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

Fingerprint

Hyperoxia
Acute Lung Injury
Lung Injury
Critical Illness
DNA Damage
Oral Administration
1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole
Transcription Factors
Up-Regulation
Antioxidants
Body Weight
Oxygen
Gene Expression
Lung
Health
Enzymes
Therapeutics

Keywords

  • Antioxidants
  • Keap1
  • Nrf2
  • Stress response

ASJC Scopus subject areas

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

Cite this

The triterpenoid CDDO-imidazolide confers potent protection against hyperoxic acute lung injury in mice. / Reddy, Narsa M.; Suryanaraya, Vegiraju; Yates, Melinda S.; Kleeberger, Steven R.; Hassoun, Paul M; Yamamoto, Masayuki; Liby, Karen T.; Sporn, Michael B.; Kensler, Thomas W; Reddy, Sekhar P.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 180, No. 9, 01.11.2009, p. 867-874.

Research output: Contribution to journalArticle

Reddy, Narsa M. ; Suryanaraya, Vegiraju ; Yates, Melinda S. ; Kleeberger, Steven R. ; Hassoun, Paul M ; Yamamoto, Masayuki ; Liby, Karen T. ; Sporn, Michael B. ; Kensler, Thomas W ; Reddy, Sekhar P. / The triterpenoid CDDO-imidazolide confers potent protection against hyperoxic acute lung injury in mice. In: American Journal of Respiratory and Critical Care Medicine. 2009 ; Vol. 180, No. 9. pp. 867-874.
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AU - Kleeberger, Steven R.

AU - Hassoun, Paul M

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