LOW-DOSE N-ACETYLCYSTEINE PROTECTS RATS AGAINST ENDOTOXIN-MEDIATED OXIDATIVE STRESS, BUT HIGH-DOSE INCREASES MORTALITY

We evaluated the effect of the antioxidant N-acetylcysteine (NAC) on o xidative stress, lung damage, and mortality induced by an endotoxin (l ipopolysaccharide, or LPS) in the rat. Continuous intravenous infusion of 275 mg NAC/kg in 48 h, starting 24 h before LPS challenge, decreas ed hydrogen peroxide (H2O2) concentrations in whole blood (p < 0.01). This decrease was accompanied by fewer histologic abnormalities of the lung and decreased mortality (p < 0.025), compared with rats receivin g LPS alone. N-Acetylserine, which has no sulfhydryl group, did not pr otect rats against LPS toxicity. Improved survival was not associated with an increase in pulmonary reduced glutathione, nor with inhibition of serum tumor necrosis factor (TNF) activity. In vitro, TNF producti on and DNA binding of nuclear factor kappa B (NF-kappa B) in human Mon o Mac 6 cells was only inhibited at concentrations of NAC above 20 mM. High-dose NAC treatment (550 and 950 mg/kg in 48 h) decreased lung GS H (p < 0.05) and resulted in a significantly smaller number of survivi ng animals when compared with the low-dose NAC group (p < 0.025). In v itro, NAC increased hydroxyl radical generation in a system with Fe(II I)-citrate and H2O2 by reducing ferric iron to its catalytic, active F e2+ form. We conclude that low-dose NAC protects against LPS toxicity by scavenging H2O2 while higher doses may have the opposite effect.