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. chronic obstructive pulmonary disease ͉ oxidative stress

Extracellular superoxide dismutase protects against pulmonary emphysema by attenuating oxidative fragmentation of ECM

“…Unfortunately, currently available antioxidants (e.g., NAC) and antiinflammatory therapies (e.g., corticosteroids and the anti-TNF-α antibody infliximab) are ineffective or show limited efficacy in improving lung function and quality of life, with patients becoming resistant or having side effects from the use of these therapies (40)(41)(42). Recently, a redox-sensitive transcription factor, Nrf2, has been suggested to be an interesting target to intervene in the progression of experimental COPD/emphysema (43). However, it remains to be seen how effective Nrf2 activators will be in the treatment of COPD/emphysema, as it is posttranslationally modified, destabilized, and degraded in lungs of patients with COPD, and in rodent lungs exposed to CS (44)(45)(46)(47).…”

“…Mice received two 1-h exposures (1 h apart) daily for 3 consecutive d, and were killed at 24 h after last exposure. For 2-, 4-, and 6-mo CS exposures, 3R4F cigarettes were used to generate a mixture of sidestream smoke (89%) and mainstream smoke (11%) by a Teague smoking machine (model TE-10; Teague Enterprises) at a concentration of approximately 100 mg TPM/m 3 to avoid the possible toxicity to mice at a high concentration of long-term CS exposure (32,43). Mice received 5-h exposures per day, 5 d/wk, for 2, 4, or 6 mo, and were killed at 24 h after last CS exposure.…”

Reactive Oxygen Species in Inflammation and Tissue Injury

“…Nrf2 activators such as triterpenoids (CDDO-Im) that target cysteine residues of Keap1 have been used to specifically disrupt Keap1:Nrf2 interactions, thereby promoting Nrf2 nuclear accumulation and leading to Nrf2-target gene induction (247) in Nrf2-sufficient but not in Nrf2-deficient cells in vitro and in vivo, suggesting that specific targeting of Nrf2-ARE signaling may provide a novel therapeutic strategy for treating human diseases. We and others have shown reduced levels of acute lung injury and inflammation (360) and emphysema in mice treated with CDDO-Im (402). Recently, triterpenoid analogue, bardoxolone methyl, showed improved renal function in early-stage chronic kidney disease in type 2 diabetes; however, Phase III clinical trial with this compound for very severe-stage patients was halted due to undisclosed safety issues (Reata Phamaceuticals) (Clinical Trials.gov; NCT01351675).…”

Nuclear Factor–Erythroid-2–Related Factor 2 in Aging and Lung Fibrosis

“…Activation of Nrf2 by dietary phytochemicals and chemical inducer has been reported to mediate protective effects in certain cellular and animal models of disease. 118,119 SFN, an organosulfur compound derived from cruciferous vegetables, is well-recognized for its robust action on induction of Nrf2. 119 Activation of Nrf2 by SFN in IPF lung fibroblasts inhibited transforming growth factorbeinduced profibrotic effects and induced myofibroblasts to dedifferentiate, 116 an effect that may be important in fibrosis resolution.…”

“…128 Dibenzoylmethane, an analog of curcumin, has been shown to activate the Nrf2-mediated detoxification pathway and inhibits benzo(a)pyrene-induced DNA adduct formation in lungs. 129 Induction of Nrf2 with the triterpenoid CDDO-imidazolide (bardoxolone) and its analogs attenuates cigarette smokeeinduced emphysema and cardiac dysfunction in mice, 118 and diabetic nephropathy in preclinical models. 130 However, in a recent phase II clinical trial of bardoxolone in chronic kidney disease, the study was terminated because of increased rate of heart-related adverse events, including heart failure, hospitalizations, and deaths.…”