MODULATION OF LIPOPOLYSACCHARIDE-MEDIATED ACTIVATION IN RAT KUPFFER CELLS BY ANTIOXIDANTS

Activation of Kupffer cells, the resident macrophage population of the liver, has been implicated in the pathogenesis of several types of li ver injury. The aim of this study was to investigate whether the antio xidants N-acetylcysteine (NAG) and alpha-tocopherol succinate (alpha-T OC) suppress lipopolysaccharide (LPS)-induced activation of rat Kupffe r cells. LPS activated NF-kappa B in Kupffer cells, and this response was inhibited by NAC and alpha-TOC. NAC and alpha-TOC also markedly su ppressed LPS-induced tumor necrosis factor-alpha (TNF-alpha) mRNA leve ls and secretion. We further show that LPS was unable to increase TNF- alpha mRNA in drug-treated cells even when stimulation occurred after NAC or alpha-TOC were removed. These results indicate that antioxidant s persistently suppress LPS activation in Kupffer cells, and suggest t hat the mechanism responsible for this involves more than mere quenchi ng of free radical production. The demonstration that NAC and alpha-TO C have inhibitory effects on LPS-mediated Kupffer cell activation sugg ests that these compounds may have a beneficial effect in liver injury involving oxidative stress and endotoxemia.