Mechanistic evaluation of broccoli sprout extract in preclinical COPD models

描述（由申请人提供）：项目概述细菌性急性加重导致显著的发病率和死亡率，占COPD相关医疗保健费用的70-80%。COPD患者表现出类固醇抵抗，因此，吸入性皮质类固醇在减少COPD急性加重方面仅显示出适度的作用。目前，没有有效的治疗方法来预防COPD恶化。氧化应激通过经由改变的HDAC 2活性诱导表观遗传染色质修饰，损害肺抗细菌先天免疫防御并增强COPD患者的肺上皮细胞和肺泡巨噬细胞中的炎症反应，在COPD急性加重的发病机制中起核心作用。我们的实验室已经确定，转录因子Nrf 2是适应性反应的主要调节因子，该适应性反应抵消香烟烟雾暴露小鼠和COPD患者肺中的氧化应激、炎症和宿主防御。转录因子Nrf 2的缺乏损害了CS暴露小鼠的宿主防御并增强了氧化应激和肺气肿，而COPD患者的肺显示出Nrf 2活性降低。相反，通过小分子增加Nrf 2可减弱CS暴露小鼠的肺部先天免疫功能障碍、炎症和肺泡破坏，并改善类固醇敏感性。西兰花芽含有萝卜硫素，这是一种有效的Nrf 2激活剂。来自几项动物和人类研究的证据已经证明了西兰花芽提取物（BSE）或萝卜硫素的抗氧化、抗炎和抗癌特性，其主要通过增强Nrf 2途径介导。我们已经完成了对65名COPD患者的GMP生产的BSE的测试，以确定安全性和剂量耐受性。在本申请中，我们将评估在临床前模型中，膳食补充BSE是否能减轻细菌性急性加重。我们将研究BSE改善肺部抗菌防御和皮质类固醇敏感性以及保护暴露于慢性香烟烟雾的小鼠免受肺泡破坏的机制。我们将确定Nrf 2的机制证据PD生物标志物，这些生物标志物可以转化为临床试验。成功完成我们提出的研究将有助于我们设计一个明确的预防COPD急性加重的临床试验。

DESCRIPTION (provided by applicant): Project Summary Bacterial exacerbations cause significant morbidity and mortality and account for 70-80% of COPD-related health care costs. COPD patients exhibit steroid resistance and therefore, inhaled corticosteroids show only modest effects in reducing COPD exacerbations. Currently, there are no effective therapies to prevent COPD exacerbations. Oxidative stress plays a central role in the pathogenesis of COPD exacerbations by impairing pulmonary anti-bacterial innate immune defenses and augmenting inflammatory responses in lung epithelial cells and alveolar macrophages of COPD patients by inducing epigenetic chromatin modifications via altered HDAC2 activity. Our laboratory has established that the transcription factor Nrf2 is a major regulator of an adaptive response that counteracts oxidative stress, inflammation and host defense in lungs of cigarette smoke exposed mice and COPD patients. Deficiency of the transcription factor, Nrf2, impairs host defense and augments oxidative stress and emphysema in CS-exposed mice, while lungs of COPD patients show diminished Nrf2 activity. On the contrary, augmenting Nrf2 by a small molecule attenuates pulmonary innate immune dysfunction, inflammation, and alveolar destruction and improves steroid sensitivity in CS-exposed mice. Broccoli sprouts contain sulforaphane, which is a potent activator of Nrf2. Evidence from several animal and human studies have demonstrated antioxidant, anti- inflammatory and anti-cancer properties of broccoli sprout extract (BSE) or sulforaphane, which is largely mediated by enhancing the Nrf2 pathway. We have completed testing of GMP-manufactured BSE on 65 COPD patients for determining safety and dose tolerance. In this application, we will evaluate whether dietary supplementation of BSE attenuates bacterial exacerbations in preclinical models. We will investigate the mechanisms by which BSE improves pulmonary anti-bacterial defenses and corticosteroid sensitivity and protects from alveolar destruction in mice exposed to chronic cigarette smoke. We will identify proof-of- mechanism PD biomarkers of Nrf2, which could be translated to clinical trial. Successful completion of our proposed research will help us in designing a definitive clinical trial for prevention of COPD exacerbations.