The triterpenoid CDDO-imidazolide confers potent protection against hyperoxic acute lung injury in mice.
BACKGROUND
Oxygen supplementation (e.g., hyperoxia) is used to support critically ill patients with noninfectious and infectious acute lung injury (ALI); however, hyperoxia exposure can potentially further contribute to and/or perpetuate preexisting ALI. Thus, developing novel therapeutic agents to minimize the side effects of hyperoxia is essential to improve the health of patients with severe ALI and respiratory dysfunction. We have previously shown that mice with a genetic disruption of the Nrf2 transcription factor, which squelches cellular stress by up-regulating the induction of several antioxidant enzymes and proteins, have greater susceptibility to hyperoxic lung injury. Moreover, we have recently demonstrated that Nrf2-deficiency impairs the resolution of lung injury and inflammation after nonlethal hyperoxia exposure.


OBJECTIVE
To test the hypothesis that amplification of endogenous Nrf2 activity would prevent or dampen ALI induced by hyperoxia.


METHODS
Here, we tested our hypothesis using a synthetic triterpenoid compound CDDO-imidazole (CDDO-Im) (1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl] imidazole) in Nrf2-sufficient and Nrf2-deficient mice subjected to hyperoxia-induced ALI.


RESULTS
We demonstrate that oral administration of CDDO-Im at a dose of 30 micromol/kg body weight during the hyperoxic exposure is sufficient to markedly attenuate hyperoxia-induced ALI in Nrf2-sufficient but not Nrf2-deficient mice. This protection by the CDDO-Im against hyperoxic insult was accompanied by increased levels of Nrf2-regulated cytoprotective gene expression and reduced levels of DNA damage in the lung.


CONCLUSIONS
These results suggest that up-regulation of Nrf2 signaling by CDDO-Im or its analogs may provide a novel therapeutic strategy to minimize the adverse effects of hyperoxia.
Reddy
Narsa M
NM
Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205, USA.
Suryanaraya
Vegiraju
V
Yates
Melinda S
MS
Kleeberger
Steven R
SR
Hassoun
Paul M
PM
Yamamoto
Masayuki
M
Liby
Karen T
KT
Sporn
Michael B
MB
Kensler
Thomas W
TW
Reddy
Sekhar P
SP
D055371:Acute Lung Injury / Q000517:prevention & control*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D004195:Disease Models, Animal; D018496:Hyperoxia / Q000150:complications*; D007093:Imidazoles / Q000494:pharmacology*; D020287:In Situ Nick-End Labeling; D008168:Lung / Q000187:drug effects; D051379:Mice; D008813:Mice, Inbred ICR; D051267:NF-E2-Related Factor 2; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D018384:Oxidative Stress; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation / Q000187:drug effects
C472829:1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole; D000975:Antioxidants; D007093:Imidazoles; D051267:NF-E2-Related Factor 2; D009828:Oleanolic Acid
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