Forms of Vitamin E Have Opposing Effects on Inflammation

描述（由申请人提供）：维生素E已被认为具有抗炎作用，并在欧洲几个国家（芬兰和意大利）的实验哮喘小鼠和哮喘患者的研究中被证明有效减少炎症。令人失望的是，维生素E在美国的试验未能显示出对哮喘的益处。我们最近发现了维生素E异构体的未知特性(？-生育酚和？——生育酚)，这或许可以解释这些临床研究中令人惊讶的截然不同的结果。？-生育酚和？-生育酚是美国人摄入的两种主要形式的维生素E。我们已经证明了？？-生育酚会加剧炎症。此外,?-生育酚，低至10%的组织浓度？-生育酚，消炎消融的好处？-生育酚对实验性哮喘小鼠及体外白细胞迁移的影响。此外，这些生育酚在白细胞迁移过程中对内皮有直接影响。自吗?-生育酚在美国人的饮食中含量很高，但在大多数欧洲人的饮食中含量并不高，这种生育酚异构体的拮抗作用可能具有重要的临床意义。几份报告显示血浆中？美国人的生育酚含量是欧洲人的2-5倍。此外，研究表明？-生育酚在动物模型炎症中的作用与极低水平的？-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是非常重要的。本提案中描述的实验的目标是测试关于抗炎作用机制的假设？-生育酚以及-生育酚对这些作用的拮抗作用我们会用纯天然的吗？-然后呢？-生育酚，并结合体外和体内方法，在小鼠和培养细胞中建立良好的模型系统。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摄入量产生重大影响。假设：维生素E是一种复杂的生育酚和生育三烯醇的混合物，在不同形式的生育酚中具有不同的抗炎作用。自然的d - ? ?-生育酚通过清除ROS和抑制PKC直接作用于内皮细胞，从而抑制白细胞运输信号。相反，自然d-?？-生育酚与？-生育酚，并在炎症期间通过提高内皮功能表现出非抗氧化的促炎作用。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。目标2。我们将决定是否？-生育酚阻滞和？-生育酚通过调节内皮细胞粘附分子VCAM-1激活的信号，促进白细胞迁移。目标3。我们将决定是否？-生育酚阻滞和？-生育酚通过调节内皮细胞粘附分子ICAM-1激活的信号，促进白细胞迁移。

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.