ROLE OF OXIDANT STRESS IN THE ADULT-RESPIRATORY-DISTRESS-SYNDROME - EVALUATION OF A NOVEL ANTIOXIDANT STRATEGY IN A PORCINE MODEL OF ENDOTOXIN-INDUCED ACUTE LUNG INJURY

Reactive oxygen metabolites (ROMs) are thought to play a key role in t he pathogenesis of the adult respiratory distress syndrome (ARDS). Acc ordingly, the use of ROM scavengers, such as N-acetylcysteine or dimet hylthiourea, as therapeutic adjuncts to prevent oxidant-mediated damag e to the lung have been evaluated extensively in animal models of ARDS . Results with this approach have been quite variable among studies. A nother strategy that has been examined in animal models of ARDS is the administration of various enzymes, particularly superoxide dismutase (SOD) or catalase (CAT), in an effort to promote the conversion of ROM s to inactive metabolites. In theory, this strategy should be more eff ective than the use of ROM scavengers since a single molecule of a cat alytically active molecule can neutralize a targe number of molecules of a reactive species, whereas most scavengers act in a stoichiometric fashion to neutralize radicals on a mole-for-mole basis. This notion is supported by studies showing that prophylactic treatment with CAT p rovides impressive protection against acute lung injury induced in exp erimental animals by the administration of lipopolysaccharide (LPS). R esults with SOD have been more variable. Recently, we have utilized a porcine model of LPS-induced ARDS to investigate the therapeutic poten tial of EUK-8, a novel, synthetic, low molecular salen-manganese compl ex that exhibits both SOD-like and CAT-like activities in vitro. Using both pre- and post-treatment designs, we have documented that treatme nt with EUK-8 significantly attenuates many of the features of LPS-ind uced acute lung injury, including arterial hypoxemia, pulmonary hypert ension, decreased dynamic pulmonary compliance, and pulmonary edema. T hese findings support the view that salen-manganese complexes warrant further evaluation as therapeutic agents for treatment or prevention o f sepsis-related ARDS in humans.