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Anesth Analg 2000;90:206
© 2000 International Anesthesia Research Society

GENERAL ARTICLES

Ketamine Modulates the Stimulated Adhesion Molecule Expression on Human Neutrophils In Vitro

Markus A. Weigand, MD, Heinfried Schmidt, MD, DEAA, Qingyu Zhao, Konstanze Plaschke, PhD, Eike Martin, MD FANZCA, and Hubert J. Bardenheuer, MD

Department of Anesthesiology, University of Heidelberg, Heidelberg, Germany

Address correspondence and reprint requests to Hubert J. Bardenheuer, MD, Prof, Department of Anesthesiology, University of Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany. Address e-mail to Hubert_Bardenheuer{at}med.uni-heidelberg.de


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Cytokine production, neutrophil adhesion to endothelial cells, and release of reactive oxygen species are thought to be critical events in sepsis or ischemia/reperfusion. Modulation of leukocyte responses by anesthetics may have an important role in limiting tissue injury under these conditions. Therefore, we investigated the effect of ketamine on the expression of CD18, CD62L, and oxygen radical production of human neutrophils in vitro and on interleukin-6 production in endotoxin-stimulated human whole blood. Ketamine inhibited both the N- formyl-methionyl-leucyl-phenylalanine- and phorbol 12-myristate 13-acetate-induced up-regulation of CD18 and shedding of CD62L, determined by flow cytometry, in a concentration-dependent manner. Ketamine also caused a significant suppression of oxygen radical generation of isolated human neutrophils. In addition, there was a significant decrease in endotoxin-stimulated interleukin-6 production in human whole blood. The inhibitory effects were similar for racemic ketamine and its isomers S(+)-ketamine and R(-)-ketamine, suggesting that the inhibition of stimulated neutrophil function is most likely not mediated through specific receptor interactions.

Implications: Modulation of leukocyte responses by anesthetics may have an important role in limiting tissue injury in sepsis or ischemia/reperfusion. Therefore, we examined the effect of ketamine on stimulated neutrophil functions in vitro. These neutrophil functions were significantly inhibited by ketamine, independent of whether the racemic mixture or isomers were tested.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
In sepsis, excessive production of a variety of proinflammatory cytokines, followed by endothelial adhesion and sequestration of neutrophils, is a critical step in the development of multiple organ failure (1). Adhesion of leukocytes to the endothelium takes place in three (or more) steps, which are mediated by distinct families of adhesion molecules (2).

First, selectins mediate initial leukocyte tethering to the vessel wall and rolling along the endothelial lining. The second step is the activation of neutrophils by chemoattractants and chemokines, such as N-formyl-methionyl-leucyl-phenylalanine (FMLP), platelet-activating factor, and interleukin-8. This results in an up-regulation of ß2-integrin (CD11/CD18) expression on neutrophils and an enhanced avidity of ß2-integrins to their ligands (3). The final step is firm adhesion through neutrophil ß2-integrins with members of the immunoglobulin superfamily on the endothelium. Destruction of the endothelial integrity, which results in increased capillary permeability and tissue injury, are observed in severe sepsis caused by leukocyte-derived oxygen radicals and proteases.

Ketamine, a phencyclidine derivative, has been recommended for anesthesia and sedation of septic patients because of its ability to stabilize the cardiovascular function during sepsis (4,5). Furthermore, ketamine attenuated the endotoxin-induced leukocyte adherence in rat mesenteric venules by a shear rate-independent mechanism, suggesting reduced expression of adhesion molecules (6). However, the effect of ketamine on the stimulated expression of adhesion molecules has not been studied. To characterize the role of ketamine in the modulation of immune functions, we investigated the effect of ketamine on the expression of CD18, CD62L (L-selectin) and oxygen radical production of human neutrophils in vitro and on interleukin-6 (IL-6) production in endotoxin-stimulated human whole blood. We studied the effects of ketamine on the IL-6 production, because this cytokine reflects activation of the cytokine cascade and correlates with the patient outcome (7,8).


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Reagents
Hanks’ balanced salt solution (HBSS) was purchased from ICN Biochemicals (Costa Mesa, CA). Endotoxin (LPS), FMLP, phorbol 12-myristate 13-acetate (PMA), and cytochrome C from horse heart were purchased from Sigma (St. Louis, MO). Antibodies were purchased from Becton Dickinson (Ontario, Canada) or Coulter Immunotech (Hamburg, Germany). Racemic ketamine and its isomers were provided by Parke Davis (Freiburg, Germany). Stock solutions were prepared in HBSS.

Determination of Adhesion Molecule Expression
Venous blood (10 mL, anticoagulated with heparin 20 U/mL) was obtained by antecubital venipuncture from nonsmoking healthy volunteers (n = 24). White blood cell counts were between 5000 and 9000 cells/µL. Blood samples were washed two times with HBSS at room temperature to remove plasma proteins. Washed blood cells were reconstituted to the initial hematocrit with HBSS (9). Aliquots (0.2 mL) of washed blood cells were then incubated in the absence and presence of ketamine at 37°C for 30 min. Thereafter, neutrophils were stimulated with FMLP (10-6 mol/L) or PMA (100 ng/mL) for 20 min at 37°C. Preliminary experiments showed that maximal changes in the expression of CD18 or CD62L were achieved with 10-6 mol/L FMLP or 100 ng/mL PMA after 20 min of incubation. Expression of adhesion molecules was determined at the end of the incubation by flow cytometry and compared with adhesion molecule expression of untreated cells.

In detail, blood cells were incubated for 30 min on ice with saturating concentrations of fluorescein isothiocyanate (FITC)-labeled monoclonal antibodies directed against CD18 (anti-CD18-FITC; Becton Dickinson) or CD62L (anti-CD62L-FITC, Coulter Immunotech) in phosphate-buffered saline containing 5% heat-inactivated fetal calf serum to block surface Fc receptors. Then, red blood cells were lysed, and leukocytes were fixed with 2 mL of a lysing medium (FACS Lysing Solution; Becton Dickinson). The samples were then centrifuged, washed, and resuspended in phosphate-buffered saline containing 1% paraformaldehyde and stored at 4°C in the dark until fluorocytometric analysis.

Analysis of immunofluorescence as a measure of CD18 or CD62L surface expression was performed on a FACSCalibur flow cytometer (Becton Dickinson) using the channel number (log scale) representing the mean fluorescence intensity of 10,000 cells. Neutrophils, monocytes, and lymphocytes were discriminated in terms of forward and side scatter (Figure 1). Forward scatter is correlated to cell size, whereas side scatter is related to cell granularity. The threshold was set at 200 in the forward scatter to exclude cell debris from measurement. The specific mean fluorescence intensity for cells stained by each antibody is reported as the ratio of the CD18 or CD62L fluorescence to that of the negative control antibody (isotype-matched immunoglobulin-FITC, IgG1-FITC; Becton Dickinson). For each sample, 10,000 cells were analyzed.



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  		Figure 1. Dot plot of blood samples subjected to flow cytometric analysis for adhesion molecule expression on neutrophils.

 
The expression of adhesion molecules was studied by using washed whole blood cells to avoid up-regulation of CD18 which can occur on the neutrophil surface during the process of isolation and purification (10).

Determination of Superoxide Anion Generation
Heparinized venous blood was obtained from healthy volunteers. Human neutrophils were isolated from whole blood by means of Hypaque-Ficoll gradients (PolymorphprepTM; Nycomed Pharma AS, Oslo, Norway) followed by hypotonic lysis of red blood cells (11). The purified cell population contained 98% ± 2% neutrophils with a few contaminating erythrocytes. Vitality tests were performed by trypan dye exclusion. Viability in separated cells was more than 95%.

Superoxide anion generation was monitored by determination of cytochrome C reduction in the presence or absence of superoxide dismutase (SOD) (60 µg/mL) (12,13). Neutrophils (2 x 106/mL) were incubated with 1 mg/mL horse heart ferricytochrome C and ketamine at the desired concentrations in a final volume of 0.5 mL for 30 min at 37°C. Thereafter, cells were stimulated with FMLP (10-6 mol/L) or PMA (100 ng/mL) at 37°C. Fifteen minutes after stimulation, cells were centrifuged at 4°C and 1000 g for 10 min, and the supernatants were collected. Absorption at 550 nm was determined spectrophotometrically. The data were expressed as percentage of inhibition of superoxide anion generation. Stimulated superoxide anion generation was calculated as the difference between the optical density of the supernatant of unstimulated neutrophils in the presence of SOD and stimulated neutrophils in the absence of SOD and ketamine at the end of the incubation period.

Determination of IL-6 Production in Endotoxin-Stimulated Human Whole Blood
Blood from healthy volunteers was drawn into heparinized syringes (20 U/mL heparin; endotoxin contamination < 5 pg/mL heparin). Aliquots of 1 mL of blood were placed in sterile 24-well tissue culture plates (Greiner, Frickenhausen, Germany). One sample was processed immediately to serve as the zero-hour time point. The other blood samples were stimulated with 1 µg/mL endotoxin (Escherichia coli serotype 026:B6) in the presence or the absence of ketamine at the desired concentrations. In previous studies, LPS concentrations of 1 µg/mL induced a maximal synthesis and release of proinflammatory cytokines (14). The blood was incubated at 37°C in a 5% carbon dioxide atmosphere for 6 h. After incubation, the samples were removed and immediately centrifuged at 4°C and 1000 g for 10 min and the supernatants collected and stored immediately at -80°C until assayed.

After hypotonic lysis, viability of isolated leukocytes (>95%) was evaluated in whole blood assays by using trypan dye exclusion and was found not to change significantly over the 6 h incubation period. In addition, the absolute percentages of subpopulations in whole blood determined by fluorescence-activated cell sorter analysis were unaltered during the incubation time.

IL-6 in the supernatant was measured by commercially available enzyme-linked immunosorbent assays (Bender MedSystems, Vienna, Austria). Briefly, an anti-IL-6 monoclonal antibody was adsorbed to 96-well microtitre plates. Fifty microliters of standard or diluted test sample were pipetted into each well. Then, biotin-conjugated monoclonal antibody directed to a second epitope of IL-6 was added and incubated for 2 h at room temperature. Optical density was measured at 450 nm after the addition of streptavidin-horseradish peroxidase and substrate.

Results were expressed as mean ± SEM. All data were tested for normal distribution by the Kolmogorov-Smirnov test. Statistical comparisons were made by analysis of variance followed by Scheffé multiple comparisons. Statistical significance is at the P <= 0.05 level.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Ketamine Modulates the Stimulated Adhesion Molecule Expression and Oxygen Radical Production of Neutrophils
In the absence of ketamine, 10-6 mol/L FMLP induced a 2.1-fold increase in specific CD18 fluorescence compared with untreated neutrophils (P <= 0.05). At concentrations of 200 µmol/L and higher, racemic ketamine significantly inhibited the increase in CD18 expression in a concentration-dependent fashion (Figure 2A). FMLP led to a significant down-regulation of CD62L on neutrophils, which was also significantly attenuated by racemic ketamine (Figure 2B). In the dose range tested, racemic ketamine had no effect on CD18 or CD62L expression on neutrophils incubated in HBSS alone (data not shown).



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  		Figure 2. Effects of ketamine on the N-formyl-methionyl-leucyl-phenylalanine (FMLP)-stimulated surface expression of CD18 and CD62L on human neutrophils. Washed whole blood was incubated in the absence and presence of varying concentrations of racemic ketamine. Thereafter, neutrophils were stimulated with FMLP (10-6 mol/L) and the expression of CD18 (A) and CD62L (B) was measured by flow cytometry as described in Methods. Values are the ratio of the CD18 or CD62L fluorescence to that of the negative control antibody. Basal = adhesion molecule expression at the end of the incubation period. Control = stimulated adhesion molecule expression without ketamine. Results are the mean ± SEM of seven experiments with cell preparations from different donors. #P <= 0.05 versus control.

 
To further characterize the modulation of the neutrophil activation by ketamine, we studied the effect of racemic ketamine on neutrophil CD18 and CD62L expression stimulated by PMA, which is a direct activator of protein kinase C (PKC). In the absence of ketamine PMA (100 ng/mL) induced similar changes in the surface expression of CD18 and CD62L as FMLP (Figure 3A, B). These changes in adhesion molecule surface expression were also significantly suppressed by ketamine. Racemic ketamine inhibited the FMLP- and PMA-stimulated up-regulation of CD18 expression when given to the medium before or even at the same time when FMLP and PMA were added. Racemic ketamine showed no effect when added after stimulation of CD18 expression (data not shown).



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  		Figure 3. Effects of ketamine on the phorbol 12-myristate 13-acetate- (PMA) stimulated surface expression of CD18 and CD62L on human neutrophils. Washed whole blood was incubated in the absence and presence of varying concentrations of racemic ketamine. Thereafter, neutrophils were stimulated with PMA (100 ng/mL) and the expression of CD18 (A) and CD62L (B) was measured by flow cytometry as described in Methods. Values are the ratio of the CD18 or CD62L fluorescence to that of the negative control antibody. Basal = adhesion molecule expression at the end of the incubation period. Control = stimulated adhesion molecule expression without ketamine. Results are the mean ± SEM of seven experiments with cell preparations from different donors. #P <= 0.05 versus control.

 
Since the expression of adhesion molecules can be modulated by oxygen radicals (15), we studied the effect of ketamine on neutrophil oxygen radical production. Ketamine dose-dependently inhibited both the FMLP and PMA-induced oxygen radical production (Table 1).


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  		Table 1. Percentage Inhibition of the FMLP- and PMA-Stimulated Oxygen Radical Production of Neutrophils by Racemic Ketamine
 
Inhibition of Up-Regulation of CD18 by Ketamine Is Not Stereospecific
The stereospecifity of the racemic ketamine and its isomers on the suppression of CD18 up-regulation was determined in additional experiments. There was no significant difference in the extent of inhibition of FMLP-stimulated CD18 up-regulation between the racemic mixture and the isomers of ketamine (Table 2).


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  		Table 2. Inhibition of FMLP-Stimulated CD18 Expression on Neutrophils by the Racemic Mixture and the Isomers of Ketamine
 
Ketamine Inhibits Interleukin-6 Production in Endotoxin-Stimulated Human Whole Blood
The mean value of IL-6 determined in the plasma of unstimulated human whole blood from healthy volunteers was 2.7 ± 0.4 pg/mL (data not shown).

Ketamine suppressed the LPS-induced IL-6 production in a dose-dependent manner at concentrations between 100 µmol/L and 1000 µmol/L (Figure 4). Concentrations below 100 µmol/L exhibited no effect. Ketamine did not affect the viability of the cells as determined by their ability to exclude trypan blue, indicating that the inhibitory effect was not due to cell death. Ketamine (1000 µmol/L) suppressed LPS-induced IL-6 production even when added 2h after LPS-stimulation (IL-6 production without ketamine: 90.7 ± 2.1 ng/mL vs 56.7 ± 2.8 ng/mL with 1000 µmol/L racemic ketamine).



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  		Figure 4. Ketamine suppresses interleukin-6 production in endotoxin-stimulated human whole blood. Whole blood was incubated in the absence and presence of varying concentrations of racemic ketamine in the presence of endotoxin (1 µg/mL). The concentrations of interleukin-6 in plasma were determined by an enzyme-linked immunosorbent assay. Results are the mean ± SEM of five experiments with cell preparations from different donors. #P <= 0.05 plus versus minus ketamine.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The novel aspect of our study is that ketamine attenuates the FMLP- and PMA-stimulated up-regulation of CD18 and shedding of CD62L adhesion molecules of human neutrophils in vitro. FMLP is a physiological chemoattractant that arises during bacterial protein processing and activates neutrophils through G protein-coupled chemoattractant receptors (16). Activation of G protein stimulates phospholipase C, which results in rapid generation of diacylglycerol and inositol 1,4,5-triphosphate. Both diacylglycerol and inositol 1,4,5-triphosphate can activate the PKC through the release of Ca2+. Stimulation of PKC is probably involved in the activation and expression of adhesion molecules, as well as in the induction of the respiratory burst (17,18). Because ketamine inhibited the FMLP- and the PMA-stimulated changes in the surface expression of CD18 and CD62L, the effect of ketamine could possibly be caused by an inhibition of the PKC or later steps in intracellular signal transduction. PKC activation is inhibited by barbiturates and local anesthetics (19). However, there are also other efficient routes of intracellular signal transduction (18). Obviously, ketamine does not promote re-internalization of CD18, because this substance showed no effect when added after the increase in CD18 expression. The attenuation of the stimulated shedding of CD62L indicates an inhibition of neutrophil activation by ketamine. Ketamine had no effect on the unstimulated surface expression of CD18 or CD62L on human neutrophils in vitro. These results are in agreement with a study conducted by Ramamoorthy et al. (20), who demonstrated that ketamine administration in vivo does not significantly alter the resting neutrophil expression of CD18 and CD62L in adult rabbits.

Ketamine suppresses neutrophil oxygen radical production in vitro (21). Because there is a close interrelation between oxygen radicals and the up-regulation of CD18 on neutrophils (15), we compared the effect of ketamine on the stimulated CD18 up-regulation and oxygen radical production by neutrophils to exclude the possibility that the inhibition of CD18 up-regulation is caused by the suppression of oxygen radical formation. As can be seen from our data, ketamine attenuated both neutrophil functions to a similar extent. Therefore, the inhibitory effect of ketamine via a common pathway of neutrophil signal transduction seems likely. Using similar concentrations of ketamine as in the present study, Weiss et al. (21) have demonstrated that the suppression of oxygen radical production by ketamine cannot be explained by the scavenger function of ketamine because of its phenol-containing chemical structure.

S(+)-ketamine and a 1:1 racemic mixture of both optically active isomers, which differ in their analgesic and psychomimetic effects, are in clinical use. S(+)-ketamine is more potent in terms of its analgesic and hypnotic effects than R(-)-ketamine (22). The finding of central stereoselectivity for ketamine is consistent with a higher affinity of the more potent isomer to its receptor. Interestingly, there was no stereoselective suppression of neutrophil functions in our study. Therefore, our data suggest that in contrast to the anesthetic function of ketamine inhibition of stimulated neutrophil function is most likely not mediated through specific receptor interactions.

We used human whole blood as an ex vivo model to characterize the effect of ketamine on IL-6 production after stimulation with endotoxin. This model provides particular advantages, because any activation of monocytes caused by the isolation procedure, e.g., density-gradient centrifugation and further cell preparation techniques, is completely eliminated (23). In addition, the physiologic environment regarding cellular interactions and the influence of complement factors and inhibitory peptides is totally preserved under these conditions (24). Ketamine dose dependently suppressed IL-6 production in endotoxin-stimulated human whole blood. For instance, the highest concentration of ketamine we applied decreased IL-6 production in endotoxin-stimulated human whole blood by 60%. This finding is in accordance with a study of Takenaka et al. (25), who also showed a ketamine-dependent suppression of tumor necrosis factor {alpha} production in murine peritoneal macrophages. We investigated the effects of ketamine on the IL-6 production, because IL-6 is an important mediator of the early systemic host response to infection and, in contrast to tumor necrosis factor {alpha}, appears to be a good marker of outcome after major surgery, trauma, and in sepsis (8,26).

We used ketamine over a wide concentration range to take the large variability of protein binding of ketamine in plasma and blood into consideration (27,28) and to account for the differences in the anesthetic potencies of the isomers. The concentrations we used approximate concentrations in blood after the induction (100 µmol/L) and maintenance (25 µmol/L) of anesthesia with racemic ketamine (29). Because ketamine concentrations of 100 µmol/L and larger were required to produce significant inhibition of the neutrophil functions studied, it is questionable whether the described in vitro effects of ketamine contribute to its antiinflammatory effects observed in animal studies (6) or during clinical anesthesia (30).

In summary, our results indicate that ketamine can attenuate important pro-inflammatory key functions of neutrophils in vitro. Because the inhibitory effects were similar for racemic ketamine and its isomers, the inhibition of stimulated neutrophil functions is most likely not mediated through specific receptor interactions.


   Acknowledgments
 
The authors thank Prof. Dr. G. M. Hänsch (Institute of Immunology, University of Heidelberg, Germany) for giving us the opportunity to perform fluorocytometric measurements, Dr. W. Schütte (Parke Davis, Freiburg, Germany) for providing the racemic mixture and isomers of ketamine, Ms. Bettina Reis for excellent technical assistance, and Dr. H. Bauer for statistical assistance.


   References
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 Introduction
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 Results
 Discussion
 References
 

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Accepted for publication September 21, 1999.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press