Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany.
German Center for Lung Research (DZL), Partner Site BREATH (Biomedical Research in Endstage and Obstructive Lung Disease Hannover), Hannover, Germany.
Lab Invest. 2019 Jun;99(6):830-852. doi: 10.1038/s41374-019-0189-x. Epub 2019 Jan 30.
In human idiopathic pulmonary fibrosis (IPF), collapse of distal airspaces occurs in areas of the lung not (yet) remodeled. Mice lungs overexpressing transforming growth factor-β1 (TGF-β1) recapitulate this abnormality: surfactant dysfunction results in alveolar collapse preceding fibrosis and loss of alveolar epithelial type II (AE2) cells' apical membrane surface area. Here we examined whether surfactant dysfunction-related alveolar collapse due to TGF-β1 overexpression is linked to septal wall remodeling and AE2 cell abnormalities. Three and 6 days after gene transfer of TGF-β1, mice received either intratracheal surfactant (Surf-groups: Curosurf®, 100 mg/kg bodyweight) or 0.9% NaCl (Saline-groups). On days 7 (D7) and 14 (D14), lung mechanics were assessed followed by design-based stereology at light and electron microscopic level to quantify structures. Compared with Saline, Surf showed significantly improved tissue elastance, increased numbers of open alveoli, as well as reduced alveolar size heterogeneity on D7. Deterioration in lung mechanics was highly correlated to the loss of open alveoli. On D14, lung mechanics, number of open alveoli, and alveolar size heterogeneity remained significantly improved in the Surf-group. Volumes of extracellular matrix and collagen fibrils in septal walls were significantly reduced, whereas the apical membrane surface area of AE2 cells was increased in Surf compared with Saline. In remodeled tissue with collapsed alveoli, three-dimensional reconstruction of AE2 cells based on scanning electron microscopy array tomography revealed that AE2 cells were trapped without contact to airspaces in the TGF-β1 mouse model. Similar observations were made in human IPF. Based on correlation analyses, the number of open alveoli and of alveolar size heterogeneity were highly linked with the loss of apical membrane surface area of AE2 cells and deposition of collagen fibrils in septal walls on D14. In conclusion, surfactant replacement therapy stabilizes alveoli and prevents extracellular matrix deposition in septal walls in the TGF-β1 model.
在人类特发性肺纤维化（IPF）中，远端气腔的塌陷发生在尚未重塑的肺部区域。过表达转化生长因子-β1（TGF-β1）的小鼠肺重现了这种异常：表面活性剂功能障碍导致肺泡塌陷，继纤维形成和肺泡上皮细胞 II 型（AE2）细胞顶膜表面积丧失之前。在这里，我们研究了 TGF-β1 过表达导致的表面活性剂功能障碍相关的肺泡塌陷是否与间隔壁重塑和 AE2 细胞异常有关。在 TGF-β1 基因转移后 3 天和 6 天，小鼠接受了气管内表面活性剂（Surf 组：Curosurf®，100mg/kg 体重）或 0.9%NaCl（盐水组）。在第 7 天（D7）和第 14 天（D14），评估了肺力学，然后在光镜和电子显微镜水平上进行基于设计的体视学定量结构。与盐水组相比，Surf 组在 D7 时表现出显著改善的组织弹性、更多的开放肺泡以及降低的肺泡大小异质性。肺力学的恶化与开放肺泡的丧失高度相关。在 D14 时，Surf 组的肺力学、开放肺泡数量和肺泡大小异质性仍显著改善。间隔壁的细胞外基质和胶原纤维体积显著减少，而 AE2 细胞的顶膜表面积在 Surf 组中增加。在具有塌陷肺泡的重塑组织中，基于扫描电子显微镜阵列断层扫描对 AE2 细胞进行三维重建发现，在 TGF-β1 小鼠模型中，AE2 细胞被困且与肺泡无接触。在人类特发性肺纤维化中也观察到类似的现象。基于相关分析，在 D14 时，开放肺泡数量和肺泡大小异质性与 AE2 细胞顶膜表面积的丧失以及间隔壁胶原纤维的沉积高度相关。总之，表面活性剂替代疗法可稳定肺泡并防止 TGF-β1 模型中间隔壁的细胞外基质沉积。
