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

TitleDecline in NRF2-regulated antioxidants in chronic obstructive pulmonary disease lungs due to loss of its positive regulator, DJ-1.
Publication TypeJournal Article
Year of Publication2008
AuthorsMalhotra D, Thimmulappa R, Navas-Acien A, Sandford A, Elliott M, Singh A, Chen L, Zhuang X, Hogg J, Pare P, Tuder RM, Biswal S
JournalAm J Respir Crit Care Med
Volume178
Issue6
Pagination592-604
Date Published2008 Sep 15
ISSN1535-4970
KeywordsAnimals, Antioxidants, Cells, Cultured, Epithelial Cells, Female, Glutathione, Humans, Intracellular Signaling Peptides and Proteins, Lipid Peroxidation, Lung, Male, Mice, Mice, Inbred Strains, Middle Aged, NAD(P)H Dehydrogenase (Quinone), NF-E2-Related Factor 2, Oncogene Proteins, Oxidative Stress, Pulmonary Disease, Chronic Obstructive, Signal Transduction, Smoking, Thiobarbituric Acid Reactive Substances
Abstract

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.

DOI10.1164/rccm.200803-380OC
Alternate JournalAm. J. Respir. Crit. Care Med.
PubMed ID18556627
PubMed Central IDPMC2542433
Grant ListP50 HL084945 / HL / NHLBI NIH HHS / United States
P50 HL084945-010004 / HL / NHLBI NIH HHS / United States
P50ES015903 / ES / NIEHS NIH HHS / United States
P50HL084945 / HL / NHLBI NIH HHS / United States
P50HL084948-01 / HL / NHLBI NIH HHS / United States
R01 CA140492 / CA / NCI NIH HHS / United States
R01 HL081205 / HL / NHLBI NIH HHS / United States
R01 HL081205-04 / HL / NHLBI NIH HHS / United States
R01HL081205 / HL / NHLBI NIH HHS / United States
R01HL66554 / HL / NHLBI NIH HHS / United States