N-acetylcysteine and alpha-tocopherol reverse the inflammatory response in activated rat Kupffer cells

Activation of the resident macrophage populations of the reticuloendothelial system is a key component of the complex pathophysiology of sepsis. Macrophage activation leads to production and secretion of inflammatory mediators such as cytokines, vasoactive substances, free radicals, and chemokines, which have been associated with high morbidity and mortality in the septic patient. The goal of the present study was to determine whether antioxidants could suppress Kupffer cell activation at points beyond the initiation of activation. Kupffer cells were studied since they are central to the clearance of bacteria and endotoxins, and have been associated with hepatocellular dysfunction in sepsis. Cells were activated with 10 ng/ml LPS for various times whereupon N-acetylcysteine (30 mM) and alpha-tocopherol (50 microM) were added. Steady state levels of cytokine mRNA, activation of nuclear factor-kappaB, and TNF-alpha secretion were determined when expression was maximal in control cells. The results of this study show that antioxidants can be used to suppress Kupffer cell activation at points beyond the initiation of activation. Furthermore, we show that N-acetylcysteine-mediated inhibition of activation requires secondary protein synthesis, but does not modulate IkappaB-alpha mRNA expression. The inhibitory effect of these drugs occurs at the very earliest steps of the LPS signal transduction cascade as it is currently understood. The results of the present study suggest that the inflammatory response to sepsis may be controlled through appropriate antioxidant therapy.