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

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    Idiopathic Pulmonary Fibrosis
    Glutathione Transferase
    Fibrosis
    Lung
    Protein S
    Epithelial Cells
    Bleomycin
    Glutathione
    Collagen
    Apoptosis
    Caspases
    Lung Diseases
    Oxidation-Reduction
    Cysteine
    Fibroblasts
    Therapeutics

    Keywords

    • Pulmonology
    • Therapeutics

    Cite this

    McMillan, D. H., van der Velden, J. L. J., Lahue, K. G., Quan, X., Schneider, R. W., Iberg, M. 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
    McMillan, David H. ; van der Velden, Jos L. J. ; Lahue, Karolyn G. ; Quan, Xi ; Schneider, Robert W. ; Iberg, Martina S. ; Nolin, James D. ; Abdalla, Sarah ; Casey, Dylan T. ; Tew, Kenneth D. ; Townsend, Danyelle M. ; Henderson, Colin J. ; Wolf, C. Roland ; Butnor, Kelly J. ; Taatjes, Douglas J. ; Budd, Ralph C. ; Irvin, Charles G. ; van der Vliet, Albert ; Flemer, Stevenson ; Anathy, Vikas ; Janssen-Heininger, Yvonne M. W. / Attenuation of lung fibrosis in mice with a clinically relevant inhibitor of glutathione-S-transferase π. In: JCI Insight. 2016 ; Vol. 1, No. 8.
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    title = "Attenuation of lung fibrosis in mice with a clinically relevant inhibitor of glutathione-S-transferase π",
    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.",
    keywords = "Pulmonology, Therapeutics",
    author = "McMillan, {David H.} and {van der Velden}, {Jos L. J.} and Lahue, {Karolyn G.} and Xi Quan and Schneider, {Robert W.} and Iberg, {Martina S.} and Nolin, {James D.} and Sarah Abdalla and Casey, {Dylan T.} and Tew, {Kenneth D.} and Townsend, {Danyelle M.} and Henderson, {Colin J.} and Wolf, {C. Roland} and Butnor, {Kelly J.} and Taatjes, {Douglas J.} and Budd, {Ralph C.} and Irvin, {Charles G.} and {van der Vliet}, Albert and Stevenson Flemer and Vikas Anathy and Janssen-Heininger, {Yvonne M. W.}",
    note = "This research is funded by NIH grants T32 HL076122, R01 HL079331, R01 HL122383, and F32 HL124902. We thank Page Spiess for her technical assistance.",
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    McMillan, DH, van der Velden, JLJ, Lahue, KG, Quan, X, Schneider, RW, Iberg, MS, Nolin, JD, Abdalla, S, Casey, DT, Tew, KD, Townsend, DM, Henderson, CJ, Wolf, CR, Butnor, KJ, Taatjes, DJ, Budd, RC, Irvin, CG, van der Vliet, A, Flemer, S, Anathy, V & Janssen-Heininger, YMW 2016, 'Attenuation of lung fibrosis in mice with a clinically relevant inhibitor of glutathione-S-transferase π', JCI Insight, vol. 1, no. 8, e85717. https://doi.org/10.1172/jci.insight.85717

    Attenuation of lung fibrosis in mice with a clinically relevant inhibitor of glutathione-S-transferase π. / McMillan, David H.; van der Velden, Jos L. J.; Lahue, Karolyn G.; Quan, Xi; Schneider, Robert W.; Iberg, Martina S.; Nolin, James D.; Abdalla, Sarah ; Casey, Dylan T.; Tew, Kenneth D.; Townsend, Danyelle M.; Henderson, Colin J.; Wolf, C. Roland; Butnor, Kelly J.; Taatjes, Douglas J.; Budd, Ralph C.; Irvin, Charles G.; van der Vliet, Albert; Flemer, Stevenson; Anathy, Vikas; Janssen-Heininger, Yvonne M. W. (Lead / Corresponding author).

    In: JCI Insight, Vol. 1, No. 8, e85717, 02.06.2016.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Attenuation of lung fibrosis in mice with a clinically relevant inhibitor of glutathione-S-transferase π

    AU - McMillan, David H.

    AU - van der Velden, Jos L. J.

    AU - Lahue, Karolyn G.

    AU - Quan, Xi

    AU - Schneider, Robert W.

    AU - Iberg, Martina S.

    AU - Nolin, James D.

    AU - Abdalla, Sarah

    AU - Casey, Dylan T.

    AU - Tew, Kenneth D.

    AU - Townsend, Danyelle M.

    AU - Henderson, Colin J.

    AU - Wolf, C. Roland

    AU - Butnor, Kelly J.

    AU - Taatjes, Douglas J.

    AU - Budd, Ralph C.

    AU - Irvin, Charles G.

    AU - van der Vliet, Albert

    AU - Flemer, Stevenson

    AU - Anathy, Vikas

    AU - Janssen-Heininger, Yvonne M. W.

    N1 - This research is funded by NIH grants T32 HL076122, R01 HL079331, R01 HL122383, and F32 HL124902. We thank Page Spiess for her technical assistance.

    PY - 2016/6/2

    Y1 - 2016/6/2

    N2 - 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.

    AB - 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.

    KW - Pulmonology

    KW - Therapeutics

    U2 - 10.1172/jci.insight.85717

    DO - 10.1172/jci.insight.85717

    M3 - Article

    C2 - 27358914

    VL - 1

    JO - JCI Insight

    JF - JCI Insight

    SN - 2379-3708

    IS - 8

    M1 - e85717

    ER -

    McMillan DH, van der Velden JLJ, Lahue KG, Quan X, Schneider RW, Iberg MS et al. Attenuation of lung fibrosis in mice with a clinically relevant inhibitor of glutathione-S-transferase π. JCI Insight. 2016 Jun 2;1(8). e85717. https://doi.org/10.1172/jci.insight.85717