Simvastatin reduces endotoxin-induced nuclear factor kappaB activation and mortality in guinea pigs despite lowering circulating low-density lipoprotein cholesterol.

Statins, which are effective lipid-lowering drugs, also possess anti-inflammatory potential. However, circulating lipoproteins may also play a protective role during acute inflammatory diseases because of their ability to bind bacterial toxins. Low cholesterol levels have been reported in inflammatory conditions, and plasma cholesterol concentrations inversely correlate with severity and clinical outcome in septic patients. It is thus paradoxical that statins, which drastically reduce circulating cholesterol levels, should be beneficial in patients with inflammatory disease who are already hypocholesterolemic. We investigated the effect of simvastatin on LPS-induced nuclear factor kappaB (NF-kappaB) activation, TNF release, and mortality in guinea pigs, an animal model with a lipoprotein profile and pattern similar to humans. In the present study, simvastatin reduced circulating total and low-density lipoprotein cholesterol levels by 68% and 76%, respectively, and LPS-induced mortality from 73% to 20%. This reduction was accompanied by a significant reduction of NF-kappaB activation in the liver tissue, splenocytes, and plasma TNF levels by about 80%, 50%, and 77%, respectively. Our data suggest that simvastatin, despite lowering circulating low-density lipoprotein cholesterol, decreased LPS toxicity by reduction of NF-kappaB activation and subsequent release of TNF by modulating 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and therefore deserves consideration as a possible adjuvant therapy in acute inflammatory disease.