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Anesth Analg 2002;95:583-587
© 2002 International Anesthesia Research Society

ANESTHETIC PHARMACOLOGY

The Effect of Isoflurane on Neutrophil Selectin and ß2-Integrin Activation In Vitro

Lothar W. de Rossi, MD*, Nicola A. Horn, MD*, Wolfgang Buhre, MD*, Florian Gass{dagger}, Gabriele Hutschenreuter, MD{ddagger}, and Rolf Rossaint, MD*

*Department of Anesthesiology and {ddagger}Institute of Transfusion Medicine, {dagger}University Hospital, Rheinisch-Westfälische Technische Hochschule Aachen, Aachen, Germany

Address correspondence and reprint requests to Lothar W. de Rossi, MD, Department of Anesthesiology, University Hospital, Rheinisch-Westfälische Technische Hochschule Aachen, Pauwelsstr. 30, D-52074 Aachen, Germany. Address e-mail to L.derossi{at}gmx.de


   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Isoflurane is reported to reduce ischemia-reperfusion injury. Lower expression of CD11b may be responsible for attenuated postischemic neutrophil adhesion to vascular endothelium. However, neutrophil adhesion to vascular endothelium is a multistep process involving several selectins and ß2-integrins. Therefore, we assessed whether isoflurane affects the activation of the selectins P-selectin glycoprotein ligand-1 (PSGL-1) and L-selectin and the ß2-integrins CD11a and CD11b. Whole blood was incubated for 60 min with 0.5 or 1 minimum alveolar anesthetic concentration (MAC) isoflurane. After incubation, neutrophils were activated with N-formyl-methionyl-leucyl-phenylalanine (FMLP) or phorbol-12-myristate-13-acetate (PMA). Activation of adhesion molecules was evaluated via flow cytometry, and 1 MAC isoflurane reduced the expression of CD11a in the unstimulated samples. After stimulation with FMLP and PMA, shedding of L-selectin was lower in the presence of isoflurane. Furthermore, 1 MAC isoflurane reduced FMLP-induced activation of CD11a and CD11b compared with unexposed blood samples. These results demonstrate that isoflurane affects the activation of three adhesion molecules involved in the multistep process of neutrophil recruitment. First, isoflurane inhibits the activation of L-selectin, which mediates the neutrophil tethering and rolling on the vascular endothelium. Second, isoflurane attenuates the activation of both ß2-integrins—CD11a and CD11b—which mediate firm adhesion and transendothelial migration.

IMPLICATIONS: Adhesion of neutrophils to endothelial cells in reperfusion injury is mediated by different adhesion molecules. This study indicates that the inhibiting effect of isoflurane on neutrophil recruitment may be mediated by a decreased activation of the L-selectin and by attenuation of the activation of the ß2-integrins CD11a and CD11b.


   Introduction
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 Abstract
 Introduction
Methods
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 Discussion
 References
 
Recruitment of neutrophils through vascular endothelium to inflamed organ tissue is critical for host defense against invading pathogens, but it paradoxically contributes to organ dysfunction in conditions such as ischemia-reperfusion injury. Neutrophil accumulation during ischemia-reperfusion injury begins with neutrophil tethering and rolling, which is mediated by the interaction of the selectins P-selectin glycoprotein ligand-1 (PSGL-1) and L-selectin with their endothelial counterligands. In the next step, tight attachment to endothelium cells involves the neutrophil ß2-integrin CD11b. Finally, neutrophils transmigrate into the interstitial compartment via the binding of CD11a to endothelial intercellular adhesion molecule (ICAM)-1 (1). Tissue injury occurs because of the release of oxygen free radicals and cytotoxic enzymes and increased cytokine release from activated neutrophils (1–3). Furthermore, microvascular occlusion by platelet-leukocyte aggregates (4) and increased endothelium permeability have also been demonstrated to contribute to ischemia-reperfusion injury (5).

Inhibiting neutrophil rolling and attachment to vascular endothelium as a therapeutic approach is an attractive way to potentially prevent reperfusion injury at a very early stage. In animal models, monoclonal antibodies (MAbs) against adhesion molecules and soluble adhesion molecules have been effective in attenuating ischemia-reperfusion injury (1,6).

Several investigations revealed that anesthesiologists have been using anesthetics with antiadhesive activity regularly in clinical practice for decades. In animal models, isoflurane, sevoflurane, and even halothane protected against myocardial ischemia-reperfusion injury (7–11). One suggested mechanism was the attenuated expression of CD11b on activated neutrophils after exposure to volatile anesthetics (12). However, CD11b is not the sole adhesion molecule involved in the process of neutrophil recruitment. The initial step, tethering and rolling, is primarily mediated by selectins, such as PSGL-1 (13) and L-selectin (14), whereas firm attachment depends on the ß2-integrins CD11a and CD11b with counterligands on the endothelium (15). Thus, we investigated the effect of isoflurane at 0.5 and 1 minimum alveolar anesthetic concentration (MAC) on the activation of selectins and ß2-integrins involved in the multistep process of neutrophil recruitment, by using an established whole-blood model. Furthermore, adhesion molecule activation was determined during basal conditions and after stimulation with N-formyl-methionyl-leucyl-phenyla-lanine (FMLP) and phorbol-12-myristate-13-acetate (PMA).


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
In accordance with the approved IRB protocol, venous blood from healthy adult donors (10 men and 6 women) was collected into sterile blood collection tubes (Sarstedt, Nümbrecht, Germany) containing a 1:10 volume of 3.2% sodium citrate. Afterward, citrated blood was diluted 1:1 with modified Hanks’ buffered salt solution (without Ca2+ or Mg2+; Sigma Chemical Co., St. Louis, MO). The MAC value used in this study was 1.2% for isoflurane. Incubation of blood samples was performed as previously described (16). In brief, blood samples were incubated in a small chamber with 21% oxygen and 5% carbon dioxide at 37°C. Isoflurane was delivered with a standard anesthetic machine (Sulla 909; Dräger, Lübeck, Germany), and concentrations of all gases were continuously monitored with a multigas analyzer (Datex Compact; Datex, Helsinki, Finland). Blood samples were exposed to either 0.5 or 1.0 MAC isoflurane for 60 min. Untreated control blood samples were placed in a standard incubator (BB 16; Heraeus, Hanau, Germany) providing identical atmospheric conditions. After the end of the incubation time, all samples were immediately processed for stimulation and staining procedures.

The effect of isoflurane on the expression of neutrophil selectins and ß2-integrins was investigated with unstimulated blood samples and after activation of neutrophils by using two different stimuli. FMLP is a physiological agonist of the FMLP receptor on the neutrophil cell surface. Activation of the FMLP receptor results in downregulation of PSGL-1 and L-selectin, whereas expression of CD11a and CD11b is increased. In contrast, PMA directly activates protein kinase C (PKC), which also leads to downregulation of the two selectins and upregulation of both ß2-integrins. Stimulation of blood samples with FMLP (final concentration, 100 nM; Sigma) and PMA (100 nM; Sigma) was performed in sealed polypropylene tubes to avoid evaporation of isoflurane. Blood samples were incubated with the stimulating agent for 10 min at 37°C. Thereafter, 100 µL of blood was added to polystyrene tubes (Falcon; Becton-Dickinson, San Jose, CA) containing fluorochrome-conjugated MAbs. Activation of selectins and ß2-integrins was evaluated by using the following MAbs: the PSGL-1 binding MAb KPL-1, the L-selectin binding MAb Dreg 56, the CD11a binding MAb HI111, and the CD11b binding MAb ICRF44 (all from Pharmingen, San Diego, CA). Leukocytes were stained with anti-CD45 (clone HI30), and negative immunoglobulin G1-PE (clone MOPC-21) was used as isotype control. Before the beginning of this study, all MAbs were titrated by flow cytometry to determine saturating conditions.

Blood cells were stained for 30 min at 4°C in the dark. Staining was stopped by adding 2 mL of lysing solution (FACS Lysing Solution; Becton-Dickinson) for 10 min. After centrifugation (5 min, 350g, 4°C), the samples were washed with 2 mL of phosphate-buffered saline containing 1% bovine serum albumin and centrifuged, and the cell pellet was resuspended in 400 µL of phosphate-buffered saline containing 1% bovine serum albumin and 2% paraformaldehyde.

Blood cells were analyzed on a FACSCalibur flow cytometer (Becton-Dickinson), which was calibrated before each measurement with CaliBRITE beads (Becton-Dickinson). Neutrophils were identified by their scatter characteristics and CD45 staining in the FL1 channel. The data of 20,000 neutrophils were stored in list mode. The activation of PSGL-1, L-selectin, CD11a, and CD11b on the neutrophil cell surface was analyzed by measuring the mean fluorescence intensity (MFI) of the specific MAb in the FL2 channel.

If not indicated otherwise, data are presented as mean and SD. Differences between isoflurane-exposed and untreated control samples assessed in parallel were evaluated with Student’s t-tests. P < 0.05 was considered significant.


   Results
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Discussion
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One MAC isoflurane reduced the MFI of CD11a in comparison with the unexposed samples. All other measured adhesion molecules were not affected by isoflurane under unstimulated conditions (Tables 1 and 2).


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  		Table 1. Table 1 Effect of 0.5 MAC Isoflurane on the Activation of L-Selectin, PSGL-1, CD11a, and CD11b on Neutrophils In Vitro
 

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  		Table 2. Table 2. Effect of 1.0 MAC Isoflurane on the Activation of L-Selectin, PSGL-1, CD11a, and CD11b on Neutrophils In Vitro
 
The results of the effect of isoflurane on the FMLP-induced activation of neutrophil adhesion molecules are shown in Tables 1 and 2. In the presence of 0.5 MAC isoflurane, FMLP-induced shedding of L-selec-tin was significantly inhibited, whereas expression of PSGL-1, CD11a, and CD11b was not affected. In the 1 MAC isoflurane group, we observed a reduced shedding of L-selectin and an inhibition of the upregulation of the CD11a and CD11b MFI. As shown in Tables 1 and 2, isoflurane at 1 MAC also inhibited the downregulation of L-selectin from the neutrophil surface after stimulation with PMA, whereas the MFI of the ß2-integrins was not altered.


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Our results indicate that isoflurane affects the activation of three adhesion molecules involved in the multistep process of neutrophil recruitment. First, isoflurane inhibits the activation of L-selectin, which mediates the neutrophil tethering and rolling on the vascular endothelium. Second, isoflurane attenuates the activation of both ß2-integrins CD11a and CD11b, which mediate firm adhesion and transendothelial migration.

Evidence from animal models suggests that halothane, isoflurane, and sevoflurane protect the heart against ischemia-reperfusion injury (7–11). Proposed mechanisms are reduced production of hydroxyl radicals (7); activation of myocardial adenosine receptors (8), PKC (9), inhibitory guanine regulatory proteins (17), mitochondrial and sarcolemmal adenosine tri-phosphate-regulated potassium channels (18,19), and stretch-activated channels (20); and inhibition of neutrophil adhesion to endothelial cells (10,11). One investigation revealed that adhesion of neutrophils to endothelial cells may be reduced because of an attenuated upregulation of CD11b, whereas endothelial adhesion molecules were not affected (12). However, binding of neutrophils mediated by CD11b with their counterligands on endothelial cells is preceded by neutrophil tethering and rolling on the vascular endothelium, which is an early step of neutrophil recruitment during the inflammatory reaction. Neutrophil tethering and rolling depends on the interaction of the selectins PSGL-1 and L-selectin with their respective endothelial counterligands in a series of adhesion and de-adhesion events (13–15). Therefore, the aim of this study was to investigate whether isoflurane affects the expression of selectins and ß2-integrins involved in the multistep process of neutrophil adhesion and migration through endothelial cells, by using an established whole-blood assay.

An important function of L-selectin for the initial contact with endothelial cells has been shown in studies using MAbs (21) and several polysaccharides (22). L-selectin is constitutively expressed on the cell surface of neutrophils, and signal transduction through chemoattractant receptors results in rapid activation of L-selectin by phosphorylation (23), followed by proteolytic cleavage from the neutrophil cell surface (24). Activation of L-selectin increases its binding activity, enabling initial contact with endothelial mucin-like carbohydrate ligands (25). Furthermore, recent studies showed that phosphorylation of L-selectin after chemoattractant activation occurs in conjunction with the dissociation of calmodulin from the cytoplasmatic domain of L-selectin before proteolysis from the neutrophil cell surface (26,27). In this study, isoflurane inhibited the chemoattractant-induced downregulation of L-selectin. Spontaneous shedding of L-selectin from unstimulated leukocytes (26), which is mediated by a membrane-associated L-selectin sheddase, could be inhibited by metalloproteinase inhibitors (24). Accordingly, a direct effect of isoflurane on the proteolytic sheddase seems unlikely, because L-selectin expression was not altered on unstimulated neutrophils. Therefore, we suggest that inhibition of the chemo-attractant-induced downregulation of L-selectin by isoflurane might be due to a reduced activation of L-selectin. Because activation of L-selectin enables initial contact to endothelial cells, our findings may provide a further mechanism of the isoflurane-induced inhibition of neutrophil adhesion to endothelial cells in ischemia-reperfusion injury.

The leukocyte ß2-integrins CD11a and CD11b are involved in numerous aspects of leukocyte function, including tight adhesion to endothelial cells, transmigration phagocytosis, and neutrophil activation (15). Patients lacking these integrins are susceptible to severe infections (28), but excessive activation contributes to sustained inflammation, reperfusion injury, and tissue damage (1,2). The results of this study confirmed those from Möbert et al. (12), who suggested that inhibition of the upregulation of CD11b is one relevant mechanism responsible for the reduced adhesion of neutrophils to endothelial cells. As a possible underlying mechanism, the authors speculated that the volatile anesthetics might have entered the plasma membrane, resulting in membrane expansion and thereby decreasing the upward regulation of CD11b. In this study we used two different chemoattractants to gain further insight into the underlying mechanism of the isoflurane-induced inhibition of CD11b. The ability of PMA, a direct activator of PKC, to induce activation of CD11b not inhibited by isoflurane supports the conclusion that plasma membrane expansion is unlikely to be the underlying mechanism.

Engagement of FMLP at the G protein-linked receptor leads to the activation of phospholipase C and D, generation of inositol triphosphate, activation of PKC, and calcium influx (29). However, signaling events downstream of PKC leading to CD11b activation are only incompletely established but seem to involve the activation of Src family kinases and mitogen-activated protein kinase p38 (30). However, two investigations showed that FMLP-induced activation of CD11b also occurs independently of PKC and mitogen-activated protein kinase p38 (30,31), suggesting an alternative signaling pathway. Because isoflurane did not affect PMA-induced activation of CD11b, we speculate that isoflurane may alter either the signaling pathway upstream of PKC or the PKC-independent signaling pathway. However, further studies are required to identify the effect of isoflurane on chemoattractant-induced neutrophil signaling pathways.

CD11a is expressed on neutrophils and mediates interactions of neutrophils with the endothelium and transendothelial migration via binding to endothelial ICAM-1 (32,33). After activation with either FMLP or PMA, CD11a is redistributed over the cell membrane, thus forming high-avidity clusters and inducing ligand binding activity (34). In this study, stimulation with either FMLP or PMA resulted in increased CD11a MFI on the neutrophil surface, representing activation of the CD11a ligand binding activity. Because isoflurane reduced the mean CD11a fluorescence intensity in the unstimulated samples and after stimulation with FMLP, it is possible that isoflurane may inhibit the binding of CD11a to endothelial ICAM-1. We suggest that the inhibition of CD11a ligand binding activity might be another reason for the reduced adhesion of neutrophils to endothelial cells in the presence of isoflurane.

In conclusion, the results of this study indicate that the inhibiting effect of isoflurane on neutrophil recruitment may be mediated by a decreased activation of L-selectin and by attenuation of activation of the ß2-integrins CD11a and CD11b on the neutrophil surface.


   Acknowledgments
 
Supported by START, a research grant of the Rheinisch-Westfälische Technische Hochschule Aachen, Germany.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication May 14, 2002.




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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