Vitamin E metabolism and lung toxicology

描述（由申请方提供）：氧化剂诱导的呼吸道损伤（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（例如抗氧化微量营养素，GSH）和酶抗氧化防御的影响。本研究的目的是建立一个合适的模型来研究β-生育酚转运蛋白（β-TTP）基因敲除小鼠在肺中的转运以及β-T对氧化和炎症免疫细胞损伤的影响。为了验证肺（-T状态是1）由肺II型细胞跨膜和细胞内脂质转运蛋白主动调节，2）这些转运蛋白在由暴露于CS、O3或脂多糖诱导的炎症诱导的氧化应激下调节，和3）由这些毒物诱导的炎症通过以下方式调节：（-T和（-T），我们提出三个目标：（i）确定（-肺II型细胞中的T调节和代谢;（二）确认-T特异性通过喂养仅含有-T至-TTP敲除小鼠的饮食来减轻氧化应激，其具有非常低的血浆和组织β-T水平;和（iii）进一步确定β-T和β-T在调节呼吸道对CS、O3和LPS诱导的肺激发的炎症反应中的作用。我们的研究策略将首先集中在II型细胞的β-T代谢，因为这些细胞分泌β-T进入肺衬里液，并具有不完全特征的受体，转运和分泌途径特异性的β-T。将β-T-充满小鼠与β-T-充满小鼠进行比较，这将减轻氧化剂作用并允许评价对肺氧化/炎性损伤反应的调节的可能的不一致作用。我们的研究计划还包括旨在评估β-T与β-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维生素E的最佳形式和摄入量的重要信息，以预防和/或改善肺部疾病，特别是那些以激活炎症免疫系统反应为特征的疾病。

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.