Infection of mice with influenza A/WSN/33 (H1N1) virus alters alveolar type II cell phenotype
Infection of mice with influenza A/WSN/33 (H1N1) virus alters alveolar type II cell phenotype
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DOI：
10.1152/ajplung.00373.2014
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发表时间：
2015-04-01
影响因子：
4.9
通讯作者：
Davis, Ian C.
中科院分区：
文献类型：
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作者：
Hofer, Christian C.;Woods, Parker S.;Davis, Ian C.
流感病毒引起对公共卫生极为重要的急性呼吸道疾病。肺泡II型（ATII）呼吸道上皮细胞是正常肺功能的中心，是远端肺中甲型流感病毒复制的部位。然而，感染对ATII细胞功能的后果知之甚少。为了确定流感感染对ATII细胞的影响，我们使用了在表面活性蛋白-C（SP-C）启动子控制下表达绿色荧光蛋白（GFP）的C57 BL/6-同源SP-CGFP小鼠，所述表面活性蛋白-C（SP-C）启动子仅在ATII细胞中有活性。从未感染SP-C-GFP小鼠的肺中分离的大多数细胞为GFP（+），但不表达肺泡I型（ATI）抗原podoplanin（PODO）。ATII细胞也是EpCAM（+）和α（2，3）连接唾液糖（+）。流感病毒A/WSN/33感染引起严重低氧血症和肺水肿。这伴随着全肺GFP荧光的丧失、ATII细胞产量的降低、ATII细胞凋亡的增加、ATII细胞裂解物中SP-C基因和蛋白表达的降低以及PODO基因和蛋白水平的增加。流式细胞术显示感染减少GFP（+）/PODO（+）细胞，增加GFP（+）/PODO+和GFP（+）/PODO+细胞。可检测到非常少的GFP（+）/PODO+细胞。最后，感染导致PODO+细胞的EpCAM表达显着下降，但对α（2，3）连接的唾液糖的影响有限。我们的研究结果表明，流感感染导致ATII细胞逐步分化为ATI样细胞，可能通过SP-C+/PODO+中间体，以取代垂死或死亡的ATI细胞。然而，受损的SP-C合成可能会显着降低感染小鼠的肺顺应性。
Influenza viruses cause acute respiratory disease of great importance to public health. Alveolar type II (ATII) respiratory epithelial cells are central to normal lung function and are a site of influenza A virus replication in the distal lung. However, the consequences of infection for ATII cell function are poorly understood. To determine the impact of influenza infection on ATII cells we used C57BL/6-congenic SP-CGFP mice that express green fluorescent protein (GFP) under the control of the surfactant protein-C (SP-C) promoter, which is only active in ATII cells. Most cells isolated from the lungs of uninfected SP-C-GFP mice were GFP(+) but did not express the alveolar type I (ATI) antigen podoplanin (PODO). ATII cells were also EpCAM(+) and alpha(2,3)-linked sialosaccharide(+). Infection with influenza A/WSN/33 virus caused severe hypoxemia and pulmonary edema. This was accompanied by loss of whole lung GFP fluorescence, reduced ATII cell yields, increased ATII cell apoptosis, reduced SP-C gene and protein expression in ATII cell lysates, and increased PODO gene and protein levels. Flow cytometry indicated that infection decreased GFP(+)/PODO(+)cells and increased GFP(+)/PODO+ and GFP(+)/PODO+ cells. Very few GFP(+)/PODO+ cells were detectable. Finally, infection resulted in a significant decline in EpCAM expression by PODO+ cells, but had limited effects on alpha(2,3)-linked sialosaccharides. Our findings indicate that influenza infection results in a progressive differentiation of ATII cells into ATI-like cells, possibly via an SP-C+/PODO+ intermediate, to replace dying or dead ATI cells. However, impaired SP-C synthesis is likely to contribute significantly to reduced lung compliance in infected mice.