EUK-8, a synthetic superoxide dismutase and catalase mimetic, ameliorates acute lung injury in endotoxemic swine.

Abstract

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-manganese complex that exhibits both superoxide dismutase and catalase activities in vitro. We hypothesized that treatment with EUK-8 would ameliorate pulmonary dysfunction in a porcine model of LPS-induced adult respiratory distress syndrome. At T = -18 h, pigs received an intravenous priming dose of LPS (20 micrograms/kg). Anesthetized ventilated swine were randomized to receive 1) no further treatment (n = 5); 2) LPS (250 micrograms/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, significantly attenuated many of the features of LPS-induced acute lung injury, including arterial hypoxemia, pulmonary hypertension, decreased dynamic pulmonary compliance and pulmonary edema. LPS caused an increase in lung tissue malondialdehyde content that was abrogated in both EUK-8-treated groups. EUK-8 treatment had no effect on circulating plasma levels of tumor necrosis factor-alpha, thromboxane B2 or 6-keto-prostaglandin F1 alpha. We conclude that EUK-8 prevents many of the manifestations of LPS-induced adult respiratory distress syndrome in pigs by detoxifying reactive oxygen metabolites without affecting the release of other important proinflammatory mediators.