Mechanisms of Actions of Botanical Lipids on Effector Cells of/Joshua A. Boyce

口服萝卜油和湿润油可导致哮喘患者的运动能力下降 外周血白细胞产生白三烯(LT)。从以下方面来说，这是一个潜在的重要结果 他解释了植物油的治疗益处，但其作用机制(S)尚不清楚。 这个项目的主要目标是在人类细胞中精确定义这些机制(S)，这些机制与 哮喘的病理生理学。在目标1中，我们将确定是否补充萝卜叶和 附子油对慢性阻塞性肺疾病患者血液中嗜碱性粒细胞、中性粒细胞和单核细胞PI-3K信号转导的影响 哮喘，以及这是否会转化为重要的病理生理脂质的减少 介体和细胞因子。在目标2中，我们将确定是否补充萝卜油和玉米油 前列腺素E_2和血栓素A_2(TXA_2)(A)外周血单核细胞产生前列腺素的变化 一种被认为具有有效抗炎作用的介质PGE1 属性。我们还将确定主要的环氧合酶(COX)和前列腺素E合成酶(PGE)亚型 负责PGE1的产生，以及是否在饮食中补充萝卜油和茜草油 PPARy在外周血单核细胞中的表达和功能因缺乏抑制而上调 内源PGE2的PL-3K/Akt信号转导。PPARy的表达和功能上调将 有望通过抑制转录抑制来减轻哮喘患者的呼吸道炎症 促炎细胞因子。这些研究将补充项目1(J.Parks)中的研究，这些研究侧重于 植物油促进血管保护性PARY驱动的巨噬细胞发育的能力 表型。最后，在目标3中，我们将测定PGE1的抗哮喘作用，并测定其 受体的利用基于其“稳定”人类MOS的能力。后一项研究是必不可少的，因为 哮喘患者呼吸道炎症的始发和持续过程中MC激活的关键性质。 这些研究对PPG作为一个整体来说是非常完整的，并将对机制提供实质性的了解 植物油治疗哮喘和其他炎症性疾病的有效性基础。

Oral adminstration of borage and echium oils to subjects with asthma results in a decreased capacity for leukotriene (LT) generation by peripheral blood leukocytes. This is a potentially important outcome in terms of explaining the therapeutic benefits of botanical oils, but the mechanisms(s) responsible are not known. The major goal ofthis Project is to precisely define these mechanism(s) in human cells that are relevant to the pathophysiology of asthma. In Aim 1, we will determine whether supplementation with borage and echium oils impairs PI-3K signaling in basophils, neutrophils, and monocytes in the blood of patients with asthma, and whether this translates into diminished production of pathophysiologically important lipid mediators and cytokines. In Aim 2, we will determine whether supplementation with borage and echium oils shifts the profile of PG production by peripheral blood monocytes from PGE2 and thromboxane A2 (TXA2) (a powerful bronchoconstrictor) to PGE1, a mediator that has been proposed to have potent anti-inflammatory properties. We will also determine the dominant cyclooxygenase (COX) and PGE synthase (PGES) isoforms responsible for the generation of PGE1, and whether dietary supplementation with borage and echium oils uprgulates the expression and function of PPARy in peripheral blood monocytes due to a loss of suppressive Pl-3K/Akt signaling from endogenous PGE2. Upregulation of the expression and function of PPARy would be expected to reduce ainway inflammation in asthmatic subjects through suppression of transcription of proinflammatory cytokines. These studies will complement the studies in Project 1 (J. Parks) that focus on the ability of botanical oils to facilitate the development of a vasoprotective PPARy-driven macrophage phenotype. Lastly, in Aim 3, we will determine the anti-asthmatic potential of PGE1 and determine its receptor utilization based on its ability to "stabilize" human MOs. The latter studies are essential because of the critical nature of MC activation in both the initiation and perpetuation of airway inflammation in asthma. These studies are highly integral to the PPG as a whole, and will shed substantial light onto the mechanistic basis for the efficiacy of botanical oils in asthma and other inflammatory disorders.