Vitamin E metabolism and lung toxicology

描述（由申请人提供）：氧化剂引起的呼吸道损伤（由香烟烟雾（CS）、臭氧（03）或内源性炎症免疫过程引起）受到低分子量（例如抗氧化微量营养素，GSH）和酶促抗氧化防御的影响。拟议的研究围绕这样的论点建立：(-生育酚转移蛋白((-TTP))敲除小鼠是研究(-T在肺中运输和(-T对氧化和炎症免疫细胞损伤的影响的)分子机制的合适模型。为了检验肺(-T状态为1)受肺II型细胞跨膜和细胞内脂质转运蛋白主动调节的假设，2)这些转运蛋白在暴露于CS诱导的氧化应激下受到调节， 03 或脂多糖诱导的炎症，以及 3) 这些毒物诱导的炎症受 (-T 和 (-T) 调节，我们提出了三个目标：(i) 确定 (-T) 在肺 II 型细胞中的调节和代谢机制；(ii) 通过喂养仅含有 (-T) 的饮食来减轻氧化应激来确认 (-T 特异性) 到 (-TTP 敲除小鼠，其血浆和组织 ((-T 水平) 非常低；(iii) 进一步定义(-T 和 (-T) 调节呼吸道对 CS、03 和 LPS 诱导的肺部攻击的炎症反应。我们的研究策略最初将集中在 II 型细胞 (-T 代谢) 上，因为这些细胞将 (-T) 分泌到肺衬液中，并拥有不完全表征的 (-T) 特异性受体、转运和分泌途径。(-T-replete 小鼠将与 (-T-replete 小鼠) 进行比较，这将减轻氧化作用，并允许评估可能的不一致效应我们的研究计划还包括旨在评估（-T）与（-T）相比的“非抗氧化”功能的方案。我们提出的研究结果预计将提供有关预防和/或改善肺部疾病（尤其是那些以激活炎症免疫系统反应为特征的疾病）的维生素 E 最佳形式和摄入量的重要信息。

DESCRIPTION (provided by applicant): Oxidant-induced respiratory tract injury (caused by cigarette smoke (CS), ozone (03) or endogenous inflammatory-immune processes) is influenced by both low molecular weight (e.g. antioxidant micronutrients, GSH) and enzymatic antioxidant defenses. The proposed studies are built around the thesis that the (-tocopherol transfer protein ((-TTP) knockout mouse is an appropriate model to study molecular mechanisms underlying (-T trafficking in the lung and (-T's influence on oxidative and inflammatory-immune cell injury. To test the hypothesis that lung (-T status is 1) actively regulated by lung Type II cell transmembrane and intraceilular lipid transporters, 2) these transporters are modulated under oxidative stress induced by exposure to CS, to 03 or inflammation induced by lipopolysaccharide, and 3) inflammation induced by these toxicants is modulated by (-T and (-T, we propose three aims: (i) to identify mechanisms of (-T regulation and metabolism in lung Type II cells; (ii) to confirm (-T specificity by alleviating oxidative stress by feeding diets containing exclusively (-T to (-TTP knockout mice, which have very low plasma and tissue ((-T levels; and (iii) to further define the roles of (-T and (-T in modulating inflammatory responses of the respiratory tract to CS, 03 and LPS-induced lung challenge. Our research strategies will initially center on Type II cell (-T metabolism because these cells secrete (-T into lung lining fluid and possess incompletely characterized receptor, transport and secretory pathways specific for (-T. (- T-replete-mice will be compared with (-T-replete mice, which will alleviate oxidant effect and allow evaluation of possible discordant effects on modulation of lung oxidative/inflammatory injurious responses. Our research plan also includes protocols designed to evaluate for "non-antioxidant" functions of (-T as compared with (-T. The results of our proposed studies are expected to provide important information regarding optimal forms and intakes of vitamin E for prevention and/or amelioration of pulmonary diseases, most notably those characterized by activated inflammatory-immune system responses.