6poj 2 BOJHOCAHHTETCKJ1fTPErJ1ElI Crpalla 139 UDC616.83 I-(105.4:576.52
ORIGINAL ARTICLES
Cerebrospinal fluid and plasma
concentration of soluble intercellular
adhesion molecule!, vascular cell adhesion
molecule! and endothelial leukocyte adhesion
molecule in patients with acute ischemic
brain disease
Vesna Sclakovic*, MJodrag
Colic·,
Marina Jovanovic·, Ranko Raiccvict, Aco Jovicic'Military Medical Academy, *Institu{c of Medical Research, 'Clinic of Neurology, Belgrade
Backgrollnd. Leukocytemigrflliollimo tlie ischemic area is a complex process, COIl/rolled byadheJioll molecules (AM);11 leukocytes C1nd endothelium, bymigratory capacity of leu-kocytes and the presence oj hemotaxicClgetHSin the fissue. In111is researchitlVassupposed that illthe blood and cerebrospinal fluid (CSF) of patiefllsill theGClIlephase oj ischemic brain disease (/DD) there were relevalll changes;11 theCOI/Cellifatioll of soluble AM (51-CAM-), sVCAM· } and sE·selectin), that could Jlm'e been the itulictllors oj the imellsity oj damaging processes ill cemraillervolls system (CNS). Methods, The study illdllded45 180 patiellls, 15witli trallsient ischemic auack (TlA), /5witli reversible ischemicarrack(RIA),
wuJ 15with brain i,ljarction(81), oj borJl sexes, mea"age 66±7,Comrol group cOl/sisred of 15 patients with radicular lesions of discal origin, subjected10diagnostic radiculography, without the signs of interruptioll ill tht! passage of CSF. Challges of selected biochemical parameters were determined illallpatiellts illJrame72hours shleetheocc:urellceoj au is-chemic episode. Conee1l1rations of soluble AM were determined ill plasma and CSF by ELISA. Toral Illlmber oj leukocytes (TNL) in peripheral blood was determined by hemato-logical analyzer. Res"lls. The results sllOlI'ed tlwt dllring theftrst 72 Jlrs ofIBDsignificant i"cremes occuredill TNL and that the increase was progressive compared to tile severe-ness oj the disease. Signijic(ul1 increase oj soluble AM eOflcell1ratioll was shown ill plasma ofIBDpaziems.The increaseWa.Ihighest in 81,samen-hal/owerinRIA and the (owesl illTJA patiems compared10 rile control. III CSF concentrations of sleAM-I, sVCAM-1 and sE-se/eeIiI/ denuJIlstmred similar increasi"g tre"d as in plasma.COllclusio".TNL as well as rile solubleAM collcemrOliolls illplasma andeSF, were inrreasedduring lile (lcute IJ3Dphase and progressil'l' ill relarion to the severcness of the disease, so that they might IUlI'c bee" the indicators of eNS inflammatory refletioll imensity. Furthermore, the results indicated tlleir rotei/l180par/wgellesis alJ(l offered Ille possibility of researclling flie applicarjoll of antago-nists (lIuVor (lctivit)' modulators ofsome ojthemin IBD therapy.
Key words: brain ischemia; blood; cerebrospinal fluid; leukocytes; intercellular adhesion moleculc41;vascular cell adhesion molecule-I; E-selectin; inflammation.
Introduction
Most recent studies indicme the existence andt:1C de-velopmenl of inflammJtory reaclion during ischemic brain
discase (180). Two bJsic processes .Ire responsible for the development of inOammatory reaction in eNS during ischemia: local reaction of brain cells and leukocyte migra-tion from circulamigra-tion into the ischemic parenchyma (1-7).
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Local reaction of brain cells occurs during a few minutes (neurons and microglia), or hours (astrocytcs) after ische-mia. Atthe neuron level the cClllral event is the increase of intracellular concentration of Ca2+. uncontrolled release of
neurotransmilters. increased production of free radicals. lipid mediators. derivatives of arachidonic acid, acidosis, etc. The process ofexilotoxicity leads to cellular death, and to the damages of the surrounding neurons, glial and endo-thelial cells (8-12). Furthermore. microglia activated with ischemia andastrocylcsbylhe secretion of large amounlS of citotoxic mediators playa significant role in additional neu-ronal and endothelial cell damage as well as in the devel-opmcnt of the second phase of inflammatory reaction (12-14). Pharmacological modulation of microglia effects might contribute(Q thc improvement of structural and
fune-tiona I outcome of brain ischemia.
The second phase of inflammatory reaction develop-ment includes infiltration of peripheral inflammatory cells (neutrophils, monocytes and lymphocytes) in ischemic pa-renchyma. Leukocyte migralion into the ischemic area is a complex process. controlled by adhesion molecules in leu-kocytes and endothclium, by migratory c3pacity of leuko-cytes and the presence of hemotaxic agents in the tissue(3. 15-18). Human data are scarce: a high number of radio-labeled polymorphonuclear leukocyles that occur in slightly perfused brain areas 6 to 12 hours after the ictus. and au-topsy show intense leukocyte infiltration of brain paren-chyma 2103 days aflcr Ihe stroke(I.3). Experimental stud-ies suggest that the carly occurence of leukocytes in 10 the brain parenchyma is independent from the presence of ne-crosis, which leads to the hypothesis that these cells havc a role in the progression from ischemia to brain infarction (3. 15).
The occurence of leukocytes in the ischemic area is a multistep process (4, 5). They marginate in the venu!es, then adhere to endothelial cells, and finally migrme into the brain parenChyma. During each of these steps, their functions are regulmed by the inflammation-related molecules that are be-ing produced soon after the onset of cerebral ischemia. The signuls mediming Ihe entry of leukocytes into the ischemic area have not yet been completely unfolded, but a number of clues suggest thal cytokines playa significant role in this process. Cytokincs may have various functions during cere-bral ischemia: they can attract leukocytes and stimulate syn-thesis of the adhesion molecules in leukocytes, endothelial cells. and other cells. thus promoting the inflammatory re-sponse of the damaged cerebr.1 lissue (3. 5, 7. 18).
Migration of peripheral blood lcukocytes requires prior adhesion to cerebral endothelial cells, which is medi-ated by thc adhesion molecules on Ihe surface of cerebral endotheli.l cells and peripheral blood leukocytes (3. 4. 16). In cerebral ischemia at least3 different adhesion molecules have merited special interest so far: intercellular adhesion molecule I (ICAM-I), responsible for the adhesion of mononuclear cells and granulocytes. vascular cell adhesion molecule 1 (VCAM-l) which predominantly mcdiatcs
ad-hesion of mOtlocytes. and endothelial leukocyle adad-hesion molecule (E-selectin), expressed only by cndothelial cells and facilitates adhesion of monocyte!) and granulocytcs (3. 4.7. 16-22).
In physiologic conditions. adhesion molecules are scarcely expressed 011 cell surface. but their expression might be induced by diverse palhophysiological processes (3. 4. 18-22). Circul.ting. soluble forms of the molecules are formed in the proteolytic release of their extracellular domains (16-18). Raised levels of soluble adhesion mole-cules have beer. described in various inflammatory and ma-lignant diseases or infeclions, and it has been suggested that they were markers of dise.ses .clivity (4. 16. 18.20.22).
The exact pathogenic role of the mentioned adhesion molecules during brain ischemia in human has still not been completely defincd. Previous studies do not offer data whether the expression of these adhesion molecules and concentration of their soluble forms is related to clinical disorders and recovering of the patients with IBD. Besidcs, there are no data on the dynamics of the adhesion molecules expression in patients with the different types of IBO. The question of differences between soluble adhesion molecule level in plasma and CSF in patients during the initial phase of IBO remains to be clarified. Responses to the opened questions could be significantly involved intO the funher therapy strategy of ISD directed at inflammatory reaction. but could also be important for clinical practice in determin-ing the severeness of the disease and the recovery durdetermin-ing the IDD initial phase.
In this research it was supposed that there were rele· vant changes in the concentration of soluble adhesion mole-cules (sICAM-1. sVCAM-1 and sE-seleclin) in Ihe blood and cerebrospinal fluid of patients in the acute phase of IBO. Those changes were the indicators of the intcnsity of damaging processes in eNS. The concentration of soluble adhesion molecules in plasma and cerebrospinal fluid. as well as the tot.1 number of leukocytes io peripheral blood was monitored in IBD patienls in framc 72 hours since the formation of an ischemic episode.
Methods
Gpoj 2 BOJHOCAHMTETCKM nPErJlE.1\ Crpalla 141
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fig. 2 - Concentration of sICAM-l. sYCAM-I and sE-selcctin in plasma of patients with br<lin infarction (BI),rcvcr~iblc
ischemic attack (RIA). and transient ischemic attack (TIA)
dur-ing the first 72 hours after insults. Values;:Ifegivcn as meant
SD. "'(p<0.05), "(p<O.OI). "'''(1'<0.001)- signific:mcc10
cor-responding control values.
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Fig.J - Touli number of leukocytes(x109/1) in peripheral
blood ofpatienLs with brain infarction (81), reversible ischemic auack (RIA), and transient ischemic attack (TIA) during lhe
first 72 hours after insults. Values arc given as lllcan±SD.
*(p<0.05), "(1'<0.01). ***(p<O.OO 1)- ;ignificance to
corre-sponding control values,
693.84
±
91.12 ngiml for sfCAM-I. (p<O.ool); for sVCAM-I was 687.24±
156.96 ngim!. (p<O.ool); and for sE-seleClin was 51.13±17.57 ng/ml. (p<O.ool compared to Ihe conllol). (Figure 2).The results showed that during the first 72 hours of ISO the significant increase in leukocytc number in periph-eral blood occured being progressivc according to the
severeness of lhe disease. In 81 patients valucs were 9.29±
1.89 x 10'/1 . (1'<0.00 I compared to the conllol). (Figure I).
The results showed significJI1l increase of sICAM-I,
sVCAM~l and sE·selectin conccntration in plasma of ISO
patients, while the increase W;,l~ the highest in 81 patients,
somewhat lower in RIA patients. and the lowest in TIA pa-tients. Plasma concentration of sAM in 81 patients was
Resulls
In all IBO patients the level of soluble adhesion mole-cules. as well as the lOla Inumber of leukocytes was
deter-mined within the 72 hours since the occurence of ischemic
episode.
COOirol group consisled of 15 palients of adequate age and gender. with radicular lesions of discal origin (Ium· basacral area). subjecled 10 diagnostic radiculography.
without the imcrruptlon signs in the passage of
cerebrospi-nal Ouid. Only Ihe patienLs with the abrupt development of
motor deficit without pain and thus without 3nalgesic Iher-apy "ere included in lhe study. and cytochemical and
im-munochemical findings in CSF wcre within physiological limits. Patients with intensive radicular pains who used non-steroidal analgesics. as well as patients with anamnesis and
clinical data on current inflammatory, neurodegeneralive
and psychiatric diseascs were excluded from the study.
In all Ihe teMed patients blood and CSF samples were taken in the period of 810 10 AM. before any Iherapy was
given. Peripheral vein blood samples (3 ml) were collected
ill heparinized glasses at low temperatures. Plasma was
se-lected by Ihe centrifugation of the whole blood during 15
minat3000 rpm,at+4°C.
CSF samples (I 1111) were laken during (he lumbar
puncture illlo the glasses held on ice (+4°C). Plasma and CSF samples were kept 31 _70°C until the biochemical
:mulyses. Theun:Jly~cs were performed within 6 month ancr
the samples colection.
Concenlr:llions of soluble adhesion molecules
sICAM-I, sVCAM-1 and sE-seleclin were determined in pla~ma
and CSF by ELISA (R&D Systems Europe. Abingdon.
UK). Plnsma samples were diluted with commercial
dilu-ents for detecling sICAM-I in ratio 1:80, for s-VCAM-I
and~E-sclectin in ratio I:50, and all samples of CSF in r:Hio
I:l. Total numbers of leukocytes in peripheral blood were
determined by hematological analyzer Technicon H-I. All
samples were analyzed in duplicate, and the mean value was calculated. lnlraessay and interessay precision (coefficient
of variatIon) for all of Ihese assay were <5.9% and <10.2%.
respectively.
CTjlalla 142 BOJHOCAHI1TETCKI1 nPErJlE.ll 6poj 2 ness and its duration. The efforts of contemporary aCUle
ISO therapy are directed towards brain tissue protection be-fore the development of irreversible damage occurs. Nu-merous studies showed lhat reversible ischemic stadium gradually progressed towards infarction. CCnlral zone, with highly compromised blood flow is surrounded by the zone wilh milder ischemic level (penumbra), where electrical ac-tivity is damaged, but cell metabolism and neuron viability are partially preserved, making Ihe final outcome in this zonc is variable and dependent on numerous factors that af-fect time and spatial propagation of damaging and/or de-fense reaclions after the establishing of lhe reperfusion. Possible lhcrapy is directed to words the ischemic damage area because il is likely tocxpect that, due to the partially present cirCUlation, the remedy reaches the largeled place. The volume of the infarction area, and consequently the clinicalISO outcome depend on the outcome of the penum-bra process (25-30).
During the last few years researches were directed
to-wards the inflammatory reaction in ischemic penumbra zone. It was demonstrated on the experimental model of ISD lhat this pathophysiological event was followed with rhe leukocyte infiltration inro the brain parenchyma and the brain edema development (IS. 31-34).
Results obtained in this research showed thal in the acute brain ischemic period the important increase in number of leukocytes in the peripheral blood occured and that the increase was highest in patients with brain infarc-lion. The mechanisms leading to leukocyte migration through the blood-brain barrier into the central nervous system, however, remained incompletely established. The inflammatory process was, thought, to be initiated by lo-cally produced proinOammatory cytokines such as TNFa, IL-IP. IL-6 and lFNy (4, 5, 16-18,21). These cytokines have the capacity to induce or enhance the expression of several adhesion molecules including ICAM-1. YCAM-I. and E-selectin at least in the cultured brain vascular endo-thelium. Furthermore, in viTro stimulation of aSITOcytes and endothelial cells by prointlammatory cytokines re-sulted in the expression of chemokines - the low-moleculor-weight proteins specializ~d 10 recruit specific subpopulalions of leukocytes[Q the areas of inflammation
(3-5. 35).
There are numerous mechanisms of damaging tt-e is-chemic parenChyma by leukocytes: they may clog linle blood vessels and impede complete recuperation of blood flow in ischemic area after the establishing of reperfusion. Furthermore. by the release of cylotoxic enzymes, reactive oxidative species. nitric oxide and products of phospholipid cascade leukocyles could cause disturbance of brain artery vasoreactivity and contribute to the blood-brain barrier damage and the formation of brain postischemic edema. Also. the induced disorder of endothelial cells and basal membrane integrity, might faciliw.te erythrocyte exit into the tissue, as well as hemorrhagic infarct transformation (/9,33,36-38).
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Fig. 3 - Concentration ofsleAM-I,sVCAM-l and sE-selectin inCSFof par;cntswith brain infarction (BJ), reversible ischemic attack (RIA), and transient ischemic attack (TtA)
dur-ing the first 72 hours after insults. Values are given as mean± SD. *(p<O.05). **(p<O.O0,***(p<O'()() 1)- significance to
cor-responding control values.
Physiopathologically. ischemia represents a metabolic disorder in brain functioning caused by the circulation re-duction thaI ends in morphological damages of neural ele-ments. Namely, lhe primary stimulus, which triggers a cas-cade of metabolic changes that end in nerve cell death, is the energetic crisis or the excessive (uncontrolled) depolari-zation (12,23-25).Change from reversible into irreversible neuron damage depends above all on rhe ische nic
severe-I'
i,
Discussion
"poj 2 BOJHOCAHHTETCKH IlPErJlE.l\ Grpalla 143
Endothelial cellsaClivmion as the consequence of brain ischemia, caused adhesion molecules expression, like leAM-I, VCAM-I and E-selcctin that were released into the circula· tion during the process of proteolysis. The results of recentill viJrostudies showed thatE~seleclin was similarly upregulated only transiently during the first hours. whereas immunoglobu· lin-tipe adhesion molecules (lCAM-1 and YCAM-I) were persistently expressed atcellular surfaces for at least 72 hours aftcr cytokine stimulation (4, 17, 18,22). This corresponded with the current concepts of the initial steps of inf1ammation: selectins were considered ro sustain the phenomenon of mar-ginalionand the initial light attachment of circulating leuko-cytes to activated microvascular endothelium. The immu-noglobulin-type adhesion molecules are particularly important for the subsequent firm altachment and transendorhelial mi-gration into the surrounding tissue(17-21).The results of this research showed significant increase of sICAM-I, sYCAM-I and sE-selectin concentr:uion in plasma and CSF of palients with brain infarction in the acute period of the disease. In pa-tients with RIA and TIA, there waS a signirtcam increase of sICAM-I and sYCAM-I concentration, but the values were lower than in the brain infarction. Besides, sE-selectin con-centralion in pmients with RIA and TIA was relevantly in-creased in plasma during first 72 hours after the ischemic at-tack. The obtained results pointed to different dynamics of changes in sICAM-l, sYCAM-I and sE-selectin concentrn-tion in plasma and CSF in the acute IBD phase in dependence
011 IBD severeness, proving that there was different level of innamrnatory reaction intensity duringIBD. Brain infarction, as the severest TBD form with the highest level of morpho-logical damages of brain parenchyma, has the most pro-nounced seconda.ry inOammation asitsconsequence. It was confimled in this research with the fact that the highest levels of all tcslcd soluble adhesion molecules in plasma and CSF were obtained in the Jcute phase in patients with brain infarc-tion.
The imponance of leukocyte/cerebral endothelial cells intcractions in regulating inflammatOry responses of ischcmic brain tissue was supported by following findings: a) the in-creased leukocytc infihrJtion in the brain during ische-mia/reperfusion was accompanied by the increased expression of adhes10n molecules 111 cerebral micro\lessels~ b) depletion of circulating neutrophils (Le. neutropenia) reduced the in-farction size and edema in various experimental models of cerebral ischemia; c) the administration of antibodies against leukocyte or endothelium expressed adhesion molecules in
experimenlJll animals before and after ischemia decreased the infarction size and brnin edema; d) transgenic ICAM-I-deficient mice were less susceptible to bmin ische-mia/reperfusion injury (39-45).
The time course of the expression of adhesion molecules and proinflammatory cytokines was similar and parallel to the time course of inflammatory cell infiltration in the ischemic brain. suggesting that this coordinated molecular mechanism was responsible for the innammaLOry response in cerebral ischcmia (30, 46). The exact mechanisms by which ischemia activated the expression ofICAM~I, YCAM-I and E-selectin are still not clear. However, a possible mediator of this re-sponse might have been thc nuclear factor kB (NF-kB) which played an important role in regulating the cytokine-induced transcription of endothelial adhesion molecules, and was acti-vated by various factors induced by ischemia(47-49). Alter-natively, the stimulation of adhesion molecule expression in cerebral cndothclial cells by ischemia arisen from the autocrine effects ofIL-I
a.
and platelet-activating factor, since both were shown to stimulate leukocyte adhesion and were secreted by peripheral endothelial cells exposed to ischemia (48,50).These secondary changes (inflammation) might have po-tentiated already existing neuronal damage,and also led to the further damage spread on the preserved neurons. Because there was a certain time latency between the formation of the primary and the secondary damage, il was expectable lhat ex-actly this data offered the possibility of therapy application that impeded the fonnation and the spreading of secondary damage. According to the mentioned, it was also expectable that the relation (balance) between proinflammatory and im-munoinductive (immunomodulatory) processes would deter-mine the direction of physiopathological events in the acute IBD phase.
According to the results obtained in this research, it can be concluded that: total number of leukocytes in the periph-eral blood, as well as the soluble adhesion molecules (sI-CAM-I, sYCAM-I and sE-selectin) levels in plasma and CSF, were increased during the acute ISD phase progres~
sively compared 10 the severeness of the disease. Thus it was concluded that they might have been the indicators of the in-flammatory eNSreaction intensity. Moreover, the results \n-dicated their role in IBD pathogenesis and offered the possi-bility of researching the application of antagonists and/or the activity modulator of some of them (leukocytes, ICAM-!, YCAM-I, E-selcctin) in IBD therapy.
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The paper was received on September 13,2002.
Apstrakt
Selakovic V, Colic M, Jovanovic M, Raicevic R, JovicicA. Vojnosanlt Pregl 2003; 60(2); 139-146.
KONCENTRACIJA SOLUBILNOG INTERCELULARNOG ADHEZIJSKOG MOLEKULA 1, VASKULARNOG CELlJSKOG ADHEZIJSKOG MOLEKULA 1 I
ENDOTELNOG LEUKOCITNOG ADHEZIJSKOG MOLEKULA U CEREBROSPINALNOJ TECNOSTI I PLAZMI BOLESNIKA SA AKUTNOM
ISHEMIJSKOM BOLESCU MOZGA
CTP3H3 146 BOJHOCAHHTETCKH nPErJIE.ll
ishemijski atak (TIA), 15 reverzibilni ishemijski atak (RIA) I 15 infarkt mozga (1M). Kontrolna grupa obuhvatila je 15 ispitanika sa radiksnim lezijama diskus-nog porekla, podvrgnutih dijagnostickoj radikulografiji, bez znakova smetnji u prolasku CST. Kod svih bolesnika odabrani biohemijski parametari odredivani su prvih 72 casa nakon nastanka epizode ishemije. Koncentracije solubilnih AM u plazmi i CST odredivane su pomoeu ELISA. Ukupan broj leukocita (UBL) u perifernoj krvi odredivan je pomoeu hematoloskog analizatora. Rezultati. Rezultati su pokazali da tokom prvih 72 casa IBM dolazi do znacajnog porasta UBL i to progresivno u odnosu na tezinu bolesti. Pokazan je i znacajan porast koncentracije solubilnih AM u plazmi bolesnika sa IBM, s tim sto je porast naj-veei kod bolesnika sa 1M, nesto nizi kod RIA i najnizi kod TIA u odnosu na kon-trolu. U CST koncentracije sICAM-1, sVCAM-1 i sE-selektina pokazuju slican porast kao u plazmi. Zakljucak. Moze se zakljuciti da su UBL, kao i koncen-tracije solubilnih AM u plazmi i CST, poveeani tokom akutne faze IBM i to pro-gresivno u odnosu na tezinu bolesti, tako da mogu biti pokazatelji intenziteta inflamacijske reakcije CNS-a. Pored toga, rezultati ukazuju na ulogu solubilnih AM u patogenezi IBM, sto otvara moguenost ispitivanja primene antagonista i/ili modulatora aktivnosti nekih od njih u terapiji IBM.
Epoj 2
K Ij u c n ere c i : mozak, ishemija; krv; cerebrospinalna tecnost; leukociti; adhezijski molekul-1, intercelularni; adhezijski molekul-1, celijski, vaskularni; E-selektin; zapaljenje.
Correspondence to: Vesna Selakovic, Vojnomedicinska akademija, lnstitut za I11cdicinska isrrazivanja, 11040 Beograd,
