Statin (Cerivastatin) Protects Mice Against Sepsis-Related Death via Reduced Proinflammatory Cytokines and Enhanced Bacterial Clearance

Abstract

Death attributable to septic shock syndrome depends highly on the inflammatory response and cytokine production. Inhibition of inflammation is one of the many pleiotropic effects of statins. The aim of this study was to test the hypothesis that statins have a role in altering the host response to bacterial infections and thus would prove beneficial in the prevention of microbial sepsis. Male C57BL/6 and C3H/HeN mice received cerivastatin (4 mg/kg) or phosphate-buffered saline (PBS) intraperitoneally (i.p.), 24 and 1 h before and 24, 48, and 72 h after bacterial challenges. Sepsis was induced by i.p. injection of lipopolysaccharide (LPS) (45 mg/kg), Staphylococcus aureus (5 x 10(7) colony-forming units [CFU]/mouse), or Salmonella typhimurium (2.5 x 10(6) CFU/mouse). Administration of cerivastatin improved significantly the survival rate of mice challenged with LPS (31% vs. 19% in the PBS group; p = 0.001), S. aureus (56% vs. 20% in PBS group; p = 0.01), or S. typhimurium (48% vs. 10% in PBS group; p = 0.03). Significantly reduced release of the pro-inflammatory cytokines tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 was evident in cerivastatin-treated mice after LPS challenge. Cerivastatin-treated mice showed insignificant reductions in serum TNF-alpha and IL-6 concentrations after bacterial challenge. However, significantly accelerated bacterial clearance was demonstrated in cerivastatin-treated mice 24 h after S. typhimurium infection and 48 h after S. aureus infection. Cerivastatin protects mice against LPS- and live bacteria-induced death, an effect associated with cerivastatin-attenuated pro-inflammatory cytokine production and enhanced bacterial clearance. Hence, application of statins in the clinical setting may prove beneficial in prevention of LPS or bacterial infection-related sepsis.