Effects of Ketamine on Pulmonary Inflammatory Responses and Survival in Rats Exposed to Polymicrobial Sepsis

Min Yu1, Danbing Shao2, Rong Yang3, Xiaomei Feng1, Sihai Zhu1, Jianguo Xu4

1Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Road, Nanjing 210002
2Department of Emergency, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Road, Nanjing 210002
3Department of Urology, Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing 21008
4Jinling Hospital

Abstract


PURPOSE. Ketamine is reported to suppress production of proinflammatory cytokines and activity of nuclear factor-kappa B (NF-?B) after lipopolysaccharide (LPS) stimulation. Our study was designed to investigate the effects of ketamine on pulmonary inflammatory responses and survival in a clinically relevant model of polymicrobial sepsis, induced by cecal ligation and puncture (CLP). METHODS. After the induction of sepsis or sham-operation, animals were treated with ketamine (0.5, 5 or 10 mg/kg) or saline (10 ml/kg) at 3h after operation. At 6 h post-operation, the levels of tumor necrosis factor alpha (TNF-?) and interleukin (IL)-6, activity of NF-?B, expression of Toll-like receptor 2 (TLR2) and Toll-like receptor 4 (TLR4) of the lungs were measured. And the mortality was recorded for 7 days. RESULTS. TNF-? and IL-6 production, NF-?B activity, TLR2 and TLR4 expression in rat lungs were increased after CLP. Ketamine at the doses of 5 mg/kg and 10 mg/kg suppressed CLP-induced elevation of TNF-? and IL-6 production, NF-?B activity and TLR2 expression.

Ketamine 0.5, 5 and 10 mg/kg inhibited TLR4 expression in sepsis. Ketamine 5mg/kg and 10 mg/kg after CLP improved the survival of rats. CONCLUSIONS. Ketamine at sub-anesthetic doses could suppress the production of inflammatory cytokines such as TNF-? and IL-6, attenuate NF-?B activity, and inhibit TLR2 and TLR4 expression in polymicrobial sepsis. These anti-inflammatory effects of ketamine may correlate with improved survival in sepsis.

J Pharm Pharm Sci, 10 (4): 434-442, 2007

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