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Attenuation of lung fibrosis in mice with a clinically relevant inhibitor of glutathione-S-transferase π
David H. McMillan, … , Vikas Anathy, Yvonne M.W. Janssen-Heininger
David H. McMillan, … , Vikas Anathy, Yvonne M.W. Janssen-Heininger
Published June 2, 2016
Citation Information: JCI Insight. 2016;1(8):e85717. https://doi.org/10.1172/jci.insight.85717.
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Research Article Pulmonology Therapeutics

Attenuation of lung fibrosis in mice with a clinically relevant inhibitor of glutathione-S-transferase π

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Abstract

Idiopathic pulmonary fibrosis (IPF) is a debilitating lung disease characterized by excessive collagen production and fibrogenesis. Apoptosis in lung epithelial cells is critical in IPF pathogenesis, as heightened loss of these cells promotes fibroblast activation and remodeling. Changes in glutathione redox status have been reported in IPF patients. S-glutathionylation, the conjugation of glutathione to reactive cysteines, is catalyzed in part by glutathione-S-transferase π (GSTP). To date, no published information exists linking GSTP and IPF to our knowledge. We hypothesized that GSTP mediates lung fibrogenesis in part through FAS S-glutathionylation, a critical event in epithelial cell apoptosis. Our results demonstrate that GSTP immunoreactivity is increased in the lungs of IPF patients, notably within type II epithelial cells. The FAS-GSTP interaction was also increased in IPF lungs. Bleomycin- and AdTGFβ-induced increases in collagen content, α-SMA, FAS S-glutathionylation, and total protein S-glutathionylation were strongly attenuated in Gstp–/– mice. Oropharyngeal administration of the GSTP inhibitor, TLK117, at a time when fibrosis was already apparent, attenuated bleomycin- and AdTGFβ-induced remodeling, α-SMA, caspase activation, FAS S-glutathionylation, and total protein S-glutathionylation. GSTP is an important driver of protein S-glutathionylation and lung fibrosis, and GSTP inhibition via the airways may be a novel therapeutic strategy for the treatment of IPF.

Authors

David H. McMillan, Jos L.J. van der Velden, Karolyn G. Lahue, Xi Qian, Robert W. Schneider, Martina S. Iberg, James D. Nolin, Sarah Abdalla, Dylan T. Casey, Kenneth D. Tew, Danyelle M. Townsend, Colin J. Henderson, C. Roland Wolf, Kelly J. Butnor, Douglas J. Taatjes, Ralph C. Budd, Charles G. Irvin, Albert van der Vliet, Stevenson Flemer, Vikas Anathy, Yvonne M.W. Janssen-Heininger

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Figure 1

GSTP immunoreactivity and FAS-GSTP interaction are increased in the lungs of IPF patients.

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GSTP immunoreactivity and FAS-GSTP interaction are increased in the lung...
(A) Evaluation of GSTP immunoreactivity in human lung sections from either control or IPF patients (red, GSTP; blue, hematoxylin). Representative images of lung sections from 5 of 14 patients from each group are shown. Arrows indicate reactive type 2 pneumocytes. Scale bar: 50 μm. (B) Assessment of pro-SPC immunoreactivity in lung sections from IPF patients. Parallel sections from IPF patients were probed for either GSTP or pro-SPC by immunohistochemistry (red, GSTP or pro-SPC as indicated; blue, hematoxylin). Scale bar: 50 μm. (C) Assessment of interaction between GSTP and FAS in the lungs of IPF patients. FAS was isolated by immunoprecipitation from whole-lung homogenates of both normal and IPF patients, and GSTP was detected by Western blot. Lanes represent individual patients. (D) Evaluation of GSTP immunoreactivity in mouse lungs treated with bleomycin for 15 days or AdTGFβ for 21 days. GSTP was detected by immunohistochemistry (red, GSTP; blue, hematoxylin). Scale bar: 50 μm. IPF, idiopathic pulmonary fibrosis; FF, fibroblast foci; GSTP, glutathione-S-transferase π; SPC, surfactant protein C; ad-Ctrl, control adenoviral vector; ad-TGF-β, adenoviral vector expressing active TGF-β1.

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