Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 121, Issue 11, Pages 4289-4302Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI45144
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Funding
- NIH [HL081205]
- National Heart, Lung, and Blood Institute Specialized Centers of Clinically Oriented Research [P50HL084945]
- Flight Attendant Medical Research Institute
- National Cancer Institute [P50 CA058184]
- National Institute on Environmental Health Sciences [P50ES015903, ES03819, U01HL105569, P50HL107169, P01ES018176]
- Grace Anne Dorney fund for tobacco-related disease research
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Chronic obstructive pulmonary disease (COPD), which is caused primarily by cigarette smoking, is a major health problem worldwide. The progressive decline in lung function that occurs in COPD is a result of persistent inflammation of the airways and destruction of the lung parenchyma. Despite the key role of inflammation in the pathogenesis of COPD, treatment with corticosteroids - normally highly effective antiinflanunatory drugs - has little therapeutic benefit. This corticosteroid resistance is largely caused by inactivation of histone deacetylase 2 (HDAC2), which is critical for the transrepressive activity of the glucocorticoid receptor (GR) that mediates the antiinflanunatory effect of corticosteroids. Here, we show that in alveolar macrophages from patients with COPD, S-nitrosylation of HDAC2 is increased and that this abolishes its GR-transrepression activity and promotes corticosteroid insensitivity. Cys-262 and Cys-274 of HDAC2 were found to be the targets of S-nitrosylation, and exogenous glutathione treatment of macrophages from individuals with COPD restored HDAC2 activity. Treatment with sulforaphane, a small-molecule activator of the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2), was also able to denitrosylate HDAC2, restoring dexamethasone sensitivity in alveolar macrophages from patients with COPD. These effects of sulforaphane were glutathione dependent. We conclude that NRF2 is a novel drug target for reversing corticosteroid resistance in COPD and other corticosteroid-resistant inflammatory diseases.
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