Asian Cardiovasc Thorac Ann 2001;9:349-355
© 2001 Asia Publishing EXchange Pte Ltd
Endothelial Cell Adhesion Molecules and Cardiopulmonary Bypass
Michael P Vallely, MBBS1,2,3,
Paul G Bannon, FRACS2,3,
Clifford F Hughes, AO, FRACS2,3,
Leonard Kritharides, FRACP1,4
1 Clinical Research Group The Heart Research Institute Sydney, New South Wales, Australia
2 The Baird Centre for Heart and Lung Research Sydney, New South Wales, Australia
3 Cardiothoracic Surgical Units Royal Prince Alfred and Strathfield Private Hospitals Sydney, New South Wales, Australia
4 Department of Cardiology Concord Hospital Sydney, New South Wales, Australia
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For reprint information contact: Michael P Vallely, MBBS Tel: 61 2 9550 3560 Fax: 61 2 9550 3302 email: valsby{at}hotmail.com The Heart Research Institute, 145-147 Missenden Road, Camperdown, Sydney NSW 2050, Australia.
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ABSTRACT
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Endothelial cell activation and the cell surface expression of adhesion molecules are considered to be crucial steps in the systemic inflammatory response to cardiopulmonary bypass. Endothelial cell adhesion molecules mediate the process of leukocyte adhesion to the endothelium and their subsequent transmigration and degranulation in the subendothelial tissues. The levels of soluble endothelial adhesion molecules in plasma have been used to draw conclusions regarding the cell surface expression of these molecules; the limitations of such studies are discussed. Inhibition of cell adhesion molecules may prevent the inflammatory condition caused by cardiopulmonary bypass and reperfusion injury. Further studies are needed to define the role of endothelial cell adhesion molecules in this inflammatory response.
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INTRODUCTION
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Cardiopulmonary bypass (CPB) induces a systemic inflammatory response syndrome (SIRS) similar to that seen after disseminated sepsis, pancreatitis, multiple trauma, and severe burns.1 The use of CPB uniquely provides a defined and predictable onset of inflammatory insults, permitting baseline measurements, and affording an opportunity to study the pathophysiology and possible treatment of SIRS, which may have clinical implications beyond the field of cardiothoracic surgery.2 Future amelioration of SIRS requires an understanding of the processes involved. This review focuses on the role of endothelial cell activation and the expression of cell adhesion molecules (CAMs) as key processes in SIRS after CPB.3
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THE ENDOTHELIUM AND INFLAMMATION
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The endothelium is a dynamic and complex structure lining all blood vessels in the body. In its quiescent state, the endothelium provides an antithrombogenic surface and a barrier to leukocyte traffic between the intravascular and extravascular spaces.4 The endothelium may become activated in response to inflammatory insults such as cytokines, and physical insults including shear stress and hypoxia. Activation involves the synthesis of a number of proteins including CAMs. Adhesion molecules mediate the contact of leukocytes with the endothelium, and their subendothelial penetration (Figure 1
).4–6 Interactions between circulating leukocytes and endothelial cells are critical in mediating physiologic inflammation and main-taining vascular homeostasis. However, if dysregulated, they can contribute to inflammatory tissue injury and pathologic thrombosis.7,8
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Figure 1. The leukocyte-endothelial cell adhesion cascade. Interplay between cell surface expression of endothelial adhesion molecules and leukocyte integrins.
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Leukocyte-endothelial cell interactions are mediated by sets of CAMs and cytokine/activator molecules in a multistep process.9,10 This involves leukocyte capture, leukocyte rolling, firm adhesion, and transmigration of leukocytes across the endothelium (Figure 1
).8,11 There are 3 families of adhesion molecules involved in the leukocyte adhesion cascade: selectins, integrins, and the immunoglobulin superfamily. Selectins (P-selectin is expressed on activated platelets and endothelial cells, E-selectin is expressed on endothelial cells, L-selectin is constitutively expressed on leukocytes) initiate the adhesion cascade via the transient slowing of neutrophils in postcapillary venules. This results in neutrophil rolling and loose adhesion to the endothelium. Subsequently, firm adhesion is mediated via interaction of the ß2 integrins expressed on activated leukocytes, with endothelial ligands of the immunoglobulin superfamily, such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Transmigration of leukocytes and egress of fluid into the interstitial tissues is the final step in this cascade, and it is mediated by platelet-endothelial cell adhesion molecule-1 and the 
2 integrins on activated leukocytes. Adhesion molecules are variably constitutively expressed and acutely upregulated. For example, as ICAM-1 is constitutively expressed on endothelium, upregulation of ß2 integrins alone may be sufficient to enhance leukocyte adhesion and transmigration in states such as low cardiac output.10 Conversely, VCAM-1 expression is locally upregulated over atherosclerotic lesions, and this may mediate focal infiltration of monocytes into the arterial wall.12
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QUANTIFYING ADHESION MOLECULE EXPRESSION
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Endothelial CAMs are proteins, and their expression on the cell surface follows transcription, translation, and traffic to the cell surface. A proportion of endothelial CAMs is detectable in soluble form in circulating plasma. The factors regulating the relationship between soluble CAMs in plasma and cell expression of CAMs are poorly understood. Upregulation of CAM expression has been documented using various techniques that target different components of the adhesion molecule pathway. The expression of tissue CAMs may be measured using polymerase chain-reaction amplification and Northern blot analysis.13,14 However, the level of tissue messenger ribonucleic acid (mRNA) does not necessarily reflect the cell surface expression or plasma levels of the CAM. In homogenated tissue samples, CAM protein can be measured using Western blotting.15 This uses gel elec-trophoresis with a specific monoclonal antibody to the CAM and an enzyme-linked secondary antibody. This technique measures tissue levels of CAMs that may be intracellular or on the cell surface. Cell surface expression of CAMs may be measured directly or indirectly. Direct measurement of cell surface CAMs (ex-vivo tissue or in-vitro cell culture) involves immunostaining with fluorescence-labeled or enzyme-linked antibodies, and visualizing by microscopy.15 This is operator-dependent and provides a qualitative assessment only. Indirect measurement of cell surface CAMs is possible using an enzyme-linked immunosorbent assay (ELISA). This employs a monoclonal antibody to the CAM and an enzyme-linked secondary antibody that allows quantifi-cation by spectrophotometry. The quantification of soluble CAMs in plasma is possible with a sandwich ELISA or Western blotting technique. Western blotting has the advantage of excluding nonspecific binding, but the disadvantages of lower reproducibility and more difficult quantification. Most studies of soluble CAMs use the ELISA technique.
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SOLUBLE ADHESION MOLECULES
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Soluble CAMs are thought to be released from the surface of activated cells (such as endothelial cells, leukocytes, and platelets) by proteolytic cleavage. The cell surface expression of CAMs and the relationship between tissue CAMs and soluble levels in vivo in humans remains poorly defined. Most published literature assumes that elevated plasma levels of soluble CAMs or elevated mRNA expression parallels the concentration of CAM protein on the cell surface. There are some limitations to studies that use the plasma soluble CAM level as a marker of endothelial cell activation during CPB or other inflammatory states. First, the CAMs may be from multiple cell types. In the literature (cardiothoracic and other), it is usually assumed that increased levels of soluble CAMs (ICAM-1, VCAM-1, and P-selectin) exclusively represent increased endothelial cell surface CAM expression.16–19 Except for E-selectin (endothelial specific), cell types other than endothelial express ICAM-1, VCAM-1, and P-selectin. Therefore, it is difficult to draw conclusions regarding CAM expression at the vascular endothelial interface. In addition, higher plasma levels may derive from accelerated CAM synthesis (and thus parallel expression at the cell surface), an increased rate of CAM cleavage from the cell surface (and thus be inversely related to expression at the cell surface), or decreased clearance from the circulation (which may be independent of cell surface expression). Some of our own studies currently in progress (see below) are investigating these relationships.
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CYTOKINES, INFLAMMATORY MEDIATORS, AND THE ENDOTHELIUM
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There is extensive literature describing cytokine elevation after CPB. Endotoxin, complement, and interleukin-1ß may be particularly relevant to endothelial CAM expression. Endotoxin is known to activate endothelial cells in-vitro.20 Endotoxin levels are elevated during CPB.21 The administration of endotoxin to humans has been shown to cause SIRS with elevation of soluble E-selectin.22 Patients with naturally occurring antiendotoxin antibodies have a lower incidence of fever after cardiac operations.23 Complement factor C5a has been shown to activate endothelial cells in vitro, causing P-selectin expression.24 Recombinant complement factor C5a antagonist reduced infarct size and activated neutrophil adhesion to coronary endothelium in a porcine model of surgical revascularization.25 Interleukin-1ß is a potent pro-inflammatory cytokine known to activate endothelial cells in vitro, increasing CAM expression.26,27 These mediators have been implicated in SIRS due to CPB.21,28–34
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IN-VITRO ENDOTHELIAL CELL STUDIES
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In-vitro endothelial cell culture studies have increased our understanding of the role of CAMs in inflammation, during CPB, and during ischemia/reperfusion. Cytokines, biological molecules, and physical insults that are known to cause endothelial cell activation in vitro include endotoxin, complement, peptido-leukotrienes, tumour necrosis factor, low density lipoprotein, interleukin-1ß, hypoxia, and shear stress.24,34–40
We used in-vitro endothelial cell cultures to examine the relationship between endothelial cell surface CAM expression and plasma CAM levels after coronary artery bypass grafting with CPB (unpublished observations). Human umbilical vein endothelial cell cultures were exposed to plasma taken before, during, and up to 24 hours post-CPB for measurement of cell surface E-selectin, ICAM-1, and VCAM-1 expression using an ELISA. Soluble E-selectin, ICAM-1, and VCAM-1 levels were measured by a sandwich ELISA in the same plasma samples for comparison. Soluble plasma ICAM-1 and VCAM-1, but not E-selectin, were increased post-CPB. In contrast, endothelial cell expression of VCAM-1 and ICAM-1 was significantly decreased by exposure to post-CPB plasma. These data suggest that postoperative elevation of soluble ICAM-1 and VCAM-1 may not be due to their increased expression on endothelium. They also suggest endothelial upregulation may not be the primary pathology in SIRS after CPB.
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IN-VIVO STUDIES
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ANIMAL STUDIES
There have been several in-vivo animal studies that have shown increased adhesion molecule expression with associated neutrophil sequestration in cardiac and pulmonary tissue after reperfusion. In a canine model of CPB, Dreyer and colleagues41,42 demonstrated accumu-lation of neutrophils and increased total water in the lung, with increased expression of ICAM-1, within 30 minutes after release of the aortic crossclamp, and ICAM-1 mRNA expression 3 hours post-CPB. Further animal studies are discussed later.
HUMAN STUDIES
Soluble CAM levels are known to be elevated in some acute and chronic inflammatory states. Septic shock and endotoxemia have been associated with increased levels of circulating E-selectin.22,43 Levels of circulating ICAM-1 have predictive value in carotid artery atherosclerosis and coronary artery disease, whilst circulating E-selectin levels have a significant association with carotid artery atherosclerosis.44 This suggests a role for soluble endothelial CAMs in chronic endothelial cell activation and injury. Several researchers have examined the effects of CPB on soluble CAM levels. Some in-vivo studies in humans have demonstrated no increase in soluble CAMs during CPB.45 Boldt and colleagues18 demonstrated increased levels of soluble CAMs (E-selectin, VCAM-1, ICAM-1, and L-selectin) in patients undergoing cardiac surgery with CPB, but not in patients undergoing major abdominal (Whipple procedure) or thoracic (pneumonectomy) procedures, suggesting a CPB-related release of soluble CAMs. The source of soluble CAMs and the kinetics of their release remain unclear. Kalawski and colleagues16 showed transcardiac release of VCAM-1 and ICAM-1 during late reperfusion (coronary sinus samples had higher levels than peripheral artery or vein). Interestingly, soluble E-selectin levels were significantly lower in the coronary sinus than in the peripheral circulation.16 E-selectin is found exclusively on endothelial cells, and is considered a specific marker of endothelial cell activation.11 Liebold and colleagues46 found trans-pulmonary consumption of soluble E-selectin during and after CPB, but elevated soluble E-selectin in coronary sinus perfusate during reperfusion. This suggests regional variation between the coronary and pulmonary circula-tions, and variations between study populations.
Release of soluble CAMs during CPB has been shown to depend on several factors.47 Boldt and colleagues48 examined the effect of hypothermic versus normothermic CPB on soluble CAMs. Only soluble P-selectin was more elevated after hypothermic CPB. Komai and Haworth49 also demonstrated increased soluble P-selectin levels during and after CPB. P-selectin is expressed on platelets also, and platelet activation is known to occur on CPB, thus limiting the use of soluble P-selectin as a marker for endothelial cell activation.50 Blume and colleagues47 demonstrated increased levels of soluble P-selectin, L-selectin, E-selectin, VCAM-1, and ICAM-1 in children undergoing CPB, with the greatest increase (L-selectin and P-selectin) in children with the highest potential for vascular injury: cyanotic younger patients with longer CPB times and protracted postoperative courses. It remains unclear whether soluble CAMs have an important physiological role or if they are merely en route to clearance from the circulation.51 Interestingly, some in-vitro studies have suggested an anti-adhesion (anti-inflammatory) role for soluble CAMs: short peptides based on sequences of P-selectin, ICAM-1, and platelet-endothelial cell adhesion molecule-1 have been shown to inhibit some in-vitro leukocyte adhesion events.52–55 Tumor necrosis factor-alpha-stimulated neutrophil adhesion to resting endothelium has been inhibited in-vitro by soluble P-selectin.55
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TISSUE EXPRESSION OF ADHESION MOLECULES
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Ideally, studies would measure endothelial CAM expression and soluble CAM expression simultaneously. However, the inherent difficulties (technical and ethical considerations in in-vivo human studies) have meant that the role of cell-bound CAMs and their relevance to soluble CAM levels is still poorly defined. Many of the genes involved in the acute inflammatory response are activated by the transcription factor, nuclear factor-kappaB, found in the cytoplasm of lymphocytes, monocytes, endothelial cells, and smooth muscle cells. After stimulation by cytokines, it transcriptionally activates interleukins, interferon, tumor necrosis factor-alpha, and adhesion molecules.56 The transcription of CAM mRNA in response to endothelial cell activation can be measured.
Both ICAM-1 and E-selectin mRNA have been shown to increase in the heart and skeletal muscle of children undergoing CPB, whilst P-selectin mRNA in cardiac muscle decreased after CPB.13,14 This decrease in P-selectin expression may reflect the rapid kinetics of P-selectin expression (20 minutes after endothelial cell activation), thus maximal upregulation may have been prior to sampling.11 Different sampling times may cause variable results between studies, for all adhesion molecules. There has been no work on their in-vivo expression on endothelium in humans during CPB.
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CELL ADHESION MOLECULE INHIBITION
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Much of the early research on CAMs involved observing the effects of monoclonal antibody inhibition of CAM activity.11 In an attempt to ameliorate SIRS after CPB, several antiinflammatory pharmacological agents (corti-costeroids, aminocaproic acid, nonsteroidal antiin-flammatory drugs) have been examined in clinical trials and in-vivo animal experiments.57–59 The use of monoclonal antibodies to prevent the inflammatory response to CPB and reperfusion injury provides interesting scope for future therapeutic intervention.60,61 In isolated lamb heart studies, the blockade of selectin-mediated leukocyte adhesion after reperfusion was shown to improve cardiac function.62 In sheep CPB models, use of selectin-mediated leukocyte adhesion blockade improved post-CPB pulmonary function, myocardial and endothelial function.60,63 A monoclonal antibody to ICAM-1 has been shown to have cardiac protective effects during myocardial ischemia and reperfusion in a feline model.64 In-vivo monoclonal antibody inhibition of P-selectin protects feline myocardium and endothelium from injury during ischemia and reperfusion.65 Various animal studies have examined the protective effects of inhibiting neutrophil integrins (CD18) in reducing the inflammatory response to CPB and ischemia/reperfusion.61,65,66
The role of endothelial cell-surface CAMs in SIRS after CPB remains poorly defined.67 The relationship between soluble CAMs and cell-surface CAMs during CPB has not been accurately established. This prevents the use of soluble CAM levels as a reliable measure of endothelial cell activation. In addition, it prevents ascribing the inflammatory response after CPB to the upregulation of endothelial cell adhesion molecule expression.
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Acknowledgments
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This project was supported by the Royal Australasian College of Surgeons' Foundation and Strathfield Private Hospital.
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ABSTRACT
INTRODUCTION
