PMID- 15520857
OWN - NLM
STAT- MEDLINE
DCOM- 20041213
LR  - 20240131
IS  - 0021-9738 (Print)
IS  - 0021-9738 (Linking)
VI  - 114
IP  - 9
DP  - 2004 Nov
TI  - Genetic ablation of Nrf2 enhances susceptibility to cigarette smoke-induced 
      emphysema in mice.
PG  - 1248-59
AB  - Although inflammation and protease/antiprotease imbalance have been postulated to 
      be critical in cigarette smoke-induced (CS-induced) emphysema, oxidative stress 
      has been suspected to play an important role in chronic obstructive pulmonary 
      diseases. Susceptibility of the lung to oxidative injury, such as that 
      originating from inhalation of CS, depends largely on its upregulation of 
      antioxidant systems. Nuclear factor, erythroid-derived 2, like 2 (Nrf2) is a 
      redox-sensitive basic leucine zipper protein transcription factor that is 
      involved in the regulation of many detoxification and antioxidant genes. 
      Disruption of the Nrf2 gene in mice led to earlier-onset and more extensive 
      CS-induced emphysema than was found in wild-type littermates. Emphysema in 
      Nrf2-deficient mice exposed to CS for 6 months was associated with more 
      pronounced bronchoalveolar inflammation; with enhanced alveolar expression of 
      8-oxo-7,8-dihydro-2'-deoxyguanosine, a marker of oxidative stress; and with an 
      increased number of apoptotic alveolar septal cells--predominantly endothelial 
      and type II epithelial cells--as compared with wild-type mice. Microarray 
      analysis identified the expression of nearly 50 Nrf2-dependent antioxidant and 
      cytoprotective genes in the lung that may work in concert to counteract 
      CS-induced oxidative stress and inflammation. The responsiveness of the Nrf2 
      pathway may act as a major determinant of susceptibility to tobacco smoke-induced 
      emphysema by upregulating antioxidant defenses and decreasing lung inflammation 
      and alveolar cell apoptosis.
FAU - Rangasamy, Tirumalai
AU  - Rangasamy T
AD  - Department of Environmental Health Sciences, Bloomberg School of Public Health, 
      Johns Hopkins University, Baltimore, Maryland 21205, USA.
FAU - Cho, Chung Y
AU  - Cho CY
FAU - Thimmulappa, Rajesh K
AU  - Thimmulappa RK
FAU - Zhen, Lijie
AU  - Zhen L
FAU - Srisuma, Sorachai S
AU  - Srisuma SS
FAU - Kensler, Thomas W
AU  - Kensler TW
FAU - Yamamoto, Masayuki
AU  - Yamamoto M
FAU - Petrache, Irina
AU  - Petrache I
FAU - Tuder, Rubin M
AU  - Tuder RM
FAU - Biswal, Shyam
AU  - Biswal S
LA  - eng
GR  - R01 66554/PHS HHS/United States
GR  - R01 CA94076/CA/NCI NIH HHS/United States
GR  - R01 CA094076/CA/NCI NIH HHS/United States
GR  - P50 CA058184/CA/NCI NIH HHS/United States
GR  - R01 HL105772/HL/NHLBI NIH HHS/United States
GR  - P30 ES 03819/ES/NIEHS NIH HHS/United States
GR  - P30 ES003819/ES/NIEHS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Clin Invest
JT  - The Journal of clinical investigation
JID - 7802877
RN  - 0 (Antioxidants)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (NFE2L2 protein, human)
RN  - 0 (Nfe2l2 protein, mouse)
RN  - 0 (Trans-Activators)
RN  - 88847-89-6 (8-Hydroxy-2'-Deoxyguanosine)
RN  - G9481N71RO (Deoxyguanosine)
SB  - IM
MH  - 8-Hydroxy-2'-Deoxyguanosine
MH  - Animals
MH  - Antioxidants/chemistry/metabolism
MH  - Apoptosis
MH  - Bronchoalveolar Lavage
MH  - DNA-Binding Proteins/*genetics
MH  - Deoxyguanosine/*analogs & derivatives/metabolism
MH  - Emphysema/*genetics
MH  - Epithelial Cells/cytology/pathology
MH  - *Genetic Predisposition to Disease
MH  - Humans
MH  - Immunohistochemistry
MH  - In Situ Nick-End Labeling
MH  - Inflammation
MH  - Lung/*drug effects/pathology
MH  - Mice
MH  - Mice, Inbred ICR
MH  - Mice, Transgenic
MH  - Microscopy, Fluorescence
MH  - NF-E2-Related Factor 2
MH  - Oligonucleotide Array Sequence Analysis
MH  - Oxidation-Reduction
MH  - Phenotype
MH  - Pulmonary Alveoli/pathology
MH  - *Smoking
MH  - Time Factors
MH  - Trans-Activators/*genetics
MH  - Transcription, Genetic
MH  - Up-Regulation
PMC - PMC524225
EDAT- 2004/11/03 09:00
MHDA- 2004/12/16 09:00
PMCR- 2004/11/01
CRDT- 2004/11/03 09:00
PHST- 2004/01/23 00:00 [received]
PHST- 2004/09/07 00:00 [accepted]
PHST- 2004/11/03 09:00 [pubmed]
PHST- 2004/12/16 09:00 [medline]
PHST- 2004/11/03 09:00 [entrez]
PHST- 2004/11/01 00:00 [pmc-release]
AID - 21146 [pii]
AID - 10.1172/JCI21146 [doi]
PST - ppublish
SO  - J Clin Invest. 2004 Nov;114(9):1248-59. doi: 10.1172/JCI21146.