Quercetin and Innate Immune Responses in COPD

槲皮素和慢性阻塞性肺病的先天免疫反应

基本信息

批准号：
7529739
负责人：
Umadevi Sivanappa Sajjan
金额：
$ 37.4万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-30 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7529739
关键词：
1-Phosphatidylinositol 3-Kinase 8-hydroxy-2&apos -deoxyguanosine Alveolar Macrophages Animal Model Anti-Inflammatory Agents Anti-inflammatory Antioxidants Antiviral Response Apple Asthma Attenuated Bacteria Bacterial Infections Bacteriophages Berry Binding Biochemical Biological Assay Broccoli - dietary CCL2 gene CD14 gene CXC Chemokines Carbon Cell Count Cells Cessation of life Chemical Structure Chronic Chronic Obstructive Airway Disease Complement Factor B Conditioned Culture Media Coughing Count Country Diet Dietary intake Disease Dose Dyspnea Elastases Enzyme-Linked Immunosorbent Assay Epithelial Cells Eukaryotic Initiation Factor-2 Eukaryotic Initiation Factors European Event Extracellular Signal Regulated Kinases Flagella Flavonoids Flavonols Fluorescence Microscopy Free Radicals Fruit Gelatinase B Gene Expression Genes Gentamicins Ginkgo biloba extract Glycoproteins Goblet Cells Haemophilus influenzae Health Histologic Histology Human Hypericum perforatum Hyperplasia Immune response Infection Inflammation Inflammatory Inflammatory Response Intake Interferons Interleukin-6 Interleukin-8 Interleukins Kaempferols Label Lead Ligands Link Lipid Peroxidation Lipids Lipopolysaccharides Logic Low Density Lipoprotein Receptor Lung Lung Inflammation Lung diseases MAPK14 gene MUC5AC gene MUC5B gene Measurement Mediating Membrane Lipids Membrane Microdomains Metalloproteinase Gene Mining Minor Mitogen-Activated Protein Kinases Mitogens Monitor Mono-S Monocyte Chemoattractant Proteins Mononuclear Mucins Mucociliary Clearance Mus Natural Immunity Needles Nuclear Nutraceutical Onions Outcome Oxidative Stress Pancreatic Elastase Pathogenesis Pathway interactions Patients Phenols Phosphatidylinositols Phosphorylation Phosphotransferases Physiological Pilot Projects Plants Polymerase Chain Reaction Property Protein Biosynthesis Protein-Serine-Threonine Kinases Proteins Pseudomonas aeruginosa Public Health Pulmonary Emphysema Pulmonary Function Test/Forced Expiratory Volume 1 Pulmonary function tests Quercetin Reactive Oxygen Species Rhinovirus Route Signal Transduction Simulate TLR2 gene Tea Testing Tissues Toll-like receptors Tumor Necrosis Factor-alpha Tumor Necrosis Factors Tyrosine U937 Cells Viral Load result Viral Proteins Virus Virus Diseases Week airway hyperresponsiveness airway inflammation airway obstruction base chemokine cigarette smoking cytokine cytotoxic day disability extracellular flavanoid human MAPK14 protein human TNF protein in vivo kaempferol macrophage monocyte morphometry mortality mouse model peflavit peroxidation phenoxy radical polyphenol prevent pulmonary function response uptake

项目摘要

DESCRIPTION (provided by applicant): Quercetin (3,3',4',5,7-pentahydroxyflavone) is the major flavonoid in the human diet. It is found in onions, broccoli, apples, berries and tea, and present in extracts from Ginko biloba and St. John's Wort, both popular health supplements. Flavonoids share a common chemical structure consisting of two phenol rings linked through three carbons. Quercetin has potent antioxidant effects, combining with free radical species to form considerably less reactive phenoxy radicals. Quercetin also has inhibitory effects on several lipid, protein tyrosine and serine/threonine kinases, including phosphatidylinositol (PI) 3-kinase. Chronic obstructive pulmonary disease (COPD) is characterized by airway inflammation with goblet cell hyperplasia, irreversible airway obstruction, chronic bacterial infection of the lower airways, reduced mucociliary clearance, emphysema; and impaired innate immunity. Flavonoids with antioxidant and anti-inflammatory properties may influence chronic inflammatory diseases such as COPD. Dietary intake of flavonols (a subclass of flavonoids including quercetin and kaempferol) has been positively associated with pulmonary function (FEV1) and inversely associated with chronic cough and breathlessness in Dutch COPD patients (6). Further, intake of polyphenol-containing fruit was inversely correlated with 20-yr COPD mortality in three European countries (7). Together these studies suggest that quercetin and other flavanoids may positively influence outcome in COPD. We have shown that quercetin, administered by gavage needle, blocks airways hyper-responsiveness and monocyte chemoattractant protein (MCP-1/CCL2) expression in a mouse model of asthma by attenuating signaling through a PI 3-kinase/Akt/nuclear factor (NF)-?B pathway. In the latter study, quercetin also increased airway epithelial cell eukaryotic initiation factor (eIF)-2? phosphorylation, a key event in the antiviral response which limits viral protein synthesis and replication. In addition, results from our pilot studies suggest that quercetin inhibits interleukin (IL)-8/CXCL8 expression from airway epithelial cells and human monocyte- derived macrophages in response to P. aeruginosa infection. Quercetin also decreased invasion of epithelial cells by P. aeruginosa. Quercetin reduced lung inflammation and loss of elastic recoil in lipopolysaccharide (LPS) and elastase-treated mice with physiologic and histologic changes typical of COPD, as well as the inflammatory response of these "COPD" mice to non-typeable H. influenzae. Finally, quercetin inhibited internalization of rhinovirus (RV) in cultured airway epithelial cells and reduced RV-induced neutrophilic inflammation in vivo. Based on these observations, we offer the general hypothesis that quercetin modulates innate immune responses in COPD. To test this hypothesis, we propose the following Specific Aims. Specific Aim 1: Determine the effects of quercetin on airway inflammation and tissue destruction in a mouse model of COPD. We hypothesize that: 1) quercetin attenuates airways inflammation and emphysematous changes caused by elastase and LPS, a constituent of cigarette smoke; 2) quercetin reduces LPS-induced inflammatory responses in alveolar macrophages by inhibiting recruitment of CD14, extracellular signal regulated kinase (ERK) and p38 mitogen-activated protein (MAP) kinase to lipid rafts; 3) reduction of LPS-induced tumor necrosis factor (TNF)-1 expression, in turn, attenuates epithelial cell expression of C-X-C chemokines and mucin glycoproteins; and 4) quercetin prevents LPS-induced oxidative stress in macrophages and airway epithelial cells. Specific Aim 2: Determine the effects of quercetin on the innate response to bacterial infection in a mouse model of COPD. We hypothesize that: 1) after infection with H. influenzae or P. aeruginosa, quercetin inhibits lung inflammation in LPS and elastase-treated "COPD mice;" 2) quercetin inhibits Toll-like receptor (TLR)-mediated pro-inflammatory responses in airway epithelial cells; 3) quercetin attenuates PI 3-kinase- dependent bacterial uptake in airway epithelial cells; and 4) quercetin reduces cytotoxic effects by inhibiting bacteria-induced oxidative stress in epithelial cells. Specific Aim 3: Determine the effects of quercetin on the innate response to rhinoviral infection in a mouse model of COPD. We have developed an animal model of RV infection using RV1B, a minor group RV which binds to the low-density lipoprotein receptor (LDL-R). We hypothesize that: 1) quercetin inhibits neutrophilic airway inflammation in RV-infected LPS- and elastase-treated "COPD mice;" 2) quercetin inhibits internalization of RV in airway epithelial cells; 3) quercetin decreases airway epithelial cell C-X-C chemokine expression; and 4) quercetin increases the expression of interferon (IFN)-3 in mononuclear cells and increases the phosphorylation of eukaryotic initiation factor (eIF)-a1 in airway epithelial cells, thereby reducing viral load. Understanding the basic mechanisms by which quercetin modulates inflammation in a mouse model of COPD may lead to a new treatment for this devastating disease. PUBLIC HEALTH REVELANCE: Chronic obstructive pulmonary disease (COPD) is increasingly common cause of disability and death in the U.S. There are few effective treatments for this disease. This proposal examines the effects of quercetin, a plant derivative with antioxidant and anti-inflammatory actions, on the innate immune response in a mouse model of COPD. We will examine the effects of quercetin on the pathogenesis of COPD, as well as exacerbations of COPD caused by bacterial and viral infections. Underlying cellular and biochemical mechanisms will also be examined. This proposal may lead to a new nutraceutical treatment for COPD.

描述（由申请人提供）：槲皮素（3,3',4',5,7-五羟基黄酮）是人类饮食中的主要类黄酮。它存在于洋葱、西兰花、苹果、浆果和茶中，也存在于银杏和圣约翰草的提取物中，这两种都是流行的保健补充剂。类黄酮具有共同的化学结构，由通过三个碳连接的两个酚环组成。槲皮素具有有效的抗氧化作用，与自由基结合形成反应性相当低的苯氧基自由基。槲皮素还对多种脂质、蛋白酪氨酸和丝氨酸/苏氨酸激酶（包括磷脂酰肌醇 (PI) 3-激酶）具有抑制作用。慢性阻塞性肺疾病（COPD）的特点是气道炎症伴杯状细胞增生、不可逆性气道阻塞、下气道慢性细菌感染、粘液纤毛清除能力降低、肺气肿；和先天免疫力受损。具有抗氧化和抗炎特性的黄酮类化合物可能会影响慢性阻塞性肺病等慢性炎症疾病。黄酮醇（类黄酮的一个亚类，包括槲皮素和山奈酚）的膳食摄入量与荷兰 COPD 患者的肺功能 (FEV1) 呈正相关，与慢性咳嗽和呼吸困难呈负相关 (6)。此外，在三个欧洲国家，含多酚水果的摄入量与 20 年慢性阻塞性肺病死亡率呈负相关 (7)。这些研究共同表明，槲皮素和其他黄酮类化合物可能对慢性阻塞性肺病的治疗结果产生积极影响。我们已经证明，通过灌胃针施用槲皮素，可以通过减弱 PI 3 激酶/Akt/核因子 (NF) 的信号传导，阻断哮喘小鼠模型中的气道高反应性和单核细胞趋化蛋白 (MCP-1/CCL2) 的表达。 )-?B途径。在后一项研究中，槲皮素还增加了气道上皮细胞真核起始因子（eIF）-2？磷酸化是抗病毒反应中的一个关键事件，限制病毒蛋白质的合成和复制。此外，我们的初步研究结果表明，槲皮素可抑制气道上皮细胞和人单核细胞来源的巨噬细胞对铜绿假单胞菌感染的反应，从而抑制白细胞介素 (IL)-8/CXCL8 的表达。槲皮素还可以减少铜绿假单胞菌对上皮细胞的侵袭。槲皮素减少了脂多糖（LPS）和弹性蛋白酶处理的具有慢性阻塞性肺病（COPD）典型生理和组织学变化的小鼠的肺部炎症和弹性回缩力的丧失，以及这些“慢性阻塞性肺病”小鼠对不可分型流感嗜血杆菌的炎症反应。最后，槲皮素抑制鼻病毒（RV）在培养的气道上皮细胞中的内化，并减少 RV 诱导的体内中性粒细胞炎症。基于这些观察，我们提出了槲皮素调节慢性阻塞性肺病先天免疫反应的一般假设。为了检验这一假设，我们提出以下具体目标。具体目标 1：确定槲皮素对 COPD 小鼠模型气道炎症和组织破坏的影响。我们假设：1）槲皮素可以减轻由弹性蛋白酶和脂多糖（香烟烟雾的一种成分）引起的气道炎症和肺气肿变化； 2) 槲皮素通过抑制 CD14、细胞外信号调节激酶 (ERK) 和 p38 丝裂原激活蛋白 (MAP) 激酶向脂筏的募集来减少 LPS 诱导的肺泡巨噬细胞炎症反应； 3) LPS诱导的肿瘤坏死因子(TNF)-1表达减少，进而减弱上皮细胞C-X-C趋化因子和粘蛋白糖蛋白的表达； 4) 槲皮素可防止巨噬细胞和气道上皮细胞中 LPS 诱导的氧化应激。具体目标 2：确定槲皮素对慢性阻塞性肺病小鼠模型对细菌感染的先天反应的影响。我们假设：1）感染流感嗜血杆菌或铜绿假单胞菌后，槲皮素可抑制 LPS 和弹性蛋白酶治疗的“COPD 小鼠”的肺部炎症； 2）槲皮素抑制气道上皮细胞中Toll样受体（TLR）介导的促炎反应； 3) 槲皮素减弱气道上皮细胞中PI 3激酶依赖性细菌摄取； 4) 槲皮素通过抑制细菌诱导的上皮细胞氧化应激来降低细胞毒性作用。具体目标 3：确定槲皮素对 COPD 小鼠模型对鼻病毒感染的先天反应的影响。我们使用 RV1B 开发了 RV 感染的动物模型，RV1B 是一种与低密度脂蛋白受体 (LDL-R) 结合的小类 RV。我们假设：1) 槲皮素抑制 RV 感染的 LPS 和弹性蛋白酶处理的“COPD 小鼠”中的中性粒细胞气道炎症； 2)槲皮素抑制气道上皮细胞中RV的内化； 3)槲皮素降低气道上皮细胞C-X-C趋化因子表达； 4)槲皮素可增加单核细胞中干扰素(IFN)-3的表达，并增加气道上皮细胞中真核起始因子(eIF)-a1的磷酸化，从而减少病毒载量。了解槲皮素调节慢性阻塞性肺病小鼠模型炎症的基本机制可能会为这种破坏性疾病带来新的治疗方法。公众健康启示：慢性阻塞性肺病（COPD）在美国日益成为导致残疾和死亡的常见原因。这种疾病的有效治疗方法很少。该提案研究了槲皮素（一种具有抗氧化和抗炎作用的植物衍生物）对慢性阻塞性肺病小鼠模型先天免疫反应的影响。我们将研究槲皮素对慢性阻塞性肺病发病机制的影响，以及细菌和病毒感染引起的慢性阻塞性肺病恶化。还将检查潜在的细胞和生化机制。该提案可能会带来一种新的慢性阻塞性肺病营养治疗方法。