Role of cell adhesion molecules in acute ischemic stroke
2011; King Faisal Specialist Hospital and Research Centre; Volume: 31; Issue: 4 Linguagem: Inglês
10.4103/0256-4947.83217
ISSN0975-4466
AutoresVišnja Supanc, Zrinka Biloglav, Vanja Bašić Kes, Vida Demarin,
Tópico(s)Neuroinflammation and Neurodegeneration Mechanisms
Resumooriginal articleRole of cell adhesion molecules in acute ischemic stroke Visnja Supanc, Zrinka Biloglav, Vanja Basic Kes, and Vida Demarin Visnja Supanc From the Department of Neurology, University Hospital Sestre Milosrdnice, Zagreb, Croatia , Zrinka Biloglav School of Public Health "Andrija Stampar, School of Medicine, University of Zagreb, Zagreb, Croatia , Vanja Basic Kes From the Department of Neurology, University Hospital Sestre Milosrdnice, Zagreb, Croatia , and Vida Demarin From the Department of Neurology, University Hospital Sestre Milosrdnice, Zagreb, Croatia Published Online:4 Aug 2011https://doi.org/10.4103/0256-4947.83217SectionsPDF ToolsAdd to favoritesDownload citationTrack citations ShareShare onFacebookTwitterLinked InRedditEmail AboutAbstractBACKGROUND AND OBJECTIVES: The expression of soluble adhesion molecules inter-cellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1), besides activation of endothelial cells and transendothelial migration of leukocytes, play an important role in inflammation and progression of ischemic injury after acute stroke. The aim of this study was to determine serum levels of soluble ICAM-1 and VCAM-1 in patients with acute ischemic stroke and controls and correlate them according to etiological subtypes (thromboembolic or lacunar stroke), stroke severity and disability after acute stroke.PATIENTS AND METHODS: Hospital-based prospective study of acute stroke patients hospitalized between December 2008 and September 2009 at the University Hospital Sestre Milosrdnice in Zagreb, Croatia.METHODS: We enrolled 110 patients with acute ischemic stroke and 93 healthy individuals as controls. Serum concentrations of VCAM-1 and ICAM-1 were determined by means of quantitative sandwich enzyme immunoassay. Patients were classified according to etiological subtype, clinical severity of stroke and disability after stroke.RESULTS: There was no significant difference between levels of soluble adhesion molecules VCAM-1 and ICAM-1 in patients and in controls. Levels of VCAM-1 were significantly higher in patients with thromboembolic stroke than in controls. There was no significant correlation between levels of soluble adhesion molecules VCAM-1 and ICAM-1 and stroke severity and disability. There was marked biological interindividual variability in all patient groups.CONCLUSION: This study confirms the role of adhesion molecule VCAM-1 in the pathogenesis of acute thromboembolic stroke.IntroductionMany risk factors have been found for the appearance of a stroke and new factors are continually recognized.1,2 The awareness that atherosclerosis is partially an inflammatory disease has lead to the acceptance of inflammation and its markers as new and significant risk factors for the development of cardiovascular and cerebrovascular diseases. The results of many recent studies suggest that the role of inflammation in the occurrence and development of ischemic brain damage is an important one.3 Molecular adhesion and the development of cytokines occur in the early stage of ischemia and reperfusion, and they represent the foundation for an ischemic injury evolving into an inflammatory one.4–7Acute stroke patients demonstrate alterations in the concentration of ICAM-1 and lymphocyte adhesion molecule 1 (L-selectin) similar to those seen in patients with vascular risk factors.8 Former studies have demonstrated that acute stroke patients have increased levels of lymphocyte function-associated antigen 1 (LFA-1) and macrophage 1 antigen (Mac-1) on leukocytes.9 Today, as thrombolytic therapy has become available outside of clinical studies, a decrease in reperfusion damage has become a promising therapeutic goal. The application of anti-adhesion therapy can prolong the time frame for the application of recombined tissue plasminogen, which could increase the effectiveness of thrombolytic therapy in the treatment of acute ischemic stroke.10The objectives of this research were defining and comparing the serum levels of adhesive VCAM-1 and ICAM-1 molecules in patients who had an acute ischemic stroke and a control group, comparing the VCAM-1 and ICAM-1 levels in the thromboembolic and lacunar ischemic stroke and comparing the VCAM-1 and ICAM-1 levels with the severity of the stroke and the outcome of the patients with acute ischemic stroke. By discovering the role of the inflammation in the occurrence and development of the acute ischemic stroke, it might be possible to recognize patients at a high risk of stroke and applying anti-inflammatory therapeutic strategies to decrease the ischemic brain damage and restrict the neurological damage to the patient.PATIENTS AND METHODSThe research was performed at the Neurology department, Sestre Milosrdnice, University Hospital, which is the Reference Centre for Neurovascular Disorders of the Ministry of Health of the Republic of Croatia. We consecutively included 110 acute stroke patients hospitalized in the period between December 2008 and September 2009. For each patient, we obtained the anamnesis, determined the somatic and neurological status and performed computerized brain tomography (CT), color Doppler sonography of carotid arteries and electrocardiograph (ECG). In patient blood samples, we defined the serum concentrations of adhesion molecules VCAM-1 and ICAM-1, the complete blood picture, the erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and the blood sugar. Only patients with acute ischemic stroke hospitalized within 24 hours from the occurrence of symptoms were included in the study.The diagnosis of acute ischemic stroke was set based on clinical signs and symptoms of a sudden focal or global disorder of brain functions caused by an ischemic event and based on CT results.2 The CT excluded the existence of cerebral hemorrhage and other possible causes of a brain damage (eg, a tumor) that can imitate the clinical picture of ischemic stroke. For patients who underwent CT within the first 12 hours from the occurrence of symptoms and had normal findings, a control screening was performed between the third and the fifth day of hospitalization. Patients with a transitory ischemic stroke, cerebral hemorrhage and those who during the admittance demonstrated increased ESR (>30 mm/h), increased body temperature (>37.5°C), increased values of C-reactive protein (>10mg/L) or clinical signs of respiratory, urinary of other system infection, were not included in the study.The control group consists of 93 examinees of the same age and sex who suffered from headaches and/or dizziness. They were afebrile with no signs of respiratory, urinary or system infection, ESR or C-reactive protein were within the referential values and they had normal CT findings.Patients with acute ischemic stroke were divided according to the pathogenic stroke form into two groups: patients with thromboembolic (TE) and patients with lacunar stroke.The diagnosis and the determination of the pathogenic ischemic stroke form were performed by a neurologist experienced in diagnosing and treating the acute ischemic stroke based on anamnesis, somatic-neurological examination, CT, color Doppler sonography of carotid arteries and EKG. CT was read by a neuroradiologist experienced in the neuroradiological picture diagnostics of acute ischemic stroke. Patients with lacunar ischemic stroke caused by embolism from the internal carotid artery or heart were not included in the study.All blood samples were taken into test tubes that contained ethylenediaminetetraacetic acid (EDTA) as anticoagulant and were centrifuged within 30 minutes after they had been taken and stored at the temperature of -20°C until the measuring procedure started. The serum concentrations of ICAM-1 and VCAM-1 were defined by quantitative enzyme immunoassay (RandD Systems, Minneapolis, USA).The severity of a stroke was determined during the blood sampling, i.e. within 24 hours from the occurrence of stroke symptoms. The severity was determined based on neurological status that was evaluated according to the National Institute of Health Stroke Scale (NIHSS). The outcome of a stroke was determined on the tenth day after the disease had occurred according to the Barthel Index (BI).For statistic analyses we used Statistical Analysis System (SAS) software (Institute Inc., Cary, North Carolina) for Windows 95/98/NT/Me/2000. As most of the variables did not follow the normal distribution, non-parametric tests were applied. For comparison of more than two groups the Kruskal-Wallis test was used, while the Mann-Whitney test with a correction was used for comparing pairs because of multiple testing. For comparing quantitative marks the chi-square test was applied. Numeric marks were graphically portrayed in "box-plot" form.All ethical principles of the medical profession were followed according to the Helsinki Declaration and Good Clinical Practice. All examinees were informed in advance about the procedures that were to be used during the research and they signed an approval for the participation in the research. The Ethical Committee of the Clinical Hospital Sestre Milosrdnice concluded that the research followed the Good Clinical Practice and accepted the research protocol.RESULTSThe research included 110 patients with acute stroke and 93 examinees as controls. The distribution of patients according to their age, stroke severity and its outcome, as well as the distribution of controls according to their age is shown in Table 1. The patient group included 62 men (56.4%) and 48 women (43.6%). The control group included 52 men (55.9%) and 41 women (44.1%). There was no significant differences between the two groups regarding age (P=0.815; Mann-Whitney test) and sex (P=.949; χ2 test). There was no significant difference in the concentration of VCAM-1 and ICAM-1 in patients with acute ischemic stroke and examinees from the control group (Table 2). The patients with thromboembolic stroke included 67 examinees, 35 men and 32 women, whereas the the patients with lacunar stroke included 43 examinees, 27 men and 16 women. The patients with thromboembolic and lacunar stroke showed no statistically significant difference to the control group in age (P=.259; Kruskal-Wallis test) and sex (P=.552; χ2 test). The serum concentrations of adhesion molecules in patients with thromboembolic or lacunar ischemic stroke are represented in Table 3. Serum values of VCAM-1 were statistically significantly higher (P=.023; Mann-Whitney test) in the group of patients with thromboembolic stroke than in the control group, but this was not the case when we compared serum values of ICAM-1 in these two groups (P=.204; Mann-Whitney test)Table 1 Distribution of patients according to age, stroke severity and outcome and distribution of examinees in the control group according to their age.Table 1 Distribution of patients according to age, stroke severity and outcome and distribution of examinees in the control group according to their age.Table 2 Serum concentrations of adhesion molecules intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) in patients and controls.Table 2 Serum concentrations of adhesion molecules intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) in patients and controls.Table 3 Serum concentrations of adhesion molecules inter-cellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) in examinees according to stroke type and controls.Table 3 Serum concentrations of adhesion molecules inter-cellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) in examinees according to stroke type and controls.The group of patients with light stroke included 45 examinees, the group with moderate stroke included 37 patients and the group with severe stroke included 28 examinees. The values of serum concentrations of VCAM-1 and ICAM-1 did not differ significantly between the examined groups (Table 4).Table 4 Serum concentrations of adhesion molecules Intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) according to stroke severity.Table 4 Serum concentrations of adhesion molecules Intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) according to stroke severity.The patients with thromboembolic stroke included 67 examinees, 15 of whom had a light stroke, 27 suffered from a moderate one and 25 had a severe stroke. The group of patients with lacunar stroke included 43 examinees, 30 of whom had a light stroke, 10 suffered from a moderate one and three patients had a severe stroke. Serum concentrations of VCAM-1 and ICAM-1 did not differ significantly between the examined groups (Table 5). Poor recovery was observed among 43 of 110 patients (BI 37.5°C), leukocytosis or an increased ESR. In this way the possibility that increased concentrations of adhesion molecules VCAM-1 and ICAM-1 indicate the existence of a systemic inflammation and not local ischemic brain damage was eliminated. In the research of Bitsch and colleagues,14 in which a significant increase in concentrations of adhesion molecules ICAM-1 and VCAM-1 appeared in patients with acute ischemic stroke, the patients who showed signs of a system inflammation were recognized, but not excluded from the research.In this study, the control group included examinees with normal morphological CT results who had no clinical or laboratory signs of a system infection. However, examinees with hypertension and diabetes, smokers, overweight examinees and examinees with a heart or vascular disease were not excluded from the research. The existence of vascular risk factors of atherosclerosis in these examinees allows for the possibility that their concentrations of adhesion molecules VCAM-1 and ICAM-1 are increased.15 Research of Frijns and colleagues,16 and DeGraba and colleagues17 showed that in humans endothelial cells above the atherosclerotic plaque extensively produce adhesion molecules P-selectin, ICAM-1 and VCAM-1. This could be one of the reasons why our research failed to show any increase in concentrations of adhesion molecules VCAM-1 and ICAM-1 in patients with acute ischemic stroke.Increased concentrations of serum inflammatory adhesion molecules VCAM-1 and ICAM-1 were noticed in patients with ischemic stroke, although the results are contradictory. The research of Bitsch and authors14 showed that ICAM-1 concentrations reached their highest values within 24 hours from the moment of occurrence of acute ischemic stroke, whereas VCAM-1 values reached highest levels after five days. In the research performed by Šimundić and authors18 the values of VCAM-1 and ICAM-1 were increased in patients with acute ischemic stroke, but the research did not exclude patients with laboratory or clinical signs of inflammation. Fassbender and colleagues19 demonstrated increased concentrations of ICAM-1 in patients who had risk factors for the development of vascular diseases, but a statistically significant difference between this group of examinees and patients with acute ischemic stroke was not proved. Clark and colleagues20 did not prove the increase of concentrations of ICAM-1 in patients with ischemic stroke; the reason could be the fact that blood samples were taken within 72 hours from the moment when symptoms occurred.Possible explanations for contradictory results include the differences between control groups, laboratory tests and time frames of blood sampling. Various drugs can also alter the expression of adhesion molecules, e.g. aspirin, corticosteroids and non-steroid anti-inflammatory drugs. In the research performed by Fassbender and colleagues19 patients with acute ischemic stroke were treated by heparin and did not receive acetylsalicylic acid, which has anti-inflammatory effects and alters the response of an organism to an inflammation. The existence of other diseases, e.g. infections, diabetes or some system disease could affect the results.21 Increased levels of ICAM-1 and VCAM-1, along with normal levels of E-selectin, were found in patients suffering from diabetes, especially those with silent stroke detected by MRI.22The MITICO study23 and study by Pinto and colleagues24 have shown that, respectively, values of Interleukin-6 (IL-6), VCAM-1 and tumor necrosis factor (TNF-alpha), Von Willebrand factor (vWF), but not VCAM-1, are predictors of a new, recurrent vascular event. However, in this research we determined levels of VCAM-1 and ICAM-1 in acute stroke patients and it was not designed to assess the risk of recurrence of vascular disease.The significance of this research can be related to the fact that the connection between the adhesion molecule VCAM-1 and the pathogenesis of thromboembolic acute ischemic stroke was proven. Due to a large interindividual variability there are no indications in the current clinical practice that would determine these molecules as markers of a local inflammatory event within the acute stroke. The clinical significance of the role of these molecules in the inflammatory response after the acute ischemic stroke opens a new therapeutic area in treating acute ischemic stroke by means of combined effects of anti-inflammatory anti-adhesion therapy that would be able to prolong the time frame for the application of reperfusion-thrombolytic therapy.ARTICLE REFERENCES:1. Gorelick PB. "Stroke prevention therapy beyond antithrombotics: Unifying mechanisms in ischemic stroke pathogenesis and implications for therapy" . Stroke. 2002; 33:862-75. Google Scholar2. In: Demarin V, Lovrencic-Huzjan A, Trkanjec Z, Vukovic V, Vargek-Solter V, Seric V , et al.. "Recommendations for stroke management 2006 update" . Acta Clin Croat. 2006; 45:219-85. Google Scholar3. In: Rodriguez-Yanez , Castillo J. "Role of inflammatory markers in brain ischemia" . Curr Opin Neurol. 2008; 21:353-7. Google Scholar4. In: Huang J, Upadhyay UM, Tamargo RJ. "Inflammation in stroke and focal cerebral ischemia" . Surg Neurol. 2006; 66:232-45. Google Scholar5. In: Lo EH, Moskowitz MA, Jacobs TP. "Exciting Radical, Suicidal – How brain cells die after stroke" . Stroke. 2005; 36:189-92. Google Scholar6. In: Tsai NW, Chang WN, Shaw CF, Jan CR, Huang CR, Chen CR , et al.. "The value of leukocyte adhesion molecules in patients after ischemic stroke" . J Neurol. 2009; 256:1296-302. Google Scholar7. In: Xia W, Han J, Huang G, Ying W. "Inflammation in Ischemic Brain Injury: Current advances and future perspectives" . Clin Exp Pharmacol Physiol. 2010; 37:253-8. Google Scholar8. In: Frijns CJ, Kappelle LJ, van Gijn J, Nieuwenhuis HK, Sixma JJ, Fijnheer R. "Soluble adhesion molecules reflect endothelial cell activation in ischemic stroke and in carotid atherosclerosis" . Stroke. 1997; 28:2214-8. Google Scholar9. In: Caimi G, Canino B, Ferrara F, Montana M, Musso M, Porretto F , et al.. "Granulocyte integrins before and after activation in acute ischemic stroke" . J Neurol Sci. 2001; 186:23-6. Google Scholar10. In: Albers GW, Amarenco P, Easton JD, Sacco RL, Teal P. "Antithrombotic and trombolytic therapy for ischemic stroke" . Chest. 2001; 119:300-20. Google Scholar11. DeGraba TJ. "The role of inflammation after acute stroke: utility of pursuing anti-adhesion molecule therapy" . Neurology. 1998; 51(3 Suppl 3):S62-8. Google Scholar12. In: Tuttolomondo A, Di Raimondo D, di Sciacca R, Pinto A, Licata G. "Inflammatory cytokines in acute ishemic stroke" . Curr Pharm Des. 2008; 14:3574-89. Google Scholar13. In: Yilmaz G, Granger DN. "Cell adhesion molecules and ischemic stroke" . Neurol Res. 2008; 30:783-93. Google Scholar14. In: Bitsch A, Kleine W, Murtada L, Prange H, Rieckmann P. "A longitudinal prospective study of soluble adhesion molecules in acute stroke" . Stroke. 1998; 29:2129-35. Google Scholar15. In: Ridker PM, Buring JE, Rifai N. "Soluble P-selectin and the risk of future cardiovascular events" . Circulation. 2001; 103:1336-42. Google Scholar16. In: Frijns CMJ, Kappelle LJ. "Inflammatory cell adhesion molecules in ischemic cerebrovascular disease" . Stroke. 2002; 33:2115-22. Google Scholar17. De Graba TJ. "Expression of inflammatory mediators and adhesion molecules in human atherosclerotic plaque" . Neurology. 1997; 49:S15-9. Google Scholar18. In: Simundic AM, Basic V, Topic E, Demarin V, Vrkic N, Kunovic B , et al.. "Soluble adhesion molecules in acute ischemic stroke" . Clin Invest Med. 2004; 27:86-92. Google Scholar19. In: Fassbender K, Mossner , Motsch L, Kischka U, Grau A, Hennerici M. "Circulating Selectin and Immunoglobulin-Type Adhesion Molecules in Acute Ischemic stroke" . Stroke. 1995; 26:1361-4. Google Scholar20. In: Clark WM, Coull BM, Briley DP, Mainolfi E, Rothlein R. "Circulating intercellular adhesion molecule-1 levels and neutrophil adhesion in stroke" . J Neuroimmunol. 1993; 44:123-5. Google Scholar21. In: Matsumoto K, Sera Y, Ueki Y, Inukai G, Niiro E, Miyake S. "Comparison of serum concentrations of soluble adhesion molecules in diabetic microangiopathy and macroangiopathy" . Diabet Med. 2002; 19:822-6. Google Scholar22. In: Kawamura T, Umemura T, Kanai A, Uno T, Matsumae H, Sano T , et al.. "The incidence and characteristics of silent cerebral infarction in elderly diabetic patients: Association with serum-soluble adhesion molecules" . Diabetologia. 1998; 41:911-7. Google Scholar23. In: Castillo J, Alvarez-Sabin J, Martinez-Vila E, Montaner J, Sobrino T, Vivancos J. "Inflammation markers and prediction of post-stroke vascular disease recurrence: The MITICO study" . J Neurol. 2009; 256:217-24. Google Scholar24. In: Pinto A, Tuttolomondo A, Casuccio A, Di Raimondo D, Di Sciacca R, Arnao V , et al.. "Immuno-inflammatoriy predictors of stroke at follow-up in patients with chronic non-valvular atrial fibrillation (NVAF)" . Clin Sci (Lond). 2009; 116:781-9. Google Scholar Previous article Next article FiguresReferencesRelatedDetails Volume 31, Issue 4Jul–Aug 2011 Metrics History Accepted1 October 2010Published online4 August 2011 InformationCopyright © 2011, Annals of Saudi MedicineThis is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.PDF download
Referência(s)