Effects of ketamine on proinflammatory cytokines and nuclear factor kappaB in polymicrobial sepsis rats

Department of Anesthesiology, Zhongnan Hospital, University of Wuhan, Wuhan 430071, Hubei Province, China.
World Journal of Gastroenterology (Impact Factor: 2.37). 01/2007; 12(45):7350-4.
Source: PubMed


To explore the effects of ketamine on hemo-dynamics, plasma proinflammatory cytokine (TNF-alpha and IL-6) levels and nuclear factor kappa B (NF-kappaB) activation during polymicrobial sepsis.
Male Sprague-Dawley rats were subjected to cecal ligation and puncture (CLP) or sham operation. The rats were randomly assigned into four equal groups: sham CLP group, CLP group, ketamine (KT) I group and KT II group. Thirty minutes before CLP, ketamine (5 mg/kg per hour and 10 mg/kg per hour, respectively) was infused continuously through the left femoral vein cannula in KT I group or KT II group. Sham CLP group and CLP group received 0.9% saline only (5 mL/kg per hour). The right femoral artery was cannulated to monitor mean arterial pressure (MAP) and heart rates (HR),and draw blood samples. The proinflammatory cytokine (TNF-alpha and IL-6) levels of plasma were measured using enzyme-linked immunosorbent assays (ELISA). The hepatic NF-kappaB activation was determined by Western blot and HPIAS 2000 image analysis system. Twenty hours after CLP, the rats were killed by right femoral artery phlebotomization.
CLP produced progressive hypotension, and a first increase followed by a decrease in HR. The hypotension was prevented, and the HR was slightly steady in ketamine treated rats. TNF-alpha levels of plasma reached a peak value at 2 h after CLP. Ketamine (KT I group or KT II group) caused a significant decrease compared with CLP group at 2, 5 and 9 h time points after CLP (14.3 +/- 1.9 vs 4.3 +/- 0.9, 9.7 +/- 1.4 vs 4.3 +/- 0.9; 9.3 +/- 1.5 vs 4.3 +/- 0.9, 8.7 +/- 1.4 vs 4.3 +/- 0.9; 6.0 +/- 1.5 vs 5.0 +/- 1.7, 5.3 +/- 0.8 vs 5.0 +/- 1.7; P < 0.01, respectively). The IL-6 levels of plasma firstly ascended and then descended in CLP group, and reached a peak value at 9 h after CLP. Ketamine (KT I group or KT II group) caused a significant decrease compared with CLP group at 5, 9 or 20 h after CLP (135.0 +/- 52.6 vs 60.0 +/- 16.3, 112.5 +/- 52.6 vs 60.0 +/- 16.3; 410.0 +/- 68.7 vs 62.5 +/- 12.5, 250.0 +/- 28.0 vs 62.5 +/- 12.5; 320.0 +/- 25.9 vs 52.5 +/- 10.1, 215.0 +/- 44.6 vs 52.5 +/- 10.1; P < 0.05, respectively). The IL-6 levels of plasma in KT II group were lower than those of KT I group at 9 h after CLP (250.0 +/- 28.0 vs 410.0 +/- 68.7; P < 0.05). In addition, CLP increased hepatic NF-kappaB expression compared with sham CLP. Ketamine suppressed NF-kappaB activation in a dose-dependent manner at 4 h after CLP (237.7 +/- 3.5 vs 246.9 +/- 3.1; P < 0.05).
Ketamine stabilizes the hemodynamics, attenuates the proinflammatory cytokine responses, and inhibits hepatic NF-kappaB activation. These findings suggest that ketamine has protective effects against polymicrobial sepsis in rats.

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    ABSTRACT: In dieser Arbeit wurde in einem Vollblut-Assay der Einfluss der in der Anästhesie gebräuchlichen i.v. Anästhetika Ketamin, Propofol und Etomidat sowie des Barbiturats Thiopental auf die spontane und LPS-induzierte Aktivität von PMN bestimmt. Hierbei wurden das Adhäsionsmolekül CD62L (L-Selektin), die Komplementrezeptoren CR1 (CD35), CR3 (CD11b/CD18) und CD16 (Fc gamma RIII) sowie der NB1-Rezeptor (HNA-2a, CD177) als entzündungsrelevante, granulozytäre Oberflächenmoleküle mittels Durchflusszytometrie genauer untersucht. Die Bestimmung des u.a. von PMN synthetisierten, proinflammatorischen Zytokins Interleukin-8 erfolgte mittels Sandwich-ELISA. Unsere Ergebnisse bestätigen immunmodulierende Wirkungen aller vier getesteten Medikamente auf Rezeptorebene. Es konnten differente Effekte der einzelnen Pharmaka auf die spontane und LPS-induzierte granulozytäre Aktivität in konzentrations- und zeitabhängiger Weise dargestellt werden. Das LPS-induzierte Shedding von CD62L wurde durch klinisch relevante Konzentrationen aller vier getesteten Substanzen signifikant gesteigert. Gleichzeitig wurde die LPS-induzierte Expression des CD11b-Rezeptors signifikant vermindert. Die LPS-induzierte Expression der Rezeptoren CD16 und CD35 wurde lediglich durch supraklinische Konzentrationen von Ketamin und Thiopental signifikant vermindert. Die LPS-induzierte Produktion des Zytokins Interleukin-8 wurde durch supraklinische Konzentrationen von Ketamin und Propofol signifikant gesteigert. Der NB1-Rezeptor wurde durch keines der untersuchten Medikamente beeinflusst, was auf einen anderen Induktionsweg hindeutet. Seine Rolle im Entzündungsgeschehen muss in weiteren Studien genauer untersucht werden. In this study we examined the influence of the commonly used i.v. anaesthetics Ketamine, Propofol and Etomidate as well as the barbiturate Thiopentone on spontaneous and LPS-induced activity of PMN in a whole blood assay. We studied the complement receptors CR1 (CD35), CR3 (CD11b/CD18) and CD16 (Fc gamma RIII), the adhesion molecule CD62L and the NB1-receptor (HNA-2a, CD177) as infection-relevant granulocytic surface-molecules via flow cytometry. One of the players involved in the production of IL-8 as a pro-inflammatory cytokine are known to be PMN. The quantification of IL-8 production was evaluated by Sandwich-ELISA. Our Results confirm immune-modulating effects on a cellular level by all four tested drugs on the level of receptor-expression. We could show different specific effects induced by all drugs in terms of spontaneous and LPS-induced activity in a concentration- and time-dependant matter. The LPS-induced shedding of L-Selectin was statistically significant enhanced by clinical relevant concentrations of all four tested drugs. Furthermore the LPS-induced expression of CD11b was significantly suppressed at the same time. Only high concentrations of ketamine and thiopentone showed a statistically significant reduction in the LPS-induced expression of CD16 and CD35. The LPS-induced production of proinflammatoric cytokin Interleukin-8 was significantly enhanced by high concentrations of ketamine and propofol. The NB1-Receptor was not influenced by any of the tested drugs. Its role during infection must be further investigated in upcoming studies.
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    ABSTRACT: This study was designed to investigate the effects of ketamine on levels of inflammatory cytokines, nuclear factor-kappa B (NF-kappaB) and Toll-like receptors (TLRs) in rat intestine during polymicrobial sepsis, induced by cecal ligation and puncture (CLP). After the induction of sepsis or sham-operation, the rats were treated with ketamine (2.5, 5 or 10 mg/kg) or saline (10 ml/kg). At 2, 4 or 6 h post-operation, the intestinal concentrations of inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-6, were determined by enzyme-linked immunosorbent assay (ELISA). Activity of NF-kappaB in rat intestine was assessed by electrophoretic mobility shift assay (EMSA). And expressions of Toll-like receptor 2 (TLR2) and Toll-like receptor 4 (TLR4) of rat intestine were examined by reverse transcription-polymerase chain reaction (RT-PCR). We found that TNF-alpha and IL-6 concentrations, NF-kappaB activity, TLR2 and TLR4 expressions in rat intestine were increased after CLP. At the doses of 5 and 10 mg/kg, ketamine suppressed CLP-induced elevation of IL-6. Ketamine 2.5, 5 and 10 mg/kg after CLP decreased intestinal TNF-alpha level and NF-kappaB activity, and inhibited TLR2 and TLR4 expressions as well. These results suggest that ketamine may have anti-inflammatory effects, such as suppressing the levels of inflammatory cytokines and attenuating NF-kappaB activity, during polymicrobial sepsis. And these anti-inflammatory effects possibly correlate with the inhibitory influence of ketamine on TLR2 and TLR4 expressions.
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    Preview · Article · Oct 2007 · BJA British Journal of Anaesthesia
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