABCA 3蛋白的脆弱结构域。在II型肺泡上皮细胞的电子致密体中，表面活性蛋白B的前体（pro-SP-B）表达较强，但成熟表面活性蛋白B（SP-B）的水平较低，且呈聚集状态，在电子致密体基质中，我们检测到SP-C的前体（pro-SP-C）和组织蛋白酶D。SP-A定位于细胞内的小泡，但不是在电子致密体。SP-A和pro-SP-B被证明积累在肺泡内空间，而成熟的SP-B和SP-C减少或缺席，分别。结论：我们的数据提供的证据表明，ABCA 3突变不仅与ABCA 3的缺陷，但也与一个异常的处理和路由的SP-B B和SP-C，导致严重改变的表面活性物质的稳态和呼吸窘迫综合征。为了确定婴儿遗传性ABCA 3缺乏症，我们建议一个综合的诊断方法，包括免疫组化，超微结构和突变分析。
Rationale: ABCA3 mutations are known to cause fatal surfactant deficiency. Objective: We studied ABCA3 protein expression in full-term new-borns with unexplained respiratory distress syndrome (URDS) as well as the relevance of ABCA3 mutations for surfactant homeostasis.Methods: Lung tissue of infants with URDS was analyzed for the expression of ABCA3 in type II pneumocytes. Coding exons of the ABCA3 gene were sequenced. Surfactant protein expression was studied by immunohistochemistry, immunoelectron microscopy, and Western blotting.Results: ABCA3 protein expression was found to be greatly reduced or absent in 10 of 14 infants with URDS. Direct sequencing revealed distinct ABCA3 mutations clustering within vulnerable domains of the ABCA3 protein. A strong expression of precursors of surfactant protein B (pro-SP-B) but only low levels and aggregates of mature surfactant protein B (SP-B) within electron-dense bodies in type II pneumocytes were found. Within the matrix of electron-dense bodies, we detected precursors of SP-C (pro-SP-C) and cathepsin D. SP-A was localized in small intracellular vesicles, but not in electron-dense bodies. SP-A and pro-SP-B were shown to accumulate in the intraalveolar space, whereas mature SP-B and SP-C were reduced or absent, respectively.Conclusion: Our data provide evidence that ABCA3 mutations are associated not only with a deficiency of ABCA3 but also with an abnormal processing and routing of SP-B and SP-C, leading to severe alterations of surfactant homeostasis and respiratory distress syndrome. To identify infants with hereditary ABCA3 deficiency, we suggest a combined diagnostic approach including immunohistochemical, ultrastructural, and mutation analysis.