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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 December 6, 2010
Citation Information: J Clin Invest. 2011;121(1):277-287. https://doi.org/10.1172/JCI42090.
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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 2

Generation and validation of TβRII conditional knockout alleles.

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Generation and validation of TβRII conditional knockout alleles.
   
(A)...
(A) Schematic map of the mouse TβRII floxed locus. Arrowheads designate loxP sequences. Primers a, b and c, used in genotyping the mice, are also shown. (B) PCR genotyping using the 3 primers in A. Heart (lanes 1, 3, and 5) and lung tissue (lanes 2, 4, and 6) from floxed alleles and wild-type alleles can be distinguished by their size using primers a and b. Primers for Cre detection are provided in Methods. Deleted TβRII allele is detected using primers a and b. (C and D) Immunohistochemical analysis for TβRII protein in TβRIIfl/fl and TβRIINkx2.1-cre lungs, respectively. Arrows show alveolar type II–appearing cells in TβRIIfl/fl and TβRIINkx2.1-cre adult lungs. (E and F) Western blot analysis and densitometric quantification of total protein homogenates from TβRIIfl/fl (control) and TβRIINkx2.1-cre (mutant) lungs, respectively. Values were normalized against α-tubulin. (G) p-Smad2 and p-Smad3, normalized against total Smad2 and Smad3, respectively. (H) Densitometric quantification of the Western blot in G. (I and J) p-ERK normalized against total ERK and densitometric quantification. **P < 0.01; *P < 0.05. n = 3. Scale bar: 40 μm.

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