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

David H. McMillan, Jos L. J. van der Velden, Karolyn G. Lahue, Xi Quan, 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 AnathyYvonne M. W. Janssen-Heininger

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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.
    Original languageEnglish
    Article numbere85717
    Number of pages16
    JournalJCI Insight
    Volume1
    Issue number8
    DOIs
    Publication statusPublished - 2 Jun 2016

    Keywords

    • Pulmonology
    • Therapeutics

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  • Cite this

    McMillan, D. H., van der Velden, J. L. J., Lahue, K. G., Quan, X., Schneider, R. W., Iberg, M. S., Nolin, J. D., Abdalla, S., Casey, D. T., Tew, K. D., Townsend, D. M., Henderson, C. J., Wolf, C. R., Butnor, K. J., Taatjes, D. J., Budd, R. C., Irvin, C. G., van der Vliet, A., Flemer, S., ... Janssen-Heininger, Y. M. W. (2016). Attenuation of lung fibrosis in mice with a clinically relevant inhibitor of glutathione-S-transferase π. JCI Insight, 1(8), [e85717]. https://doi.org/10.1172/jci.insight.85717