Decline in NRF2-regulated antioxidants in chronic obstructive pulmonary disease lungs due to loss of its positive regulator, DJ-1.
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.



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



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.



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.



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.
Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Room E7624, 615 North Wolfe St., Baltimore, MD 21205, USA.
Deepti
D
Malhotra
Rajesh
R
Thimmulappa
Ana
A
Navas-Acien
Andrew
A
Sandford
Mark
M
Elliott
Anju
A
Singh
Linan
L
Chen
Xiaoxi
X
Zhuang
James
J
Hogg
Peter
P
Pare
Rubin M
RM
Tuder
Shyam
S
Biswal
D000818:Animals; D000975:Antioxidants / Q000032:analysis; D002478:Cells, Cultured; D004847:Epithelial Cells; D005260:Female; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D015227:Lipid Peroxidation; D008168:Lung / Q000737:chemistry*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008875:Middle Aged; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000032:analysis; D051267:NF-E2-Related Factor 2 / Q000032:analysis* / Q000502:physiology; D015513:Oncogene Proteins / Q000502:physiology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D000071617:Protein Deglycase DJ-1; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism / Q000503:physiopathology*; D015398:Signal Transduction / Q000502:physiology; D012907:Smoking / Q000378:metabolism / Q000503:physiopathology*; D017392:Thiobarbituric Acid Reactive Substances / Q000032:analysis
D000975:Antioxidants; D047908:Intracellular Signaling Peptides and Proteins; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D015513:Oncogene Proteins; D017392:Thiobarbituric Acid Reactive Substances; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; C105131:PARK7 protein, human; D000071617:Protein Deglycase DJ-1; D005978:Glutathione