A novel intervention strategy for emphysema by targeting the Nrf2 pathway

描述(申请人提供)：慢性阻塞性肺疾病(COPD)目前是第五大死亡原因，影响全球超过2.1亿人。这种衰弱疾病的临床定义是肺内不可逆转的气流受限，主要归因于肺气肿和香烟烟雾(CS)引起的慢性支气管炎。慢性阻塞性肺疾病的特征是异常炎症、空气空间扩大和肺泡结构丢失。目前的治疗方法，如消炎药或支气管扩张剂，不足以治疗慢性阻塞性肺疾病，因为它们不能改变潜在的疾病过程，因此也不能减缓疾病的发展。由于COPD的患病率在未来几十年内估计会增加，因此迫切需要寻找新的治疗方法，通过靶向与COPD发病机制相关的途径来减缓COPD的进展。我们实验室发现，核因子-红系P45相关因子2(Nrf2)是一种氧化还原敏感的转录因子，它正向调节抗氧化剂和外源解毒酶基因的表达，并对香烟烟雾暴露后肺组织的氧化应激和炎症具有细胞保护作用。在正常情况下，Kelch样ECH相关蛋白1(Keap1)通过靶向Nrf2降解蛋白酶体来负向调节Nrf2的活性。然而，在氧化应激期间(例如，暴露在香烟烟雾中)，转录因子从其抑制物中解离，移位到细胞核，并激活抗氧化和解毒基因的表达。破坏小鼠的Nrf2基因会导致更大的氧化剂-抗氧化剂失衡和炎症，这会导致由于长期吸烟而更早发病和更严重的肺气肿。因此，我们假设增强Nrf2活性(通过遗传或小分子方法)可以通过上调抗氧化和解毒基因来减轻CS诱导的肺气肿，从而减少肺内的氧化应激、炎症和细胞凋亡。具体目的1将在小鼠模型中用遗传方法测试Nrf2活性增强将减少CS诱导的肺气肿的进展的假设，方法是产生条件基因敲除小鼠，其中Keap1基因通过他莫昔芬诱导系统被破坏，这将导致Nrf2活性的全球增加。特殊目的2将测试一种有效的Nrf2小分子激活剂(CDDO-Me)的有效性，它将被用于干预CS诱导的小鼠肺气肿的发展。这项拟议的翻译研究将提供有关Nrf2途径在COPD发病机制中的新见解，并有助于开发一种干预COPD的新治疗方法。

DESCRIPTION (provided by applicant): Chronic obstructive pulmonary disease (COPD) is currently the fifth leading cause of death and affects more than 210 million people worldwide. This debilitating disease is clinically defined by irreversible airflow limitation in the lung that is primarily attributed to pulmonary emphysema and chronic bronchitis due to cigarette smoke (CS). COPD is characterized by abnormal inflammation, air space enlargement, and the loss of alveolar structure. Current treatments such as anti-inflammatories or bronchodilators are inadequate in treating COPD because they do not alter the underlying disease process and as a result do not reduce the progression of the disease. Because the prevalence of COPD is estimated to increase in the coming decades, it is imperative to identify novel therapeutic approaches to reduce the progression of COPD by targeting pathways identified to be involved in COPD pathogenesis. Our laboratory has discovered that nuclear factor-erythroid 2 p45-related factor 2 (Nrf2), a redox-sensitive transcription factor, positively regulates the expression of genes encoding antioxidants and xenobiotic detoxification enzymes and confers cytoprotection against oxidative stress and inflammation in the lungs after exposure to cigarette smoke. Kelch-like ECH-associated protein 1 (Keapl) negatively regulates Nrf2 activity by targeting Nrf2 for proteasomal degradation under normal conditions. However, during oxidative stress (e.g. exposure to cigarette smoke) the transcription factor dissociates from its inhibitor, translocates to the nucleus and activates the expression of antioxidant and detoxifying genes. Disruption of the Nrf2 gene in mice causes greater oxidant-antioxidant imbalance and inflammation, which results in an earlier onset and more severe emphysema due to chronic cigarette smoke exposure. Therefore, we hypothesize that enhancing Nrf2 activity (by a genetic or small molecule approach) can attenuate CS-induced emphysema by decreasing oxidative stress, inflammation and apoptosis in the lung by up-regulating antioxidant and detoxifying genes. Specific Aim 1will test the hypothesis that enhancement of Nrf2 activity will reduce the progression of CS- induced emphysema using a genetic approach in a mouse model by generating conditional knockout mice in which the Keapl gene is disrupted through a tamoxifen inducible system that will lead to a global increase in Nrf2 activity. Specific Aim 2 will test the efficacy of a potent small molecule activator of Nrf2 (CDDO-Me), which will be used to intervene during the development of CS-induced emphysema in mice. The proposed translational study will provide new insights of Nrf2 pathways in the pathogenesis of COPD and aid in the development of a novel therapeutic approach for intervening in COPD.