DJ-1 Modulates Nuclear Erythroid 2-Related Factor-2-Mediated Protection in Human Primary Alveolar Type II Cells in Smokers.
Cigarette smoke (CS) is a main source of oxidative stress and a key risk factor for emphysema, which consists of alveolar wall destruction. Alveolar type (AT) II cells are in the gas exchange regions of the lung. We isolated primary ATII cells from deidentified organ donors whose lungs were not suitable for transplantation. We analyzed the cell injury obtained from nonsmokers, moderate smokers, and heavy smokers. DJ-1 protects cells from oxidative stress and induces nuclear erythroid 2-related factor-2 (Nrf2) expression, which activates the antioxidant defense system. In ATII cells isolated from moderate smokers, we found DJ-1 expression by RT-PCR, and Nrf2 and heme oxygenase (HO)-1 translocation by Western blotting and immunocytofluorescence. In ATII cells isolated from heavy smokers, we detected Nrf2 and HO-1 cytoplasmic localization. Moreover, we found high oxidative stress, as detected by 4-hydroxynonenal (4-HNE) (immunoblotting), inflammation by IL-8 and IL-6 levels by ELISA, and apoptosis by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay in ATII cells obtained from heavy smokers. Furthermore, we detected early DJ-1 and late Nrf2 expression after ATII cell treatment with CS extract. We also overexpressed DJ-1 by adenovirus construct and found that this restored Nrf2 and HO-1 expression and induced nuclear translocation in heavy smokers. Moreover, DJ-1 overexpression also decreased ATII cell apoptosis caused by CS extract in vitro. Our results indicate that DJ-1 activates the Nrf2-mediated antioxidant defense system. Furthermore, DJ-1 overexpression can restore the impaired Nrf2 pathway, leading to ATII cell protection in heavy smokers. This suggests a potential therapeutic strategy for targeting DJ-1 in CS-related lung diseases.
1 Department of Thoracic Medicine and Surgery.|2 Center for Inflammation, Translational and Clinical Lung Research, and.
Karim
K
Bahmed
3 Department of Medicine, National Jewish Health, Denver, Colorado.
Elise M
EM
Messier
4 Department of Medicine, Division of Clinical Pharmacology, University of Colorado Denver, Aurora, Colorado; and.
Wenbo
W
Zhou
5 Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado School of Medicine, Aurora, Colorado.
Rubin M
RM
Tuder
4 Department of Medicine, Division of Clinical Pharmacology, University of Colorado Denver, Aurora, Colorado; and.
Curt R
CR
Freed
3 Department of Medicine, National Jewish Health, Denver, Colorado.
Hong Wei
HW
Chu
1 Department of Thoracic Medicine and Surgery.|2 Center for Inflammation, Translational and Clinical Lung Research, and.
Steven G
SG
Kelsen
3 Department of Medicine, National Jewish Health, Denver, Colorado.
Russell P
RP
Bowler
3 Department of Medicine, National Jewish Health, Denver, Colorado.
Robert J
RJ
Mason
1 Department of Thoracic Medicine and Surgery.|2 Center for Inflammation, Translational and Clinical Lung Research, and.|6 Department of Physiology, Temple University, Philadelphia, Pennsylvania.|3 Department of Medicine, National Jewish Health, Denver, Colorado.
Beata
B
Kosmider
D000256:Adenoviridae / Q000378:metabolism; D000447:Aldehydes / Q000378:metabolism; D056809:Alveolar Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D017209:Apoptosis / Q000235:genetics; D002469:Cell Separation; D019610:Cytoprotection; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D000071617:Protein Deglycase DJ-1 / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012907:Smoking / Q000009:adverse effects*
D000447:Aldehydes; D015850:Interleukin-6; D016209:Interleukin-8; D051267:NF-E2-Related Factor 2; D012333:RNA, Messenger; C105131:PARK7 protein, human; D000071617:Protein Deglycase DJ-1; C027576:4-hydroxy-2-nonenal
DJ-1; alveolar type II cells; cigarette smoke; nuclear erythroid 2–related factor-2