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Am J Respir Crit Care Med. 2009 Nov 1;180(9):867-74. doi: 10.1164/rccm.200905-0670OC. Epub 2009 Aug 13.

The triterpenoid CDDO-imidazolide confers potent protection against hyperoxic acute lung injury in mice.

Author information

1
Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205, USA.

Abstract

RATIONALE:

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.

OBJECTIVES:

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.

MEASUREMENTS AND MAIN 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.

PMID:
19679692
PMCID:
PMC2773914
DOI:
10.1164/rccm.200905-0670OC
[Indexed for MEDLINE]
Free PMC Article

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