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Anesth Analg 2001;92:1322-1326
© 2001 International Anesthesia Research Society

GENERAL ARTICLES

Surgical Stress Induces Endotoxin Hyporesponsiveness and an Early Decrease of Monocyte mCD14 and HLA-DR Expression During Surgery

Takashi Kawasaki, MD*, Masanori Ogata, MD*, Chika Kawasaki, MD*, Tomoko Tomihisa*, Kohji Okamoto, MD{dagger}, and Akio Shigematsu, MD*

*Department of Anesthesiology and {dagger}First Department of Surgery, University of Occupational and Environmental Health, School of Medicine, Kitakyushu, Japan

Address correspondence and reprint requests to Masanori Ogata, MD, Department of Anesthesiology, University of Occupational and Environmental Health, 1-1-1 Iseigaoka, Yahatanishiku, Kitakyushu, 807-0555, JAPAN. Address e-mail to mogata{at}med.uoeh-u.ac.jp


   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
It is generally accepted that major surgery is associated with severe alterations of the host-defense mechanisms. We investigated the effect of surgical stress on the immune system. Specifically, we studied the relationship between perioperative lipopolysaccharide (LPS) hyporesponsiveness and monocyte human leukocyte antigen-DR (HLA-DR) and CD14 expression during the perioperative period in 20 patients who underwent partial gastrectomy. This study demonstrated that surgical stress rapidly depressed monocyte mCD14 and HLA-DR expression in comparison with preanesthesia levels. Monocyte mCD14 expression recovered to preoperative levels on the first postoperative day, and monocyte HLA-DR expression recovered by the seventh postoperative day. Consistent with our previous study, LPS-induced tumor necrosis factor (TNF)-{alpha} production ex vivo was significantly suppressed from the beginning of the operation. On the contrary, the plasma interleukin-10 concentration started to increase after the surgical incision was made. LPS hyporesponsiveness was least at the end of the operation and returned to preoperative levels on the first postoperative day. In conclusion, the present study demonstrated that LPS responsiveness, plasma interleukin-10 concentration, and monocytes mCD14 and HLA-DR expression altered from the early period of surgery. These alterations may be related to the impairment of the immune system during the perioperative period.

Implications: Recent studies demonstrate that surgical stress induces immune dysfunction. We found that surgical stress rapidly decreased monocyte mCD14 and human leukocyte antigen-DR expression, and endotoxin responsiveness. These findings suggest that early changes of the immune system caused by surgical stress contribute to postoperative complications such as sepsis and multiple organ failure.


   Introduction
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 Abstract
 Introduction
Methods
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 Discussion
 References
 
Various injuries, including trauma, burn, hemorrhage, and surgery, lead to impairment of immunological functions. The impaired immune system increases the risk of developing systemic inflammatory response syndrome, sepsis, and multiple organ failure. Lipopolysaccharide (LPS) contained in the outer membrane of Gram-negative bacteria is thought to contribute to the pathogenesis of sepsis. In whole blood, LPS is bound to LPS-binding protein, which facilitates the transfer of LPS to CD14 molecules on the cell membranes of monocytes and polymorphonuclear cells. Membrane CD14 (mCD14), a 55-kD glycoprotein on the cell membrane of monocytes and polymorphonuclear cells, plays a key role in transmitting LPS signals intracellularly and ultimately activating tumor necrosis factor (TNF)-{alpha} production (1). Not only does CD14 exist on the surface of white blood cells, it is also found in serum as soluble CD14 (sCD14) (2). sCD14 also binds LPS and mediates LPS activation.

In patients with sepsis or after major surgery, the ability of whole blood to produce proinflammatory cytokines in response to LPS is reduced (3–7). This hyporesponsiveness to endotoxin correlated with the severity of sepsis (5) and injury (6). Furthermore, it also correlated with the postoperative course (7).

Mononuclear human leukocyte antigen-DR (HLA-DR) is one of the major histocompatibility complex (MHC) class 2 proteins. Its expression has a central role in antigen presentation to lymphocytes and initiation of the immune response (8). After trauma or in surgical patients, monocyte HLA-DR expression is also decreased, and this is associated with an increased risk of developing severe sepsis (9–12). Loss of cell surface HLA-DR has been suggested to reduce the antigen-presenting capacity of monocytes, resulting in impaired T cell stimulation. A previous study reported that monocyte HLA-DR expression was regulated by interleukin (IL)-10 in vitro(13).

Recently, we demonstrated that surgical stress rapidly induces transient hyporesponsiveness of blood cells to endotoxin from 2 h after incision and that plasma IL-10, which increases during surgery, participates in this hyporesponsiveness (14). These findings suggest that surgical stress affects the immune system from the early period of surgery. However, this study was observed until the first postoperative day, and the mechanisms of endotoxin tolerance and perioperative immunosuppression remain unclear. We, therefore, designed this study to investigate the effect of surgical stress on plasma sCD14 concentration and monocyte mCD14 and HLA-DR expression to identify the cause of immunosuppression, such as endotoxin hyporesponsiveness, until the seventh postoperative day.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
After obtaining approval from our committee on human research, we received informed consent for this study from 20 volunteers classified as ASA physical status I and II, who were scheduled for elective partial gastrectomy. None had any infectious diseases or metabolic disturbances, and none was taking any medication.

All patients were premedicated with brotizolam 0.25 mg orally 2 h before surgery. General anesthesia was induced with 2 mg/kg propofol, tracheal intubation was accomplished with vecuronium bromide 0.1 mg/kg, and anesthesia was maintained with 60% nitrous oxide and isoflurane (end-tidal concentration 0.8%–1.5%). Ventilation was controlled to maintain an end-tidal PCO2 of 30–35 mm Hg. Body temperature was maintained adequately by monitoring core and skin surface temperature. Postoperative analgesia was provided by continuous epidural anesthesia (5 mL/h with 1% mepivacaine and 5 µg/mL fentanyl). No patients had blood transfusions during the perioperative period. All patients were discharged from the hospital without any major complications.

In our previous study (14) and preliminary study, we confirmed that a clinically useful concentration of inhaled anesthetics, such as isoflurane and nitrous oxide, had no effect on LPS-induced TNF production, plasma IL-10 concentration, plasma sCD14 concentration, monocyte HLA-DR expression, or monocyte CD14 expression. Therefore, we obtained blood samples (5 mL) before anesthesia was induced (Pre.OPE), 2 h after skin incision (OPE2H), at the end of surgery (Post.OPE), 24 h after surgery (1POD), and on postoperative Days 2 (2POD), 4 (4POD), and 7 (7POD). To measure the plasma IL-10 and sCD14 concentrations, blood was placed in tubes containing heparin (1 U/mL final concentration) or EDTA-2Na (1.5 mg/mL final concentration) and centrifuged. The supernatant samples were collected and stored at -80°C until assayed.

LPS-induced TNF-{alpha} production in whole blood was measured as previously reported (15). In brief, blood samples were drawn into a heparinized syringe and diluted with 5 volumes of RPMI 1640 (Nissui Pharmaceutical, Tokyo, Japan). The diluted blood (990 µL) was then placed into a 24-well plate (Becton Dickinson, Lincoln Park, NJ). After incubation at 37°C in 95% air/5% CO2 for 4 h in the presence of LPS (10 µL) at a final concentration of 10 ng/mL, the blood was centrifuged at 700g for 10 min to remove blood cells. The supernatants were collected and stored at -80°C until assayed.

TNF activity in plasma was determined by colorimetric measurement of L929 cell cytotoxicity as described previously (16). TNF activity was expressed in units per milliliter, which is the reciprocal of the dilution necessary for 50% lysis of the cells. Plasma IL-10 was measured in duplicate by using a commercially available enzyme-linked immunoassay (MEDGENIX; BioSource Europe S.A., Fleurus, Belgium). According to the manufacturer, cross-reactivity with other cytokines is negligible in this assay. Plasma sCD14 was measured in duplicate by using a commercially available enzyme-linked immunoassay (MEDGENIX). According to the manufacturer, no plasma proteins show any cross-reactivity in this assay.

Monocyte HLA-DR expression and mCD14 expression were measured by using dual monoclonal antibody staining and flow cytometry. One hundred microliters of anticoagulated whole blood was mixed with 20 µL of fluorescein isothiocyanate-coupled RMO52 monoclonal antibody (IMO645; Coulter Immunology, Hialeah, FL) and with 20 µL of phycoerythrin-coupled B8.12.2 monoclonal antibody (IMO464; Coulter Immunology). After incubation in the dark at room temperature for 45 min, a lysing medium (Immunolyse; Coulter Immunology) was added to lyse erythrocytes, and the samples were incubated for an additional 10 min. The samples were then washed twice and fixed with 0.2% paraformaldehyde. All samples were analyzed immediately by using a flow cytometer and XL software (EPICS-XL; Coulter Electronics). The results were described as the mean fluorescence intensity (MFI). The monocyte gate was set by using the routine position for monocytes in the sideways-scatter and the forward-scatter for mononuclear cells.

All data were presented as the mean ± SEM. Statistical analysis was performed with repeated measures analysis of variance when values were compared with the control (Pre.OPE) value. A significant difference was presumed at a probability value <0.05.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
LPS-induced TNF-{alpha} productions in whole blood during the perioperative period are shown in Figure 1. The preoperative TNF-{alpha} level was 346.7 ± 131.3 U/mL. Consistent with our previous study (14), TNF-{alpha} production decreased significantly 2 h after the start of surgery (71.1 ± 18.3 U/mL) and reached a minimum at the end of the operation (53.3 ± 8.8 U/mL). LPS-induced TNF-{alpha} production recovered to the preoperative level by the first postoperative day.



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  		Figure 1. Perioperative changes of lipopolysaccharide-induced tumor necrosis factor (TNF)-{alpha} production in whole blood ex vivo. Values are mean ± SEM (n = 20). Pre.OPE = preoperation (before anesthesia), OPE2H = 2 h after incision, Post.OPE = the end of operation, POD = postoperative day. *P < 0.05 versus control (Pre.OPE).

 
In contrast, plasma IL-10 concentrations increased significantly 2 h after the start of surgery and reached a peak at the end of the operation ( Fig. 2). The IL-10 concentrations recovered to the preoperative level by the fourth postoperative day.



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  		Figure 2. Perioperative changes of plasma interleukin (IL)-10 concentration. Values are mean ± SEM (n = 20). Pre.OPE = preoperation (before anesthesia), OPE2H = 2 h after incision, Post.OPE = the end of operation, POD = postoperative day. *P < 0.05 versus control (Pre.OPE).

 
Because mCD14 plays an essential role in transmitting LPS signals intracellularly, and ultimately activates TNF-{alpha} production (1), we investigated whether perioperative LPS hyporesponsiveness is related to monocyte mCD14 expression. Similar to LPS-induced TNF-{alpha} production, monocyte mCD14 expression decreased significantly 2 h after the start of surgery (15.4 ± 1.3 MFI) and recovered to the preoperative level by the first postoperative day ( Fig. 3). However, plasma sCD14 concentrations did not change during the operation ( Fig. 4), although it started to increase significantly on the first postoperative day and remained increased until the seventh postoperative day.



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  		Figure 3. Perioperative changes of monocyte mCD14 expression (mean fluorescence intensity). Values are mean ± SEM (n = 20). Pre.OPE = preoperation (before anesthesia), OPE2H = 2 h after incision, Post.OPE = the end of operation, POD = postoperative day, MFI = mean fluorescence intensity. *P < 0.05 versus control (Pre.OPE).

 


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  		Figure 4. Perioperative changes of sCD14 concentration. Values are mean ± SEM (n = 20). Pre.OPE = preoperation (before anesthesia), OPE2H = 2 h after incision, Post.OPE = the end of operation, POD = postoperative day. *P < 0.05 versus control (Pre.OPE).

 
Perioperative changes in monocyte HLA-DR expression are shown in Figure 5. Monocyte HLA-DR expression decreased significantly 2 h after the operation started (9.1 ± 0.7 MFI) and recovered to the preoperative level by the seventh postoperative day.



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  		Figure 5. Perioperative changes of monocyte HLA-DR expression (mean fluorescence intensity). Values are mean ± SEM (n = 20). Pre.OPE = preoperation (before anesthesia), OPE2H = 2 h after incision, Post.OPE = the end of operation, POD = postoperative day, MFI = mean fluorescence intensity. *P < 0.05 versus control (Pre.OPE).

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
This study demonstrated that surgical stress rapidly depressed monocyte mCD14 and HLA-DR expression. LPS-induced TNF-{alpha} production in whole blood ex vivo was suppressed from early in the operation. On the contrary, the plasma IL-10 concentration started to increase after the surgical incision was made. The LPS hyporesponsiveness reached a minimum at the end of the operation and recovered to the preoperative level on the first postoperative day.

As shown in Figures 1 and 3, monocyte mCD14 expression was significantly suppressed during the operative period, as was LPS-induced TNF-{alpha} production. IL-4, IL-6, IL-13, and interferon-{gamma} down-regulate mCD14 expression on human blood monocytes (17,18). In contrast, IL-10 up-regulates the expression of human monocyte mCD14 in vitro(18). Despite the increasing plasma IL-10 concentration, however, monocyte mCD14 expression decreased during the operation (Figs. 2 and 3). The mechanism for the depression of monocyte mCD14 is unclear, but the expression of monocyte mCD14 is not regulated by plasma IL-10 during surgery.

Our previous study demonstrated that anti-IL-10 antibody partially restored the ability of LPS to induce TNF activity (14). This suggested that IL-10 and other factors contribute to LPS hyporesponsiveness. LPS-induced TNF-{alpha} production is significantly suppressed in CD14-deficient mice (19). In contrast, transgenic mice strongly expressing human CD14 on the surface of their monocytes were hypersensitive to LPS (20). These results indicate that depression of monocyte mCD14 is one of the factors that play an important role in LPS hyporesponsiveness. We consider that the inhibition of LPS-induced TNF-{alpha} production is explained not only by the increasing plasma IL-10 concentration but also by the reduction of monocyte mCD14 expression during surgery.

Because sCD14 acts as a scavenger of endotoxins by neutralizing circulating LPS (21), it may modify LPS hyporesponsiveness during the operative period. Our results show that the plasma concentration of sCD14 started to increase after the operation, but not during the operative period, when LPS hyporesponsiveness occurred. These results indicate that the sCD14 concentration does not directly affect LPS hyporesponsiveness. Frey et al. (22) showed that sCD14 might play a harmful role by transmitting LPS effects to endothelial cells. Pugin et al. (23) also reported that complexes of sCD14 with LPS activate endothelial cells. Landmann et al. (24) demonstrated that the plasma sCD14 concentration increased in Gram-negative septic shock patients, and that increased circulating sCD14 was associated with increased mortality. In our study, the sCD14 concentration increased in the postoperative period; however, none of the patients had complications during their entire clinical course. The significance of the role of an increased sCD14 concentration in the postoperative period is still not clear. Further study is needed to elucidate the function of sCD14.

Depression of HLA-DR expression impairs the immune system by suppressing the effect on MHC class II-dependent antigen presentation of the antigen-presenting cell. Sepsis and trauma decrease monocyte HLA-DR expression (25,26). Several studies have demonstrated that IL-10 depresses the antigen-presenting capacity of monocytes/macrophages by down-regulating the expression of MHC class II (13,18). Other substances released by macrophages, such as prostaglandin E2, may also down-regulate subsequent cytokine release and monocyte HLA-DR expression (27). Klava et al. (28) demonstrated that IL-10 gene expression is correlated with a decrease in monocyte HLA-DR antigen expression in patients undergoing abdominal surgery. They also showed that monocyte HLA-DR expression was significantly reduced 24 hours after surgery and remained decreased during the first postoperative week. In our study, monocyte HLA-DR expression decreased significantly within 2 hours after the surgical incision was made, and remained decreased until the fourth postoperative day. Like LPS-induced TNF-{alpha} production, surgical stress rapidly depressed monocyte HLA-DR expression. Consistent with previous studies (14,29), the plasma IL-10 concentration increased during the perioperative period and returned to the preoperative level by the fourth postoperative day. The increase in the plasma IL-10 concentration may partially contribute to decreased monocyte HLA-DR expression.

Consistent with our previous study (14) and animal experiment that showed that LPS induced cytokine productions such as IL-2, IL-3, and IL-6 in macrophage and splenocyte was suppressed at two hours after laparotomy (30), the present study demonstrated that surgical stress-induced immunosuppression occurred at two hours after incision. Recently, The Center for Disease Control and Prevention recommended that preoperative antimicrobial drug administration must be effective against the postoperative surgical site infection (31). These findings suggest that paying attention to immunosuppression during the early period of surgery is important in preventing postoperative infections.

In conclusion, we demonstrated that monocyte mCD14 and HLA-DR expression decreased from the early period of surgery. Both increasing serum IL-10 concentration and depressed monocyte mCD14 expression might contribute to endotoxin tolerance. Monocyte HLA-DR expression and LPS responsiveness decreased rapidly under surgical stress during an operation. These results may in part explain the impairment of the host-defense mechanisms during an operation.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication January 23, 2001.




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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