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.
|Number of pages||8|
|Journal||American journal of respiratory and critical care medicine|
|Publication status||Published - 2009 Nov 1|
- Stress response
ASJC Scopus subject areas
- Pulmonary and Respiratory Medicine
- Critical Care and Intensive Care Medicine