Plant Polyphenols for the Treatment of Chronic Obstructive Pulmonary Disease

描述(申请人提供)：慢性阻塞性肺疾病(COPD)是一种呼吸系统疾病，其特征是由于慢性炎症造成不可逆的气流阻塞。吸烟是慢性阻塞性肺疾病发展的主要病因，目前尚无治愈方法。虽然在COPD的治疗中使用了支气管扩张剂和类固醇，但只有氧气被证明可以延长患者的生存时间。抗氧化剂和抗炎药可能在COPD的治疗中有用。许多可食用水果含有丰富的多酚抗氧化剂和抗炎化合物，富含水果和蔬菜的饮食与男性患慢阻肺的风险降低相关。我们的初步数据表明，从巴西桃金娘果实中提取的两种植物多酚--新型多酚类化合物Jobticabin和花青素Delphinidin 3-葡萄糖苷均具有抗氧化和抗炎活性。Jaboticabin和Delphinidin3-Gogoside均可抑制香烟烟雾提取物对细胞白介素8的诱导。我们假设，多酚类物质，如Jobticabin和Delphinidin 3-葡萄糖苷，将调节香烟诱导的肺部炎症、氧化和蛋白分解反应。我们将通过从杜鹃科(蓝莓)和桃金娘科(桃金娘)这两个富含多酚的植物科的四种可食用水果中分离出一组多酚来测试这一点。纯化的多酚将在体外进行抗氧化剂测试，包括2，2-二苯基-1-苦基肼和氧自由基吸收能力的测试，以及IL-8和环氧合酶的抗炎测试。根据这些分析中的活性以及它们的结构独特性，将优先对多酚进行进一步研究。其中三种多酚将进行进一步的机理研究。结果将被用于选择最有希望的化合物，该化合物将在COPD的活体动物模型中进行测试。该模型已被证明在确定COPD的致病机制方面很有价值，也为药物开发提供了一个重要的载体。这个项目的另一个目的是让PI参与职业发展活动，使他在NIH R01资金方面更具竞争力。 我们预计该项目将导致新的和/或有效的多酚的发现，这些多酚将作为预防和/或治疗COPD的新治疗剂的模型。

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.