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Anesth Analg 2005;100:1007-1013
© 2005 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000146432.39090.D4

ANESTHETIC PHARMACOLOGY

The In Vitro Effect of Desflurane Preconditioning on Endothelial Adhesion Molecules and mRNA Expression

Zhu Biao, MD, PhD, Xue Zhanggang, MD, Jiang Hao, MD, Miao Changhong, MD, PhD, and Cang Jing, MD, PhD

Department of Anesthesiology and Intensive Care Unit, Zhongshan Hospital, Shanghan Medical College, FuDan University, Shanghai, China

Address correspondence and reprint requests to Xue Zhanggang, MD, Zhongshan Hospital, Fudan University'Xuhui district, No.180 Fenglin Road, Shanghai, China. Address e-mail to xuezgang{at}online.sh.cn or xuezgang{at}zshospital.net.


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Lower expression of intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), and E-selectin may be responsible for attenuated ischemic-reperfusion neutrophil adhesion to vascular endothelium. Desflurane reduces ischemia-reperfusion injury. Therefore, we assessed whether desflurane affects the protein expression of ICAM-1 and E-selectin and mRNA expression of ICAM-1 and VCAM-1 of human umbilical venous endothelial cells (HUVEC) stimulated with tumor necrosis factor-{alpha} (TNF-{alpha}). HUVEC were preconditioned for 60 min with 1 minimum alveolar concentration desflurane before stimulating with TNF-{alpha}. Protein expression of adhesion molecules ICAM-1 and E-selectin of HUVEC were evaluated via immunocytochemical techniques combined with image cytometry. ICAM-1 and VCAM-1 mRNA expression of HUVEC were determined via reverse transcription-polymerase chain reaction. Desflurane not only reduced the protein expression of ICAM-1 and E-selectin but also ICAM-1 and VCAM-1 mRNA expression of the HUVEC. The adhesion rate of neutrophils with desflurane-treated HUVEC was slower. The decreased neutrophil adhesion on the desflurane-treated HUVEC correlated well with the decrease in adhesion molecule expression. These results show that desflurane affects the expression of adhesion molecules involved in the multistep process of neutrophil recruitment. Desflurane related ischemia-reperfusion injury reduction correlates well with expression inhibition of ICAM-1, VCAM-1, and E-selectin that mediates neutrophil rotation and firm adhesion on the vascular endothelium.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Recruitment of neutrophils through vascular endothelium to inflamed tissues 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 rolling, which is mediated by the interaction of selectins such as P-selectin and E-selectin with their counter ligands. In the next step, tight attachment to endothelium cells involves the neutrophil integrin Mac-1 (CD11b/CD18) and endothelial cell adhesion molecules intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1(VCAM-1). Finally, neutrophils transmigrate into the interstitial compartment via the binding of leukocyte function-associated antigen one (LFA-1, CD11a/CD18) to endothelial ICAM-1 (1). Tissue injury occurs because of the release of oxygen free radicals and cytotoxic enzymes as well as increased cytokine release from activated neutrophils (2,3). Furthermore, microvascular occlusion by platelet-leukocyte aggregates (4) and increased endothelium permeability also contributes to ischemia-reperfusion injury (5). Inhibition of neutrophil rolling and attachment to vascular endothelium as a therapeutic approach is an attractive way to potentially prevent early reperfusion injury. In animal models, monoclonal antibodies (MAbs) against adhesion molecules and soluble adhesion molecules attenuate ischemia-reperfusion injury (6,7). One investigation revealed that anesthesiologists have used volatile anesthetics with antiadhesive activity in clinical practice for decades (8). In animal models, isoflurane, sevoflurane, and even halothane protect against myocardial ischemia-reperfusion injury (9–12). One suggested mechanism was the attenuated expression of CD11b on activated neutrophils after exposure to volatile anesthetics (13,14). However, CD11b is not the sole adhesion molecule involved in the process of neutrophil recruitment. There were many other adhesion molecules, such as E-selectin, (15) ICAM-1, and VCAM-1, on the endothelium with counter ligands integrins CD11a and CD11b on neutrophils (16). Thus, we investigated the effect of 1 minimum alveolar concentration (MAC) desflurane on the protein expression of E-selectin, ICAM-1 and mRNA expression of ICAM-1 and VCAM-1 of human umbilical venous endothelial cells (HUVEC) by using an established HUVEC model. Furthermore, adhesion molecule activation was determined via assaying neutrophil-HUVEC adhesion rate.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
HUVECs were isolated and grown in culture as described by Jaffe et al. (17). Briefly, cells were isolated from human umbilical vein cords by enzymatic digestion using collagenase type II (Worthington Chemical Company, Freehold, NJ) and grown in M199 supplemented with 20% fetal bovine serum (FBS) and penicillin/streptomycin (100 U). Endothelial cell mitogen (Biogenesis, Poole, UK) was solubilized with heparin (1000 U) and added at a final concentration of 100 µg/mL. Cells were grown to confluence on 0.2% gelatin-coated 75-cm2 flasks (Costar, Cambridge, MA) in humidified atmosphere at 37°C in 5% CO2. Confluent primary cultures were routinely passaged by trypsin/EDTA or EDTA digestion and expanded through passages 2–3. Ethical approval for use of umbilical cords for isolation of HUVEC collected from Zhongshan Hospital was given by the ethics committee of Fudan University of China.

The MAC value used in this study was 7.0% for desflurane. Control group HUVEC was placed in a standard airtight incubator (BB 16; Heraeus, Hanau, Germany) providing a gas mixture of 5%CO2 and 95% oxygen. Treatment group HUVEC was exposed to 1.0 MAC desflurane for 60 min in a same incubator and desflurane was delivered with a standard anesthetic machine (Sulla 909; Dräger, Lueck, Germany), and concentrations of all gases at outlet were continuously monitored with a multigas analyzer (Datex Compact; Datex, Helsinki, Finland). At the end of the incubation time, all HUVEC were immediately processed, then neutrophil-HUVEC adhesion assays, reverse transcription-polymerase chain reaction (RT-PCR), and staining procedures for adhesion molecule expression were completed simultaneously.

Binding of monoclonal antibodies to HUVEC stimulated with tumor necrosis factor-{alpha} (TNF-{alpha}) 10 ng/mL for 0, 1, 4, 8, and 12 h was performed according to avidin-biotin-peroxidase complex (ABC) methods (18). The HUVEC cell sections were treated with 0.1 M L-lysine-HCl in phosphate-buffered saline (PBS) for 30 min to prevent background staining, washed with PBS, and treated with 0.3% H2O2 in PBS for 1 h to inhibit endogenous peroxidase activity. After rinsing in PBS, the sections were placed in a moist chamber. They were preincubated with 3% normal goat serum (NGS) diluted in a solution consisting of 1% bovine serum albumin (BSA), 0.1 M L-lysine-HCl and 0.02% NaN3 in PBS for 15 min to block nonspecific sites. They were then incubated for 90 min with each specific antibody to E-selectin and ICAM-1 (rabbit anti-rat cathepsin B immunoglobulin [Ig] G 20 µg/mL, rabbit anti-rat cathepsin H IgG 20 µg/mL, or rabbit anti-rat cathepsin L IgG 30 µg/mL) diluted in PBS containing 1% BSA, 0.1 M L-lysine-HCl and 0.02% NaN3.

The specimens were washed with PBS and incubated with biotinylated goat anti-rabbit IgG diluted 1:200 in PBS for 45 min. After washing with PBS they were incubated with ABC diluted 1:100 in PBS for 60 min. The specimens were rinsed in PBS and allowed to react with diaminobenzidine (DAB) solution containing 0.02% DAB and 0.006% H2O2 in 0.05 M Tris-HCl buffer, pH 7.6, for 2–3 min. After washing them with distilled water, the sections were counterstained with toluidine blue. As controls, sections were incubated in the same manner, but the specific antibody was replaced by nonimmune rabbit serum or incubated with neither the specific antibody nor the nonimmune rabbit serum.

To quantify endothelial adhesion molecules ICAM-1 and E-selectin expression at different time points, the ICAM-1 and E-selectin expression rates and the ICAM-1 and E-selectin expression areas were analyzed with the KS400 Image Analysis System (KS400, Zeiss, Germany). Briefly, five areas in each section were observed with the Image Analysis System. The size of each area was 512 x 512. The data were analyzed with software of the Image Analysis System.

Routine isolation of neutrophils was performed under sterile conditions using Ficoll-Hypaque endotoxin-free Histopaque with a gradient density centrifugation technique followed by erythrocyte lysis (19). Whole blood was drawn from five donors on acid/citrate/dextrose, carefully layered on the gradient, and centrifuged at 2500 rpm for 25 min at room temperature. Lysing buffer (0.154 M ammonium chloride, 19 mM potassium bicarbonate, 1 mM EDTA) was added to the pellet containing erythrocytes and neutrophils for 10 min and centrifuged at 1500 rpm for 5 min. The neutrophil pellet was then washed three times with PBS. Cells were washed twice in PBS in RPMI 1640 medium for adhesion studies.

HUVEC added to M199/2.5% FBS were grown to confluence on 24-well plates, preconditioned with 1 MAC of desflurane for 60 min and then stimulated with TNF-{alpha} 10 ng/mL. Isolated neutrophils were suspended in RPMI media at 0.5–1 x 106 cells/mL then added to each of the 24-well plates and incubated for 20–30 min at 37°C. Wells were then washed carefully three times to remove unbound neutrophils and bound cells were also lysed and assayed for myeloperoxidase (MPO) activity (20,21). Lysed cells were added with HEPES-buffered Hanks' balanced salt solution (0.3 mL), phosphate buffer (pH 6.4, 0.2 mL), dimethoxybenzidine (O-dianisidine HCl (50 µL), and H2O2 (50 µL). The color product was measured spectrophotometrically (Titertek Multiscan, Huntsville, AL) at 450 nm. Standard curves were plotted for each assay using neutrophils ranging between 0.03 x 105 and 2 x 105 cells/mL and the number of adherent cells determined from this. There is no MPO in HUVEC (21).

Semiquantitative RT-PCR was performed according to Chang et al. (22). At the end of the experiments endothelial cells were collected and total RNA was isolated (RNeasy kit, Qiagen, Hilden, Germany). RNA samples (5 µg) were heated at 70°C for 5 min and quickly chilled on ice. Reaction buffer (6* Avian myeloblastosis virus reverse transcriptase [AMV] buffer, Oligo(dT)18 1 µg/µL, dNTP 10 mM, RNase Inhibitor 50 U/µL, AMV 10 U/µL) (Life Technologies, St. Paul, MN) were added in a final volume of 25 µL. Reactions were incubated at 42°C for 1 h followed by inactivation at 95°C for 5 min. cDNA was diluted to a final volume of 100 µL and aliquots (5 µL) were used for PCR amplification. Cycling variables were optimized to remain in the exponential phase of amplification. Amplification conditions (cycle number, annealing temperature) were 30, 51°C for h-glyceraldehyde phosphate dehydrogenase (GAPDH), 30, 62°C for ICAM-1, and 30, 50°C for VCAM-1. The PCR mix contained cDNA 5 µL, 10 x Taq buffer 5 µL, MgCl2 25 mM 5 µL, dNTP 10 mM 1 µL, primer sequences 1 µL, Taq 5 U/µL 1 µL, and diethylprocarbonate water 31 µL. Primers (Advanced Biotechnology, UK) were added at a final concentration of 1 µM (ICAM-1) or 20 nM GAPDH. Primer sequences were 5'-tccctcaagattgtcagcaa and 5'-agatccacaacggatacatt for GAPDH (Acc. No. NM-017008), 5'-ctcaccgtgtactggactcc and 5'-agctgtagatggtcactgtc for ICAM-1 (Acc. No:x06990), and 5'-catttgacaggctggagata and 5'-gaacaggtcatggtcacaga (Acc. No:x53051) for VCAM-1. After amplification, PCR products were separated on agarose gels, stained with ethidium bromide, and subjected to image analysis (ONE-Dscan; Scanalytics, Fairfax, VA). Optical density ratio indicates the ratio between the optical densities of ICAM-1 and VCAM-1 and that of GAPDH.

Results are expressed as mean ± sd. Statistical significance was determined by Student's t-test within groups between 0 time and different times and between two groups at different times. Statistical evaluation within groups among different times was performed using one-way analysis of variance. Student-Newman-Keuls testing was used for multiple comparisons within groups among different times. A value of P < 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
HUVEC was exposed to TNF-{alpha}10 ng/mL with a time course of 0, 1, 4, 8, and 12 h. With time, E-selectin and ICAM-1expression increased gradually for both groups (P < 0.01). The maximum E-selectin and ICAM-1expression after stimulation in the control group occurred at 12 h. In the desflurane group, the maximum E-selectin expression occurred at 12 h and the maximum ICAM-1 expression at 8 h. Compared with the control group, there was a significant reduction for ICAM-1 except at 0 time (P < 0.01) and for E-selectin except under basal conditions and at 1 h (P < 0.01) in the desflurane group. Compared with controls, there were 76%, 51%, 54%, and 67% decreases in the absorbance readings for ICAM-1 respectively at 1, 4, 8, and 12 h in the desflurane group and 82%, 51%, and 52% decreases in the absorbance readings for E-selectin at 4, 8, and 12 h, respectively, in the desflurane group (Fig. 1, 2, 3).



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  		Figure 1. Time course results of quantified endothelial adhesion molecules intercellular adhesion molecule-1 (ICAM-1) expression. Data (arbitrary units) are mean ± sd of 9 independent experiments. *P < 0.01 versus 0 h; #P < 0.01 versus desflurane.

 



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  		Figure 2. A, the image of the stained human umbilical venous endothelial cells (HUVEC) stimulated by tumor necrosis factor-{alpha} (TNF-{alpha}) of adhesion molecule intercellular adhesion molecule-1 (ICAM-1) expression from the control group at 12 h. B, the image of the stained HUVEC stimulated by TNF-{alpha} of adhesion molecule ICAM-1 expression from desflurane-treated group at 12 h. These two images showed that desflurane obviously down-regulated the ICAM-1 expression on the surface of HUVEC.

 



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  		Figure 3. Time course results of quantified endothelial adhesion molecules E-selectin expression. Data (arbitrary units) are mean ± sd of 9 independent experiments. *P < 0.01 versus 0 h; #P < 0.01 versus desflurane.

 
HUVEC were exposed to 1 MAC desflurane for 60 min in a standard incubator and then stimulated with TNF-{alpha} 10 ng/mL at baseline and 1, 4, 8, and 12 h. The expression of ICAM-1 and VCAM-1 mRNA was analyzed by RT-PCR. The maximum mRNA expression increase of VCAM-1 and ICAM-1 after stimulation occurred at 12 h. With time there was a significant gradual increase for ICAM-1 and VCAM-1 gradually in both groups (P < 0.01). Compared with controls, desflurane preconditioning strongly down-regulated the ICAM-1 mRNA expression 15%, 52%, 48% and 54% at 1, 4, 8, and 12 h (P < 0.01). Desflurane preconditioning also strongly down-regulated VCAM-1 mRNA expression 38%, 58%, 55%, and 57% at 1, 4, 8, and 12 h, respectively (P < 0.01) (Figs. 4, 5).



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  		Figure 4. Tumor necrosis factor-{alpha} (TNF-{alpha})-induced up-regulation of intercellular adhesion molecule-1 (ICAM-1) was attenuated by desflurane. Data (ICAM-1 to GAPDH ratio) are mean ± sd of 9 independent experiments. *P < 0.01 versus 0 h; #P < 0.01 versus desflurane.

 



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  		Figure 5. Tumor necrosis factor-{alpha} (TNF-{alpha})-induced up-regulation of vascular adhesion molecule-1 (VCAM-1) was attenuated by desflurane. Data (VCAM-1 to GAPDH ratio) are mean ± sd of 9 independent experiments. *P < 0.01 versus 0 h; #P < 0.01 versus desflurane.

 
Neutrophils were isolated from freshly drawn blood and layered onto HUVEC for 30 minutes. There was a significant gradual increase for adhesion of neutrophils to HUVEC with time in the desflurane and control groups (P < 0.01). Compared with controls, desflurane preconditioning strongly down-regulated adhesion of neutrophils to HUVEC 27%, 32%, 21%, and 30% at 1, 4, 8, and 12 h, respectively (P < 0.01) (Fig. 6).



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  		Figure 6. Desflurane preconditioning reduced tumor necrosis factor-{alpha} (TNF-{alpha}) -induced neutrophil-HUVEC adhesion rate increasing. Data (adhesion rate) are mean ± sd of 9 well experiments. #P < 0.01 versus desflurane; *P < 0.01 versus 0 h.

 


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Evidence from animal models suggests that halothane, isoflurane, sevoflurane, and desflurane protect the heart against ischemia-reperfusion injury. The proposed mechanisms are reduced production of hydroxyl radicals (9), activation of myocardial adenosine receptors (10), protein kinase C (11), inhibitory guanine regulatory proteins (23), mitochondrial and sarcolemmal adenosine triphosphate-regulated potassium (mito KATP and sarc KATP) channels (24,25), and stretch-activated channels (26) as well as inhibition of neutrophil adhesion to endothelial cells (8,12). A recent report (27) demonstrated that reactive oxygen species (ROS) seems to be one of the mediators in the mechanism of isoflurane's actions on the cardiac sarc KATP channel that involves preconditioning by volatile anesthetics. Another study indicates that mito KATP channel opening acts as a trigger for isoflurane-induced preconditioning by generating ROS in vivo (28). One investigation also revealed that adhesion of neutrophils to endothelial cells might be reduced because of attenuated up-regulation neutrophil adhesion molecules CD11b/CD18 and L-selectin by volatile anesthetics (13). The expression of endothelial adhesion molecules is up-regulated by TNF-{alpha}. Ischemia followed by reperfusion rapidly leads to the expression of inflammatory cytokines, especially TNF-{alpha}, which stimulate a cascade of events involving local endothelial cells including an up-regulation of cell adhesion molecules. Our study was based on the view that inhabitation expression of endothelial adhesion molecules up-regulated by TNF-{alpha} may reduce ischemia/reperfusion injury. Therefore we can assume that the endothelial adhesion molecules, such as ICAM-1, VCAM-1, and E-selectin expression inhibition by volatile anesthetics such as desflurane, may be the underlying mechanism for reduction of myocardial ischemia-reperfusion injury.

Binding of endothelial cells mediated by E-selectin, ICAM-1, and VCAM-1 with their counter ligands on neutrophils is involved in the adhesion of neutrophils and transendothelial migration on the vascular endothelium. This is a two-step process of neutrophil recruitment during the inflammatory reaction. Many clinical studies have proven that E-selectin is increased after ischemia-reperfusion injury. The aim of this study was to investigate whether desflurane affects the expression of E-selectins, ICAM-1, and VCAM-1 involved in the multistep process of neutrophil adhesion and migration through endothelial cells by using an established semiquantitative RT-PCR assay, immunocytochemistry, and neutrophil-HUVEC adhesion rate.

Our results indicate that desflurane attenuated the expression of these adhesion molecules involved in the multistep process of neutrophil recruitment. First, it inhibited the activation of E-selectin after stimulation for 4, 8, and 12 hours, and ICAM-1 at 1, 4, 8, and 12 hours, respectively, which mediated the neutrophil's firm adhesion on the vascular endothelium. Second, it attenuated the expression of mRNA of ICAM-1 and VCAM-1, which mediated the expression of ICAM-1 and VCAM-1 and then firm adhesion and transendothelial migration. Desflurane did not change the protein expression principle of gradual increasing of E-selectin and ICAM-1 and the mRNA expression principle of ICAM-1 and VCAM-1 with time. Our results showed that ICAM-1 is continuously present in small amounts on the membranes of endothelial cells. ICAM-1 synthesized after stimulation and expressed on the endothelial cell membrane after 1–2 hours. Many studies have produced the same results.

An important function of ICAM-1 for the firm adhesion with endothelial cells has been shown in studies using MAbs and several polysaccharides (29). ICAM-1 mediates the interactions of neutrophils with the endothelium and transendothelial migration via binding to integrin CD11b/CD18 and CD11a/CD18 (30,31). In this study, desflurane reduced the ICAM-1 mRNA expression and the ICAM-1 binding activity on the HUVEC stimulated with TNF-{alpha}. It is possible that desflurane may inhibit the binding of endothelial ICAM-1 to CD11b/CD18 and CD11a/CD18 of neutrophils. The inhibition of ICAM-1 binding activity might be the reason for the reduced adhesion of neutrophils to endothelial cells in the presence of desflurane. These data implied that inhibition of the up-regulation of ICAM-1 is one relevant mechanism responsible for the reduced adhesion of neutrophils to endothelial cells after ischemia-reperfusion injury. VCAM-1 had the same condition as ICAM-1. In contrast, Mobert et al. (13) simulated features of the early phase of inflammation by incubating endothelial cells with 1 mM H2O2 for 10 minutes for activation. The endothelial cells that responded to stimulation with H2O2 with immediate (within minutes) membrane expression of the adhesion molecule were not ICAM-1, E-selectin, and VCAM-1. Thus the effect of volatile anesthetics on adhesion molecule expression may indicate discrepancies in our study. The particular mechanisms of such discrepancies are not well understood.

E-selectin is synthesized after stimulation by cytokines such as TNF-{alpha} and is expressed on the endothelial cell membrane after 4–6 hours (32). Our study had similar results. The target cells of E-selectin are neutrophils and monocytes. Counter receptors on these white blood cells are carbohydrate structures on membrane glycoproteins (33). In this study, desflurane inhibited the TNF-{alpha}-induced up-regulation of E-selectin. Therefore, we suggest that inhibition of the TNF-{alpha}-induced up-regulation of E-selectin by desflurane might be due to a reduced activation of E-selectin. Because such activation enables firm adhesion to endothelial cells and contributes to sustained inflammation, reperfusion injury, and tissue damage (2,6), our findings may provide a further understanding of the mechanism of the desflurane-induced inhibition of neutrophil adhesion to endothelial cells in ischemia-reperfusion injury.

In this study we used TNF-{alpha} to gain further insight into the underlying mechanism of the desflurane-induced inhibition of adhesion molecules. However, signaling events downstream of TNF-{alpha} leading to E-selectin, ICAM-1, and VCAM-1 activation are incompletely understood. However, they seem to involve the activation of Src family kinases and mitogen-activated protein kinase p38 (34). Two investigations suggest an alternative signal pathway: that of PKC-zeta inducing the TNF-{alpha}-induced nuclear factor-kappa B binding to the ICAM-1 promoter and the resultant ICAM-1 gene transcription. (35,36) These data imply a critical role for the activation of nuclear factor-kappa B in regulating TNF-{alpha}-induced oxidant generation and E-selectin, ICAM-1, and VCAM-1 transcription in endothelial cells. Further studies are required to identify the effect of desflurane on TNF-{alpha}-induced endothelial signaling pathways.

In conclusion, the results of this study indicate that the inhibiting effect of desflurane on neutrophil recruitment may be mediated by a decreased activation of ICAM-1 and VCAM-1 and attenuation of activation of E-selectin on the endothelial cell surface.


   Footnotes
 
Accepted for publication September 14, 2004.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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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