LEUKOTOXIN, 9,10-EPOXY-12-OCTADECENOATE INHIBITS MITOCHONDRIAL RESPIRATION OF ISOLATED-PERFUSED RAT LUNG

To investigate how mitochondrial function was affected in leukotoxin ( Lx)-, 9,10-epoxy-12-octadecenoate-induced lung injury, lung mitochondr ia were extracted from isolated perfused rat lung with or without Lx-i nduced edematous injury. In the lung treated with 30 mu mol of Lx, the mitochondrial respiration rate in states 3 and 4 significantly decrea sed (without mitochondrial uncoupling) concomitantly with increased re lease of lactate dehydrogenase (LDH), a parameter for cellular damage, into the perfusate and decreased ATP content in the lung tissue compa red with those of untreated lung. Moreover, 30 mu mol of Lx resulted i n significant inhibition of cytochrome-e oxidase activity (vs. vehicle control). In contrast, lower doses of Lx (10 mu mol) caused lung edem a and cellular damage without evidence for mitochondrial dysfunction. We also examined cellular and mitochondrial damage in hydrostatic lung edema. Such edema showed neither suppressed mitochondrial respiration nor elevated LDH activity in perfusate, although lung wet weight incr eased as much as it did after 30 mu mol Lx treatment. Our results sugg est that the ex vivo mitochondrial dysfunction is one of the secondary (vs. initial augmented permeability) but specific manifestations of t oxicity of Lx, and together with the previous reports, the ex vivo dam aging effect of Lx against mitochondria may be ascribed not to its dir ect action on mitochondria but to Lx-derived cellular mechanism(s).