Journal
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
Volume 310, Issue 11, Pages L1260-L1271Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajplung.00065.2016
Keywords
TGF-beta 1; TTF-1; AE2C polarity; surfactant; pulmonary fibrosis
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Funding
- Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH)
- Cluster of Excellence REBIRTH (Regenerative Biology to Reconstructive Therapy)
- Alexander von Humboldt Foundation
- German Research Foundation (DFG) [KN 916/1-1]
- Spanish Ministry of Economy [BIO2012-30733]
- Regional Government of Madrid [P2013/MIT-2807]
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Transforming growth factor-beta(1) (TGF-beta 1) is involved in regulation of cellular proliferation, differentiation, and fibrogenesis, inducing myofibroblast migration and increasing extracellular matrix synthesis. Here, TGF-beta 1 effects on pulmonary structure and function were analyzed. Adenovirus-mediated gene transfer of TGF-beta 1 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-beta 1 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-beta 1 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.
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