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

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 TβRII Nkx2.1-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, TβRII Nkx2.1-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, TβRII Nkx2.1-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.

Interactions Between β-Catenin and Transforming Growth Factor-β Signaling Pathways Mediate Epithelial-Mesenchymal Transition and Are Dependent on the Transcriptional Co-activator cAMP-response Element-binding Protein (CREB)-binding Protein (CBP)

“…Overall, these results suggest a key role for Smad3 in coordinately regulating ␣-SMA gene expression through requisite interactions with ␤-catenin/CBP in TGF-␤1-induced EMT in AEC. Together with our recent demonstration that lung epithelial-specific knock-out of TGF-␤ receptor type II reduced phosphorylation of Smad3 in response to TGF-␤ and increased survival in and resistance to bleomycin-induced pulmonary fibrosis (59), our data suggest that Smad3 is a key factor in TGF-␤-mediated EMT/fibrosis.…”

miR-18a-5p Inhibits Sub-pleural Pulmonary Fibrosis by Targeting TGF-β Receptor II

“…29 It has been shown that activation of TGF-b-Smad signaling induces the expression of specific miRNAs that, in turn, may modulate TGF-b-Smad signaling in a feedback manor. [30][31][32] For example, TGF-b1 induces miR-9-5p expression, while overexpression of miR-9-5p in lung fibroblasts inhibits TGFbRII expression and prevents myofibroblast differentiation, ECM deposition, and organ fibrogenesis.…”

Blocking follistatin-like 1 attenuates bleomycin-induced pulmonary fibrosis in mice

“…We further identified that Fstl1 regulates epithelial injury through modulating TGF-1/BMP signaling. Activation of TGF-1 (Sime et al, 1997;Munger et al, 1999;Zhao et al, 2002;Li et al, 2011) and inadequate BMP signaling (but not BMP expression; regulates TGF- and BMP signaling, leading to epithelial injury and fibroblast activation. The precise mechanisms by which FSTL1 exerts its function, if and how FSTL1 regulates epithelial apoptosis, fibroblast proliferation/migration, and myofibroblasts' prolonged survival, are actively pursued in our laboratories.…”