EUK-8, A SYNTHETIC SUPEROXIDE-DISMUTASE AND CATALASE MIMETIC, AMELIORATES ACUTE LUNG INJURY IN ENDOTOXEMIC SWINE

Reactive oxygen metabolites are believed to be important mediators of sepsis- or lipopolysaccharide (LPS)-induced adult respiratory distress syndrome. EUK-8 is a novel, synthetic, low-molecular-weight salen-man ganese complex that exhibits both superoxide dismutase and catalase ac tivities in vitro. We hypothesized that treatment with EUK-8 would ame liorate pulmonary dysfunction in a porcine model of LPS-induced adult respiratory distress syndrome. At T = -18 h, pigs received an intraven ous priming dose of LPS (20 mu g/kg). Anesthetized ventilated swine we re randomized to receive 1) no further treatment (n = 5); 2) LPS (250 mu g/kg from T = 0 to 60 min, n = 6); 3) LPS and a low dose of EUK-8 ( 10-mg/kg bolus at T = -15 min and 1 mg/kg h from T = 0 to 240 min, n = 6) or 4) LPS and a higher dose of EUK-8 (10-mg/kg bolus and 3 mg/kg h , n = 6). Treatment with EUK-8, particularly at the higher dose, signi ficantly attenuated many of the features of LPS-induced acute lung inj ury, including arterial hypoxemia, pulmonary hypertension, decreased d ynamic pulmonary compliance and pulmonary edema. LPS caused an increas e in lung tissue malondialdehyde content that was abrogated in both EU K-8-treated groups. EUK-8 treatment had no effect on circulating plasm a levels of tumor necrosis factor-alpha, thromboxane B-2 or 6-keto-pro staglandin F-1 alpha. We conclude that EUK-8 prevents many of the mani festations of LPS-induced adult respiratory distress syndrome in pigs by detoxifying reactive oxygen metabolites without affecting the relea se of other important proinflammatory mediators.