Research in the Center for Clinical pharmacology and Drug Toxicology addresses the pharmacology, metabolism, and function of eicosanoids. The pharmacology of drugs that inhibit lipid peroxidation will be investigated in humans, employing a novel approach to quantifying lipid peroxidation in vivo developed by investigators in the Center, based on their discovery of the F2-isoprostanes that are produced by free radical catalyzed peroxidation of arachidonic acid. The relationship between dose and reduction of F2-isoprostanes by vitamin E, vitamin C, and beta carotene given singly and in combinations will be established in patients with hyperlipidemia. The metabolic fate of 8-iso-PGF2alpha will be determined as a basis for enhancing the assessment of endogenous production of F2- isoprostanes. The association of isoprostane levels in plasma lipids with lipid peroxidation in the vessel wall and atherosclerosis will be determined in animal models. The contribution of the 12/15 lipoxygenase to lipid peroxidation in vivo will be examined in mice with targeted deletion of the 12/15 lipoxygenase gene. Concerted investigations will address the pharmacology of PGF2 as an immunomodulator. The expression of four prostaglandin E (EP) receptor subtypes in human and murine immune cells will be explored, and ligand binding, second messenger generation and functional responses will be characterized. Examination of tissue expression of EP receptor subtypes will take advantage of novel information that tissue expression is a function of the inflammatory process. The EP receptor subtype responsible for inhibition of the eosinophilic infiltrate and airway hyperreactivity by PGE2 in a mouse model of allergic airway disease will be characterized with selective agonists and studies in a mouse with targeted deletion of the EP2 receptor gene. EP2 receptor mediated immunomodulation in allergic airway disease and anaphylaxis also will be examined in the EP2 receptor deficient mouse. The pharmacology of PGE2 in human asthma will be addressed in studies examining the mechanism whereby PGE2 inhibits the acute and delayed allergic bronchoconstriction. The effect of PGE2 on the consequences of mast cell activation, including cytokine production, will be examined, together with its actions on the cellular and cytokine antecedents of the late phase infiltration of eosinophils. EP receptor subtypes on cells infiltrating the airway during late allergic bronchoconstriction will be determined. Potent inhibition of late allergic bronchoconstriction by PGE2 forms the basis for an examination of the effects of inhaled PGE2 on the cellular infiltrate and airway hyperreactivity in chronic asthma.
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