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

描述（由申请人提供）：慢性阻塞性肺疾病（COPD）是一种高度病态的疾病，在美国主要由吸烟引起，影响2400万人。慢性阻塞性肺病的特点是异常持续的气道炎症，在细菌、病毒和其他环境污染物引起的急性加重期间，气道炎症经常被放大。异常气道炎症被认为有助于慢性支气管炎，小气道阻塞和肺气肿。皮质类固醇是治疗多种炎症性疾病最有效的抗炎药物；然而，它们对慢性阻塞性肺病的治疗效果不佳。因此，迫切需要开发抑制炎症和改善COPD患者皮质类固醇反应的治疗方法。越来越多的证据表明，组蛋白去乙酰化酶2 （HDAC2）的降低有助于COPD患者的皮质类固醇抵抗。肺泡巨噬细胞和外周肺组织HDAC2水平随着COPD的进展而显著下降。氧化和/或亚硝化应激诱导的HDAC2翻译后修饰是COPD患者HDAC2不稳定的主要原因。核因子红细胞2相关因子2 （Nrf2）是一种bZIP转录因子，通过上调包括抗氧化防御在内的强大细胞保护反应来防止氧化应激。我们等人发现慢性阻塞性肺病患者外周肺组织和肺泡巨噬细胞中Nrf2通路明显下降。我们假设增加nrf2调节的抗氧化防御可以防止HDAC2缺乏活性并改善COPD患者的皮质类固醇反应性。该应用的目的有两个：首先，验证Nrf2信号缺陷是否与慢性阻塞性肺病患者HDAC2缺乏活性和皮质类固醇抵抗有关；第二个测试是否药理学Nrf2激活剂抑制HDAC2失活并改善从COPD患者或小鼠模型中分离的肺细胞的皮质类固醇反应性。该提案的积极结果将支持Nrf2作为改善COPD患者皮质类固醇反应性的分子靶点，并将有助于将萝卜硫素或其他Nrf2上调剂快速推向临床试验。相关性（见说明书）；慢性阻塞性肺病是一种病态疾病，主要由吸烟引起，是美国第四大死亡原因。发现可以提高类固醇抑制静脉/静脉炎症的药物靶点，可以显著降低疾病的发病率和进展。该项目旨在临床前开发一种潜在的药物靶点，可用于临床环境，以改善慢性阻塞性肺病患者的类固醇反应性。

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.