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Decline in NRF2-regulated Antioxidants in Chronic Obstructive Pulmonary Disease Lungs Due to Loss of Its Positive Regulator, DJ-1

¹ Environmental Health Sciences, Johns Hopkins School of Public Health, Baltimore, Maryland; ² Department of Medicine, Respiratory Division, University of British Columbia, and The James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, St. Paul's Hospital, Vancouver, British Columbia, Canada; ³ Department of Neurobiology, The University of Chicago, Chicago, Illinois; ⁴ Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado, Denver, Colorado; and ⁵ Division of Pulmonary and Critical Care Medicine, Department of Medicine, and ⁶ Department of Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland

Correspondence and requests for reprints should be addressed to Shyam Biswal, Ph.D., Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Room E7624, 615 North Wolfe St., Baltimore, MD 21205. E-mail: sbiswal{at}jhsph.edu

Rationale: Oxidative stress is a key contributor in chronic obstructive pulmonary disease (COPD) pathogenesis caused by cigarette smoking. NRF2, a redox-sensitive transcription factor, dissociates from its inhibitor, KEAP1, to induce antioxidant expression that inhibits oxidative stress.

Objectives: To determine the link between severity of COPD, oxidative stress, and NRF2-dependent antioxidant levels in the peripheral lung tissue of patients with COPD.

Methods: We assessed the expression of NRF2, NRF2-dependent antioxidants, regulators of NRF2 activity, and oxidative damage in non-COPD (smokers and former smokers) and smoker COPD lungs (mild and advanced). Cigarette smoke–exposed human lung epithelial cells (Beas2B) and mice were used to understand the mechanisms.

Measurements and Main Results: When compared with non-COPD lungs, the COPD patient lungs showed (1) marked decline in NRF2-dependent antioxidants and glutathione levels, (2) increased oxidative stress markers, (3) significant decrease in NRF2 protein with no change in NRF2 mRNA levels, and (4) similar KEAP1 but significantly decreased DJ-1 levels (a protein that stabilizes NRF2 protein by impairing KEAP1-dependent proteasomal degradation of NRF2). Exposure of Bea2B cells to cigarette smoke caused oxidative modification and enhanced proteasomal degradation of DJ-1 protein. Disruption of DJ-1 in mouse lungs, mouse embryonic fibroblasts, and Beas2B cells lowered NRF2 protein stability and impaired antioxidant induction in response to cigarette smoke. Interestingly, targeting KEAP1 by siRNA or the small-molecule activator sulforaphane restored induction of NRF2-dependent antioxidants in DJ-1–disrupted cells in response to cigarette smoke.

Conclusions: NRF2-dependent antioxidants and DJ-1 expression was negatively associated with severity of COPD. Therapy directed toward enhancing NRF2-regulated antioxidants may be a novel strategy for attenuating the effects of oxidative stress in the pathogenesis of COPD.

Key Words: chronic obstructive pulmonary disease • NRF2 • DJ-1 • oxidative stress • antioxidants

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Chronic obstructive pulmonary disease (COPD) remains a major killer with no effective therapy. Host ability to defend the cigarette smoke–induced oxidative stress by up-regulating lung antioxidant defenses may be one of the critical events that determines the severity and progression of COPD. What This Study Adds to the Field The decline in NRF2-mediated antioxidant transcriptional program in COPD patient lungs is due to decreased NRF2 protein stability. NRF2 may be an important therapeutic target for intervention in the pathogenesis of COPD.

 

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