Enhancing Nrf2 by Sulforaphane Treatment in COPD

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DESCRIPTION (provided by applicant): Chronic Obstructive Pulmonary Disease (COPD) is a major cause of morbidity and mortality in the United States and is a growing cause of chronic disease internationally. Presently, there are limited treatment options for this disease to modify the progression of airflow obstruction and decrease periodic exacerbations. Recent evidence has emphasized the central role of oxidative stress as a mechanism of COPD pathobiology. Evidence from our group has shown that COPD patients and animals exposed to cigarette smoke have impairment of antioxidant defenses which are caused by a defect in activity of Nrf2, a prolific regulator of anti-oxidant enzymes, glutathione homeostasis, and cytoprotective proteins. Activation of Nrf2 protects mice from developing emphysema with chronic smoke exposure, decreases oxidative stress, increases proteasomal anti-apoptotic cytoprotective responses, improves bacterial phagocytosis and killing, and reverses tobacco-smoke induced corticosteroid resistance. Similarly, in vitro Nrf2 activation in human COPD lung cells has shown improved cytoprotection, improved bacterial clearance, and restoration of steroid sensitivity. This trial focuses on sulforaphane, a derivative of cruciferous vegetables, which is a potent in-vitro and in-vivo stimulator of Nrf2 activity. We want to know whether ingestion of sulforaphane by COPD patients will increase Nrf2 activity and expression of downstream antioxidants in alveolar macrophages and bronchial epithelial cells. Accordingly, we are proposing a placebo-controlled randomized proof of principle trial of 25 and 150 micromoles of sulforaphane for 4 weeks in 90 COPD patients. Collections of alveolar macrophages by BAL, bronchial epithelial cells by endobronchial brushings will be performed at baseline and 4 weeks. Other biospecimens will include nasal epithelial cells, PBMCs, and expired breath condensate. If we can establish a safe and tolerable dose of sulforaphane and proof of concept that it improves in-vivo antioxidants via Nrf2, then we will have a novel candidate treatment for longer-term efficacy trials. Ancillary studies are proposed to explore the efficacy and mechanisms of sulforaphane to increase bacterial clearance and to restore steroid sensitivity in COPD lung cells. RELEVANCE: Treatments that modify the course of COPD is a major unmet health need in the US. Compelling preliminary evidence in animals and human tissues suggests sulforaphane, a chemical derived from cruciferous vegetables such as broccoli and cabbage, has beneficial effects to disrupt the progression of COPD. If this trial is successful, it will represent a major new avenue for treatment of this serious chronic disease. (End of Abstract)