Quercetin Treatment of Airway Inflammation
槲皮素治疗气道炎症
基本信息
- 批准号:7037366
- 负责人:
- 金额:$ 19.04万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2005
- 资助国家:美国
- 起止时间:2005-09-30 至 2007-08-31
- 项目状态:已结题
- 来源:
- 关键词:Pseudomonas aeruginosaallergensalternative medicineasthmabiological signal transductioncell sortingchronic bronchitisclinical researchcockroachcolony stimulating factorcystic fibrosisdisease /disorder modelelectrochemistryenzyme linked immunosorbent assayhigh performance liquid chromatographyhistologyhydrogen peroxideimmune responseimmunocytochemistryinflammationinterleukin 8laboratory mousephosphatidylinositol 3 kinaseplant extractsquercetintissue /cell culturetumor necrosis factor alpha
项目摘要
DESCRIPTION (provided by applicant): Inflammatory airways diseases - asthma, chronic bronchitis and cystic fibrosis - remain important causes of morbidity and mortality in the U.S. The purpose of this application is to study the effects of the dietary flavonol quercetin, an antioxidant and inhibitor of phosphatidylinositol (PI) 3-kinase, on airway inflammation. We will examine the effects of quercetin on biochemical signaling pathways regulating innate immune responses in cultured airway epithelial cells, and on two mouse models of airways disease, cockroach allergen sensitization (mimicking asthma) and Pseudomonas endobronchial infection (mimicking cystic fibrosis and chronic bronchitis). Our pilot data suggest that quercetin attenuates airway epithelial cell expression of inter- leukin (IL)-8, a neutrophil chemoattractant, and granulocyte macrophage-colony stimulating factor (GM- CSF), an eosinophil chemoattractant, in response to pro-inflammatory stimuli. We propose the general hypothesis that quercetin blocks airway inflammation by attenuating epithelial cell chemoattractant expression via both PI 3-kinase-dependent and -independent mechanisms. To test this, we propose the following Aims:
Specific Aim 1. Examine the effects of quercetin on airway epithelial cell signaling pathways regulating the innate immune response to pro-inflammatory stimuli. We will measure airway epithelial cell IL-8 and GM-CSF expression in response to stimuli relevant to asthma, cystic fibrosis and chronic bronchitis - TNFalpha, cockroach extract and Pseudomonas aeruginosa. 16HBE14o- human airway epithelial cells will be studied, with key experiments repeated in primary cells. IL-8 and GM-CSF expression will be assessed by ELISA and reporter assays. The requirement of PI 3-kinase activation, Akt and intracellular H2O2 generation will be assessed using chemical and dominant-negative inhibitors. The effects of quercetin on IL- 8 and GM-CSF expression, PI 3-kinase and Akt activation, and H2O2 generation will be measured.
Specific Aim 2. Examine the anti-inflammatory effects of quercetin in two mouse models of inflammatory airways diseases. We will pre-treat cockroach allergen-sensitized and challenged mice, as well as mice infected with Pseudomonas aeruginosa in the airways, with quercetin or vehicle. Airway inflammation will be assessed by histological methods and cell counts. Airway chemokine expression will be assessed by ELISA and immunohistochemistry. Akt phosphorylation and activation will be assessed by immunohistochemistry and in vitro kinase assay. Airways responsiveness will be measured by methacholine challenge testing. Blood and lung quercetin levels will be assessed by HPLC with electrochemical detection.
This project examines the value of quercetin, a plant pigment, in preventing airway inflammation in mouse models of disease. This work may lead to new treatments for asthma, cystic fibrosis or chronic bronchitis.
描述(由申请人提供):炎症性气道疾病 - 哮喘,慢性支气管炎和囊性纤维化 - 仍然是美国发病率和死亡率的重要原因。该应用的目的是研究饮食中饮食中的黄酮醇槲皮素,一种抗氧化和抗氧化剂和抑制剂气道炎症上的磷脂酰肌醇(PI)3-激酶。我们将研究槲皮素对调节培养气道上皮细胞中先天免疫反应的生物化学信号通路的影响,以及两种气道疾病的小鼠模型,蟑螂过敏蛋白敏化(模仿哮喘)和假单胞菌性卵子内无体性感染(模拟肠环纤维纤维纤维化和慢性疾病)。我们的试点数据表明,槲皮素减弱了leukin(IL)-8的气道上皮细胞表达,中性粒细胞趋化因子和粒细胞巨噬细胞巨粒子刺激因子(GM-CSF),一种嗜酸性刺激性刺激性的嗜酸性刺激剂。我们提出了一个普遍的假设,即槲皮素通过通过PI 3-激酶依赖性和非依赖性机制来衰减上皮细胞化学吸引剂表达来阻止气道炎症。为了测试这一点,我们提出以下目的:
具体目标1。检查槲皮素对调节促炎性刺激的先天免疫反应的气道上皮细胞信号通路的影响。我们将测量与哮喘,囊性纤维化和慢性支气管炎有关的刺激,测量气道上皮细胞IL-8和GM-CSF表达 - TNFALPHA,蟑螂提取物和铜绿假单胞菌。将研究16HBE14O-人类气道上皮细胞,并在原代细胞中重复进行关键实验。 IL-8和GM-CSF表达将由ELISA和记者测定法进行评估。将使用化学和显性阴性抑制剂评估PI 3-激酶激活,AKT和细胞内H2O2的需求。槲皮素对IL-8和GM-CSF表达,PI 3-激酶和AKT激活以及H2O2生成的影响。
具体目的2。检查槲皮素在两种炎症气道疾病模型中的抗炎作用。我们将预处理蟑螂过敏原敏感和挑战的小鼠,以及带有槲皮素或媒介物的呼吸道中铜绿假单胞菌感染的小鼠。气道炎症将通过组织学方法和细胞计数评估。气道趋化因子表达将通过ELISA和免疫组织化学评估。 AKT磷酸化和激活将通过免疫组织化学和体外激酶测定法进行评估。 Airways的响应能力将通过甲基苯胺挑战测试来衡量。血液和肺槲皮素水平将通过HPLC和电化学检测来评估。
该项目研究了植物色素的槲皮素对防止疾病小鼠模型中气道炎症的价值。这项工作可能导致有关哮喘,囊性纤维化或慢性支气管炎的新治疗方法。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Marc B. Hershenson其他文献
Marc B. Hershenson的其他文献
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