Activating the lung's antioxidant defense by targeting Nrf2 inhibits the development of emphysema
Using a molecule similar to one found in an experimental cancer drug, researchers at the Johns Hopkins Bloomberg School of Public Health demonstrated that activation of a key component of the lung's antioxidant defense system, Nrf2, can prevent emphysema in mice. The researchers believe that activation of Nrf2 could be a novel target for therapies to prevent chronic obstructive pulmonary disease (COPD), which comprises emphysema and chronic bronchitis. COPD is a major public health problem and it is the fourth leading cause of death in the U.S. The study is published in the online Early Edition of PNAS: Proceeding of the National Academy of Sciences.
"There are no effective therapies for COPD and there is an urgent need to develop novel intervention strategies. Targeting the Nrf2 pathway presents a novel strategy which needs to be tested for their efficacy in intervening COPD in patients," said Shyam Biswal, PhD, senior author of the study and an associate professor in the Bloomberg School of Public Health's Department of Environmental Health Sciences and the Division of Pulmonary and Critical Care Medicine at the Johns Hopkins School of Medicine.
Nrf2 (nuclear factor erythroid-derived 2-related factor 2) works as a "master gene" that turns on numerous antioxidant and pollutant-detoxifying genes to protect the lungs from environmental pollutants, such as cigarette smoke. Biswal previously identified that disruption of Nrf2 expression in mice caused early onset and severe emphysema. More recently, his team demonstrated for the first time a close correlation between the Nrf2 decline and the progression of COPD in humans.
For the current study, Biswal, along with postdoctoral fellows, Thomas Sussan, PhD, Tirumalai Rangasamy, PhD, and David J. Blake, PhD, observed mice exposed to cigarette smoke to determine if activation of Nrf2 could prevent emphysema. Exposed mice—fed a diet containing CDDO-Im, which is known to activate Nrf2—were significantly less likely to have oxidative stress and lung cell damage associated with emphysema. The researchers also noted substantially improved function in the portion of the heart responsible circulating oxygenated blood through the body—a function that is typically diminished with emphysema. CDDO-Im is closely related to CDDO-Me, an experimental cancer drug approved for phase II clinical trials.
"Nrf2 is an important regulator of the body's antioxidant defense system, and activation of Nrf2 is a promising therapeutic strategy for attenuating COPD progression in patients," said Thomas Sussan, PhD, lead author of the study.
According to the researchers, COPD affects more than 16 million Americans and it is the only disease among the top 10 causes of death with a rising mortality rate in the United States. It is predicted to be the third largest cause of death by 2020 and has already reached worldwide epidemic proportions.
Is there anyone who knows more about the mentioned clinical trials?
The mentioned study (
full text):
Targeting Nrf2 with the triterpenoid CDDO- imidazolide attenuates cigarette smoke-induced emphysema and cardiac dysfunction in mice.
Sussan TE,Rangasamy T,Blake DJ,Malhotra D,El-Haddad H,Bedja D,Yates MS,Kombairaju P,Yamamoto M,Liby KT,Sporn MB,Gabrielson KL,Champion HC,Tuder RM,Kensler TW,Biswal S.
Department of Environmental Health Sciences, Bloomberg School of Public Health.
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.
Also strongly related:
Nrf2-dependent sulfiredoxin-1 expression protects against cigarette smoke-induced oxidative stress in lungs.
Singh A, Ling G, Suhasini AN, Zhang P, Yamamoto M, Navas-Acien A, Cosgrove G, Tuder RM, Kensler TW, Watson WH, Biswal S. Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 212045, USA.
Oxidative stress results in protein oxidation and is involved in the pathogenesis of lung diseases such as chronic obstructive pulmonary disorder (COPD). Sulfiredoxin-1 (Srx1) catalyzes the reduction of cysteine sulfinic acid to sulfenic acid in oxidized proteins and protects them from inactivation. This study examined the mechanism of transcriptional regulation of Srx1 and its possible protective role during oxidative stress associated with COPD. Nrf2, a transcription factor known to influence susceptibility to pulmonary diseases, upregulates Srx1 expression during oxidative stress caused by cigarette smoke exposure in the lungs of mice. Disruption of Nrf2 signaling by genetic knockout in mice or RNAi in cells downregulated the expression of Srx1. In silico analysis of the 5'-promoter-flanking region of Srx1 identified multiple antioxidant-response elements (AREs) that are highly conserved. Reporter and chromatin-immunoprecipitation assays demonstrated that ARE1 at -228 is critical for the Nrf2-mediated response. Attenuation of Srx1 expression with RNAi potentiated the toxicity of hydrogen peroxide (H(2)O(2)), whereas overexpression of Srx1 protected against H(2)O(2)-mediated cell death in vitro. Immunoblot analysis revealed dramatic decreases in Srx1 expression in lungs from patients with COPD relative to nonemphysematous lungs together with a decline in Nrf2 protein. Thus, Srx1, a key Nrf2-regulated gene, contributes to protection against oxidative injury in the lung.
Edited by Shinigami, 25 December 2008 - 05:16 AM.