Project 3-Mechanism of Leukotriene Inhibition by Oils

哮喘是一种影响超过2000万人的疾病，其在美国的患病率从1980年到1995年增加了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。在过去的十年中，我的实验室与维克森林大学医学院的一般临床研究中心和昆泰跨国公司的I期临床试验中心合作，在240多名受试者中进行了6项早期（发现和I期样）临床试验，检查膳食补充剂中发现的脂肪酸对健康和哮喘受试者中白三烯生物合成的影响。这些研究表明，脂肪酸如γ-亚麻酸（GLA）和 二十碳五烯酸（EPA）可诱导对白三烯生成的适度抑制。然而，我们的假设是，如果最有效的油中脂肪酸的作用机制是有效的，那么可以优化白三烯抑制以达到与药理学试剂类似的结果。（即琉璃苣油乳液）可以被确定，如果其他植物油可以安全地替代含有EPA的油，以增强白三烯抑制，如果我们可以确定为什么脂肪酸乳剂阻止一些健康受试者的白三烯产生，对一些哮喘患者有效，而对另一些患者无效。这项提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集中在脂肪酸，特别是GLA，抑制白三烯生物合成的生物化学基础上。实验旨在测量这些脂肪酸对关键代谢物产生的体外和体内作用。 在白三烯生成途径中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联，并确定某些个体的效力是否与参与白三烯生物合成的酶中存在遗传变异有关。本申请的第二个目的是研究来自蓝蓟的相对新的种子油中的脂肪酸十八碳四烯酸阻断健康人中δ-5去饱和酶活性和白三烯产生的潜力。我们相信这些研究将增加植物油如琉璃苣和蓝蓟可用于阻止炎症性疾病中白三烯产生的可能性。

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.