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Epithelium-specific deletion of TGF-β receptor type II protects mice from bleomycin-induced pulmonary fibrosis
Min Li, … , Zea Borok, Parviz Minoo
Min Li, … , Zea Borok, Parviz Minoo
Published January 4, 2011; First published December 6, 2010
Citation Information: J Clin Invest. 2011;121(1):277-287. https://doi.org/10.1172/JCI42090.
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Categories: Research Article Pulmonology

Epithelium-specific deletion of TGF-β receptor type II protects mice from bleomycin-induced pulmonary fibrosis

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Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic fibroproliferative pulmonary disorder for which there are currently no treatments. Although the etiology of IPF is unknown, dysregulated TGF-β signaling has been implicated in its pathogenesis. Recent studies also suggest a central role for abnormal epithelial repair. In this study, we sought to elucidate the function of epithelial TGF-β signaling via TGF-β receptor II (TβRII) and its contribution to fibrosis by generating mice in which TβRII was specifically inactivated in mouse lung epithelium. These mice, which are referred to herein as TβRIINkx2.1-cre mice, were used to determine the impact of TβRII inactivation on (a) embryonic lung morphogenesis in vivo; and (b) the epithelial cell response to TGF-β signaling in vitro and in a bleomycin-induced, TGF-β–mediated mouse model of pulmonary fibrosis. Although postnatally viable with no discernible abnormalities in lung morphogenesis and epithelial cell differentiation, TβRIINkx2.1-cre mice developed emphysema, suggesting a requirement for epithelial TβRII in alveolar homeostasis. Absence of TβRII increased phosphorylation of Smad2 and decreased, but did not entirely block, phosphorylation of Smad3 in response to endogenous/physiologic TGF-β. However, TβRIINkx2.1-cre mice exhibited increased survival and resistance to bleomycin-induced pulmonary fibrosis. To our knowledge, these findings are the first to demonstrate a specific role for TGF-β signaling in the lung epithelium in the pathogenesis of pulmonary fibrosis.

Authors

Min Li, Manda Sai Krishnaveni, Changgong Li, Beiyun Zhou, Yiming Xing, Agnes Banfalvi, Aimin Li, Vincent Lombardi, Omid Akbari, Zea Borok, Parviz Minoo

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Figure 1

Epithelial specificity of recombination induced by Nkx2.1-cre in organs of double-transgenic Nkx2.1-cre;Rosa26R mice.

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Epithelial specificity of recombination induced by Nkx2.1-cre in organs ...
LacZ staining was observed in the brain (arrowheads) and thyroid primordium (arrows) in E9.5 embryos (A). Nkx2.1-cre–mediated recombination in the lung was first visible in E11 lungs (arrow in B and outlined in C). In E13, E15, and E17 embryonic lungs, LacZ staining was restricted to epithelial cells in the lung (D, F, G, I, and J), but was also expressed in the tracheal epithelium (E and H). In Pn7 neonates (K), LacZ staining was localized to the bronchoalveolar duct junction (arrowheads) and alveolar type II cell progenitors (arrows). Scale bar: 2 mm (B and G); 800 μm (A and D); 400 μm (H and J); 200 μm (E); 100 μm (F, I, and K); and 40 μm (C).
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