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Surfactant dysfunction during over-expression of TGF-β1 precedes profibrotic lung remodeling in vivo

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López Rodríguez, Elena and Boden, Caroline and Echaide Torreguitar, Mercedes and Pérez Gil, Jesús and Kolb, Martin and Gauldie, Jack and Maus, Ulrich A. and Ochs, Matthias and Knudsen, Lars (2016) Surfactant dysfunction during over-expression of TGF-β1 precedes profibrotic lung remodeling in vivo. American journal of physiology lung cellular and molecular physiology, 310 (11). L1260-L1271. ISSN 1040-0605; Online ISSN: 1522-1504

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Official URL: http://ajplung.physiology.org/content/310/11/L1260



Abstract

Surfactant dysfunction during overexpression of TGF-1 precedes profibrotic lung remodeling in vivo. Am J Physiol Lung Cell Mol Physiol 310: L1260 –L1271, 2016. First published April 22, 2016; doi:10.1152/ajplung.00065.2016.— Transforming growth factor-1 (TGF-1) is involved in regulation of cellular proliferation, differentiation, and fibrogenesis, inducing myofi- broblast migration and increasing extracellular matrix synthesis. Here, TGF-1 effects on pulmonary structure and function were analyzed. Adenovirus-mediated gene transfer of TGF-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-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-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. TGF-1


Item Type:Article
Uncontrolled Keywords:TGF-1; TTF-1; AE2C polarity; Surfactant; Pulmonary fibrosis
Subjects:Medical sciences > Biology > Biochemistry
ID Code:43478
Deposited On:27 Jun 2017 11:01
Last Modified:01 Sep 2017 10:58

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