We hypothesize that important characteristics of the lung vascular barrier can be measured by multiple indicator methods based on small molecules which passively cross the capillary barrier, are taken up by the endothelium or react with free radicals generated in the microcirculation during lung injury. To test this hypothesis, we will compare 14C-urea permeability surface area (PS) and other transport parameters to quantities derived from the extraction of flow limited tracers (3H-water), tracers which are both hydrophilic and lipophilic (14C- butanediol), tracers which are taken up by the endothelium (3H- norepinephrine) and tracers which react with free radicals (dimethylsulfoxide). We will examine the abilities of these substances (alone or by comparison to urea PS, CO diffusing capacity and lymph flow and protein content) to measure capillary surface area effects, to quantify lung vascular damage, to measure flow and flow distribution effects and to quantitate free radical production in the living lung. Experiments will be performed in isolated, perfused and ventilated dog lungs, the in situ perfused sheep lung with lymph cannulation in intact sheep. Lung vascular surface and flow distribution will be altered by flow variation, lung mass removal, glass bead injection, vasoconstriction and vasodilation with pharmacological agents. Lung injury will be generated by alloxan infusion in dog lungs and by perilla ketone and E. coli endotoxin infusion in sheep lungs. The results will be analyzed with the goal of improving understanding of the interplay of hemodynamic and transport factors in normal and injured lung and of developing practical methods for characterizing microvascular transport in the lungs of intact animals and patients.
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