Reducing protein oxidation reverses lung fibrosis

化学 肺纤维化 内科学 炎症 病理
作者
Vikas Anathy,Karolyn G. Lahue,David G. Chapman,Shi B. Chia,Dylan T. Casey,Reem Aboushousha,Jos van der Velden,Evan Elko,Sidra M. Hoffman,David H. McMillan,Jane T. Jones,James D. Nolin,Sarah Abdalla,Robert W. Schneider,David J. Seward,Elle C. Roberson,Matthew D. Liptak,Morgan E. Cousins,Kelly J. Butnor,Douglas J. Taatjes,Ralph C. Budd,Charles G. Irvin,Ye-Shih Ho,Razq Hakem,Kevin K. Brown,Reiko Matsui,Markus Bachschmid,Jose L. Gomez,Naftali Kaminski,Albert van der Vliet,Yvonne M. W. Janssen-Heininger
出处
期刊:Nature Medicine [Springer Nature]
卷期号:24 (8): 1128-1135 被引量:47
标识
DOI:10.1038/s41591-018-0090-y
摘要

Idiopathic pulmonary fibrosis is characterized by excessive deposition of collagen in the lung, leading to chronically impaired gas exchange and death1-3. Oxidative stress is believed to be critical in this disease pathogenesis4-6, 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.
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