Vitamin E metabolism and lung toxicology

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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.