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)受低分子量(例如抗氧化剂微量营养素，GSH)和酶类抗氧化剂防御的影响。本研究围绕着这样一个主题：(-生育酚转移蛋白((-TTP)基因敲除小鼠是研究(-T在肺内转运的分子机制以及(-T对氧化和炎症免疫细胞损伤的影响)的合适模型。为了验证肺(-T状态为1)受肺II型细胞跨膜和细胞内脂质转运体主动调节的假设，2)这些转运体在CS、TO_3或脂多糖诱导的炎症诱导的氧化应激下被调节，以及(3)这些毒物诱导的炎症是由(-T和(-T)调节的，我们提出三个目的：(1)确定肺II型细胞(-T)调节和代谢的机制；(Ii)通过喂饲血浆和组织((-T)水平很低的(-T)基因敲除小鼠来减轻氧化应激，以确认(-T的特异性；及(Iii)进一步确定(-T和(-T)在调节呼吸道对CS、03和脂多糖诱导的肺挑战的炎症反应中的作用。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分泌到肺衬里液体中，并拥有不完全确定的针对(-T的受体、运输和分泌途径)。(-T-REPLETE-小鼠将与(-T-REPLETE小鼠进行比较，这将减轻氧化效应，并允许评估在调节肺氧化/炎症损伤反应方面可能存在的不协调效应。我们的研究计划还包括为评估(-T与(-T)的“非抗氧化”功能而设计的方案。我们建议的研究结果有望为预防和/或改善肺部疾病提供有关维生素E的最佳形式和摄入量的重要信息，尤其是那些以激活的炎症免疫系统反应为特征的肺部疾病。

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.