Cerivastatin improves survival of mice with lipopolysaccharide-induced sepsis.
Development of severe sepsis is thought to result from the overproduction of cytokines, such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta), 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-alpha and IL-1beta transiently increased, and peaked at 2 h. After the peak responses of TNF-alpha and IL-1beta, 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-alpha and IL-1beta 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.
Ando
H
H
The First Department of Internal Medicine, School of Medicine, Kanazawa University, Japan.
Takamura
T
T
Ota
T
T
Nagai
Y
Y
Kobayashi
K
K
D000818:Animals; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007375:Interleukin-1 / Q000097:blood; D008070:Lipopolysaccharides; D051379:Mice; D009566:Nitrates / Q000097:blood; D009573:Nitrites / Q000097:blood; D011725:Pyridines / Q000494:pharmacology*; D018805:Sepsis / Q000139:chemically induced / Q000188:drug therapy* / Q000401:mortality; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007375:Interleukin-1; D008070:Lipopolysaccharides; D009566:Nitrates; D009573:Nitrites; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; C086276:cerivastatin