The Effect of Oxygen-Derived Free Radicals on Pulmonary Endothelial Cell Function in the Isolated Perfused Rat Lung

Abstract

Oxygen-derived free radicals have been shown to damage endothelial cells in tissue culture. We have extended these observations to demonstrate a direct toxic action of oxy radicals on endothelial cell function in the isolated perfused rat lung model. Using an enzymatic system of hypoxanthine and xanthine oxidase, we generated a superoxide flux of 5 – 7 nmoljmin within the pulmonary circulation. This resulted in alteration of endothelial cell function, including a progressive fall in the cellular transport of (¹⁴C) 5-hydroxytryptamine, edema formation manifested by a falling dry to wet weight ratio and increasing mean transit times, appearance of thiobar-bituric acid reactive material in the perfusate indicating lipid peroxidation, and histologic evidence of edema formation with disruption of the endothelial cell plasma membrane. Inhibitor studies confirmed that the observed effects were due to superoxide radical generation. Oxygen-derived free radicals may play a role in the pulmonary endothelial cell damage seen in inflammatory disorders and oxidant lung injury.