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.
RATIONALE: Oxygen supplementation (e.g., hyperoxia) is used to support critically illpatients 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.
Authors: Michael A Matthay; Sunita Bhattacharya; Donald Gaver; Lorraine B Ware; Lina H K Lim; Olga Syrkina; Fabien Eyal; Rolf Hubmayr Journal: Am J Physiol Lung Cell Mol Physiol Date: 2002-10 Impact factor: 5.464
Authors: Hye-Youn Cho; Anne E Jedlicka; Sekhar P M Reddy; Thomas W Kensler; Masayuki Yamamoto; Liu-Yi Zhang; Steven R Kleeberger Journal: Am J Respir Cell Mol Biol Date: 2002-02 Impact factor: 6.914
Authors: Hye-Youn Cho; Anne E Jedlicka; Sekhar P M Reddy; Liu-Yi Zhang; Thomas W Kensler; Steven R Kleeberger Journal: Am J Respir Cell Mol Biol Date: 2002-01 Impact factor: 6.914
Authors: Albena T Dinkova-Kostova; W David Holtzclaw; Robert N Cole; Ken Itoh; Nobunao Wakabayashi; Yasutake Katoh; Masayuki Yamamoto; Paul Talalay Journal: Proc Natl Acad Sci U S A Date: 2002-08-22 Impact factor: 11.205
Authors: Morgan L Locy; Lynette K Rogers; Justin R Prigge; Edward E Schmidt; Elias S J Arnér; Trent E Tipple Journal: Antioxid Redox Signal Date: 2012-06-25 Impact factor: 8.401