Mechanistic evaluation of broccoli sprout extract in preclinical COPD models

西兰花芽提取物在临床前慢性阻塞性肺病模型中的作用机制评估

• 批准号: 8628259
• 负责人: Shyam Biswal
• 金额: $ 44.72万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8628259
• 关键词: Accounting; Acute; Adrenal Cortex Hormones; Air; Alveolar Macrophages; Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Apoptosis; Archives; Attenuated; Bacteria; Bacterial Infections; Biological Factors; Biological Markers; Breathing; Broccoli - dietary; Cause of Death; Cells; Chronic; Chronic Obstructive Airway Disease; Clinical Trials; Development; Diet; Dietary Supplementation; Dose; Drug Metabolic Detoxication; Elastin; Enzymes; Epigenetic Process; Epithelial Cells; Evaluation; Exhibits; Foamy Macrophage; Genes; Genetic; Glucosinolates; Goals; HDAC2 gene; Health Care Costs; Host Defense; Human; Immune; Immune System Diseases; Impairment; Infection; Inflammation; Inflammatory Response; Intake; Laboratories; Lung; Lung Inflammation; Malignant Neoplasms; Mediating; Modeling; Morbidity - disease rate; Mus; Myrosinase; Nontypable Haemophilus influenza; Oxidative Stress; Pathogenesis; Pathway interactions; Patients; Peptide Hydrolases; Peptides; Phagocytosis; Pharmacodynamics; Phenotype; Phospholipids; Play; Pneumonia; Post-Translational Protein Processing; Pre-Clinical Model; Prevention; Property; Pseudomonas aeruginosa; Pulmonary Emphysema; Quality of life; Research; Risk; Role; Safety; Specificity; Steroid Resistance; Steroids; Streptococcus pneumoniae; Sulforaphane; Testing; Therapeutic; Translating; alveolar destruction; antimicrobial; burden of illness; chromatin modification; cigarette smoking; design; effective therapy; feeding; improved; killings; mortality; mouse model; nitrosative stress; pre-clinical; prevent; public health relevance; response; scavenger receptor; small molecule; transcription factor; transcriptomics; trial comparing

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.

描述(由申请人提供)：项目摘要细菌恶化会导致严重的发病率和死亡率，占慢性阻塞性肺病相关医疗费用的70%-80%。COPD患者表现出类固醇抵抗，因此，吸入皮质类固醇在减轻COPD恶化方面仅显示出温和的效果。目前，还没有有效的治疗方法来预防COPD的恶化。氧化应激通过改变HDAC2活性，损害肺抗菌天然免疫防御，并通过诱导染色质表观遗传修饰，增强COPD患者肺上皮细胞和肺泡巨噬细胞的炎症反应，在COPD加重的发病机制中发挥核心作用。我们的实验室已经证实，转录因子Nrf2是适应性反应的主要调节因子，这种适应性反应可以对抗香烟烟雾暴露小鼠和COPD患者肺部的氧化应激、炎症和宿主防御。转录因子Nrf2的缺失会损害宿主防御，增加CS暴露小鼠的氧化应激和肺气肿，而COPD患者的肺部则表现出Nrf2活性降低。相反，通过小分子增强Nrf2可以减轻CS暴露小鼠的肺固有免疫功能障碍、炎症和肺泡破坏，并提高类固醇的敏感性。西兰花芽含有萝卜硫素，这是一种有效的Nrf2激活剂。一些动物和人类研究的证据表明，西兰花芽提取物(BSE)或萝卜硫素具有抗氧化、抗炎和抗癌的特性，这在很大程度上是通过增强Nrf2途径来调节的。我们已经在65名COPD患者身上完成了GMP生产的BSE的测试，以确定安全性和剂量耐受性。在这项应用中，我们将评估饮食补充疯牛病是否减轻临床前模型中的细菌恶化。我们将研究BSE改善暴露在慢性香烟烟雾中的小鼠的肺抗菌防御和皮质类固醇敏感性以及保护肺泡免受破坏的机制。我们将确定Nrf2的机制验证PD生物标记物，这可能会转化为临床试验。我们建议的研究的成功完成将有助于我们设计一项预防COPD恶化的最终临床试验。