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The Triterpenoid CDDO-Imidazolide Confers Potent Protection against Hyperoxic Acute Lung Injury in Mice

¹ Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland; ² National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina; ³ Department of Medicine, Johns Hopkins University, Baltimore, Maryland; ⁴ Department of Medical Biochemistry, Tohoku University, Sendai, Japan; and ⁵ Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire

Correspondence and requests for reprints should be addressed to Sekhar P. Reddy, Ph.D., The Johns Hopkins Bloomberg School of Public Health, Department of Environmental Health Sciences, Room E7610, 615 North Wolfe Street, Baltimore, MD 21205. E-mail: sreddy{at}jhsph.edu

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 µmol/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.

Key Words: Nrf2 • Keap1 • antioxidants • stress response

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Although oxygen supplementation and ventilation are used as therapy to improve oxygenation and the morbidity and mortality in patients with acute lung injury (ALI), oxidant stress generated by hyperoxic ventilation or the initial injurious process itself is believed to play a major role in perpetuating ALI and preventing some patients from recovery. Direct antioxidant strategies to stoichiometrically scavenge the reactive intermediates present in the lungs of patients with ALI or generated by hyperoxic ventilation therapy remain of uncertain benefit. What This Study Adds to the Field The results of the present study suggest that targeting Nrf2-ARE signaling with an indirect antioxidant triterpenoid, CDDO-imidazolide, which potently up-regulates several antioxidative and stress-response pathways, intermittently during the hyperoxia exposure may provide an effective therapy to limit the potential adverse effects of oxygen supplementation in clinical settings.