title: Targeting Nrf2 with the triterpenoid CDDO-imidazolide attenuates cigarette smoke-induced emphysema and cardiac dysfunction in mice.
abstract: Chronic obstructive pulmonary disease (COPD), which comprises emphysema and chronic bronchitis resulting from prolonged exposure to cigarette smoke (CS), is a major public health burden with no effective treatment. Emphysema is also associated with pulmonary hypertension, which can progress to right ventricular failure, an important cause of morbidity and mortality among patients with COPD. Nuclear erythroid 2 p45 related factor-2 (Nrf2) is a redox-sensitive transcription factor that up-regulates a battery of antioxidative genes and cytoprotective enzymes that constitute the defense against oxidative stress. Recently, it has been shown that patients with advanced COPD have a decline in expression of the Nrf2 pathway in lungs, suggesting that loss of this antioxidative protective response is a key factor in the pathophysiological progression of emphysema. Furthermore, genetic disruption of Nrf2 in mice causes early-onset and severe emphysema. The present study evaluated whether the strategy of activation of Nrf2 and its downstream network of cytoprotective genes with a small molecule would attenuate CS-induced oxidative stress and emphysema. Nrf2(+/+) and Nrf2(-/-) mice were fed a diet containing the potent Nrf2 activator, 1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im), while being exposed to CS for 6 months. CDDO-Im significantly reduced lung oxidative stress, alveolar cell apoptosis, alveolar destruction, and pulmonary hypertension in Nrf2(+/+) mice caused by chronic exposure to CS. This protection from CS-induced emphysema depended on Nrf2, as Nrf2(-/-) mice failed to show significant reduction in alveolar cell apoptosis and alveolar destruction after treatment with CDDO-Im. These results suggest that targeting the Nrf2 pathway during the etiopathogenesis of emphysema may represent an important approach for prophylaxis against COPD.
authors.affiliation: Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Sussan
authors.forename: Tirumalai
authors.initials: T
authors.lastname: Rangasamy
authors.forename: David J
authors.initials: DJ
authors.lastname: Blake
authors.forename: Deepti
authors.initials: D
authors.lastname: Malhotra
authors.forename: Hazim
authors.initials: H
authors.lastname: El-Haddad
authors.forename: Djahida
authors.initials: D
authors.lastname: Bedja
authors.forename: Melinda S
authors.initials: MS
authors.lastname: Yates
authors.forename: Ponvijay
authors.initials: P
authors.lastname: Kombairaju
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Karen T
authors.initials: KT
authors.lastname: Liby
authors.forename: Michael B
authors.initials: MB
authors.lastname: Sporn
authors.forename: Kathleen L
authors.initials: KL
authors.lastname: Gabrielson
authors.forename: Hunter C
authors.initials: HC
authors.lastname: Champion
authors.forename: Rubin M
authors.initials: RM
authors.lastname: Tuder
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Kensler
authors.forename: Shyam
authors.initials: S
authors.lastname: Biswal
mesh_terms: D000818:Animals; D017209:Apoptosis; D016503:Drug Delivery Systems; D006331:Heart Diseases / Q000188:drug therapy / Q000517:prevention & control*; D006976:Hypertension, Pulmonary; D007093:Imidazoles; D051379:Mice; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000502:physiology*; D009569:Nitric Oxide / Q000037:antagonists & inhibitors; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D018384:Oxidative Stress / Q000187:drug effects; D011650:Pulmonary Alveoli / Q000473:pathology; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy / Q000209:etiology; D011656:Pulmonary Emphysema / Q000188:drug therapy / Q000517:prevention & control*; D012906:Smoke / Q000009:adverse effects*
chemical_list: C116817:2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid; D007093:Imidazoles; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D012906:Smoke; D009569:Nitric Oxide; D009828:Oleanolic Acid