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

Narsa M. Reddy, Vegiraju Suryanaraya, Melinda S. Yates, Steven R. Kleeberger, Paul M. Hassoun, Masayuki Yamamoto, Karen T. Liby, Michael B. Sporn, Thomas W. Kensler, Sekhar P. Reddy

Research output: Contribution to journalArticle

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 toimprovethe health of patients with severe ALIandrespiratory dysfunction. We have previouslyshownthatmice 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 in-flammation 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 mmol/kg body weight during the hyperoxic exposure is sufficient to markedly attenuate hyperoxiainduced 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.

Original languageEnglish (US)
Pages (from-to)867-874
Number of pages8
JournalAmerican journal of respiratory and critical care medicine
Volume180
Issue number9
DOIs
StatePublished - Nov 1 2009

Keywords

  • Antioxidants
  • Keap1
  • Nrf2
  • Stress response

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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