LEUKOTOXIN (9,10-EPOXY-12-OCTADECENOATE) IMPAIRS ENERGY AND REDOX STATE OF ISOLATED-PERFUSED RAT LUNG

We investigated the perturbation of energy balance and redox state in leukotoxin (9, 10-epoxy-12-octadecenoate) (Lx)- and endothelin-1 (ET-1 )-induced lung injury, using isolated perfused rat lungs. To examine a ny relationship between these parameters, intracellular levels of aden ine nucleotides, pyridine coenzymes and glutathione were determined by reversed-phase high-performance liquid chromatography (HPLC) in the f reeze-dried tissues of isolated rat lungs. The tissue samples were per fused with a physiological salt solution containing either Lx only, Lx plus N-G-monomethyl-L-arginine (L-NMMA), Lx plus N-G-monomethyl-D-arg inine (D-NMMA), Lx plus superoxide dismutase (SOD) or ET-1 only. In is olated perfused lung tissue, 10 mu mol of Lx caused permeability-incre ased lung injury, and 10 nM of ET-1, which caused a comparable increas e in wet lung weight, evoked pulmonary capillary hypertensive lung inj ury. Lx-injured lungs showed decreases in the contents of ATP, NADPH, NADH, reduced glutathione (GSH), (2ATP + ADP)/2(ATP + ADP + AMP) ratio (energy charge) and NADH/NAD(+) ratio, and increased the contents of ADP and AMP compared with the vehicle control and ET-1-injured lungs. Such effects of Lx were significantly attenuated by pretreatment with 0.4 mM L-NMMA or 500 units/ml of SOD, but not with 0.4 mM D-NMMA. On t he other hand, the ET-1-injured lung evidenced decreased tissue GSH. T hese findings indicate that Lx shifted the lung redox state toward oxi dation and that Lx-induced lung injury was involved in the imbalance o f the energy and redox state via production of nitric oxide and/or sup eroxide anion. (C) 1998 Elsevier Science Inc.