SUPEROXIDE-DISMUTASE POTENTIATES PLATELET-ACTIVATING FACTOR-INDUCED INJURY IN PERFUSED LUNG

Platelet-activating factor (PAF) causes pulmonary hypertension and lun g edema in animals and isolated perfused lungs by poorly understood me chanisms. Because oxidative mechanisms have been implicated in PAF-med iated cellular injury, we tested the hypothesis that superoxide anion (O-2(-).) contributes to PAF-induced lung injury by determining whethe r superoxide dismutase (SOD) could prevent the lung injury. Isolated r abbit lungs were perfused with PAF (100 nM) at a dose that caused tran sient hypertension and mild edema. Lungs pretreated with Cu,Zn SOD (10 0 U/ml) for 10 min developed persistent pulmonary hypertension and mor e lung edema formation in response to PAF. Enhanced responses to PAF a lso were observed in lungs perfused with 200 U/ml Cu,Zn SOD, but not w ith 10 or 40 U/ml Cu,Zn SOD. The higher doses of SOD also decreased th romboxane B-2 levels in the perfusate. Potentiation of the PAF effect by Cu,Zn SOD was eliminated if the enzyme was inactivated or if the lu ng was treated with an anion channel blocker. The augmented PAF respon se in the presence of SOD was not altered by catalase (200 U/ml) or by nitric oxide synthase inhibitor. The data suggest that excessive Cu,Z n SOD enzyme activity potentiates PAF-induced injury in perfused rabbi t lung presumably by overscavenging extracellular O-2(-). generated fr om intercellular sources. The augmented responses to PAF are not direc tly attributable to increased hydrogen peroxide, nitric oxide-related products, or thromboxane A(2) production. These results suggest the ne w hypothesis that a balance between O-2(-). production and its metabol ism determines vascular and endothelial responses to PAF. oxygen; hydr ogen peroxide;