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.
Footnotes
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Send reprint requests to: Toshinari Takamura, M.D., Ph.D., The First Department of Internal Medicine, School of Medicine, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa 920-8641, Japan. E-mail: tt{at}medf.m.kanazawa-u.ac.jp
- Abbreviations:
- LPS
- lipopolysaccharide
- TNF-α
- tumor necrosis factor-α
- IL-1β
- interleukin-1β
- iNOS
- inducible nitric-oxide synthase
- NO
- nitric oxide
- HMG CoA
- 3-hydroxy-3-methylglutaryl coenzyme A
- NOx
- nitrite and nitrate
- NF-κB
- nuclear factor-κB
- Received February 21, 2000.
- Accepted May 15, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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