Polyethylene Glycol-conjugated Superoxide Dismutase Attenuates Septic Lung Injury in Guinea Pigs

Reactive oxygen species (ROS), including Superoxide anions, play an important role in mediating acute lung injury. We examined whether polyethylene glycol-conjugated superoxide dismutase (PEG-SOD) attenuates lung injury in Escherichia coll-treated guinea pigs. Twenty-four guinea pigs were divided into four groups: (1) control group; (2) septic group, in which live E. coli (2 × 109/kg) were injected intravenously; (3) pretreatment group, in which PEG-SOD (2,000 lU/kg) was injected intravenously 15 min before E. coli; and (4) posttreatment group, in which PEG-SOD (2,000 lU/kg) was injected intravenously 30 min after E. coli; Lung injury was assessed by the concentration ratio of 125I-labeled albumin in lung tissue and bronchoalveolar lavage (BAL) fluid relative to plasma (UP and BAL/P), lung wet-to-dry weight ratio, and the number of neutrophils in BAL fluid. Plasma half-life of PEG-SOD in normal guinea pigs was 13.5 h. L/P, lung wet-to-dry weight ratio, and the number of neutrophils in BAL fluid decreased in both pretreatment and posttreatment groups compared with the septic group. BAL/P decreased in the pretreatment group but not in the posttreatment group compared with the septic group. After the animal model studies, we investigated the effect of PEG-SOD on the human neutrophil extracellular generation of ROS stimulated by phorbol myristate acetate (PMA) in lucigenin-dependent chemiluminescence (CL). PEG-SOD at concentrations ⩾ 0.1 U/ml inhibited PMA-induced CL in a dose-dependent manner. We also examined the effect of PEG-SOD on the neutrophil intracellular generation of ROS using flow cytometry to assess intracellular hydroethidine oxidation. PEG-SOD at concentrations of 10 and 100 U/ml reduced the fluorescence caused by hydroethidine oxidation in neutrophils stimulated by PMA. These results suggest that (1) pretreatment and posttreatment with PEG-SOD attenuated septic lung injury in guinea pigs; (2) PEG-SOD inhibited the extracellular generation of ROS in PMA-stimulated neutrophils; and (3) PEG-SOD reduced the intracellular generation of ROS in PMA-stimulated neutrophils.