Plant Polyphenols for the Treatment of Chronic Obstructive Pulmonary Disease

描述（由申请人提供）：慢性阻塞性肺疾病（COPD）是一种以慢性炎症引起的不可逆气流阻塞为特征的呼吸系统疾病。吸烟是与慢性阻塞性肺病发展相关的主要病因，慢性阻塞性肺病目前尚无治愈方法。虽然支气管扩张剂和类固醇被用于治疗COPD，但只有氧气被证明可以延长患者的生存期。抗氧化剂和抗炎剂可能对慢性阻塞性肺病的治疗有用。许多可食用水果富含多酚类抗氧化剂和抗炎化合物，富含水果和蔬菜的饮食与降低男性患慢性阻塞性肺病的风险有关。我们的初步数据表明，两种植物衍生的多酚，新型depside jaboticabin和花青素delphinidin 3-glucoside，均来自巴西水果桃金娘花椰菜，具有抗氧化和抗炎活性。Jaboticabin和delphinidin 3-glucoside均能抑制暴露于香烟烟雾提取物的细胞中白细胞介素-8的诱导。我们假设多酚类物质，如jaboticabin和delphinidin 3-glucoside，会调节香烟引起的肺部炎症、氧化和蛋白水解反应。我们将通过从富含多酚的植物科蓝莓科和桃金娘科的四种可食用水果中分离出一组多酚来验证这一点。纯化的多酚将在体外进行抗氧化测试，包括2,2-二苯基-1-吡啶肼和氧自由基吸收能力，以及IL-8和环加氧酶的抗炎测试。根据这些实验的活性及其结构的独特性，多酚将被优先用于进一步的研究。其中三种多酚将进行进一步的机理研究。结果将用于选择最有希望的化合物，将在COPD的体内动物模型中进行测试。该模型已被证明在确定慢性阻塞性肺病的致病机制方面是有价值的，并且也为药物发现提供了重要的载体。该项目的另一个目的是让PI参与职业发展活动，使他在NIH R01基金中更具竞争力。

DESCRIPTION (provided by applicant): Chronic obstructive pulmonary disease (COPD) is a respiratory condition characterized by irreversible airflow obstruction due to chronic inflammation. Cigarette smoke is the main etiologic factor associated with the development of COPD, for which there is no cure. Although bronchodilators and steroids are used in the treatment of COPD, only oxygen has been demonstrated to prolong survival of patients. Antioxidants and anti-inflammatory agents may be useful in the treatment of COPD. Many edible fruits are rich sources of polyphenolic antioxidants and anti-inflammatory compounds, and diets rich in fruits and vegetables are correlated with a reduced risk of COPD in men. Our preliminary data demonstrate that two plant-derived polyphenols, the novel depside jaboticabin and the anthocyanin delphinidin 3-glucoside, both from the Brazilian fruit Myrciaria cauliflora, have antioxidant and anti-inflammatory activities. Jaboticabin and delphinidin 3-glucoside both inhibit interleukin-8 induction in cells exposed to cigarette-smoke extract. We hypothesize that polyphenols, like jaboticabin and delphinidin 3-glucoside, will modulate the cigaretteinduced inflammatory, oxidative, and proteolyitic responses of the lung. We will test this by isolating a group of polyphenols from four edible fruits in the Ericaceae (blueberry) and Myrtaceae (myrtle), plant families rich in polyphenols. The purified polyphenols will be tested in vitro using antioxidant assays including 2,2- diphenyl-1-picrylhydrazyl and oxygen radical absorbance capacity, and anti-inflammatory assays for IL-8 and cyclooxygenase. The polyphenols will be prioritized for further study based on the activity in these assays as well as their structural uniqueness. Three of the polyphenols will undergo further mechanistic studies. The results will be used to select the most promising compound that will be tested in an in vivo animal model for COPD. This model has proved to be valuable in identifying causative mechanisms of COPD, and also provides an essential vehicle for drug discovery. An additional aim of this project is for the PI to participate in career developmental activities to make him more competitive for NIH R01 funding. We anticipate that the project will lead to the discovery of new and/or potent polyphenols that will serve as models for new therapeutic agents for the prevention and/or treatment of COPD.