Effects of cardiopulmonary bypass on leukocyte and endothelial adhesion molecules

CURRENT REVIEWS

Effects of Cardiopulmonary Bypass on Leukocyteand Endothelial Adhesion MoleculesGeorge Asimakopoulos, FRCS, and Kenneth M. Taylor, FRCSCardiothoracic Unit, Hammersmith Hospital, Imperial College School of Medicine, London, England

During the inflammatory response, triggered by cardio-pulmonary bypass, interaction between activated leuko-cytes, platelets, and endothelial cells is mediated throughthe expression of three main groups of adhesion mole-cules: the selectins, the integrins, and the immunoglob-ulin superfamily. The selectins, which mediate the initialrolling of the leukocyte on the endothelium, are dividedin three subgroups: L-selectin is expressed on all threeleukocyte types, P-selectin is expressed on platelets andendothelial cells, and E-selectin is only expressed onendothelial cells. Integrins can be found on most celltypes, consist of an a and a b subunit and mediate firmadhesion of the leukocyte and migration into the tissues.They are classified into subgroups according to the type

of their b subunit. Immunoglobulins such as ICAM-1and VCAM-1 are expressed mainly on endothelium andact as ligands for certain integrins. This review articlesummarizes the existing, and rapidly expanding, litera-ture concerning the effects of cardiopulmonary bypass onthe expression of leukocyte and endothelial adhesionmolecules. Deeper understanding of the behavior andthe role of adhesion molecules during cardiopulmonarybypass may facilitate effective intervention in the inflam-matory response process and suppression of its adverseeffects.

(Ann Thorac Surg 1998;66:2135–44)© 1998 by The Society of Thoracic Surgeons

Systemic Inflammatory Response andCardiopulmonary Bypass

The highly regulated cellular and humoral defensemechanism of the organism against potentially threaten-ing situations is often proved to be hazardous for thehost, causing “exaggerated” inflammatory response. Sur-geons are often faced with conditions associated withlocalized or systemic inflammation. These conditionsinclude inflammatory processes such as sepsis and pan-creatitis, response to major trauma and major surgery,ischemia–reperfusion, burn, shock, or more specific re-actions such as rejection to transplantation and inflam-matory response to cardiopulmonary bypass (CPB).

The clinical syndrome produced through the abovemechanisms is often described in the literature as sys-temic inflammatory response syndrome. In practice, theclinical signs and symptoms of systemic inflammatoryresponse syndrome can vary from insignificant to verysevere. An extreme, albeit not uncommon, form of sys-temic inflammatory response syndrome is the multior-gan dysfunction syndrome with the potential develop-ment of multiorgan failure [1]. Multiorgan failureincludes clinical conditions such as acute lung injury withthe development of adult respiratory distress syndromeand acute renal failure.

Cardiac surgery is a discipline in which the problem ofsystemic inflammatory response syndrome is faced on adaily basis. Despite the fact that the incidence of life-threatening morbidity and mortality after CPB has sig-nificantly decreased in recent years [2], a “postperfusion”

syndrome with accumulation of interstitial fluid, organdysfunction, and occasionally, organ failure, is still acommonly recognized consequence of cardiac opera-tions. Surgical trauma, contact of blood components withthe artificial surface of the bypass circuit, and lungreperfusion injury after reestablishing lung circulationare generally regarded as the main causative factors ofthe postperfusion morbidity [3].

Irrespective of the cause, the inflammatory responsefollows qualitatively similar activation patterns. Differentforms of injury or infection result in activation of anumber 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 proco-agulant state. However, the decisive step in tissue injuryis the cytokine-mediated activation of platelets and leu-kocytes. In particular, granulocytes and monocytes arerecruited into tissue, causing edema [4, 5].

During CPB, complement activation through the alter-native and also the classic pathway leads to the formationof the anaphylatoxins C3a and C5a [6, 7]. Activation ofcomplement components is regarded as an importantinitiator of neutrophil activation and aggregation, even-tually leading to endothelial and parenchymal cell dam-age [8, 9]. In one study, the use of a monoclonal antibodyagainst the complement component C3 reduced leuko-cyte activation in an experimental model of CPB [10].

Activation of factor XII contributes further to neutro-phil activation and to secretion of proteolytic enzymes,such as neutrophil elastase, from neutrophil granules[11]. Elastase release from neutrophils has been reportedduring CPB [12]. With regard to plasma concentrations of

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

© 1998 by The Society of Thoracic Surgeons 0003-4975/98/$19.00Published by Elsevier Science Inc PII S0003-4975(98)00727-9

leukocytes during CPB, an initial neutropenia is followedby leukocytosis [13].

Cytokines are small soluble proteins that participate in avariety of biological activities. They can have multiplebiological effects and are produced by nearly every cell.Despite some inconsistencies in the literature, the release ofproinflammatory cytokines, such as tumor necrosis factor-a(TNF-a), interleukin-1 (IL-1), and of the inflammatory cyto-kines IL-6 and IL-8, appears to be of particular importanceduring CPB. The TNF-a, although undetectable in somestudies [14, 15], displays increased plasma levels at thebeginning of CPB [16–18] or after release of the aorticcross-clamp [19]. The IL-1 levels increased during the first24 hours after CPB in some trials [17, 18, 20], but remainedundetectable in others [14, 21, 22]. The failure to detectTNF-a and IL-1 is probably attributable to the fact that theplasma concentrations of these molecules increase at anearly stage of the inflammatory response and decreaserapidly through degradation.

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

The expression and release of cytokines comprise oneof the main mechanisms regulating the next step of theinflammatory response, that is, the cell–cell interactionmediated through adhesion molecules.

Although, over the past 10 years, a very large amountof work has been carried out on the mechanisms leadingto inflammation and systemic inflammatory responsesyndrome, several questions related to the importance ofdifferent inflammatory mediators are yet to be answered.Owing to the fact that, irrespective of the nature of theinitial injury, inflammation tends to follow similar path-ways, it is likely that the pattern of the systemic inflam-matory response in the cardiac surgical patient is similarto the one in the noncardiac surgical patient. Further-more, studying these changes in cardiac operations hasan important advantage: it is known when the insult thatinitiates the response is going to occur [25]. This “stan-dardization” of conditions makes the cardiac patient aunique in vivo model for exploring the molecular mech-anisms involved in the inflammatory response. Deeperunderstanding of these mechanisms will bring us closerto the ultimate goal of any research undertaken in thefield of inflammation; that is, the ability to manipulate

effectively the process of inflammation at a molecularlevel and to ameliorate its adverse effects without endan-gering host protection.

Adhesion Molecules

More than 100 years ago scientists documented the fact thatleukocytes bind to endothelium before they transmigrateinto sites of inflammation. However, a deeper understand-ing of the molecular mechanisms involved in leukocyteadhesion has developed only in the past decade. Specificadhesion molecules, which are expressed on leukocytes,platelets, and endothelial cells, were shown to participate inthis process [26]. Leukocyte activation with expression ofadhesion molecules also takes place during cardiac opera-tions and is thought to be the result of operative traumaand, most important, of contact between leukocytes and theartificial surface of the bypass circuit. In conditions ofendothelial dysfunction, such as after reperfusion injury ofischemic myocardium, upregulation of adhesion moleculesenhances neutrophil-led tissue damage. Monoclonal anti-bodies against a variety of adhesion molecules amelioratedneutrophil infiltration and tissue damage of ischemic-reperfused myocardium in animal experiments [27]. Adhe-sion molecules that regulate leukocyte–endothelial cell in-teraction can be divided into three main families: theselectins, the integrins, and the immunoglobulin superfam-ily [26].

Selectins

The initial contact in the leukocyte adhesion cascade ismade through the so-called rolling of the leukocyte andits loose attachment on the endothelium under hydrody-namic shear flow, by glycoproteins named selectins, theprimary sequence of which was first described in 1989[28]. The selectins comprise a group of three moleculesthat are closely related in structure and function (Table1): L-, E-, and P-selectin.

L-SelectinL-selectin is found on the surface of most circulatinghuman neutrophils, monocytes, and lymphocytes, andparticipates in the initiation of adhesion of these leuko-cytes to activated endothelium. The expression of L-selectin increases transiently after leukocyte activation,before it is rapidly shed [28]. Therefore, reduced pres-

Table 1. Selectins

Name Old Names Cell type Ligand

L-selectin (CD62L) mLHR, Leu8, TQ-1,gp90MEL, Lam-1, Lecam-1, MEL-14 antigen

Lymphocytes, Monocytes,Neutrophils,

CD34, GlyCAM-1, Peripheral lymph nodeaddressin (PNAd), PSGL-1, MAdCAM-1

P-selectin (CD62P) PADGEM, GMP-140 Platelets, Endothelium P-selectin glycoprotein ligand (PSGL-1),Sialyl-Lewis, other oligo- andpolysaccharides

E-selectin (CD62E) ELAM-1 Endothelium ESL-1, CLA, Sialyl-Lewis, other oligo- andpolysaccharides, PSGL-1

2136 REVIEW ASIMAKOPOULOS AND TAYLOR Ann Thorac SurgADHESION MOLECULES AND CPB 1998;66:2135–44

ence of L-selectin on the leukocyte surface reflects pre-vious leukocyte activation. The shedding of L-selectin is apotential antiinflammatory control mechanism that ren-ders the leukocyte less adhesive. In any case, the degreeof L-selectin expression on the leukocyte serves as a goodmarker of activation.

The effect of CPB on the expression of L-selectin hasbeen investigated in a number of clinical and experimen-tal trials (Tables 2 to 4). In all these studies, expression ofadhesion molecules on leukocytes and platelets wasdetermined by immunofluorescence staining and flowcytometry. The values of L-selectin expression, as forother adhesion molecules, were expressed as the ratio ofthe mean fluorescence intensity, in arbitrary units, tononspecific background fluorescence.

Leukocyte surface expression of L-selectin was shownto increase [29] or remain unchanged during CPB [30–32]. Downregulation of neutrophil L-selectin was repro-duced in a dog model of CPB, but was not observed in acontrol group of animals that underwent thoracotomyand aortic cannulation without CPB [33].

Several potential antiinflammatory strategies havebeen studied in groups of cardiac surgical patients, usingL-selectin as a marker of inflammation. Heparin coatingof the bypass circuit, cooling, leukocyte filters, and treat-ment with soluble complement receptor 1 have eachdisplayed inconsistent and usually unconvincing effec-tiveness in influencing leukocyte L-selectin expressionduring CPB (Tables 2 to 4) [14, 15, 34–38].

The results of the above studies are in reality lessconflicting than they appear to be. As the expression ofL-selectin on cell surface increases and subsequentlydecreases during leukocyte activation, it is likely thatdifferent investigators “caught” the leukocytes at differ-ent stages of activation. Furthermore, the profile of leu-kocyte L-selectin expression may be affected by therelease of L-selectin-rich neutrophils from bone marrowduring normothermic CPB [39].

P-SelectinP-selectin is a glycoprotein that is stored intracellularly ina-granules of resting platelets and in the Weibel-Paladebodies of endothelial cells and can rapidly reach the cellsurface upon activation [40, 41]. P-selectin supports bind-ing of leukocytes to platelets and endothelial cells [42, 43].The expression of P-selectin may be induced by theproinflammatory cytokines IL-1 and TNF and declinessignificantly within minutes after activation [44]. There isevidence that P-selectin participates in neutrophil-mediated cardiac tissue injury caused by myocardialischemia [45, 46] and that neutralization of P-selectinresults in better recovery of cardiac function after aperiod of ischemia [46, 47]. Blockade of L- and P-selectins, with the oligosaccharide fucoidin, resulted inbetter recovery of left ventricular function, coronaryblood flow, and myocardial oxygen consumption after 2hours of cold cardioplegic ischemia in a model of isolatedblood-perfused lamb heart [47].

Changes in platelets, such as degranulation and func-tion defect, are known to occur during CPB [48]. Despite

the existence of evidence that the platelet function defectis related to a lack of extrinsic platelet agonists [49], somedegree of platelet activation is expected to occur duringCPB, resulting in upregulation of P-selectin on plateletsurface. P-selectin expression on platelets was shown toincrease early [34, 50], whereas soluble P-selectin plasmaconcentrations were increased toward the end of CPB inadult and pediatric patients [51, 52]. Aprotinin and theadenosine regulator acadesin did not affect platelet sur-face P-selectin expression in two other studies [53, 54].Overall, trials investigating P-selectin during CPB con-firm the development of detectable platelet activation.

E-SelectinE-selectin (ELAM-1) is transiently expressed on activatedendothelium and has been shown to support the adhe-sion of most leukocyte groups. It mediates neutrophiladhesion distinct from that mediated through integrinsand, like L-selectin, it functions at an early stage ofneutrophil binding to endothelium [55]. Due to its mini-mal expression on resting endothelial cells, increases ofE-selectin on endothelium and of its soluble form arevery good markers of endothelial activation [56].

During CPB, soluble E-selectin concentrations fail toincrease significantly above baseline [51, 57–59], althoughin 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 detectableplasma levels during CPB does not exclude E-selectinupregulation on endothelial cell surface and therefore, itdoes not mean that CPB does not cause endothelialactivation. The fact that E-selectin is not detectable inplasma during CPB could simply mean that it is “con-sumed” by activated leukocytes. One study of pediatricpatients revealed that E-selectin mRNA induction occursin cardiac and noncardiac tissues during CPB [60]. Futurestudies of E-selectin endothelial cell expression areneeded to investigate the timing and the extent of endo-thelial activation during cardiac operations.

Integrins

Integrins comprise the largest group of adhesion recep-tors and are found on most cell types, including leuko-cytes. They are transmembrane cell-surface proteins thatrespond to signals of cellular activation, and mediatetheir function by binding to specific ligands. Each inte-grin contains a noncovalently associated a and b chain,with characteristic structure [61]. Integrins are classifiedinto subgroups based on the b chain. Table 5 shows themembers of the integrin family that are expressed onleukocytes.

After leukocyte activation and rolling on the endothe-lium by means of selectin expression, binding of inte-grins to their endothelial ligands regulate many leuko-cyte responses including firm adhesion to endothelium,migration into tissues, degranulation, and phagocytosis[62]. The following paragraphs discuss the effects of realand simulated CPB on the most commonly investigatedleukocyte integrins.

2137Ann Thorac Surg REVIEW ASIMAKOPOULOS AND TAYLOR1998;66:2135–44 ADHESION MOLECULES AND CPB

Table 2. Adhesion Molecules in Humans During Cardiopulmonary Bypass

First Author, Year[Reference] Patient Groups Duration Cell Type L-sel Sol. E-sel P-sel b2(CD18) aL(CD11a) aM(CD11b) aX(CD11c)

Galinanes, 1996 [30] Adults, CABG 48 h Neutrophils 7 — — 2 at 24 hrs — 2 at 2 h 2 at 2 hLe Deist, 1995 [32] Adults, warm(33°C) vs cold(27°C) CPB 30 min Neutrophils 7 both

groups— — — 7 both

groups1 warm gr.5 min on CPB

1 warm group5 min on CPB

Moen, 1997 [34] Adults, heparin coated vs uncoated CPBcircuit

10 minprotamin

Neutrophils 2 uncoated — — 1 uncoated — 1 uncoated 1 uncoated

Monocytes 2 uncoated — — 1 uncoated 1 uncoated 1 uncoatedPlatelets — — 1both gr. — — —

Boldt, 1995 [57] Children vs adults 48 h — — 2 children — — — — —Cremer, 1996 [59] Adults, elective vs unstable patients 72 h — — 7 both groups — — — — —Ernofsson, 1996 [71] Adults, heparin coated vs uncoated CPB

circuit20 h Neutrophils — — — — — 1 both groups 1 both groups

Monocytes — — — — — 1 both groups 1 both groupsGillinov, 1993 [66] Adults, membrane vs bubble oxygenator 24 h Neutrophils — — — 1 on CPB

bothgroups

— 1 on CPB bothgroups

—

Takala, 1996 [74] Adults, CABG 72 h Neutrophils — — — — — 1 2 h post —Monocytes — — — — — 1 2 h post —

Weerwind, 1995 [15] Adults, heparin coated vs uncoated CPBcircuit

24 h — — 1 at 12 hrs bothgroups

— — — — —

Le Deist, 1996 [31] Adults, mixed pathology 30 min Neutrophils 7 — — — 7 1 15 min onCPB

1 15 min onCPB

Wahba, 1996 [54] Adults, aprotinin vs control 6 h Platelets — — 2 1hr CPBbothgroups

— — — —

Boldt, 1995 [58] Adults, aprotinin vs control 24 h — — 7 both groups — — — — —Komai, 1994 [52] Children, high vs low pulmonary blood flow 24 h — — — (soluble)1

bothgroups

— — — —

McBride, 1995 [29] Adults, CABG 24 h Neutrophils 1 on CPB — — 1 on CPB — 1 end CPB —Monocytes 1 — — 2 1 —Lymphocytes 1 — — 2 2 —

Hill, 1994 [72] Adults, methylprednisol vs control 24 h Neutrophils — — — — 7 bothgroups

1 control7 steroids

7 both groups

Mathew, 1995 [53] Adults, acadesine vs placebo 18 h Neutrophils — — — — 7 both gr. 1 placebo early —Monocytes — — — 1 both gr. 1 placebo late —Platelets — — 1 both gr. —

Menasche, 1995 [51] Adults, warm (32°C) vs cold (26°C) CPB 30 min — — 2 both groups 1 both gr.(soluble)

— — — —

Rinder, 1992 [73] Adults 18 h Neutrophils — — — — — 1 on CPB —Monocytes — — — — — 1 2 h post-CPB —Platelets — — 1 on CPB — — — —

Rinder, 1994 [50] Children, cyanotic vs noncyanotic disease 2 h Neutrophils — — — — — 1 on CPB —Monocytes — — — — — 1 1 h post-CPB —Platelets — — 1 on CPB — — — —

Sawa, 1995 [22] Adults, nafamostat vs control 12 h Neutrophils — — — 1 on CPB — — —

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b2-IntegrinsThe b2-integrin group, also known as the leukocyteintegrins, consists of LFA-1 (CD11a/CD18 or aLb2),MAC-1 (CD11b/CD18 or aMb2), 150,95 (CD11c/CD18 oraXb2), and aDb2 (Table 5). The aDb2 integrin appears tobe specific to monocytes. It has not yet been investigatedin patients undergoing cardiac operation and will not bediscussed any further in this article. The expression ofb2-integrins is confined to leukocytes and in particular,Mac-1 and LFA-1 are incriminated in playing an impor-tant role in the pathophysiologic mechanisms associatedwith the inflammatory response [63]. Their role in neu-trophil adhesion and transmigration are regarded ascomplementary, although in a model of the recentlydeveloped Mac-1-deficient mouse, Mac-1 was shown toplay a critical role in neutrophil binding to fibrinogenand neutrophil degranulation, whereas neutrophil trans-migration was shown to be more dependent on LFA-1[64]. After leukocyte activation, Mac-1 is rapidly mobi-

lized from intracellular secretory granules to the neutro-phil surface through chemoattractant stimulated gran-ule–plasma membrane fusion. However, the increase ofintegrin concentration in the leukocyte membrane is notnecessarily sufficient for increased adhesiveness [55].Rather than by the total population of activated Mac-1and LFA-1 molecules, ligand binding is mediated byhighly adhesive subpopulations [65].

The b2-integrins are the most extensively investigatedintegrin group in patients undergoing CPB (Tables 2 to4). Their concentration on the leukocyte membrane dur-ing and after cardiac operation can be assessed by usingmonoclonal antibodies against individual chains andimmunofluorescence analysis.

b2 Chain (CD18)Changes in the expression of the common b2 (CD18)chain can be attributable to upregulation in any of thedifferent ab2 combinations.

Table 3. Adhesion Molecules in Models of Simulated Cardiopulmonary Bypass

First author, Year[Reference No.] Duration Experiment Cell Type L-sel P-sel aL(CD11a) aM(CD11b) aX(CD11c)

Finn, 1996 [36] 120 min Solublecomplementreceptor 1versus control

Neutrophils 2 bothgroups

— 7 bothgroups

1 both groups —

Hogevold, 1997 [35] 48 h Heparin coatedversus uncoated

NeutrophilsMonocytes

2 bothgroups

— — 1 both groups 1 only incontrolgroup

Thurlow, 1995 [37] 60 min LG6 versus AV6leukocyte filter

? 2 bothgroups

— 1 AV6 7 LG67 AV6

2 LG6

El Habbal, 1995 [38] 120 min Cold (17°C, 25°C)versus warm(37°C)

Neutrophils 2 bothgroups

— — 1 all groups.Higher in 17°C

group

—

Kappelmayer, 1993 [75] 120 min Cold (28°C) versuswarm (37°C)

Neutrophils — — — 1 both groups —

Monocytes 1 only coldLymphocytes 7 both groups

Rinder, 1995 [10] 90 min Anti-human C5mAb versuscontrol

NeutrophilsPlatelets

— 1 incontrol

— 1 only incontrolgroup

—

1 5 increased; 2 5 decreased; 7 5 unchanged.

Table 4. Adhesion Molecules During Cardiopulmonary Bypass in Animals

First Author, Year Species Duration Groups Cell Type L-sel b2 (CD18)

Dreyer, 1995 [33] Dogs 3 h CPB vs opened chestwithout CPB

Neutrophils 2 only inCPB group

1 only in CPBgroup

Zehr, 1995 [68] Pigs 2 h SDZ HUL-412 (inhibitsPAF) versus control

Neutrophils — 1 in both groups

Gillinov, 1994 [67] Dogs 2 h C3 deficient dog versuscontrol

Neutrophils — 1 only in controlgroup

Gillinov, 1994 [69] Pigs 2 h NPC 15669 (blocksMac-1 upregulation)

Neutrophils — 1 in both groupsHigher incontrol group

Redmond, 1993[70]

Pigs 2 h Heparin coated versusuncoated circuit

Neutrophils — 1 in both groups

1 5 increased; 2 5 decreased; CPB 5 cardiopulmonary bypass; PAF 5 platelet activation factor.


Several in vivo human and animal studies demon-strated that the neutrophil expression of b2 increasesduring CPB, reaching a peak at 60 minutes [22, 29, 33,66–69]. Heparin coating of the bypass circuit suppressedb2 upregulation in human [34] but not in pig neutrophils[70]. Activation of the complement component C3 ap-pears to affect neutrophil b2 upregulation, as it wasshown in a group of C3-deficient dogs undergoing CPB[67]. One study demonstrated decrease of b2 on lympho-cytes and monocytes [29].

aM Chain (CD11b)Monoclonal antibodies against the aM chain of Mac-1have been commercially available for several years andhave been used extensively in studies investigating leu-kocyte activation in cardiac surgical patients. Similarly tob2, aM (CD11b) is upregulated on neutrophils andmonocytes, reaching its peak expression within 4 hoursafter discontinuation of CPB on neutrophils and after 24hours on monocytes [29, 31, 32, 34, 50, 53, 71–75].

The use of aprotinin, acadesin, steroids, and hypother-mia appears to reduce monocyte and neutrophil expres-sion of aM in human studies [32, 53, 72, 76]. The abovedescriptive studies have established Mac-1 as a marker ofleukocyte activation during CPB. As mentioned before,however, the effect of leukocyte adhesion and also theclinical relevance of Mac-1 upregulation do not necessar-ily correlate with the increased presence of the moleculeon leukocyte surface. Thus, in spite of being the moststudied member of the b2-integrin family, the apparentvariability of the above findings illustrates the impor-tance of further studies, particularly incorporating actualchanges in ligand-binding ability, to better understandwhat contribution the leukocyte integrins make towardpostoperative complications of CPB.

aX Chain (CD11c)The activation of the integrin subunit aX (CD11c) followspatterns that are similar to aM. It showed increasedexpression on neutrophils and monocytes during andshortly 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 tosuppress aX expression in an experimental CPB model[35].

aL Chain (CD11a)Despite its well-investigated significance in leukocyteadhesion, aL (CD11a) does not display increased expres-sion on neutrophils during real [31, 32, 53, 72] or simu-lated CPB [36]. The expression of aL was significantlyincreased on monocytes in one trial [72]. The specificmechanisms responsible for the difference in aL expres-sion between neutrophils and monocytes are not known.

In summary, the results of the above studies suggestthat b2 integrins increase their expression on the surfaceof leukocytes, in patients undergoing CPB. In particular,upregulation of Mac-1 can be regarded as a good markerof leukocyte activation, although whether this phenom-enon is related solely to CPB, and the extent to whichleukocyte–endothelial interaction is altered, are ques-tions yet to be clarified.

b1-IntegrinsThe b1-integrins, also known as very late antigen (VLA)integrins, are expressed on a wide number of cells. Theyshare the same b chain and are distinguished throughdifferent subunits. Leukocytes express those b1-integrinsthat contain the subunits a1, a2, a3, a4, a5, and a6 [77].The integrin a4b1 (VLA-4 or CD49d) is of particularimportance in leukocyte–endothelial cell interaction due

Table 5. Integrins Expressed on Leukocytes

b-Chain a-ChainOther

Names Cell Type Ligands

aL (CD11a) LFA-1 Neutrophils, monocytes,lymphocytes

ICAM-1, ICAM-2, ICAM-3, ICAM-4

b2aM (CD11b) MAC-1 Neutrophils, monocytes Complement iC3b, ICAM-1, ICAM-2, collagen,

Factor X, coagulation proteins, fibrinogenaX (CD11c) 150,95 Neutrophils, monocytes Complement iC3b, fibrinogenaD Macrophages ICAM-3a1 VLA-1 Collagen, laminina2 VLA-2 Collagena3 VLA-3 Fibronectin, collagen, laminin, epiligrin

b1 Monocytes, lymphocytesa4 VLA-4 VCAM-1, fibronectina5 VLA-5 Fibronectina6 VLA-6 Laminin

b3—— aV Fibronectin, vitronectinb3a—— a2b Platelets Fibrinogen

b7a4 Lymphocytes, eosinophils,

intraepithelial T cellsMAdCAM-1

aE E-cadherin

{{{

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to its ability to interact with the endothelial VCAM-1ligand. VLA-4 can mediate selectin-independent rollingof lymphocytes and eosinophils, but is not expressed onneutrophils [78]. It serves as a leukocyte receptor tosegments of fibronectin in inflamed tissues [79] and thereis evidence that it supports TNF-a-mediated leukocyteinfiltration in cardiac allografts in rats [80].

Preliminary results from our laboratory on the expres-sion of b1-integrins on leukocyte surface suggest that nosignificant increase occurs during and up to 6 days afterCPB.

Immunoglobulin Superfamily

Adhesion molecules of the immunoglobulin superfamilyare transmembrane glycoproteins that are expressedmainly by endothelial cells, which participate in celladhesion by serving as ligands for certain leukocyteintegrins. Intracellular adhesion molecule-1 (ICAM-1) isone of the primary ligands for the b2-integrins, whereasVCAM-1 binds to a4b1. ICAM-1 and VCAM-1 increasetheir expression after endothelial cell P-selectin has beenshed and can remain upregulated for days [78].

Preoperative plasma levels of soluble ICAM-1 hasbeen shown to vary widely in cardiac surgical patients.Levels decrease immediately after cross-clamping [15, 57,58], possibly attributable to binding on activated leuko-cytes, to increase significantly 24 hours postoperatively[15, 81]. Some investigators did not demonstrate anyincrease 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 orbubble oxygenator [66] failed to influence plasma con-centration of ICAM-1 during CPB. Soluble VCAM-1displayed raised plasma levels at 24 hours after CPB inone study on adult patients [58] and decreased levelsintraoperatively in a pediatric study [57] performed bythe same investigators.

The significance of the presence of soluble endothelialadhesion molecules in plasma is still not fully known.Two recent publications suggested that there is somecorrelation between high plasma levels of ICAM-1 andthe risk of atherosclerosis and ischemic heart disease [82,83], but the role of this molecule in acute situations, suchas CPB, is less well investigated. In the absence of studiesexamining endothelial expression of these ligands duringCPB, it is difficult to understand what significance alteredlevels of plasma ICAM-1 and VCAM-1 could represent.

Conclusions

Adhesion molecules have established their role as im-portant inflammatory mediators in studies of the inflam-matory response to CPB. They have been increasingly thefocus of investigation and have been shown to undergochanges of different extents during and after CPB. How-ever, there are still several gaps in our knowledge.Although the upregulation patterns of the neutrophil b2integrins are becoming clear, the role of the b1 integrinsis still not defined. Furthermore, changes on lymphocytes

and monocytes, which could predominately affect thepatients’ postoperative course, are less well known. Themajority of the studies reviewed in the previous para-graphs based their results on findings affecting changeson neutrophils. Monocytes, however, comprise a groupof leukocytes that have recently attracted considerableattention in relation to their role in atherosclerosis andacute inflammation. Monocytes display a high level ofadhesion to unstimulated, and also IL-1a and TNF-astimulated endothelial cells. It appears likely that mole-cules from all three adhesion molecule families areimportant for the interaction of monocytes with endothe-lium [84]. As there is also the suggestion that somedegree of monocyte activation occurs in response to CPB[85], it is likely that the monocyte–endothelial cell inter-action will be a future area of research in the cardiacsurgical patient.

One should also bear in mind that “upregulation” ofadhesion molecules does not equal “increased adhe-sion.” The often contradictory nature of reports concern-ing changes in surface expression of leukocyte adhesionmolecules in CPB underlines the need to understandbetter whether such changes actually correlate with al-tered ligand-binding ability. The specific contribution ofselectins and b2 integrins to the migration of leukocytesinto tissues during CPB, also needs clarification.

One of the limitations affecting almost all studiesinvestigating the inflammatory response to CPB is thatthe patient populations are small and include uncompli-cated cases. Because increased cell adhesiveness is afeature of activated leukocytes and endothelial cells, it islikely that adhesion molecules reach significantly higherlevels of expression during multiple organ failure thanduring uncomplicated postoperative recovery.

Greater understanding of the specific order of eventsduring the inflammatory response will make the devel-opment of preventive and therapeutic strategies possible.Several trials have already tested the efficacy of tech-niques and pharmacologic agents that inhibit inflamma-tion. Hypothermia and heparin coating of the bypasscircuit are two widely investigated methods of bluntingthe CPB-induced inflammatory response. The mecha-nism of their action during CPB and ischemia–reperfusion is regarded as nonspecific, although thespecific blocking effect of hypothermia on the expressionof individual adhesion molecules is also being clarified[86].

Nonspecific inhibitors, such as corticosteroids, reduceplasma levels of the complement component C5a and ofthe cytokines IL-1b, IL-6, and IL-8 [20, 23]. Corticoste-roids also suppress the leukocyte expression of the inte-grin aM(CD11b) [72]. Whether the effect on integrins is aspecific phenomenon, or whether it is the result of thenonspecific suppression of neutrophil activation, is stillnot clear. A recently published in vitro study suggeststhat corticosteroids exert specific actions on expression ofneutrophil L-selectin and b2 (CD18), mediated throughcorticosteroid receptors [87].

Aprotinin is a protease inhibitor that was used in anumber of inflammatory conditions before its effect in


reducing bleeding in patients undergoing CPB was dis-covered [88]. Aprotinin is known to reduce TNF, IL-8, andCD11b expression during CPB [76, 89]. Its clinical signif-icance as an inhibitor of CPB-related inflammation maybe clarified after the completion of ongoing trials.

A new promising area of specific inhibition of inflam-matory mediators involves the use of blocking monoclo-nal antibodies. As mentioned before, recent experimentsdemonstrated significant reduction in reperfusion injuryto the myocardium of animals subjected to myocardialischemia and reperfusion and treated with monoclonalantibodies against various adhesion molecules [27]. Theday when antibodies will be used in humans does notappear to be very far off. Finally, it is possible thatinformation gained through studying the process of in-flammation using the cardiac surgical patient as a modelwill provide us with knowledge that may be applied toseveral other medical fields where inflammatory re-sponse, although unrelated to CPB, has similarly adverseconsequences.

We thank R. Clive Landis, PhD, for his comments on themanuscript. George Asimakopoulos is supported by the BritishHeart Foundation.

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Effects of cardiopulmonary bypass on leukocyte and endothelial adhesion molecules