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

基本信息

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
项目类别：
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

项目摘要

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）：项目摘要细菌性恶化会导致显着的发病率和死亡率，占 COPD 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少 COPD 恶化方面仅显示出适度的效果。目前，没有有效的疗法来预防 COPD 恶化。氧化应激在 COPD 恶化的发病机制中发挥着核心作用，它通过 HDAC2 活性改变诱导表观遗传染色质修饰，损害肺部抗菌先天免疫防御，增强 COPD 患者肺上皮细胞和肺泡巨噬细胞的炎症反应。我们的实验室已确定转录因子 Nrf2 是适应性反应的主要调节因子，可抵消暴露于香烟烟雾的小鼠和慢性阻塞性肺病患者肺部的氧化应激、炎症和宿主防御。转录因子 Nrf2 的缺乏会损害宿主防御并加剧接触 CS 的小鼠的氧化应激和肺气肿，而 COPD 患者的肺部则显示 Nrf2 活性减弱。相反，通过小分子增强 Nrf2 可减轻肺部先天免疫功能障碍、炎症和肺泡破坏，并提高暴露于 CS 的小鼠的类固醇敏感性。西兰花芽含有萝卜硫素，它是 Nrf2 的有效激活剂。来自多项动物和人体研究的证据表明，西兰花芽提取物 (BSE) 或萝卜硫素具有抗氧化、抗炎和抗癌特性，这在很大程度上是通过增强 Nrf2 通路介导的。我们已完成对 65 名 COPD 患者进行 GMP 制造的 BSE 测试，以确定安全性和剂量耐受性。在此应用中，我们将评估在临床前模型中膳食补充 BSE 是否可以减轻细菌恶化。我们将研究 BSE 改善暴露于慢性香烟烟雾的小鼠肺部抗菌防御和皮质类固醇敏感性并防止肺泡破坏的机制。我们将确定 Nrf2 的机制证明 PD 生物标志物，这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预防慢性阻塞性肺病恶化的明确临床试验。