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.