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Ann Thorac Surg 2000;69:1192-1197
© 2000 The Society of Thoracic Surgeons

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ORIGINAL ARTICLES: CARDIOVASCULAR

Leukocyte integrin expression in patients undergoing cardiopulmonary bypass

^a Cardiothoracic Unit at Hammersmith Hospital, National Heart and Lung Institute, Imperial College School of Medicine, London, England, United Kingdom
^b Cardiovascular Medicine Unit at Hammersmith Hospital, National Heart and Lung Institute, Imperial College School of Medicine, London, England, United Kingdom

Address reprint requests to Dr Taylor, Cardiothoracic Unit, Hammersmith Hospital, Imperial College School of Medicine, Du Cane Rd, London W12 0NN, England
e-mail: scarroll{at}rpms.ac.uk

	Abstract

Top Abstract Introduction Material and methods Results Comment References

 
Background. The recruitment of leukocytes to vascular endothelium is controlled by adhesion events mediated through the ß₂ integrins, whereas the response of extravasated leukocytes within the tissues is controlled through the ß₁ integrins. Although cardiopulmonary bypass (CPB) has been shown to be associated with a systemic inflammatory response and elevated levels of ß₂ integrins on leukocytes, its effect on the ß₁ integrins is not known. This study investigated the effect of the protease inhibitor aprotinin on the expression of the ß₁ and ß₂ integrins on circulating leukocytes in patients undergoing CPB.

Methods. Patients undergoing primary elective coronary artery bypass grafting were randomized into full-dose aprotinin or placebo groups. Blood samples were obtained at nine time points preoperatively, intraoperatively, and up to 6 days postoperatively. The surface expression of the ß₁ integrins VLA-1, -3, -4, -5, and -6 and of the ß₂ integrins CD11a/CD18, CD11b/CD18, and CD11c/CD18 was measured by flow cytometry on gated neutrophil and monocyte subpopulations in whole blood.

Results. Expression of the ß₁ integrins was not significantly altered during the study period and, therefore, aprotinin had no effect on the expression of these molecules. Of the ß₂ integrins, CD11b/CD18 expression was significantly increased on neutrophils at 15 minutes after onset of CPB in the placebo group (p < 0.01) but not in the aprotinin group.

Conclusions. This study showed that expression of the ß₁ integrins on neutrophils and monocytes did not alter during the first 6 days after CPB. Expression of the ß₂ integrin CD11b/CD18 increased significantly on neutrophils during CPB in control patients but not in patients treated with full-dose aprotinin.

	Introduction

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Aprotinin is a nonspecific serine protease inhibitor that blocks pathways of complement activation and fibrinolysis, and inhibits the action of proteinases such as trypsin, plasmin, and kallikrein [1]. The efficacy of aprotinin in reducing postoperative bleeding after cardiac operations was discovered during trials investigating its antiinflammatory properties [2]. Over the last decade, aprotinin has been used extensively as a hemostatic agent, although less attention has been paid to its potential effects on the inflammatory response to cardiopulmonary bypass (CPB).

The systemic inflammatory response to CPB is a modification of the physiologic response to tissue injury or infection. Activation of leukocytes, platelets, complement, and factor XII by contact with the bypass circuit and surgical trauma is followed by systemic secretion of cytokines and other inflammatory mediators. Induced expression of adhesion molecules on activated leukocytes and endothelial cells can result in sequestration of white cells within the tissues and a clinical syndrome, the systemic inflammatory response syndrome (SIRS), which differs quite widely among patients [3]. In its extreme form, it can lead to multiple organ failure that often includes adult respiratory distress syndrome, a condition associated with massive leukocyte infiltration in the lung and high mortality [4].

Recruitment of white cells into tissues requires the stepwise interaction between adhesion molecules on the surface of leukocytes and their corresponding receptors on the lumenal surface of inflamed endothelium. This process is mediated through three main groups of adhesion molecules: (1) the selectins, which mediate the initial attachment and rolling of leukocytes along the vessel wall under hydrodynamic shear flow, (2) the ß₂ integrins, which mediate firm adhesion of leukocytes to endothelium, and (3) the immunoglobulin superfamily of adhesion molecules expressed on the endothelial side which, in conjunction with the ß₂ integrins, regulate firm adhesion and transendothelial migration [5].

Although the effects of CPB on ß₂ integrins, and in particular on CD11b/CD18, have been investigated previously, there are no reported data on leukocyte surface expression of the ß₁ integrins after cardiac operation [6]. The ß₁ integrins (also known as the very late antigens [VLA]) are expressed at low amounts on resting leukocytes but are induced upon extravasation [7] or over a more extended time course (between 3 and 14 days) after activation by mitogens [8]. They bind to components of the extracellular matrix and convey signals from the subendothelial matrix to alter protease and cytokine production by leukocytes, which may contribute toward the process of tissue injury [9, 10].

We conducted this double-blind randomized trial to investigate the hypothesis that CPB is associated with increased leukocyte surface expression of ß₁ and ß₂ integrins and that aprotinin may modify this effect.

	Material and methods

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Patient groups
The protocol of the study was approved by our Ethical Committee and informed consent was obtained from all patients. Eighteen patients, undergoing primary elective coronary artery bypass grafting (CABG), were randomized into two groups in a double-blind fashion. One group (n = 8) received full-dose aprotinin [2] and the other group (n = 10) served as a control. Patients were excluded from the study if they met any of the following criteria: episodes of unstable angina or myocardial infarction within 6 weeks preceding operation, cerebrovascular accident within 3 months preceding operation, combined valve operation, infective endocarditis, known or suspected allergy to aprotinin, previous exposure to aprotinin, coagulopathy, known bleeding diathesis, use of glucocorticoids or nonsteroidal antiinflammatory drugs, use of anticoagulants or aspirin in the week before operation, serum creatinine in excess of 177 µmol/L, pregnancy, presence of malignancy, or more than 75% carotid obstruction as shown by carotid Doppler scan. The two patient groups were well matched with regard to age, sex, preoperative risk factors, angina class, dyspnea class, and left ventricular ejection fraction (Table 1).

Myocardial protection was administered with a Bard cardioplegia delivery system using cold blood antegrade cardioplegia, mixed with St. Thomas’ crystalloid solution in a 4:1 ratio, with additional "hot shot" before the removal of the cross-clamp.

Flow cytometric analysis of leukocyte ß₁ and ß₂ integrin expression
Central venous blood samples (5 mL) were obtained from patients and placed immediately into heparin-containing tubes at the following time points: (1) before skin incision (pre-CPB), (2) 15 minutes after initiation of CPB, (3) 60 minutes after initiation of CPB, (4) 2 hours, (5) 4 hours, (6) 24 hours, (7) 48 hours, (8) 72 hours, and (9) 6 days postoperatively. Tubes containing blood were placed on ice and flow cytometric analysis was carried out within 2 hours from blood sampling. For analysis, blood samples were placed in 12 x 75 mm polystyrene tubes (Falcon, Becton Dickinson UK Ltd, Cowley, UK) using, per condition, 90 µL whole blood and 10 µL primary antibody (100 µg/mL) directed against the unique subunits of the ß₁ and ß₂ family of integrins (Table 2). Primary incubations were carried out on ice for 15 minutes. Each antibody was matched at each time point to an irrelevant isotypic control. (An irrelevant isotypic control is an antibody that is produced by the same host as the main antibody and displays nonspecific binding characteristics, typical for the host.) After two washes with phosphate-buffered saline, fluorescein isothiocyanate-conjugated secondary antibodies were added at the manufacturer’s recommended concentration (Sigma Chemical Co, Dorset, UK) and incubation was continued for a further 15 minutes. Erythrocytes were lysed for 60 seconds by the addition of 1 mL Coulter whole blood lysing reagent and fixed in 250 µL fixative solution (Coulter Electronics Ltd, Luton, UK). Lysed samples were preserved in 5% formaldehyde and read on a flow cytometer (EPICS XL, Coulter Electronics Ltd) within 24 hours. Neutrophil and monocyte cell populations were identified by their characteristic forward and side scatter profiles and confirmed by staining with anti-CD14 monoclonal antibody. Fluorescent intensity of experimental versus isotypic control antibodies was presented as the relative fluorescence intensity (RFI; ratio of experimental mean fluorescence intensity over irrelevant isotypic control mean fluorescence intensity).

	Results

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Intraoperative and postoperative characteristics of patients
There was no significant difference between aprotinin and placebo groups with regard to number of grafts, CPB time, and cross-clamp time (Table 1). All patients received internal thoracic artery graft to the left anterior descending artery. Patients in the aprotinin group lost significantly less blood through the chest drains and received significantly less blood transfusions at 12 hours postoperatively (Table 1). Patients in the two groups had a similarly low rate of postoperative complications, with the exception of atrial fibrillation, which was significantly more common in the control group. On average, patients who received aprotinin were extubated 1 hour earlier and were discharged home 1 day earlier than control patients, although these differences were not statistically significant.

Expression of integrins on circulating neutrophils and monocytes
ß₁ integrins
Integrin expression was quantitated by normalizing the staining intensity obtained with test antibody to an appropriate irrelevant isotype matched control, thereby establishing an RFI for each integrin at each of the nine time points studied on both neutrophil and monocyte cell populations (where an RFI of 1.00 = no expression). The integrity of all test antibodies was verified before use in the study by staining primary T-cell lymphoblasts or other cell lines known to express VLA antigens (data not shown). Neutrophils expressed low levels of the ß₁ integrins in the preoperative samples (RFI < 2.00) and these levels were not significantly altered either intraoperatively or up to 6 days postoperatively (Table 2). Monocytes expressed low levels of VLA-1, -4, and -6 (RFI < 2.00) and moderate levels of VLA-3 and -5 (RFI 2.00 to 4.00) in the preoperative samples, but again showed no significant differences in expression in the intraoperative or postoperative periods. Administration of aprotinin, accordingly, had no effect on the expression of these molecules at any of the time points studied up to 6 days after CPB (Table 2).

ß₂ integrins
The three ß₂ integrins tested, CD11a/CD18, CD11b/CD18, and CD11c/CD18, were present at moderate to high levels in preoperative samples on both neutrophils and monocytes (RFIs between 3.2 and 27.4), and these levels were significantly altered only at the 15-minute time point for CD11b/CD18 expression on neutrophils in the placebo group (p < 0.01, Table 2) but not in the corresponding aprotinin group. The complete time course for CD11b/CD18 expression on neutrophils within the two treatment groups is represented in Figure 1. CD11b/CD18 expression was measured on the gated neutrophil subpopulation in whole blood by flow cytometric analysis, normalizing expression at each time point with test antibody (mAb 44) to an irrelevant isotype matched control antibody. Figure 1 confirms that CPB significantly induced CD11b/CD18 expression at 15 minutes in the placebo group (p < 0.01) but not in the aprotinin group (p > 0.48). No significant differences were detected at any of the later time points with respect to expression of CD11b/CD18 or the other two ß₂ integrins tested on either neutrophils or monocytes (Table 2). We have noted that, although significant, the CD11b/CD18 response to CPB at 15 minutes was heterogeneous between individuals in the placebo group, with only 4 "responders" showing elevated CD11b/CD18 levels (between 281% and 642% of preoperative levels) and 6 "nonresponders" showing levels largely unchanged (between 69% and 124%).

View larger version (19K): [in this window] [in a new window]   Fig 1. Time course of neutrophil Mac-1 expression in cardiopulmonary bypass (CPB) patients. Blood samples were collected as described in the text from patients randomized into placebo (empty columns) or aprotinin (filled columns) groups.

	Comment

Top Abstract Introduction Material and methods Results Comment References

Consistent with their original name ("very late antigens"), most leukocyte ß₁ integrins increase their expression gradually after several days of activation [8]. The low levels of basal integrin expression observed in the preoperative samples in the present study have confirmed the prevailing view that the VLA integrins are largely absent from circulating neutrophils [14, 15], although certain conditions of activation can lead to low levels of expression and increased adhesiveness to collagen and laminin matrix components [7, 16, 17]. The absence of ß₁ integrin expression in the immediate postoperative period in this study was not necessarily surprising, but over the extended time course of the investigation suggests that uneventful cardiac operation constitutes a significant, but relatively short-lived, inflammatory insult that does not appear to induce VLA production during the first 6 postoperative days.

It should be noted that a lack of observed effect on integrin expression levels cannot be interpreted as an inevitable lack of effect of CPB on leukocyte adhesion, as the ß₁ integrins have been described to alter their adhesive capacity by exposure to chemokines, metal ions, and other pharmacologic agents in the absence of alterations in expression [18–20]. Further studies involving the ex vivo testing of patient leukocytes in static adhesion assays to purified ligands would be required to fully understand the effect of CPB on the adhesive properties of the ß₁ integrins on leukocytes.

VLA-4 is unique among ß₁ integrins in its ability to bind, in addition to matrix proteins, the endothelial ligand vascular cell adhesion molecule-1 (VCAM-1). Although not expressed on neutrophils, except after endothelial transmigration or pharmacologic stimulation [7], VLA-4 is critically involved in monocyte interactions with endothelium, both in the initial rolling phase as well as in the subsequent firm adhesion phase [21, 22]. VLA-4 antagonists also have been shown to ameliorate asthmatic responses and inflammatory bowel disease in animal models of disease [23]. It was therefore of interest to note that expression levels of VLA-4 remained unchanged on monocytes throughout the study period, although it cannot be ruled out that CPB might have altered the affinity of preexisting VLA-4 on monocyte membranes, a mechanism that has been described to regulate adhesion through this integrin [24].

The ß₂ integrins are well established as important participants in leukocyte-endothelial cell adhesion and extravasation. All three integrins are expressed on neutrophils and monocytes, of which CD11a/CD18 prominently binds the ligands intracellular adhesion molecule-1 (ICAM-1) and ICAM-2 expressed on endothelium and ICAM-3 expressed on other leukocytes [25]. CD11b/CD18 also binds to ligands such as complement factor iC3b and fibrinogen [26]. Although ß₂ integrins exist on the surface of leukocytes in a relatively inactive form under normal conditions, inflammatory insults result in increased expression and change in their activation state [5, 22]. The effect of CPB has been investigated most extensively on CD11b/CD18 expression by neutrophils [6]. Upregulation of CD11b/CD18 indicates neutrophil activation that is associated with increased ability of the neutrophil to adhere to endothelium, which is a prerequisite for neutrophil-induced tissue damage.

Nearly all literature reports have shown that CD11b/CD18 is upregulated at an early postoperative stage on the surface of neutrophils. Some articles also have shown an increase in the expression of CD11c/CD18 while CD11a/CD18 appears to be unaffected [6]. Our results demonstrated that CPB significantly upregulated CD11b/CD18 expression on neutrophils at 15 minutes of CPB, consistent with the main body of literature. The reason this effect became insignificant at 60 minutes of CPB is probably that activated neutrophil were marginalized within tissues and the CPB circuit. We also noted that this response, although significant (p < 0.01) in the placebo group, was heterogeneous between individuals, with 4 of 10 "responders" exhibiting a large increase in CD11b/CD18 expression relative to preoperative levels (between 281% and 642%) and 6 of 10 "nonresponders" exhibiting virtually unchanged levels. As CD11b/CD18 is considered a well-established marker of neutrophil activation, it is therefore likely that neutrophils from "responders" are more sensitive to the effects of CPB, resulting in exacerbated cellular activation. It is reasonable to assume that the variety in response may be attributable to genetic differences among patients or to a different "activation state" of neutrophils preoperatively. Further investigations will be necessary to determine whether such patients can be identified before operation and whether they could be targeted with specific antiinflammatory strategies, such as glucocorticosteroids or aprotinin.

Our results showing that CPB can significantly induce CD11b/CD18 on neutrophils at 15 minutes in the placebo group (p < 0.01) but not in the aprotinin group (p > 0.48) are consistent with previous findings from two randomized trials that aprotinin can blunt the effect of CABG on Mac-1 upregulation in neutrophils [12, 13]. We have taken care in our investigation to minimize any inherent variability in the flow cytometric technique over the extended time course of the study by normalizing all fluorescent staining with specific antibodies to isotype matched controls at every time point. Our studies therefore add conviction to previous investigations, which routinely reported only mean fluorescent intensities with test antibodies without normalizing data between time points, yet reached the same basic conclusions as the present study.

The small number of the studied patient group precluded clinical differences between groups from becoming significant. The lower rate of atrial fibrillation in the control group may be attributable to a statistical error type II, as aprotinin is not known to reduce dysrhythmias after CPB. Duration of hospital stay, however, has been shown previously to be shorter in patients treated with aprotinin [27].

In summary, this study showed that the expression of ß₁ integrins on neutrophils and monocytes did not increase during the first 6 days after CPB. Neutrophil expression of the ß₂ integrin CD11b/CD18 increased significantly during CPB in the control group but not in patients treated with full-dose aprotinin. The heterogeneity in the CD11b/CD18 response between individuals suggests that the degree of neutrophil activation induced by CPB may vary significantly among patients. Patients with high responses may be appropriate targets for specifically directed antiinflammatory strategies.

	References

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