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Ann Thorac Surg 1998;66:2135-2144
© 1998 The Society of Thoracic Surgeons

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Current Review

Effects of cardiopulmonary bypass on leukocyte and endothelial adhesion molecules

^a Cardiothoracic Unit, Hammersmith Hospital, Imperial College School of Medicine, London, England, UK

Address reprint requests to Dr Taylor, Cardiothoracic Unit, Hammersmith Hospital, Imperial College School of Medicine, Du Cane Rd, London W12 0NN, England

	Abstract

Top Abstract Systemic inflammatory response... Adhesion molecules Selectins Integrins Immunoglobulin superfamily Conclusions Acknowledgments References

 
During the inflammatory response, triggered by cardiopulmonary bypass, interaction between activated leukocytes, platelets, and endothelial cells is mediated through the expression of three main groups of adhesion molecules: the selectins, the integrins, and the immunoglobulin superfamily. The selectins, which mediate the initial rolling of the leukocyte on the endothelium, are divided in three subgroups: L-selectin is expressed on all three leukocyte types, P-selectin is expressed on platelets and endothelial cells, and E-selectin is only expressed on endothelial cells. Integrins can be found on most cell types, consist of an and a ß subunit and mediate firm adhesion of the leukocyte and migration into the tissues. They are classified into subgroups according to the type of their ß subunit. Immunoglobulins such as ICAM-1 and VCAM-1 are expressed mainly on endothelium and act as ligands for certain integrins. This review article summarizes the existing, and rapidly expanding, literature concerning the effects of cardiopulmonary bypass on the expression of leukocyte and endothelial adhesion molecules. Deeper understanding of the behavior and the role of adhesion molecules during cardiopulmonary bypass may facilitate effective intervention in the inflammatory response process and suppression of its adverse effects.

	Systemic inflammatory response and cardiopulmonary bypass

Top Abstract Systemic inflammatory response... Adhesion molecules Selectins Integrins Immunoglobulin superfamily Conclusions Acknowledgments References

 
The highly regulated cellular and humoral defense mechanism of the organism against potentially threatening situations is often proved to be hazardous for the host, causing "exaggerated" inflammatory response. Surgeons are often faced with conditions associated with localized or systemic inflammation. These conditions include inflammatory processes such as sepsis and pancreatitis, response to major trauma and major surgery, ischemia–reperfusion, burn, shock, or more specific reactions such as rejection to transplantation and inflammatory response to cardiopulmonary bypass (CPB).

The clinical syndrome produced through the above mechanisms is often described in the literature as systemic inflammatory response syndrome. In practice, the clinical signs and symptoms of systemic inflammatory response syndrome can vary from insignificant to very severe. An extreme, albeit not uncommon, form of systemic inflammatory response syndrome is the multiorgan dysfunction syndrome with the potential development of multiorgan failure [1]. Multiorgan failure includes clinical conditions such as acute lung injury with the development of adult respiratory distress syndrome and acute renal failure.

Cardiac surgery is a discipline in which the problem of systemic inflammatory response syndrome is faced on a daily basis. Despite the fact that the incidence of life-threatening morbidity and mortality after CPB has significantly decreased in recent years [2], a "postperfusion" syndrome with accumulation of interstitial fluid, organ dysfunction, and occasionally, organ failure, is still a commonly recognized consequence of cardiac operations. Surgical trauma, contact of blood components with the artificial surface of the bypass circuit, and lung reperfusion injury after reestablishing lung circulation are generally regarded as the main causative factors of the postperfusion morbidity [3].

Irrespective of the cause, the inflammatory response follows qualitatively similar activation patterns. Different forms of injury or infection result in activation of a number of humoral and cellular inflammatory pathways. Molecules such as complement, bradykinin, kallikrein, and different cytokines are involved in this process. Certain cytokines stimulate endothelial cells to a procoagulant state. However, the decisive step in tissue injury is the cytokine-mediated activation of platelets and leukocytes. In particular, granulocytes and monocytes are recruited into tissue, causing edema [4, 5].

During CPB, complement activation through the alternative and also the classic pathway leads to the formation of the anaphylatoxins C3a and C5a [6, 7]. Activation of complement components is regarded as an important initiator of neutrophil activation and aggregation, eventually leading to endothelial and parenchymal cell damage [8, 9]. In one study, the use of a monoclonal antibody against the complement component C3 reduced leukocyte activation in an experimental model of CPB [10].

Activation of factor XII contributes further to neutrophil activation and to secretion of proteolytic enzymes, such as neutrophil elastase, from neutrophil granules [11]. Elastase release from neutrophils has been reported during CPB [12]. With regard to plasma concentrations of leukocytes during CPB, an initial neutropenia is followed by leukocytosis [13].

Cytokines are small soluble proteins that participate in a variety of biological activities. They can have multiple biological effects and are produced by nearly every cell. Despite some inconsistencies in the literature, the release of proinflammatory cytokines, such as tumor necrosis factor- (TNF-), interleukin-1 (IL-1), and of the inflammatory cytokines IL-6 and IL-8, appears to be of particular importance during CPB. The TNF-, although undetectable in some studies [14, 15], displays increased plasma levels at the beginning of CPB [16–18] or after release of the aortic cross-clamp [19]. The IL-1 levels increased during the first 24 hours after CPB in some trials [17, 18, 20], but remained undetectable in others [14, 21, 22]. The failure to detect TNF- and IL-1 is probably attributable to the fact that the plasma concentrations of these molecules increase at an early stage of the inflammatory response and decrease rapidly through degradation.

Plasma levels of the inflammatory cytokines IL-6 and IL-8 increase greatly after CPB, reaching a peak at 3 to 24 hours [20–24]. There appears to be a direct relationship between IL-6 and IL-8 levels and duration of aortic cross-clamping [16, 24].

The expression and release of cytokines comprise one of the main mechanisms regulating the next step of the inflammatory response, that is, the cell–cell interaction mediated through adhesion molecules.

Although, over the past 10 years, a very large amount of work has been carried out on the mechanisms leading to inflammation and systemic inflammatory response syndrome, several questions related to the importance of different inflammatory mediators are yet to be answered. Owing to the fact that, irrespective of the nature of the initial injury, inflammation tends to follow similar pathways, it is likely that the pattern of the systemic inflammatory response in the cardiac surgical patient is similar to the one in the noncardiac surgical patient. Furthermore, studying these changes in cardiac operations has an important advantage: it is known when the insult that initiates the response is going to occur [25]. This "standardization" of conditions makes the cardiac patient a unique in vivo model for exploring the molecular mechanisms involved in the inflammatory response. Deeper understanding of these mechanisms will bring us closer to the ultimate goal of any research undertaken in the field of inflammation; that is, the ability to manipulate effectively the process of inflammation at a molecular level and to ameliorate its adverse effects without endangering host protection.

	Adhesion molecules

Top Abstract Systemic inflammatory response... Adhesion molecules Selectins Integrins Immunoglobulin superfamily Conclusions Acknowledgments References

 
More than 100 years ago scientists documented the fact that leukocytes bind to endothelium before they transmigrate into sites of inflammation. However, a deeper understanding of the molecular mechanisms involved in leukocyte adhesion has developed only in the past decade. Specific adhesion molecules, which are expressed on leukocytes, platelets, and endothelial cells, were shown to participate in this process [26]. Leukocyte activation with expression of adhesion molecules also takes place during cardiac operations and is thought to be the result of operative trauma and, most important, of contact between leukocytes and the artificial surface of the bypass circuit. In conditions of endothelial dysfunction, such as after reperfusion injury of ischemic myocardium, upregulation of adhesion molecules enhances neutrophil-led tissue damage. Monoclonal antibodies against a variety of adhesion molecules ameliorated neutrophil infiltration and tissue damage of ischemic-reperfused myocardium in animal experiments [27]. Adhesion molecules that regulate leukocyte–endothelial cell interaction can be divided into three main families: the selectins, the integrins, and the immunoglobulin superfamily [26].

	Selectins

Top Abstract Systemic inflammatory response... Adhesion molecules Selectins Integrins Immunoglobulin superfamily Conclusions Acknowledgments References

 
The initial contact in the leukocyte adhesion cascade is made through the so-called rolling of the leukocyte and its loose attachment on the endothelium under hydrodynamic shear flow, by glycoproteins named selectins, the primary sequence of which was first described in 1989 [28]. The selectins comprise a group of three molecules that are closely related in structure and function (Table 1 ): L-, E-, and P-selectin.

The effect of CPB on the expression of L-selectin has been investigated in a number of clinical and experimental trials (Tables 2 to 4 ). In all these studies, expression of adhesion molecules on leukocytes and platelets was determined by immunofluorescence staining and flow cytometry. The values of L-selectin expression, as for other adhesion molecules, were expressed as the ratio of the mean fluorescence intensity, in arbitrary units, to nonspecific background fluorescence.

Several potential antiinflammatory strategies have been studied in groups of cardiac surgical patients, using L-selectin as a marker of inflammation. Heparin coating of the bypass circuit, cooling, leukocyte filters, and treatment with soluble complement receptor 1 have each displayed inconsistent and usually unconvincing effectiveness in influencing leukocyte L-selectin expression during CPB (Tables 2 to 4) [14, 15, 34–38].

The results of the above studies are in reality less conflicting than they appear to be. As the expression of L-selectin on cell surface increases and subsequently decreases during leukocyte activation, it is likely that different investigators "caught" the leukocytes at different stages of activation. Furthermore, the profile of leukocyte L-selectin expression may be affected by the release of L-selectin-rich neutrophils from bone marrow during normothermic CPB [39].

P-selectin
P-selectin is a glycoprotein that is stored intracellularly in -granules of resting platelets and in the Weibel-Palade bodies of endothelial cells and can rapidly reach the cell surface upon activation [40, 41]. P-selectin supports binding of leukocytes to platelets and endothelial cells [42, 43]. The expression of P-selectin may be induced by the proinflammatory cytokines IL-1 and TNF and declines significantly within minutes after activation [44]. There is evidence that P-selectin participates in neutrophil-mediated cardiac tissue injury caused by myocardial ischemia [45, 46] and that neutralization of P-selectin results in better recovery of cardiac function after a period of ischemia [46, 47]. Blockade of L- and P-selectins, with the oligosaccharide fucoidin, resulted in better recovery of left ventricular function, coronary blood flow, and myocardial oxygen consumption after 2 hours of cold cardioplegic ischemia in a model of isolated blood-perfused lamb heart [47].

Changes in platelets, such as degranulation and function defect, are known to occur during CPB [48]. Despite the existence of evidence that the platelet function defect is related to a lack of extrinsic platelet agonists [49], some degree of platelet activation is expected to occur during CPB, resulting in upregulation of P-selectin on platelet surface. P-selectin expression on platelets was shown to increase early [34, 50], whereas soluble P-selectin plasma concentrations were increased toward the end of CPB in adult and pediatric patients [51, 52]. Aprotinin and the adenosine regulator acadesin did not affect platelet surface P-selectin expression in two other studies [53, 54]. Overall, trials investigating P-selectin during CPB confirm the development of detectable platelet activation.

E-selectin
E-selectin (ELAM-1) is transiently expressed on activated endothelium and has been shown to support the adhesion of most leukocyte groups. It mediates neutrophil adhesion distinct from that mediated through integrins and, like L-selectin, it functions at an early stage of neutrophil binding to endothelium [55]. Due to its minimal expression on resting endothelial cells, increases of E-selectin on endothelium and of its soluble form are very good markers of endothelial activation [56].

During CPB, soluble E-selectin concentrations fail to increase significantly above baseline [51, 57–59], although in one study plasma levels were elevated postoperatively, reaching peak values at 12 to 24 postoperative hours [15]. The failure of soluble E-selectin to reach detectable plasma levels during CPB does not exclude E-selectin upregulation on endothelial cell surface and therefore, it does not mean that CPB does not cause endothelial activation. The fact that E-selectin is not detectable in plasma during CPB could simply mean that it is "consumed" by activated leukocytes. One study of pediatric patients revealed that E-selectin mRNA induction occurs in cardiac and noncardiac tissues during CPB [60]. Future studies of E-selectin endothelial cell expression are needed to investigate the timing and the extent of endothelial activation during cardiac operations.

	Integrins

Top Abstract Systemic inflammatory response... Adhesion molecules Selectins Integrins Immunoglobulin superfamily Conclusions Acknowledgments References

 
Integrins comprise the largest group of adhesion receptors and are found on most cell types, including leukocytes. They are transmembrane cell-surface proteins that respond to signals of cellular activation, and mediate their function by binding to specific ligands. Each integrin contains a noncovalently associated and ß chain, with characteristic structure [61]. Integrins are classified into subgroups based on the ß chain. Table 5 shows the members of the integrin family that are expressed on leukocytes.

ß2-integrins
The ß2-integrin group, also known as the leukocyte integrins, consists of LFA-1 (CD11a/CD18 or Lß2), MAC-1 (CD11b/CD18 or Mß2), 150,95 (CD11c/CD18 or Xß2), and Dß2 (Table 5 ). The Dß2 integrin appears to be specific to monocytes. It has not yet been investigated in patients undergoing cardiac operation and will not be discussed any further in this article. The expression of ß2-integrins is confined to leukocytes and in particular, Mac-1 and LFA-1 are incriminated in playing an important role in the pathophysiologic mechanisms associated with the inflammatory response [63]. Their role in neutrophil adhesion and transmigration are regarded as complementary, although in a model of the recently developed Mac-1-deficient mouse, Mac-1 was shown to play a critical role in neutrophil binding to fibrinogen and neutrophil degranulation, whereas neutrophil transmigration was shown to be more dependent on LFA-1 [64]. After leukocyte activation, Mac-1 is rapidly mobilized from intracellular secretory granules to the neutrophil surface through chemoattractant stimulated granule–plasma membrane fusion. However, the increase of integrin concentration in the leukocyte membrane is not necessarily sufficient for increased adhesiveness [55]. Rather than by the total population of activated Mac-1 and LFA-1 molecules, ligand binding is mediated by highly adhesive subpopulations [65].

The ß2-integrins are the most extensively investigated integrin group in patients undergoing CPB (Tables 2 to 4). Their concentration on the leukocyte membrane during and after cardiac operation can be assessed by using monoclonal antibodies against individual chains and immunofluorescence analysis.

ß2 chain (CD18)
Changes in the expression of the common ß2 (CD18) chain can be attributable to upregulation in any of the different ß2 combinations.

Several in vivo human and animal studies demonstrated that the neutrophil expression of ß2 increases during CPB, reaching a peak at 60 minutes [22, 29, 33, 66–69]. Heparin coating of the bypass circuit suppressed ß2 upregulation in human [34] but not in pig neutrophils [70]. Activation of the complement component C3 appears to affect neutrophil ß2 upregulation, as it was shown in a group of C3-deficient dogs undergoing CPB [67]. One study demonstrated decrease of ß2 on lymphocytes and monocytes [29].

M chain (CD11b)
Monoclonal antibodies against the M chain of Mac-1 have been commercially available for several years and have been used extensively in studies investigating leukocyte activation in cardiac surgical patients. Similarly to ß2, M (CD11b) is upregulated on neutrophils and monocytes, reaching its peak expression within 4 hours after discontinuation of CPB on neutrophils and after 24 hours on monocytes [29, 31, 32, 34, 50, 53, 71–75].

The use of aprotinin, acadesin, steroids, and hypothermia appears to reduce monocyte and neutrophil expression of M in human studies [32, 53, 72, 76]. The above descriptive studies have established Mac-1 as a marker of leukocyte activation during CPB. As mentioned before, however, the effect of leukocyte adhesion and also the clinical relevance of Mac-1 upregulation do not necessarily correlate with the increased presence of the molecule on leukocyte surface. Thus, in spite of being the most studied member of the ß2-integrin family, the apparent variability of the above findings illustrates the importance of further studies, particularly incorporating actual changes in ligand-binding ability, to better understand what contribution the leukocyte integrins make toward postoperative complications of CPB.

X chain (CD11c)
The activation of the integrin subunit X (CD11c) follows patterns that are similar to M. It showed increased expression on neutrophils and monocytes during and shortly after CPB in the majority of studies [31, 32, 34, 71], although it remained unchanged [72] or even decreased [30] in other studies. Heparin coating was shown to suppress X expression in an experimental CPB model [35].

L chain (CD11a)
Despite its well-investigated significance in leukocyte adhesion, L (CD11a) does not display increased expression on neutrophils during real [31, 32, 53, 72] or simulated CPB [36]. The expression of L was significantly increased on monocytes in one trial [72]. The specific mechanisms responsible for the difference in L expression between neutrophils and monocytes are not known.

In summary, the results of the above studies suggest that ß2 integrins increase their expression on the surface of leukocytes, in patients undergoing CPB. In particular, upregulation of Mac-1 can be regarded as a good marker of leukocyte activation, although whether this phenomenon is related solely to CPB, and the extent to which leukocyte–endothelial interaction is altered, are questions yet to be clarified.

ß1-integrins
The ß1-integrins, also known as very late antigen (VLA) integrins, are expressed on a wide number of cells. They share the same ß chain and are distinguished through different subunits. Leukocytes express those ß1-integrins that contain the subunits 1, 2, 3, 4, 5, and 6 [77]. The integrin 4ß1 (VLA-4 or CD49d) is of particular importance in leukocyte–endothelial cell interaction due to its ability to interact with the endothelial VCAM-1 ligand. VLA-4 can mediate selectin-independent rolling of lymphocytes and eosinophils, but is not expressed on neutrophils [78]. It serves as a leukocyte receptor to segments of fibronectin in inflamed tissues [79] and there is evidence that it supports TNF--mediated leukocyte infiltration in cardiac allografts in rats [80].

Preliminary results from our laboratory on the expression of ß1-integrins on leukocyte surface suggest that no significant increase occurs during and up to 6 days after CPB.

	Immunoglobulin superfamily

Top Abstract Systemic inflammatory response... Adhesion molecules Selectins Integrins Immunoglobulin superfamily Conclusions Acknowledgments References

 
Adhesion molecules of the immunoglobulin superfamily are transmembrane glycoproteins that are expressed mainly by endothelial cells, which participate in cell adhesion by serving as ligands for certain leukocyte integrins. Intracellular adhesion molecule-1 (ICAM-1) is one of the primary ligands for the ß2-integrins, whereas VCAM-1 binds to 4ß1. ICAM-1 and VCAM-1 increase their expression after endothelial cell P-selectin has been shed and can remain upregulated for days [78].

Preoperative plasma levels of soluble ICAM-1 has been shown to vary widely in cardiac surgical patients. Levels decrease immediately after cross-clamping [15, 57, 58], possibly attributable to binding on activated leukocytes, to increase significantly 24 hours postoperatively [15, 81]. Some investigators did not demonstrate any increase in postoperative plasma ICAM-1 levels [57–59, 66]. Heparin coating [15], hypothermia at 28°C [78], high-dose aprotinin [58], and the use of membrane or bubble oxygenator [66] failed to influence plasma concentration of ICAM-1 during CPB. Soluble VCAM-1 displayed raised plasma levels at 24 hours after CPB in one study on adult patients [58] and decreased levels intraoperatively in a pediatric study [57] performed by the same investigators.

The significance of the presence of soluble endothelial adhesion molecules in plasma is still not fully known. Two recent publications suggested that there is some correlation between high plasma levels of ICAM-1 and the risk of atherosclerosis and ischemic heart disease [82, 83], but the role of this molecule in acute situations, such as CPB, is less well investigated. In the absence of studies examining endothelial expression of these ligands during CPB, it is difficult to understand what significance altered levels of plasma ICAM-1 and VCAM-1 could represent.

	Conclusions

Top Abstract Systemic inflammatory response... Adhesion molecules Selectins Integrins Immunoglobulin superfamily Conclusions Acknowledgments References

 
Adhesion molecules have established their role as important inflammatory mediators in studies of the inflammatory response to CPB. They have been increasingly the focus of investigation and have been shown to undergo changes of different extents during and after CPB. However, there are still several gaps in our knowledge. Although the upregulation patterns of the neutrophil ß2 integrins are becoming clear, the role of the ß1 integrins is still not defined. Furthermore, changes on lymphocytes and monocytes, which could predominately affect the patients’ postoperative course, are less well known. The majority of the studies reviewed in the previous paragraphs based their results on findings affecting changes on neutrophils. Monocytes, however, comprise a group of leukocytes that have recently attracted considerable attention in relation to their role in atherosclerosis and acute inflammation. Monocytes display a high level of adhesion to unstimulated, and also IL-1 and TNF- stimulated endothelial cells. It appears likely that molecules from all three adhesion molecule families are important for the interaction of monocytes with endothelium [84]. As there is also the suggestion that some degree of monocyte activation occurs in response to CPB [85], it is likely that the monocyte–endothelial cell interaction will be a future area of research in the cardiac surgical patient.

One should also bear in mind that "upregulation" of adhesion molecules does not equal "increased adhesion." The often contradictory nature of reports concerning changes in surface expression of leukocyte adhesion molecules in CPB underlines the need to understand better whether such changes actually correlate with altered ligand-binding ability. The specific contribution of selectins and ß2 integrins to the migration of leukocytes into tissues during CPB, also needs clarification.

One of the limitations affecting almost all studies investigating the inflammatory response to CPB is that the patient populations are small and include uncomplicated cases. Because increased cell adhesiveness is a feature of activated leukocytes and endothelial cells, it is likely that adhesion molecules reach significantly higher levels of expression during multiple organ failure than during uncomplicated postoperative recovery.

Greater understanding of the specific order of events during the inflammatory response will make the development of preventive and therapeutic strategies possible. Several trials have already tested the efficacy of techniques and pharmacologic agents that inhibit inflammation. Hypothermia and heparin coating of the bypass circuit are two widely investigated methods of blunting the CPB-induced inflammatory response. The mechanism of their action during CPB and ischemia–reperfusion is regarded as nonspecific, although the specific blocking effect of hypothermia on the expression of individual adhesion molecules is also being clarified [86].

Nonspecific inhibitors, such as corticosteroids, reduce plasma levels of the complement component C5a and of the cytokines IL-1b, IL-6, and IL-8 [20, 23]. Corticosteroids also suppress the leukocyte expression of the integrin M(CD11b) [72]. Whether the effect on integrins is a specific phenomenon, or whether it is the result of the nonspecific suppression of neutrophil activation, is still not clear. A recently published in vitro study suggests that corticosteroids exert specific actions on expression of neutrophil L-selectin and ß2 (CD18), mediated through corticosteroid receptors [87].

Aprotinin is a protease inhibitor that was used in a number of inflammatory conditions before its effect in reducing bleeding in patients undergoing CPB was discovered [88]. Aprotinin is known to reduce TNF, IL-8, and CD11b expression during CPB [76, 89]. Its clinical significance as an inhibitor of CPB-related inflammation may be clarified after the completion of ongoing trials.

A new promising area of specific inhibition of inflammatory mediators involves the use of blocking monoclonal antibodies. As mentioned before, recent experiments demonstrated significant reduction in reperfusion injury to the myocardium of animals subjected to myocardial ischemia and reperfusion and treated with monoclonal antibodies against various adhesion molecules [27]. The day when antibodies will be used in humans does not appear to be very far off. Finally, it is possible that information gained through studying the process of inflammation using the cardiac surgical patient as a model will provide us with knowledge that may be applied to several other medical fields where inflammatory response, although unrelated to CPB, has similarly adverse consequences.

	Acknowledgments

Top Abstract Systemic inflammatory response... Adhesion molecules Selectins Integrins Immunoglobulin superfamily Conclusions Acknowledgments References

 
We thank R. Clive Landis, PhD, for his comments on the manuscript. George Asimakopoulos is supported by the British Heart Foundation.

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Top Abstract Systemic inflammatory response... Adhesion molecules Selectins Integrins Immunoglobulin superfamily Conclusions Acknowledgments References

 

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