Our goal is to investigate the effects of both inhalational and intravenous anesthetic agents on pulmonary edema formation and arachidonate mediator production in isolated lungs exposed to hyperoxia and to other oxidants (e.g. tert-butyl hydroperoxide and Intralipid). A secondary goal is to determine whether any interaction exists between hyperoxia exposure and treatment of the lungs with anesthetic agents, both inhalational and intravenous, i.e. do these agents affect the ability of lung parenchyma to tolerate exposure to high inspired concentrations of oxygen or other oxidant substances? The answers to these questions may have clinical implications for the critically ill, mechanically ventilated patient who requires general anesthesia for surgery or any patient receiving total parenteral nutrition containing lipid emulsions. This proposal contains two groups of aims: (1) To determine the effects of various classes of intravenous agents on the pulmonary vasopressor response, arachidonate mediator production, and pulmonary edema formation during exposure to tert-butyl-hydroperoxide, graded hyperoxia, and Intralipid, and (2) to determine the effects of inhalational anesthetic agents of widely differing potencies (halothane, cyclopropane, and nitrous oxide) on the pulmonary vasopressor response, arachidonate mediator production, and pulmonary edema formation during exposure to the three oxidant challenges mentioned above. To conduct the experiments the isolated perfused rabbit lung will be used, both with and without recirculation of perfusate. Perfusate concentrations of thromboxane B2 and 6-keto-PGF-1alpha will be measured by radioimmunoassay. In preparations perfused with blood, the residual volume will be periodically determined by helium dilution and the DLCO by measuring CO uptake by perfusate. Concentrations of inhalational anesthetic agents in both perfusate and inspired gas will be determined by gas chromatography; and perfusate concentrations of intravenous agents, by the appropriate methods of analysis. This application describes a total of 270 experiments. Because of the simplicity of the experimental preparation and the briefness of each individual experiment (none lasts longer than 2.5 hr), the funding period (3 yr) should be ample time to allow for completion of the program.
