Enhancing Nrf2 by Sulforaphane Treatment in COPD

描述（由申请人提供）：慢性阻塞性肺疾病（COPD）是美国发病率和死亡率的主要原因，也是国际上日益增长的慢性疾病原因。目前，这种疾病的治疗选择有限，无法改变气流阻塞的进展并减少周期性恶化。最近的证据强调了氧化应激作为COPD病理生物学机制的核心作用。我们小组的证据表明，慢性阻塞性肺病患者和暴露于香烟烟雾的动物抗氧化防御能力受损，这是由Nrf2活性缺陷引起的，Nrf2是抗氧化酶、谷胱甘肽稳态和细胞保护蛋白的高产调节因子。Nrf2的激活可以保护慢性烟雾暴露小鼠不发生肺气肿，降低氧化应激，增加蛋白酶体抗凋亡细胞保护反应，改善细菌吞噬和杀伤，并逆转烟草烟雾诱导的皮质类固醇抗性。同样，体外Nrf2在人COPD肺细胞中的激活也显示出改善的细胞保护，改善的细菌清除和类固醇敏感性的恢复。这项试验的重点是萝卜硫素，一种十字花科蔬菜的衍生物，它是一种有效的Nrf2活性的体外和体内刺激物。我们想知道COPD患者摄入萝卜硫素是否会增加肺泡巨噬细胞和支气管上皮细胞中Nrf2活性和下游抗氧化剂的表达。因此，我们建议在90名COPD患者中进行一项安慰剂对照随机原则证明试验，分别给予25和150微摩尔萝卜硫素4周。在基线和4周时进行肺泡巨噬细胞的BAL收集，支气管上皮细胞的支气管内刷收集。其他生物标本包括鼻上皮细胞、pbmc和呼气冷凝物。如果我们能够建立一个安全且可耐受的萝卜硫素剂量，并证明它通过Nrf2提高体内抗氧化剂的概念，那么我们将有一个新的长期疗效试验的候选治疗方法。建议进行辅助研究，以探索萝卜硫素增加COPD肺细胞细菌清除率和恢复类固醇敏感性的功效和机制。相关性：在美国，改变COPD病程的治疗是一个主要的未满足的健康需求。动物和人体组织中令人信服的初步证据表明，萝卜硫素是一种从花椰菜和卷心菜等十字花科蔬菜中提取的化学物质，对阻碍慢性阻塞性肺病的进展具有有益作用。如果这项试验成功，它将为治疗这种严重慢性疾病开辟一条重要的新途径。（摘要结束）

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)