Loss of Rab27 function results in abnormal lung epithelium structure in mice
Loss of Rab27 function results in abnormal lung epithelium structure in mice
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DOI：
10.1152/ajpcell.00446.2010
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发表时间：
2011-03-01
影响因子：
5.5
通讯作者：
Hume, Alistair N.
中科院分区：
文献类型：
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作者：
Bolasco, Giulia;Tracey-White, Dhani C.;Hume, Alistair N.
Bolasco G，Tracey-White DC，Tolmachova T，Thorley AJ，Tetley TD，Seabra MC，Hume AN. Rab 27功能缺失导致小鼠肺上皮结构异常。Am J Physiol Cell Physiol 300：C466-C476，2011.首次发表于2010年12月15日; doi：10.1152/ajpcell。00446.2010.- Rab 27小GTP酶调节溶酶体相关细胞器如T细胞溶细胞颗粒和血小板致密颗粒的分泌和运动。先前的研究表明Rab 27 a和Rab 27 b在小鼠肺中表达，表明它们调节肺中的分泌过程。与这些研究一致，我们发现Rab 27 a和Rab 27 b在含有分泌颗粒的细胞类型中表达：肺泡上皮II型（AEII）和Clara细胞。然后，我们使用Rab 27 a/Rab 27 b双敲除（DKO）小鼠来检查小鼠肺中Rab 27蛋白缺失的功能后果。光学和电子显微镜显示了一些DKO小鼠肺的形态学变化时，与对照组动物。在老年DKO小鼠中，我们观察到细支气管和肺泡上皮萎缩，细胞数量减少，细支气管上皮和肺泡壁变薄，肺泡气隙扩大。在这些样品中，我们还观察到与对照组相比，活化的泡沫状肺泡巨噬细胞和含粒细胞的浸润物的数量增加，Clara细胞和AEII细胞的数量减少。在超微结构水平，我们观察到积累的细胞质膜和囊泡在克拉拉细胞。同时，AEII细胞在DKO积累大的成熟板层体，缺乏未成熟/前体板层体。我们假设，在DKO样品的超微结构水平上观察到的形态学变化是由AEII和Clara细胞的分泌缺陷引起的，并且随着时间的推移，这些缺陷导致上皮萎缩。
Bolasco G, Tracey-White DC, Tolmachova T, Thorley AJ, Tetley TD, Seabra MC, Hume AN. Loss of Rab27 function results in abnormal lung epithelium structure in mice. Am J Physiol Cell Physiol 300: C466-C476, 2011. First published December 15, 2010; doi:10.1152/ajpcell. 00446.2010.-Rab27 small GTPases regulate secretion and movement of lysosome-related organelles such as T cell cytolytic granules and platelet-dense granules. Previous studies indicated that Rab27a and Rab27b are expressed in the murine lung suggesting that they regulate secretory processes in the lung. Consistent with those studies, we found that Rab27a and Rab27b are expressed in cell types that contain secretory granules: alveolar epithelial type II (AEII) and Clara cells. We then used Rab27a/Rab27b double knockout (DKO) mice to examine the functional consequence of loss of Rab27 proteins in the murine lung. Light and electron microscopy revealed a number of morphological changes in lungs from DKO mice when compared with those in control animals. In aged DKO mice we observed atrophy of the bronchiolar and alveolar epithelium with reduction of cells numbers, thinning of the bronchiolar epithelium and alveolar walls, and enlargement of alveolar airspaces. In these samples we also observed increased numbers of activated foamy alveolar macrophages and granulocyte containing infiltrates together with reduction in the numbers of Clara cells and AEII cells compared with control. At the ultrastructural level we observed accumulation of cytoplasmic membranes and vesicles in Clara cells. Meanwhile, AEII cells in DKO accumulated large mature lamellar bodies and lacked immature/precursor lamellar bodies. We hypothesize that the morphological changes observed at the ultrastructural level in DKO samples result from secretory defects in AEII and Clara cells and that over time these defects lead to atrophy of the epithelium.