Reducing protein oxidation reverses lung fibrosis

Anathy, V; Lahue, KG; Chapman, DG; Chia, SB; Casey, DT; Aboushousha, R; van der Velden, JLJ; Elko, E; Hoffman, SM; McMillan, DH; Jones, JT; Nolin, JD; Abdalla, S; Schneider, R; Seward, DJ; Roberson, EC; Liptak, MD; Cousins, ME; Butnor, KJ; Taatjes, DJ; Budd, RC; Irvin, CG; Ho, YS; Hakem, R; Brown, KK; Matsui, R; Bachschmid, MM; Gomez, JL; Kaminski, N; van der Vliet, A; Janssen-Heininger, YMW

Reducing protein oxidation reverses lung fibrosis

Anathy, V Lahue, KG Chapman, DG

Chia, SB Casey, DT Aboushousha, R van der Velden, JLJ Elko, E Hoffman, SM McMillan, DH Jones, JT Nolin, JD Abdalla, S Schneider, R Seward, DJ Roberson, EC Liptak, MD Cousins, ME Butnor, KJ Taatjes, DJ Budd, RC Irvin, CG Ho, YS Hakem, R Brown, KK Matsui, R Bachschmid, MM Gomez, JL Kaminski, N van der Vliet, A Janssen-Heininger, YMW

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Publication Type:: Journal Article
Citation:: Nature Medicine, 2018, 24 (8), pp. 1128 - 1135
Issue Date:: 2018-08-01

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Field	Value	Language
dc.contributor.author	Anathy, V	en_US
dc.contributor.author	Lahue, KG	en_US
dc.contributor.author	Chapman, DG https://orcid.org/0000-0002-8211-1817	en_US
dc.contributor.author	Chia, SB	en_US
dc.contributor.author	Casey, DT	en_US
dc.contributor.author	Aboushousha, R	en_US
dc.contributor.author	van der Velden, JLJ	en_US
dc.contributor.author	Elko, E	en_US
dc.contributor.author	Hoffman, SM	en_US
dc.contributor.author	McMillan, DH	en_US
dc.contributor.author	Jones, JT	en_US
dc.contributor.author	Nolin, JD	en_US
dc.contributor.author	Abdalla, S	en_US
dc.contributor.author	Schneider, R	en_US
dc.contributor.author	Seward, DJ	en_US
dc.contributor.author	Roberson, EC	en_US
dc.contributor.author	Liptak, MD	en_US
dc.contributor.author	Cousins, ME	en_US
dc.contributor.author	Butnor, KJ	en_US
dc.contributor.author	Taatjes, DJ	en_US
dc.contributor.author	Budd, RC	en_US
dc.contributor.author	Irvin, CG	en_US
dc.contributor.author	Ho, YS	en_US
dc.contributor.author	Hakem, R	en_US
dc.contributor.author	Brown, KK	en_US
dc.contributor.author	Matsui, R	en_US
dc.contributor.author	Bachschmid, MM	en_US
dc.contributor.author	Gomez, JL	en_US
dc.contributor.author	Kaminski, N	en_US
dc.contributor.author	van der Vliet, A	en_US
dc.contributor.author	Janssen-Heininger, YMW	en_US
dc.date.available	2018-05-14	en_US
dc.date.issued	2018-08-01	en_US
dc.identifier.citation	Nature Medicine, 2018, 24 (8), pp. 1128 - 1135	en_US
dc.identifier.issn	1078-8956	en_US
dc.identifier.uri	http://hdl.handle.net/10453/130981
dc.description.abstract	© 2018, The Author(s). Idiopathic pulmonary fibrosis is characterized by excessive deposition of collagen in the lung, leading to chronically impaired gas exchange and death 1–3 . Oxidative stress is believed to be critical in this disease pathogenesis 4–6 , although the exact mechanisms remain enigmatic. Protein S-glutathionylation (PSSG) is a post-translational modification of proteins that can be reversed by glutaredoxin-1 (GLRX) 7 . It remains unknown whether GLRX and PSSG play a role in lung fibrosis. Here, we explored the impact of GLRX and PSSG status on the pathogenesis of pulmonary fibrosis, using lung tissues from subjects with idiopathic pulmonary fibrosis, transgenic mouse models and direct administration of recombinant Glrx to airways of mice with existing fibrosis. We demonstrate that GLRX enzymatic activity was strongly decreased in fibrotic lungs, in accordance with increases in PSSG. Mice lacking Glrx were far more susceptible to bleomycin- or adenovirus encoding active transforming growth factor beta-1 (AdTGFB1)-induced pulmonary fibrosis, whereas transgenic overexpression of Glrx in the lung epithelium attenuated fibrosis. We furthermore show that endogenous GLRX was inactivated through an oxidative mechanism and that direct administration of the Glrx protein into airways augmented Glrx activity and reversed increases in collagen in mice with TGFB1- or bleomycin-induced fibrosis, even when administered to fibrotic, aged animals. Collectively, these findings suggest the therapeutic potential of exogenous GLRX in treating lung fibrosis.	en_US
dc.relation.ispartof	Nature Medicine	en_US
dc.relation.isbasedon	10.1038/s41591-018-0090-y	en_US
dc.subject.classification	Immunology	en_US
dc.subject.mesh	Lung	en_US
dc.subject.mesh	Animals	en_US
dc.subject.mesh	Mice, Inbred C57BL	en_US
dc.subject.mesh	Mice, Transgenic	en_US
dc.subject.mesh	Glutathione	en_US
dc.subject.mesh	Proteins	en_US
dc.subject.mesh	Oxidation-Reduction	en_US
dc.subject.mesh	Female	en_US
dc.subject.mesh	Glutaredoxins	en_US
dc.subject.mesh	Idiopathic Pulmonary Fibrosis	en_US
dc.title	Reducing protein oxidation reverses lung fibrosis	en_US
dc.type	Journal Article
utslib.citation.volume	8	en_US
utslib.citation.volume	24	en_US
utslib.for	1103 Clinical Sciences	en_US
utslib.for	1101 Medical Biochemistry and Metabolomics	en_US
utslib.for	11 Medical and Health Sciences	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
utslib.copyright.status	closed_access
pubs.issue	8	en_US
pubs.publication-status	Published	en_US
pubs.volume	24	en_US

Abstract:

© 2018, The Author(s). Idiopathic pulmonary fibrosis is characterized by excessive deposition of collagen in the lung, leading to chronically impaired gas exchange and death 1–3 . Oxidative stress is believed to be critical in this disease pathogenesis 4–6 , although the exact mechanisms remain enigmatic. Protein S-glutathionylation (PSSG) is a post-translational modification of proteins that can be reversed by glutaredoxin-1 (GLRX) 7 . It remains unknown whether GLRX and PSSG play a role in lung fibrosis. Here, we explored the impact of GLRX and PSSG status on the pathogenesis of pulmonary fibrosis, using lung tissues from subjects with idiopathic pulmonary fibrosis, transgenic mouse models and direct administration of recombinant Glrx to airways of mice with existing fibrosis. We demonstrate that GLRX enzymatic activity was strongly decreased in fibrotic lungs, in accordance with increases in PSSG. Mice lacking Glrx were far more susceptible to bleomycin- or adenovirus encoding active transforming growth factor beta-1 (AdTGFB1)-induced pulmonary fibrosis, whereas transgenic overexpression of Glrx in the lung epithelium attenuated fibrosis. We furthermore show that endogenous GLRX was inactivated through an oxidative mechanism and that direct administration of the Glrx protein into airways augmented Glrx activity and reversed increases in collagen in mice with TGFB1- or bleomycin-induced fibrosis, even when administered to fibrotic, aged animals. Collectively, these findings suggest the therapeutic potential of exogenous GLRX in treating lung fibrosis.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/130981