Developing Nrf2 as a target for treatment of corticosteroid resistance in COPD

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DESCRIPTION (provided by applicant): Chronic Obstructive Pulmonary Disease (COPD) is a highly morbid disease, mainly caused by cigarette smoking in the United States, affecting 24 million people. COPD is characterized by an abnormal persistence airway inflammation, which is frequently amplified during fhe periods of acute exacerbation caused by bacteria, virus and other environmental pollutants. Abnormal airway inflammation is thought to contribute to chronic bronchitis, small-airway obstruction and emphysema. Corticosteroids are the most effective anti}} inflammatory drugs prescribed for treating multiple inflammatory disorders; however they show poor therapeutic benefit in COPD. Therefore, there is a compelling need to develop therapies to inhibit inflammation and improve corticosteroid responses in COPD patients. A growing body of evidence indicate that reduction in histone deacetylase 2 (HDAC2) contributes to corticosteroid resistance in COPD. Alveolar macrophages and peripheral lung tissue show significant decline in HDAC2 levels with progression of COPD. Oxidative and or nitrosative stress induced post-translational modifications of HDAC2 is primarily responsible for HDAC2 instability in COPD. Nuclear factor erythroid 2-related factor 2 (Nrf2) a bZIP transcription factor, protects from oxidative stress by upregulating a robust cytoprotective response that includes antioxidant defenses. We and others found a marked decline in Nrf2 pathway in peripheral lung tissue and alveolar macrophages in COPD. We hypothesize that increasing Nrf2-regulated antioxidant defenses will prevent HDAC2 inactivity and improve corticosteroid responsiveness in COPD. The goal of this application is two-fold: First, verify if defective Nrf2 signaling is associated with HDAC2 inactivity and corticosteroid resistance in COPD; second test if pharmacological Nrf2 activators inhibit HDAC2 inactivity and improves corticosteroid responsiveness in lungs cells isolated from COPD patients or mouse models. Positive outcome of the proposal will support Nrf2 as a molecular target for improving corticosteroid responsiveness in COPD and will help in rapidly moving sulforaphane or other Nrf2 upregulators into clinical trials. RELEVANCE (See instructions); COPD is a morbid condition, primarily caused by tobacco smoking and is the fourth leading cause of death in the United States. Identification of drug targets that can improve efficacy of steroids to suppress ain/vay inflammation can significantly reduce morbidity and progression of the disease. This projects aims at preclinical development of a potential drug target that can be used in the clinical setting to improve steroid responsiveness in COPD nafients.