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（由申请人提供）：槲皮素（3,3'，4'，5,7-五链球菌）是人类饮食中的主要类黄酮。它可以在洋葱，西兰花，苹果，浆果和茶中发现，并在Ginko Biloba和St. John's Wort的提取物中出现。类黄酮具有共同的化学结构，该化学结构由两个通过三个碳连接的酚环组成。槲皮素具有有效的抗氧化作用，并结合自由基物种，形成反应性稳定的自由基。槲皮素还对几种脂质，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）的特征是杯状细胞增生，不可逆的气道阻塞，下部气道的慢性细菌感染，粘膜纤毛间隙降低，肺气肿；并损害了先天免疫力。具有抗氧化剂和抗炎特性的类黄酮可能影响慢性炎症性疾病，例如COPD。黄酮醇（包括槲皮素和kaempferol在内的类黄酮的亚类）的饮食摄入量与肺功能（FEV1）呈正相关，并且与荷兰COPD患者的慢性咳嗽和呼吸困难成反比（6）。此外，在三个欧洲国家，含有多酚水果的摄入与20年的COPD死亡率成反比（7）。这些研究共同表明，槲皮素和其他类黄酮可能会积极影响COPD的结果。我们已经表明，通过烤针刺给药的槲皮素可以通过通过PI 3-激酶/AKT/akt/nou fimals（nf） - b Pathway衰减信号传导，阻止气道高反应性和单核细胞化学吸引蛋白（MCP-1/CCL2）表达。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，这是抗病毒反应中的关键事件，它限制了病毒蛋白的合成和复制。此外，我们的试点研究的结果表明，槲皮素抑制了来自气道上皮细胞和人类单核细胞衍生的巨噬细胞的白介素（IL）-8/CXCL8表达，响应于铜绿假单胞菌感染。槲皮素还降低了铜绿假单胞菌对上皮细胞的侵袭。槲皮素减少了脂多糖（LPS）和经过弹性酶处理的小鼠的肺炎症和弹性后坐力的损失，具有COPD的生理和组织学变化，以及这些“ COPD”小鼠对不可能的H. h. h. h. h. h. to h.最后，槲皮素抑制了培养的气道上皮细胞中鼻病毒（RV）的内在化，并减少了RV诱导的体内中性粒细胞炎症。基于这些观察结果，我们提供了一个总体假设，即槲皮素调节COPD中的先天免疫反应。为了检验这一假设，我们提出了以下特定目标。具体目标1：确定槲皮素对COPD小鼠模型中气道炎症和组织破坏的影响。我们假设：1）槲皮素减轻了由弹性酶和LPS引起的气道炎症和震动变化，这是香烟烟雾的组成部分； 2）槲皮素通过抑制CD14的募集，细胞外信号调节激酶（ERK）和p38有丝分裂原激活蛋白（MAP）激酶对脂质筏的募集来减少LPS诱导的肺泡巨噬细胞炎症反应； 3）减少LPS诱导的肿瘤坏死因子（TNF）-1表达，反过来减弱了C-X-C趋化因子和粘蛋白糖蛋白的上皮细胞表达； 4）槲皮素可防止LPS诱导的巨噬细胞和气道上皮细胞中的氧化应激。具体目标2：确定槲皮素对COPD小鼠模型中对细菌感染的先天反应的影响。我们假设：1）槲皮素在感染流感烟草或铜绿假单胞菌后，抑制了LPS和经弹性酶处理的“ COPD小鼠；”的肺部炎症； 2）槲皮素抑制气道上皮细胞中的Toll样受体（TLR）介导的促炎反应； 3）槲皮素减弱了气道上皮细胞中PI 3-激酶依赖的细菌摄取； 4）槲皮素通过抑制细菌诱导的上皮细胞中的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小鼠模型中鼻毒病毒感染的先天反应的影响。我们使用RV1B（一种次要的RV）开发了一种RV感染的动物模型，该模型与低密度脂蛋白受体（LDL-R）结合。我们假设：1）槲皮素抑制RV感染的LPS和弹性酶处理的“ COPD小鼠；”中嗜中性粒细胞气道炎症；” 2）槲皮素抑制气道上皮细胞中RV的内在化； 3）槲皮素降低气道上皮细胞C-x-c趋化因子的表达； 4）槲皮素增加单核细胞中干扰素（IFN）-3的表达，并增加了气道上皮细胞中真核开始因子（EIF）-A1的磷酸化，从而减少了病毒载量。了解槲皮素在COPD小鼠模型中调节炎症的基本机制可能会导致这种毁灭性疾病的新治疗方法。公共卫生的启示：在美国，慢性阻塞性肺疾病（COPD）越来越普遍造成残疾和死亡的原因，这种疾病几乎没有有效的治疗方法。该提案研究了槲皮素（一种具有抗氧化剂和抗炎作用的植物衍生物对COPD小鼠模型中先天免疫反应的影响。我们将检查槲皮素对COPD发病机理的影响，以及由细菌和病毒感染引起的COPD加剧。还将检查潜在的细胞和生化机制。该提案可能会导致针对COPD的新营养治疗。

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

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

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