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J Thorac Cardiovasc Surg 1998;115:1172-1178
© 1998 Mosby, Inc.

CARDIOPULMONARY SUPPORT AND PHYSIOLOGY

Down-regulation of surface monocyte lipopolysaccharide-receptor cd14in patients on cardiopulmonary bypass undergoing aorta-coronary bypass operation

Supported by the Deutsche Forschungsgemeinschaft (SFB 217) and by theVeru Foundation.

Received for publication April 21, 1997.Revisions requested June 6, 1997.Revisions received Nov. 20, 1997. Accepted for publication Nov. 20, 1997. Address for reprints: Matthias Blumenstein, MD, StiftsklinikAugustinum, Wolkerweg 16, 81375 München, Germany.

	Abstract

Top Abstract Introduction Patients and methods Results Discussion References

 
Objectives: Major operative trauma likeaorta-coronary bypass operation may lead to postoperative immunodisturbance,putting the patient at an increased risk for infection and sepsis. Themonocyte/macrophage system and the endotoxin receptor CD14 are important in theearly recognition and elimination of invading bacteria. The aim of this studywas to analyze changes in membrane-associated CD14 and soluble CD14 during andafter cardiac involving cardiopulmonary bypass.
Methods:We studied numbers of leukocytes, monocytes, and monocyte subpopulations,expression of monocyte membrane-associated CD14 and plasma levels of solubleCD14 in 10 patients (63 ± 8 years of age), who underwent electivecardiopulmonary bypass.
Results:Cardiopulmonary bypass induced marked postoperative monocytosis, which wasmaximal 20 hours after the operation (485 ± 242 cells/µlbefore, 1080  ± 264 cells/µl 20 hours after surgery).Expression of membrane-associated CD14 on classical CD14++ monocytes decreasedsignificantly by 40%, reaching a nadir 20 hours after surgery (p < 0.05). At the time of maximalmembrane-associated CD14 suppression, the levels of soluble CD14 measured byenzyme-linked immunosorbent assay were clearly increased (3.2 ± 1.0µg/ml before versus 5.6 ± 1.0 µg/ml 20 hours after,p < 0.001). No significant change of thepercentage of small () and large (ß) forms of soluble CD14 wasfound.
Conclusions: Cardiopulmonarybypass leads to reduced membrane-associated CD14 expression on peripheral bloodmonocytes and increased levels of soluble CD14 through shedding or secretion ofmembrane-associated CD14 from the cell surface. These findings indicate thatbypass is associated with significant monocyte activation.(J Thorac CardiovascSurg 1998;115:1172-8)

	Introduction

Top Abstract Introduction Patients and methods Results Discussion References

 
Patients undergoing cardiopulmonary bypass (CPB) frequently manifest ageneralized systemic inflammatory response syndrome. Clinically, these reactionsare reflected in postoperative leukocytosis, fever, and extravascular fluidaccumulation, which may be associated with prolonged recovery and occasionallywith serious organ dysfunction. ^1-3 Current knowledge suggests thatactivation of circulating leukocytes, platelets, and vascular wall components,such as endothelial cells, during CPB is involved in this inflammatory response.However, neither the exact mechanism(s) of activation nor the sequelae of suchinflammation are fully understood.

Complement activation and neutropenia occur during CPB, and functionalsigns of leukocyte activation after cardiac operation, including the release ofproteolytic enzymes, free radical production, and changes in leukocyteadhesiveness, have been reported. ^4-6 Furthermore, measures ofcell-mediated immunity, such as lymphocyte responsiveness to mitogens andantigen presentation, have been shown to be seriously impaired in patients afterCPB. ⁷

The monocyte/macrophage cell system is believed to play a central role inregulating acute inflammatory responses. During CPB, monocytes releaseproinflammatory mediators, such as interleukin (IL)-1ß, IL-6, and IL-8. ^3,8,9 Monocytes express specific cellsurface antigens that are of principal importance in stimulation of thesemyeloid cells. CD14 is a 55-kD glycoprotein that exists in bothmembrane-associated and soluble forms. Membrane-associated CD14 (mCD14) has beenidentified as the main lipopolysaccharide (LPS) (endotoxin) receptor onleukocytes. ¹⁰ mCD14 can bereleased by cells to yield a soluble protein (sCD14) that is able to attach toepithelial and endothelial cells. ¹¹

Activation of monocytes through mCD14 triggers a complex inflammatoryresponse, leading to cytokine release, production of reactive oxygen species,and production of prostaglandins. Elevated plasma concentrations of sCD14,together with a reduced expression of mCD14, have been reported in patients withpathologic conditions such as sepsis, infection, or multiple organ failure, andincreased serum levels of sCD14 were associated with a higher mortality. ^12,13

Because the systemic inflammatory response to CPB is mediated, in part,by monocytes and because increased plasma levels of sCD14 reflect monocyteactivation we analyzed the effect of elective coronary artery bypass graftingwith CPB on the monocyte CD14 system.

	Patients and methods

Top Abstract Introduction Patients and methods Results Discussion References

 
Study design
To test the hypothesis that CPB activates the monocyte CD14 system,markers of monocyte CD14 activity were determined before, during, and afterelective coronary revascularization operation performed with CPB. Primarymeasures of monocyte CD14 activity were the membrane expression of CD14 andplasma concentrations of sCD14. Because CPB may differentially effect thenumbers of circulating leukocytes, numbers of leukocytes, monocytes, andmonocyte subpopulations were also determined.

Blood samples were collected before anesthesia, after 15 and 60 minutesof CPB, and at 0, 6, 20, and 44 hours after completion of the operation. Bloodobtained from five healthy donors (mean age 59 ± 7 years, three menand two women) was used to establish the normal range of monocyte CD14 activity.

Patients
Ten patients (eight men, two women, mean age 63 ± 8 years)with coronary heart disease undergoing elective coronary revascularizationparticipated in the study. The study protocol was approved by the ethical boardof the Faculty of Medicine at the Ludwig-Maximilians-University of Munich, andinformed consent was obtained from each patient.

None of the patients had clinical evidence of acute infection orunderlying immune disease, and none were prescribed drugs known to interferewith the immune response before operation. Anesthesia was accomplished with astandard combination of a narcotic (isoflurane), muscle relaxant (pancuroniumbromide), and analgesic (fentanyl). In all patients a polypropylene hollow fiberoxygenator (Maxima Plus PRF, surface area 2.3 m², ethylene oxide–sterilized,mean priming volume 2280 ml, Medtronic, Anaheim, Calif.) was used. Theextracorporeal circuit was primed with standard electrolyte solution to which 50mmol bicarbonate was added. CPB was instituted at a flow rate of 4.0 ±0.4 L/min. Blood was anticoagulated by administration of 20,000 to 30,000 IU ofheparin during CPB. The heparin was neutralized by protamine at the end of CPB.The total time on CPB was 101 ± 48 minutes, and the aorta wasclamped for an average of 60 ± 31 minutes. Minimal body temperaturereached was 28.4° ± 3.6° C in 50 ± 31 minutes afterinitiation of CPB. A total of 2.6 ± 0.5 distal coronary anastomoseswere performed.

All patients were extubated on the first postoperative day andtransferred from the intensive care unit on the second postoperative day. Twopatients had a rethoracotomy within the first postoperative hours because of anintrathoracic hemorrhage, but recovery was uneventful otherwise. Two patientswere treated with antibiotics for uncomplicated urinary tract infections at theend of the first postoperative week.

Leukocyte count
The absolute number of total leukocytes was determined by use of aCoulter Counter T 840 (Coulter, Krefeld, Germany).

Immunofluorescence studies
Monocyte expression of CD14 and CD16 was studied using two-colorimmunofluorescence. Briefly, samples of ethylenediaminetetraacetic acid–anticoagulatedblood were drawn and stored on ice for a maximum of 2 hours. Whole blood, 100µl, was reacted with monoclonal antibodies against CD14 (My4-PE, Coulter)and CD16 (3G8-Fitc, Coulter) or the respective isotype controls for 20 minuteson ice. Erythrocytes were lysed, and the leukocytes fixed using the Q-Prep LysisKit (Coulter). Samples were washed twice with cold phosphate-buffered saline andthen analyzed in a FACSCan flow cytometer (Becton Dickinson, San Jose, Calif.).Monocytes (5000 events) were acquired by gating on forward and side anglescatter. The percentage of nonviable cells determined by staining with propidiumiodide (Sigma, Deisenhofen, Germany) was negligible (< 2%). Foranalysis, the data were collected in log mode. The logarithmic data weretransformed to a linear scale of specific mean fluorescence intensity, andresults are expressed as relative change from preoperative values.

Within the human monocyte/macrophage system, most monocytes areCD16-negative and exhibit strong CD14 staining. These CD14++ cells (two ++ todenote the strong expression of CD14) account for about 90% of allmonocytes and represent what is usually referred to as "monocytes."CD14+CD16+ positive cells form a subset of monocytes that is distinct from theclassical monocyte population. These cells are characterized by a more maturephenotype and by the inability to produce IL-10. ¹⁴ The number of CD14+CD16+monocytes can be dramatically increased in patients with sepsis. ¹⁵ Analysis of CD14+CD16+ positivecells was performed as previously described elsewhere ¹⁶ (also inhttp://www.med.uni-muenchen.de/immuno/ziegler). The number of total monocytes/µlblood was calculated as total leukocytes/µl blood  x %of all CD14 positive cells in the monocyte scatter gate. The number ofCD14+CD16+ monocytes per µl was calculated as total monocytes per µlblood x % CD14+CD16+ monocytes among all CD14-positivemonocytes.

sCD14 detection by Western blotting
Plasma was obtained by centrifugation of whole blood at 800g for 5minutes at 4° C and stored at –80° C. For sCD14 analysis, plasmawas thawed at 37° C and coagulated by addition of glass beads. Westernblotting was performed as previously described. ¹⁷ Briefly, plasma was diluted 1:50with Laemmli's reducing sample buffer, boiled, and loaded onto precast 12.5%polyacrylamide gels (Phastgels, Pharmacia Biotech, St. Quentin, Yvelines,France). Electrophoresis was carried out in the presence of sodiumdodecylsulfate in a PhastSystem (Pharmacia). Proteins were transferred toHybond-ECL nitrocellulose membranes (Amersham, Buckinghamshire, United Kingdom)in transfer buffer (48 nmol/L tris-hydroxymethyl-amino methane, 39 nmol/Lglycine pH 9.0 with the addition of 20% methanol) for 16 minutes at 30mA/gel using a semidry transfer cell (Bio-Rad). sCD14 glycoproteins weredetected by incubation of the blots with the My4 monoclonal antibody (1 µg/ml)and visualized by enhanced chemiluminescence (Amersham). Luminescence wasdetected by short exposures on Hyperfilm MP films (Amersham). With shortexposure times of the film, the Western blotting for sCD14 is at leastsemiquantitative because in titration experiments a linear relationship betweenamounts of sCD14 and the densitometry signal was achieved.

sCD14 detection by enzyme-linked immunosorbent assay
Plasma concentrations of sCD14 were determined using a specificenzyme-linked immunosorbent assay (IBL, Hamburg, Germany).

Statistics
To determine the effect of CPB on monocyte activity, the time courses ofmonocyte CD14 expression and plasma CD14 concentrations were analyzed by use ofan analysis of variance for repeated measures (SigmaStat, Jandel, San Rafael,Calif.). This method of analysis was chosen in recognition of the variability inmonocyte populations that can occur between individuals. Where a significanteffect of time was found, differences between individual time points wereevaluated using a Bonferroni posthoc test. Data are presented as mean ±standard deviation. For clarity of presentation, the data presented in Figs. 1and 2 are normalized to the preanesthesia value.

View larger version (26K): [in this window] [in a new window]   Fig. 1. Relative changes in theabsolute numbers of leukocytes, total monocytes, and CD14++ monocytes. Theabsolute numbers of total monocytes and monocyte subpopulations were determinedby FACS using directly fluorochrome-conjugated monoclonal antibodies againstCD14 (My4-phycoerythrin) and CD16 (3G8-fluorescein). Preoperative values (t = 0) were taken as 100%. Subsequent dataare given as relative difference to preoperative values (cells/µl[t]divided by cells/µl[t = 0]), thus reflecting the factor of decreaseor increase compared with t = 0. CPB, Cardiopulmonary bypass.

View larger version (18K): [in this window] [in a new window]   Fig. 2. Expression of mCD14 onCD14++ monocytes. Expression of mCD14 on CD14++ monocytes was analyzed with themonoclonal antibody My4-PE and the respective isotypic control. Preoperativevalues (t = 0) were taken as 100%.Subsequent data are given as relative difference to preoperative values (sMFI[t]divided by sMFI[t = 0]), thus reflecting the decrease compared witht = 0. Statistical differences aredescribed in the text. sMFI, Specific mean fluorescence; CPB, cardiopulmonarybypass.

	Results

Top Abstract Introduction Patients and methods Results Discussion References

mCD14 expression decreases on CD14++ monocytes after CPB
Before operation, mCD14 expression by CD14++ monocytes was within thenormal range compared with five healthy donors. After the start of CPB, atemporary increase in mCD14 expression was noted (Fig. 2).mCD14 expression then decreased, reaching a nadir 40% below initialvalues at 20 hours postoperatively (p <0.05). The CD14+CD16+ monocytes are not included in the above analysis. Cellsurface expression of mCD14 did not significantly change in the CD14+CD16+monocytes (data not shown).

Plasma sCD14 is increased at the time of low monocyte mCD14 expression.
At the time of maximal mCD14 suppression, the levels of sCD14 wereclearly increased by factor of 1.7 (before CPB 3.2 ± 1.0 vs 5.6 ±1.0 µg/ml 20 hours after operation, p <0.001, Fig. 3, A). Levels of sCD14 in plasma (total sCD14)derive from a small membrane form of CD14 (sCD14) and from intracellularpools (sCD14ß). ¹⁷ Inour study no significant change was found in the relative contribution of the-form and the ß-form to total sCD14 levels (-sCD14: at 0hours 55% ± 2% of total vs 51% ± 3% oftotal 20 hours after). In Fig. 3, B, representative data obtained from onepatient are shown. In this patient the relative contribution of sCD14 to totalsCD14 was essentially constant (59% at 0 hours and 64% 20 hoursafter operation). Thus secretion of intracellular material and shedding of mCD14from the monocyte surface appear to contribute equally to the increase of totalsCD14.

View larger version (11K): [in this window] [in a new window]   Fig. 3. Levels of sCD14 beforeand 20 hours after aorta-coronary bypass operation. A,Total levels of sCD14 were determined by Western blotting at 0 hours and 20hours after operation with the My4 monoclonal antibody and were visualized byenhanced chemiluminescence. Values are given as mean ± standarddeviation. Statistical differences are described in the text.B, Representative Western blot of the -formand ß-form of sCD14 in patient No. 1 at 0 hours and 20 hours afteroperation. Here, the -form (lower band) accounts for 59% of totalsCD14 before and 64% 20 hours after operation.

	Discussion

Top Abstract Introduction Patients and methods Results Discussion References

Besides generation of proinflammatory soluble cell products, monocytesexpress a specific 55-kD glycoprotein on their surface, the CD14 antigen thatexists in both the membrane-associated and soluble form. The CD14 antigen systemis of principal importance in stimulation of monocytes by endotoxin andendotoxin-like substances. In this study the effect of cardiac bypass operationon the monocyte CD14 system was investigated.

Herein a profound alteration of the monocyte CD14 system was found inpatients undergoing elective coronary revascularization. After cardiac operationwith the use of CPB, a significant monocytosis was observed, reaching a maximumat 20 hours after operation. In parallel to this increase of monocyte cellnumber, a decrease of mCD14 antigen expression and a significant increase inlevels of sCD14 antigen occurred in all patients studied.

Bacterial LPS is a potent activator of leukocytes, with CD14 on the cellmembrane as the main LPS receptor. LPS may associate with soluble serum proteins(LPS binding protein) before the resulting complex is bound by mCD14, leading tocharacteristic cell responses such as synthesis and release of inflammatorymediators. In addition, CD14 can be released by leukocytes, and the soluble formof CD14 has been shown to enable responses to LPS by cells that do not expressCD14 as an LPS receptor, ¹⁸as well as by mCD14-bearing cells. ^19,20 These activities indicate thatthe membrane form behaves as an LPS receptor, and its soluble pendant may serveas a coligand for LPS-mediated cell activation.

The decrease of membrane CD14 on blood monocytes and the concomitantincrease of sCD14 in plasma reported herein suggest that the sCD14 is derivedfrom monocytes by shedding of the cell surface molecule. In addition, it ispossible that tissue macrophages contribute to the increased sCD14 by the samemechanism. At this point it is, however, not known whether mCD14 of tissuemacrophages also becomes down-regulated after CPB.

Although anti-CD14 monoclonal antibodies preferentially stain monocytesand macrophages, reactivity with other cells, such as granulocytes, B cells, andmammary cells, is also observed. ²¹Besides activation of monocytes, CPB may lead to significant alterations ingranulocytes. Indeed, increased plasma concentrations of granulocyte proteinasesand oxygen radicals have been reported. ²²Therefore granulocytes and monocytes should be considered as the source of sCD14found after CPB.

CD14 in plasma is found as a mixture of two soluble proteins, the smallermolecular weight sCD14, deriving mainly from membrane-bound proteinmaterial by shedding, and the larger molecular weight sCD14ß, released fromintracellular pools. ¹⁷ Inthis study we found no significant difference in the ratio of the andthe ß forms of sCD14 between samples taken before and after operation.These results indicate that secretion of intracellular material and shedding ofmCD14 contribute equally to the increase of total sCD14 found in plasma aftercoronary bypass operation.

In vitro LPS stimulation of monocytes induces an increase of mCD14expression within 30 minutes followed by a slow decrease after 1 to 3 hours. ²³ Furthermore, this decrease ofmCD14 coincides with an enhanced sCD14 release by the stimulated cells. ²⁴ In our study a transient increaseof mCD14 expression immediately after the start of CPB was followed by acontinuous decrease of mCD14. Similar to the in vitro results reported, thesechanges in membrane-bound antigen activity paralleled the increasing levels ofsCD14, reaching a maximum at 20 hours after the end of operation. Our resultsindicate that CPB poses a strong stimulus to previously unaffected circulatingmonocytes.

Several mechanisms of cell activation during CPB have been proposed.Direct interaction of immunocompetent blood cells with the foreign surfaces ofthe extracorporeal circuit has been favored as the primary mechanism. ¹ However, with its biologic functionas the main LPS receptor on leukocytes, the CD14 system could mediate activationof cells by endotoxin itself. Indeed, in patients undergoing CPB, increasedintestinal permeability and significantly elevated levels of plasma endotoxinactivity measured by the Limulus amebocytelysate assay have been reported. ²⁵Furthermore, as found with other extracorporeal circuits, such as hemodialysisand hemofiltration, monocyte activation could be due to contamination of blood,tubing lines, the membrane oxygenator, or the priming solution with endotoxin orendotoxin-like material. ²⁶Interestingly, a reduced expression of mCD14, together with elevated serumlevels of sCD14, was also described in patients undergoing intermittenthemodialysis. ²⁷ In addition,the operative trauma itself, ischemia-reperfusion injury caused by crossclampingof the aorta, and reinfusion of shed blood could contribute to thecell-activating process.

On the basis of our results, we speculate that endothelial cell responsesafter CPB occur through different pathways. One pathway, probably the principalpathway, is activation of monocytes through mCD14 triggering a complexinflammatory response, including the production and release of cytokines,reactive oxygen species, and prostanoids, all of which are known to be able toinduce vascular endothelial cell damage directly. In addition, activation of theCD14 system could induce increased shedding and release of sCD14. The solubleform of CD14 then could interact with endothelial cells, promoting cellactivation indirectly in concert with inflammatory cytokines. ²¹ In our study we did not includethe measurement of cytokine production. However, in patients with sepsis,LPS-mediated signaling and cytokine transcription were reported unchangeddespite a significant decrease of CD14 expression on blood monocytes. ²⁸ Finally, endothelial cellactivation and damage may also be induced by direct leukocyte endothelialinteraction mediated by adhesion molecules. ²⁹

In conclusion, our results demonstrate that cardiac operation with theuse of CPB results in significantly decreased mCD14 and elevated sCD14 levels,indicating a profound derangement of the CD14 receptor system. The clinicalimportance of these findings is not yet clear. In septicemic patients bothdecreased as well as unchanged CD14 expression by blood monocytes has also beenreported. ^16,30 These different results mightbe explained by different subsets of patients or different times of cell surfaceantigen analysis. Furthermore, elevated plasma levels of sCD14 were associatedwith a higher mortality in patients with sepsis or multiple organ failure.However, whether these changes contribute to a quantitative and functionalimpairment of the immune response in patients undergoing cardiac operationcannot be concluded from this study.

	Acknowledgments

 
We thank A. Frank-Wanger and J. Köbler for experttechnical assistance and R. A. Ward for his assistance in the preparationof the manuscript.

	Footnotes

 
12/1/87800

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