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

对哮喘受试者口服琉璃苣和蓝蓟油会导致哮喘患者的呼吸能力降低。 外周血白细胞产生白三烯（LT）。这是一个潜在的重要成果， 解释植物油的治疗益处，但负责的机制尚不清楚。 该项目的主要目标是精确定义人类细胞中与以下相关的这些机制： 哮喘的病理生理学在目标1中，我们将确定是否补充琉璃苣， Echium油损害了前列腺癌患者血液中嗜碱性粒细胞、中性粒细胞和单核细胞中的PI-3 K信号传导 哮喘，以及这是否转化为减少生产的病理生理重要的脂质 介质和细胞因子。在目标2中，我们将确定是否补充琉璃苣和蓝蓟油 改变外周血单核细胞产生PG的模式，使其从PGE 2和血栓素A2（TXA 2）（a PGE 1是一种被认为具有强效抗炎作用的介质， 特性.我们还将确定占主导地位的环氧合酶（考克斯）和前列腺素E合酶（PGES）亚型 负责PGE 1的产生，以及是否饮食补充琉璃苣和蓝蓟油 由于抑制性单核细胞增殖的丧失， 来自内源性PGE 2的PI-3 K/Akt信号传导。PPARy的表达和功能的上调将 预期通过抑制转录来减少哮喘患者的气道炎症 促炎细胞因子这些研究将补充项目1（J. Parks）中的研究， 植物油促进血管保护性PPARy驱动的巨噬细胞发育的能力 表型。最后，在目标3中，我们将确定PGE 1的抗哮喘潜力，并确定其在哮喘中的作用。 基于其“稳定”人MO的能力，受体利用率。后一项研究是必要的，因为 MC活化在哮喘气道炎症的发生和持续中的关键性质。 这些研究是PPG作为一个整体的高度组成部分，并将揭示大量的机制， 植物油在哮喘和其他炎症性疾病中有效性的基础。

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.