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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：
8103051
负责人：
Umadevi Sivanappa Sajjan
金额：
$ 37.6万
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 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8103051
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 Conditioned Culture Media Coughing 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 IL8 gene Immune response Immunoblotting 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 MAPK14 gene MUC5AC gene MUC5B gene Measurement Mediating Membrane Lipids Membrane Microdomains Metalloproteinase Gene Mining Minor Mitogen-Activated Protein Kinases Monitor Monocyte Chemoattractant Proteins Mononuclear Mucins Mucociliary Clearance Mus Natural Immunity Needles Nuclear Nutraceutical Onions Outcome Oxidative Stress Pathogenesis Pathway interactions Patients Phenols Phosphorylation Phosphotransferases Physiological Pilot Projects Plants 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 Tyrosine U937 Cells Viral Load result Viral Proteins Virus Virus Diseases airway hyperresponsiveness airway inflammation airway obstruction base chemokine cigarette smoking cytokine cytotoxic disability effective therapy extracellular flavanoid human MAPK14 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(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类化合物。它存在于洋葱、花椰菜、苹果、浆果和茶叶中，也存在于银杏和圣约翰草的提取物中，这两种保健品都很受欢迎。黄酮类化合物共有一个共同的化学结构，由两个酚环通过三个碳相连。槲皮素具有很强的抗氧化作用，与自由基物种结合形成的反应性较低的苯氧基。此外，栎素还对多种脂质、蛋白酪氨酸和丝氨酸/苏氨酸激酶有抑制作用，包括磷脂酰肌醇(PI)3-激酶。慢性阻塞性肺疾病(COPD)的特征是以呼吸道炎症和杯状细胞增生、不可逆性呼吸道阻塞、下呼吸道慢性细菌感染、粘液纤毛清除减少、肺气肿和先天免疫受损为特征。具有抗氧化和抗炎特性的黄酮类化合物可能会影响慢性炎症性疾病，如COPD。在荷兰COPD患者中，饮食中摄入黄酮醇(包括栎素和山奈酚)与肺功能(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COPD死亡率呈负相关(7)。综上所述，这些研究表明，槲皮素和其他黄烷类化合物可能会对COPD的治疗结果产生积极影响。我们已经证明，灌胃针头给药，通过抑制PI3-激酶/Akt/核因子(NF)-？B通路的信号，阻断哮喘小鼠的气道高反应性和单核细胞趋化蛋白(MCP-1/CCL2)的表达。在后一项研究中，Quercetin还增加了呼吸道上皮细胞真核细胞启动因子(EIF)-2？磷酸化，在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，在铜绿假单胞菌感染的情况下，栎素抑制呼吸道上皮细胞和人单核细胞来源的巨噬细胞表达白介素8/CXCL8。此外，槲皮素还可减少铜绿假单胞菌对上皮细胞的侵袭。在具有COPD典型生理和组织学变化的脂多糖(LPS)和弹性酶治疗的小鼠中，槲皮素减少了肺部炎症和弹性回弹的损失，以及这些“COPD”小鼠对不可分型的流感嗜血杆菌的炎症反应。最后，在体内，Quercetin抑制鼻病毒(RV)在培养的呼吸道上皮细胞中的内化，并减少RV诱导的中性粒细胞炎症。基于这些观察结果，我们提出了一个普遍的假设，即槲皮素调节COPD患者的先天免疫反应。为了验证这一假设，我们提出了以下具体目标。具体目标1：在COPD小鼠模型中，确定槲皮素对呼吸道炎症和组织破坏的影响。我们假设：1)栎素可减轻由香烟烟雾中的弹力酶和内毒素引起的呼吸道炎症和肺气肿改变；2)槲皮素通过抑制CD14、细胞外信号调节激酶(ERK)和p38丝裂原活化蛋白(MAP)激酶向脂筏的募集来减少内毒素诱导的肺泡巨噬细胞的炎症反应；3)减少内毒素诱导的肿瘤坏死因子(TNF)-1的表达，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；以及4)槲皮素防止内毒素诱导的巨噬细胞和呼吸道上皮细胞的氧化应激。具体目标2：在COPD小鼠模型中，确定槲皮素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，槲皮素抑制内毒素和弹性酶处理的“COPD小鼠”的肺部炎症；2)栎素抑制Toll样受体(TLR)介导的呼吸道上皮细胞的促炎反应；3)槲皮素减弱呼吸道上皮细胞对PI 3-激酶依赖的细菌的摄取；4)通过抑制细菌诱导的上皮细胞的氧化应激来减少细胞毒作用。具体目标3：在慢性阻塞性肺疾病小鼠模型中，确定槲皮素对鼻病毒感染的先天反应的影响。我们使用RV1B建立了RV感染的动物模型，RV1B是一种与低密度脂蛋白受体(LDL-R)结合的小组RV。我们假设：1)栎素抑制经RV感染的内毒素和弹性酶治疗的“COPD小鼠”的中性粒细胞气道炎症；2)抑制RV在呼吸道上皮细胞的内化；3)减少呼吸道上皮细胞C-X-C趋化因子的表达；4)增加单核细胞中干扰素-3的表达，增加真核细胞启动因子-A1的磷酸化，从而减少病毒载量。了解栎素调节COPD小鼠模型炎症的基本机制可能会导致这种毁灭性疾病的新疗法。公共卫生：慢性阻塞性肺疾病(COPD)在美国日益成为导致残疾和死亡的常见原因。对这种疾病几乎没有有效的治疗方法。这项建议研究了具有抗氧化和抗炎作用的植物衍生品--槲皮素对慢性阻塞性肺疾病小鼠模型先天免疫反应的影响。我们将研究槲皮素在COPD发病机制中的作用，以及细菌和病毒感染导致的COPD恶化。潜在的细胞和生化机制也将被研究。这项提议可能会导致COPD的一种新的营养疗法。

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Aberrantly activated EGFR contributes to enhanced IL-8 expression in COPD airways epithelial cells via regulation of nuclear FoxO3A.

DOI：
10.1136/thoraxjnl-2012-201719
发表时间：
2013-03
期刊：
Thorax
影响因子：
10
作者：
Ganesan S;Unger BL;Comstock AT;Angel KA;Mancuso P;Martinez FJ;Sajjan US
通讯作者：
Sajjan US

Quercetin inhibits rhinovirus replication in vitro and in vivo.

DOI：
10.1016/j.antiviral.2012.03.005
发表时间：
2012-06
期刊：
ANTIVIRAL RESEARCH
影响因子：
7.6
作者：
Ganesan, Shyamala;Faris, Andrea N.;Comstock, Adam T.;Wang, Qiong;Nanua, Suparna;Hershenson, Marc B.;Sajjan, Uma S.
通讯作者：
Sajjan, Uma S.

Barrier function of airway tract epithelium.

DOI：
10.4161/tisb.24997
发表时间：
2013-10-01
期刊：
Tissue barriers
影响因子：
3.1
作者：
Ganesan S;Comstock AT;Sajjan US
通讯作者：
Sajjan US

Repair and Remodeling of airway epithelium after injury in Chronic Obstructive Pulmonary Disease.

DOI：
10.1007/s13665-013-0052-2
发表时间：
2013-09-01
期刊：
Current respiratory care reports
影响因子：
0
作者：
Ganesan S;Sajjan US
通讯作者：
Sajjan US

TLR2 Activation Limits Rhinovirus-Stimulated CXCL-10 by Attenuating IRAK-1-Dependent IL-33 Receptor Signaling in Human Bronchial Epithelial Cells.

DOI：
10.4049/jimmunol.1502702
发表时间：
2016-09-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
0
作者：
Ganesan S;Pham D;Jing Y;Farazuddin M;Hudy MH;Unger B;Comstock AT;Proud D;Lauring AS;Sajjan US
通讯作者：
Sajjan US