Surfactant dysfunction and alveolar collapse are linked with fibrotic septal wall remodeling in the TGF-β1-induced mouse model of pulmonary fibrosis

• Published in: Laboratory investigation Vol. 99; no. 6; pp. 830 - 852
• Main Authors: Beike, Lukas, Wrede, Christoph, Hegermann, Jan, Lopez-Rodriguez, Elena, Kloth, Christina, Gauldie, Jack, Kolb, Martin, Maus, Ulrich A., Ochs, Matthias, Knudsen, Lars
• Format: Journal Article
• Language: English
• Published: New York Elsevier Inc 01.06.2019; Nature Publishing Group US; Nature Publishing Group
• Subjects: 14/28; 14/63; 42/109; 42/44; 631/443/1784; 64/60; 692/699/1785; Abnormalities; Airway Remodeling; Alveolar Epithelial Cells - drug effects; Alveolar Epithelial Cells - ultrastructure; Alveoli; Animals; Collagen; Collapse; Correlation analysis; Deposition; Disease Models, Animal; Extracellular matrix; Female; Fibrils; Fibrosis; Gene transfer; Growth factors; Heterogeneity; Laboratory Medicine; Lung diseases; Lungs; Mechanics; Mechanics (physics); Medicine; Medicine & Public Health; Mice, Inbred C57BL; Pathology; Pulmonary fibrosis; Pulmonary Fibrosis - pathology; Pulmonary Fibrosis - prevention & control; Pulmonary Surfactants - pharmacology; Pulmonary Surfactants - therapeutic use; Respiratory Mechanics; Scanning electron microscopy; Sodium chloride; Stereology; Surface area; Surfactants; Trachea; Transforming growth factor; Transforming Growth Factor beta1; Transforming growth factor-b1; Walls
• ISSN: 0023-6837; 1530-0307; 1530-0307
• DOI: 10.1038/s41374-019-0189-x

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.