Forms of Vitamin E Have Opposing Effects on Inflammation

描述（由申请人提供）：维生素E被认为具有抗炎作用，并且在欧洲几个国家（芬兰和意大利）的研究中，在小鼠实验性哮喘和哮喘患者中显示出有效减轻炎症。令人沮丧的是，美国的维生素E试验未能显示出对哮喘的益处。我们最近发现了维生素E异构体（？-生育酚和？-生育酚），这可以解释这些令人惊讶的不同结果在临床研究中。?-生育酚和？-生育酚是美国人消耗的两种主要形式的维生素E。我们已经证明了？？-生育酚增加炎症。而且，生育酚，在低至10%的组织浓度？-生育酚，消除了？-维生素E在小鼠实验性哮喘中的作用以及在体外白细胞迁移中的作用。此外，这些生育酚在白细胞迁移过程中对内皮细胞有直接影响。从什么时候开始？-在美国人的饮食中发现高水平的生育酚，但在大多数欧洲人的饮食中没有发现，这种生育酚同种型拮抗作用可能具有显著的临床相关性。一些报告表明，血浆水平的？-美国人的生育酚是欧洲人的2-5倍。此外，研究表明？-在动物模型中，炎症期间生育酚的水平与极低水平的？动物饮食中的生育酚。在开始人体研究之前，了解这两种主要形式的维生素E对炎症的相反调节的分子机制非常重要。 本提案中所述实验的目的是检验关于？-生育酚和拮抗这些影响？-生育酚。我们将使用纯天然的？-然后呢？生育酚和体外和体内结合的方法，在小鼠和培养细胞中具有良好的模型系统。我们研究的信息将对临床研究的设计和美国人的维生素E消费产生重大影响。 假设：维生素E是生育酚和生育三烯酚的复杂混合物，具有抗炎作用，不同形式的生育酚具有不同的抗炎作用。天生的...生育酚通过清除ROS和抑制PKC β直接作用于内皮细胞，抑制白细胞运输信号。相反，天然的D-？？-生育酚会与？-生育酚，并通过在炎症期间提高内皮功能而表现出非抗氧化促炎作用。 具体目标：目标1。我们将决定是否？-生育酚消融的好处？-生育酚在实验性哮喘中是可逆的。AIM 2.我们将决定是否？生育酚块和？-生育酚通过调节由内皮细胞粘附分子VCAM-1激活的信号来提高白细胞迁移。AIM 3.我们将决定是否？生育酚块和？-生育酚通过调节由内皮细胞粘附分子ICAM-1激活的信号来提高白细胞迁移。 公共卫生相关性：我们对维生素E形式的研究揭示了维生素E形式对哮喘的新的相反作用。我们关于维生素E的数据表明，在动物与人类的研究中以及在美国人与欧洲人的研究中，维生素E结果的不同结果的来源是？维生素E的生育酚形式拮抗的作用？-维生素E的生育酚形式。此外，？与欧洲国家相比，生育酚形式在美国饮食中含量高，在美国血浆中含量高。该提案涉及的机制，反对的影响？-生育酚和？-使用体内和体外模型研究生育酚对炎症的影响。我们研究的机制数据将有助于在未来的临床研究中定义维生素E形式的改良消费。

DESCRIPTION (provided by applicant): Vitamin E has been suggested to exert anti-inflammatory actions and has been shown to be effective in reducing inflammation in experimental asthma in mice and in asthmatics in studies in several countries in Europe (Finland and Italy). Disappointingly, vitamin E trials in the United States have failed to show benefit in asthma. We have recently discovered unrecognized properties of vitamin E isoforms (?-tocopherol and ?-tocopherol) that may explain these surprisingly disparate results in the clinical studies. ?-tocopherol and ?-tocopherol are the two major forms of vitamin E that are consumed by Americans. We have demonstrated that ??-tocopherol elevates inflammation. Moreover, ?-tocopherol, at as little as 10% the tissue concentration of ?- tocopherol, ablated the anti-inflammatory benefit of ?-tocopherol in experimental asthma in mice and in vitro in leukocyte migration. Furthermore, these tocopherols had direct effects on the endothelium during leukocyte migration. Since ?-tocopherol is found at high levels in the American diet, but not in most diets of Europeans, this tocopherol isoform antagonism could be of significant clinical relevance. Several reports indicate that plasma levels of ?-tocopherol in Americans are 2-5 times higher than Europeans. Furthermore, the studies that demonstrate a benefit of ?-tocopherol during inflammation in animal models are consistent with the very low levels of ?-tocopherol in animal diets. Before initiating human studies, it is very important to understand the molecular mechanisms for the opposing modulation of inflammation by these two major forms of vitamin E. The goal of the experiments described in this proposal is to test hypotheses regarding the mechanism of the anti-inflammatory effects of ?-tocopherol and the antagonism of these effects by ?-tocopherol. We will use purified natural ?- and ?-tocopherols and a combined in vitro and in vivo approach with well-developed model systems in mice and cultured cells. Information from our studies will have significant impact on the design of clinical studies and on vitamin E consumption by Americans. Hypothesis: Vitamin E, a complex mixture of tocopherols and tocotrienols, elicits anti-inflammatory effects that vary among the forms of tocopherols. Natural d-??-tocopherol inhibits signals for leukocyte trafficking by direct effects on endothelium via scavenging ROS and inhibiting PKC??. In contrast, natural d-??- tocopherol competes against the benefit of ?-tocopherol and exhibits non-antioxidant proinflammatory effects by elevating endothelial function during inflammation. Specific Aims: Aim 1. We shall determine whether the ?-tocopherol ablation of the benefit of ?- tocopherol is reversible in experimental asthma. AIM 2. We shall determine whether ?-tocopherol blocks and ?- tocopherol elevates leukocyte migration by modulating signals activated by the endothelial cell adhesion molecule VCAM-1. AIM 3. We shall determine whether ?-tocopherol blocks and ?-tocopherol elevates leukocyte migration by modulating signals activated by the endothelial cell adhesion molecule ICAM-1. PUBLIC HEALTH RELEVANCE: Our studies on forms of vitamin E reveal novel opposing effects of forms of vitamin E on asthma. Our data with vitamin E suggest that a source for the disparate results in vitamin E outcomes in studies with animals versus humans and in studies with Americans versus Europeans is that the ?-tocopherol form of vitamin E antagonizes the action of the ?-tocopherol form of vitamin E. Furthermore, the ?-tocopherol form is high in the American diet and is high in plasma in the United States as compared to European countries. This proposal addresses mechanisms for opposing effects of ?-tocopherol and ?-tocopherol on inflammation using in vivo and in vitro models. The mechanistic data from our studies will help define modified consumption of forms of vitamin E in future clinical studies.