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Decrease in NRF2-Dependent Antioxidants Linked to Severity of COPD in Smokers NEW YORK -- September 12, 2008 -- A decrease in lung concentrations of NRF2-dependent antioxidants is linked to the severity of chronic obstructive pulmonary disease (COPD) in smokers, according to a study in the September issue of the American Journal of Respiratory and Critical Care Medicine. "NRF2-dependent antioxidants and DJ-1 expression was negatively associated with severity of COPD," said principal investigator, Shyam Biswal, PhD, Bloomberg School's Department of Environmental Health Sciences and Division of Pulmonary and Critical Care at the Johns Hopkins School of Medicine, Baltimore, Maryland. "Therapy directed toward enhancing NRF2-regulated antioxidants may be a novel strategy for attenuating the effects of oxidative stress in the pathogenesis of COPD." In this study, researchers examined tissue samples from the lungs of smokers with and without COPD to determine if there were differences in measured levels of NRF2 expression and the level of its biochemical regulators, including KEAP1, which inhibits NRF2, and DJ-1, which stabilises it. When compared to non-COPD lungs, the lungs of patients with COPD showed markedly decreased levels of NRF2-dependent antioxidants, increased oxidative stress markers, a significant decrease in NRF2 protein with no change in NRF2 mRNA levels, and similar KEAP1 levels, but a marked decrease in the level of DJ-1. While clinical trials of antioxidants to date have been disappointing in improving the clinical course of patients with COPD, this study points to a possibility of benefit from restoring NRF2 levels in damaged lungs by reducing the action of KEAP1. "Increasing NRF2 may also restore important detoxifying enzymes to counteract other effects of tobacco smoke," wrote Peter Barnes, National Heart and Lung Institute, London, United Kingdom, in an accompanying editorial. "This has been achieved in vitro and in vivo by isothiocyanate compounds, such as sulforaphane, which occurs naturally in broccoli." Sulforaphane has been shown to be able to restore antioxidant gene expression in human epithelial tissue in which DJ-1 has been reduced. Isothiocyanate compounds such as that found in broccoli inhibit KEAP1, and thus prevent it from degrading NRF2, said Dr. Barnes. "Future studies should target NRF2 as a novel strategy to increase antioxidant protection in the lungs and test its ability to decrease exacerbations and improve lung function in patients with COPD," said Dr. Biswal. SOURCE: American Thoracic Society E-mail this page to a friend or colleague! To print, use this version