Transforming growth factor-beta1 (TGF-beta1) is involved in regulation of cellular proliferation, differentiation, and fibrogenesis, inducing myofibroblast migration and increasing extracellular matrix synthesis. Here, TGF-beta1 effects on pulmonary structure and function were analyzed. Adenovirus-mediated gene transfer of TGF-beta1 in mice lungs was performed and evaluated by design-based stereology, invasive pulmonary function testing, and detailed analyses of the surfactant system 1 and 2 wk after gene transfer. After 1 wk decreased static compliance was linked with a dramatic alveolar derecruitment without edema formation or increase in the volume of septal wall tissue or collagen fibrils. Abnormally high surface tension correlated with downregulation of surfactant proteins B and C. TTF-1 expression was reduced, and, using PLA (proximity ligand assay) technology, we found Smad3 and TTF-1 forming complexes in vivo, which are normally translocated into the nucleus of the alveolar epithelial type II cells (AE2C) but in the presence of TGF-beta1 remain in the cytoplasm. AE2C show altered morphology, resulting in loss of total apical surface area per lung and polarity. These changes of AE2C were progressive 2 wk after gene transfer and correlated with lung compliance. Although static lung compliance remained low, the volume of septal wall tissue and collagen fibrils increased 2 wk after gene transfer. In this animal model, the primary effect of TGF-beta1 signaling in the lung is downregulation of surfactant proteins, high surface tension, alveolar derecruitment, and mechanical stress, which precede fibrotic tissue remodeling and progressive loss of AE2C polarity. Initial TTF-1 dysfunction is potentially linked to downregulation of surfactant proteins.
- Lopez-Rodriguez, E.; Boden, C.; Echaide, M.; Perez-Gil, J.; Kolb, M.; Gauldie, J.; Maus, U. A.; Ochs, M.; Knudsen, L.
Keywords
- Airway Remodeling
- Alveolar Epithelial Cells/metabolism
- Animals
- Cell Polarity
- DNA-Binding Proteins/metabolism
- Down-Regulation
- Fibrosis
- Gene Expression
- Lung/metabolism/pathology
- Lung Diseases, Interstitial/*metabolism/physiopathology
- Male
- Mice, Inbred C57BL
- Pulmonary Surfactants/metabolism
- Signal Transduction
- Smad3 Protein/metabolism
- Transforming Growth Factor beta1/biosynthesis/*genetics
- AE2C polarity
- TGF-beta1
- Ttf-1
- pulmonary fibrosis
- surfactant