Abstract

Development of severe sepsis is thought to result from the overproduction of cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), and nitric oxide. Recently, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, which are antihypercholesterolemic agents, have been reported to inhibit lipopolysaccharide (LPS)-induced production of cytokines and nitric oxide in vitro. In this study, we tested these effects in vivo. After LPS administration (15 mg/kg i.p.) to CD-1 mice, serum levels of both TNF-α and IL-1β transiently increased, and peaked at 2 h. After the peak responses of TNF-α and IL-1β, serum levels of nitrite and nitrate increased until at least 8 h. Pretreatment of the mice with cerivastatin (20 mg/kg i.p. 12 and 1 h before LPS injection) reduced serum levels of TNF-α and IL-1β at 2 h, and nitrite and nitrate at 8 h, by 93, 60, and 44%, respectively. In this model of sepsis, cerivastatin significantly (P= .016) improved the rate of 7-day survival from 26.7 to 73.3%. These results cast new light on the usefulness of cerivastatin in preventing severe sepsis.