Linking Fibrotic Remodeling and Ultrastructural Alterations of Alveolar Epithelial Cells after Deletion of Nedd4-2.
Linking Fibrotic Remodeling and Ultrastructural Alterations of Alveolar Epithelial Cells after Deletion of Nedd4-2.
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DOI：
10.3390/ijms22147607
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发表时间：
2021-07-16
影响因子：
5.6
通讯作者：
Ochs M
中科院分区：
文献类型：
--
作者：
Engelmann TA;Knudsen L;Leitz DHW;Duerr J;Beers MF;Mall MA;Ochs M
我们以前的研究表明，在成年小鼠中，俱乐部和肺泡上皮II型（AE 2）细胞中的条件性Nedd 4 -2缺陷导致16周内粘膜纤毛清除受损，Muc 5 b积聚和进行性终末肺纤维化。在本研究中，我们研究了肺泡上皮细胞的超微结构变化与肺泡隔间质重塑的关系，作为疾病进展的函数。在诱导Nedd 4 -2敲除后2、8和12周，固定肺并在光镜和电镜水平进行基于设计的体视学研究。与对照组相比，定量数据在8周前未显示任何异常。然而，在12周时，室间隔壁组织体积增加，而腺泡空间体积和肺泡表面积显著减少。肺泡上皮I型细胞的体积和表面积减少，这不能通过AE 2细胞的相应增加来补偿。室间隔中胶原纤维的体积增加，并与血气屏障厚度的增加有关。AE 2细胞超微结构异常与间质重构的关系密切。总之，肺泡上皮细胞的异常再生与间质间隔壁重塑相关。
Our previous study showed that in adult mice, conditional Nedd4-2-deficiency in club and alveolar epithelial type II (AE2) cells results in impaired mucociliary clearance, accumulation of Muc5b and progressive, terminal pulmonary fibrosis within 16 weeks. In the present study, we investigated ultrastructural alterations of the alveolar epithelium in relation to interstitial remodeling in alveolar septa as a function of disease progression. Two, eight and twelve weeks after induction of Nedd4-2 knockout, lungs were fixed and subjected to design-based stereological investigation at the light and electron microscopic level. Quantitative data did not show any abnormalities until 8 weeks compared to controls. At 12 weeks, however, volume of septal wall tissue increased while volume of acinar airspace and alveolar surface area significantly decreased. Volume and surface area of alveolar epithelial type I cells were reduced, which could not be compensated by a corresponding increase of AE2 cells. The volume of collagen fibrils in septal walls increased and was linked with an increase in blood–gas barrier thickness. A high correlation between parameters reflecting interstitial remodeling and abnormal AE2 cell ultrastructure could be established. Taken together, abnormal regeneration of the alveolar epithelium is correlated with interstitial septal wall remodeling.
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