PMID- 19104057
OWN - NLM
STAT- MEDLINE
DCOM- 20090213
LR  - 20240316
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 106
IP  - 1
DP  - 2009 Jan 6
TI  - Targeting Nrf2 with the triterpenoid CDDO-imidazolide attenuates cigarette 
      smoke-induced emphysema and cardiac dysfunction in mice.
PG  - 250-5
LID - 10.1073/pnas.0804333106 [doi]
AB  - Chronic obstructive pulmonary disease (COPD), which comprises emphysema and 
      chronic bronchitis resulting from prolonged exposure to cigarette smoke (CS), is 
      a major public health burden with no effective treatment. Emphysema is also 
      associated with pulmonary hypertension, which can progress to right ventricular 
      failure, an important cause of morbidity and mortality among patients with COPD. 
      Nuclear erythroid 2 p45 related factor-2 (Nrf2) is a redox-sensitive 
      transcription factor that up-regulates a battery of antioxidative genes and 
      cytoprotective enzymes that constitute the defense against oxidative stress. 
      Recently, it has been shown that patients with advanced COPD have a decline in 
      expression of the Nrf2 pathway in lungs, suggesting that loss of this 
      antioxidative protective response is a key factor in the pathophysiological 
      progression of emphysema. Furthermore, genetic disruption of Nrf2 in mice causes 
      early-onset and severe emphysema. The present study evaluated whether the 
      strategy of activation of Nrf2 and its downstream network of cytoprotective genes 
      with a small molecule would attenuate CS-induced oxidative stress and emphysema. 
      Nrf2(+/+) and Nrf2(-/-) mice were fed a diet containing the potent Nrf2 
      activator, 1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im), 
      while being exposed to CS for 6 months. CDDO-Im significantly reduced lung 
      oxidative stress, alveolar cell apoptosis, alveolar destruction, and pulmonary 
      hypertension in Nrf2(+/+) mice caused by chronic exposure to CS. This protection 
      from CS-induced emphysema depended on Nrf2, as Nrf2(-/-) mice failed to show 
      significant reduction in alveolar cell apoptosis and alveolar destruction after 
      treatment with CDDO-Im. These results suggest that targeting the Nrf2 pathway 
      during the etiopathogenesis of emphysema may represent an important approach for 
      prophylaxis against COPD.
FAU - Sussan, Thomas E
AU  - Sussan TE
AD  - Department of Environmental Health Sciences, Bloomberg School of Public Health, 
      Johns Hopkins University, Baltimore, MD 21205, USA.
FAU - Rangasamy, Tirumalai
AU  - Rangasamy T
FAU - Blake, David J
AU  - Blake DJ
FAU - Malhotra, Deepti
AU  - Malhotra D
FAU - El-Haddad, Hazim
AU  - El-Haddad H
FAU - Bedja, Djahida
AU  - Bedja D
FAU - Yates, Melinda S
AU  - Yates MS
FAU - Kombairaju, Ponvijay
AU  - Kombairaju P
FAU - Yamamoto, Masayuki
AU  - Yamamoto M
FAU - Liby, Karen T
AU  - Liby KT
FAU - Sporn, Michael B
AU  - Sporn MB
FAU - Gabrielson, Kathleen L
AU  - Gabrielson KL
FAU - Champion, Hunter C
AU  - Champion HC
FAU - Tuder, Rubin M
AU  - Tuder RM
FAU - Kensler, Thomas W
AU  - Kensler TW
FAU - Biswal, Shyam
AU  - Biswal S
LA  - eng
GR  - CA78814/CA/NCI NIH HHS/United States
GR  - R01HL66554/HL/NHLBI NIH HHS/United States
GR  - P50ES015903/ES/NIEHS NIH HHS/United States
GR  - P50 ES015903/ES/NIEHS NIH HHS/United States
GR  - ES07141/ES/NIEHS NIH HHS/United States
GR  - P50 HL084945/HL/NHLBI NIH HHS/United States
GR  - P50HL084945/HL/NHLBI NIH HHS/United States
GR  - CA94076/CA/NCI NIH HHS/United States
GR  - T32 ES007141/ES/NIEHS NIH HHS/United States
GR  - P30 ES003819/ES/NIEHS NIH HHS/United States
GR  - R01 CA094076/CA/NCI NIH HHS/United States
GR  - R01 HL081205/HL/NHLBI NIH HHS/United States
GR  - P30 CA023108/CA/NCI NIH HHS/United States
GR  - R01 CA078814/CA/NCI NIH HHS/United States
GR  - R01 HL066554/HL/NHLBI NIH HHS/United States
GR  - ES03819/ES/NIEHS NIH HHS/United States
GR  - HL081205/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20081222
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid)
RN  - 0 (Imidazoles)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (Nfe2l2 protein, mouse)
RN  - 0 (Smoke)
RN  - 31C4KY9ESH (Nitric Oxide)
RN  - 6SMK8R7TGJ (Oleanolic Acid)
SB  - IM
MH  - Animals
MH  - Apoptosis
MH  - Drug Delivery Systems
MH  - Heart Diseases/drug therapy/*prevention & control
MH  - Hypertension, Pulmonary
MH  - Imidazoles
MH  - Mice
MH  - Mice, Knockout
MH  - NF-E2-Related Factor 2/genetics/*physiology
MH  - Nitric Oxide/antagonists & inhibitors
MH  - Oleanolic Acid/*analogs & derivatives/pharmacology/therapeutic use
MH  - Oxidative Stress/drug effects
MH  - Pulmonary Alveoli/pathology
MH  - Pulmonary Disease, Chronic Obstructive/drug therapy/etiology
MH  - Pulmonary Emphysema/drug therapy/*prevention & control
MH  - Smoke/*adverse effects
PMC - PMC2629210
COIS- Conflict of interest statement: M.B.S. is receiving grant support from Reata 
      Pharmaceuticals.
EDAT- 2008/12/24 09:00
MHDA- 2009/02/14 09:00
PMCR- 2009/07/06
CRDT- 2008/12/24 09:00
PHST- 2008/12/24 09:00 [entrez]
PHST- 2008/12/24 09:00 [pubmed]
PHST- 2009/02/14 09:00 [medline]
PHST- 2009/07/06 00:00 [pmc-release]
AID - 0804333106 [pii]
AID - 6246 [pii]
AID - 10.1073/pnas.0804333106 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2009 Jan 6;106(1):250-5. doi: 10.1073/pnas.0804333106. 
      Epub 2008 Dec 22.