Project 3-Mechanism of Leukotriene Inhibition by Oils

哮喘是一种影响2000多万人的疾病，从1980年到1995年，美国的哮喘患病率增加了74%。抑制白三烯的产生是治疗哮喘和过敏性鼻炎的有效方法。在过去的十年里，我的实验室与维克森林大学医学院的综合临床研究中心和昆泰跨国公司的第一阶段临床试验中心合作，在240多名受试者中进行了六项早期(发现和类似第一阶段)临床试验，考察了膳食补充剂中的脂肪酸对健康和哮喘受试者白三烯生物合成的影响。这些研究表明，诸如伽马林烯酸(GLA)和 二十碳五烯酸(EPA)对白三烯的生成有一定的抑制作用。然而，我们的假设是，如果能够确定最有效的油(即萝卜油乳剂)中脂肪酸的作用机制，如果其他植物油可以安全地替代含有EPA的油来增强对白三烯的抑制，如果我们能够确定为什么脂肪酸乳剂在一些健康人和一些哮喘患者中阻止白三烯的产生，而在其他人中几乎没有效果，那么可以优化白三烯抑制以达到与药物类似的结果。这项建议采取了一种系统的方法来回答人类的这些问题。该提案的目标1a侧重于脂肪酸，特别是GLA抑制白三烯生物合成的生化基础。实验旨在测量这些脂肪酸在体外和体内对关键脂肪酸的产生的影响 白三烯生成途径的中间体以及参与炎症和花生四烯酸代谢的酶和细胞因子的表达。目的1b将阐明白三烯抑制和白三烯生成之间的关系，并确定某些个体的效力是否与参与白三烯生物合成的酶的遗传变异有关。这项应用的第二个目的是研究车前草籽油中一种相对较新的脂肪酸硬脂酸的潜力，它可以阻止健康人体中的Delta-5去饱和酶活性和白三烯的产生。我们相信，这些研究将增加植物油，如萝卜油和洋葱油，可用于阻止炎症性疾病中白三烯的产生。

Asthma is a disease that affects over 20 million people and its prevalence in the US increased by 74% from 1980 to 1995. Inhibition of leukotriene production is a proven approach for the management of asthma and allergic rhinitis. Over the past decade, my laboratory, in collaboration with the General Clinical Research Center at Wake Forest University School of Medicine and the Phase I Clinical Trials Center at Quintiles Transnational, have conducted six early stage (discovery and phase I-like) clinical trials in over 240 subjects examining the effects of fatty acids found in dietary supplements on leukotriene biosynthesis in both healthy and asthmatic subjects. These studies reveal that fatty acids such as gammalinolenic acid (GLA) and eicosapentaenoic acid (EPA) can induce modest inhibition of leukotriene generation. However it is our hypothesis that leukotriene inhibition can be optimized to achieve similar results as pharmacologic agents if the mechanism of action of fatty acids in the most efficacious oils (i.e.borage oil emulsions) can be determined, if other botanical oils can safely substitute for oils that contain EPA to enhance leukotriene inhibition and if we can determine why fatty acid emulsions block leukotriene production in some healthy subjects and some asthmatic patients and have little effect in others. This proposal takes a systematic approach to answer these questions in humans. Aim 1a of the proposal focuses on the biochemical basis by which fatty acids, and GLA in particular, inhibit leukotriene biosynthesis. Experiments are directed at measuring the in vitro and in vivo effects of these fatty acids on the production of critical intermediates in the leukotriene generation pathway and the expression of enzymes and cytokines that participate in inflammation and arachidonic acid metabolism. Aim 1b will clarify the association between leukotriene inhibition and leukotriene generation and determine whether the potency in some individuals is associated with the presence of genetic variants in the enzymes that participate leukotriene biosynthesis. The second aim of this application will examine the potential of a fatty acid, stearidonic acid, in a relatively new seed oil from Echium Plantagineum to block the delta-5 desaturase activity and leukotriene production in healthy humans. We believe these studies will increase the likelihood that botanical oils such as borage and echium can be utilized to block leukotriene generation in inflammatory diseases.