Serial measurements of levels of the chemokines CCL2, CCL3 and CCL5 in serum of patients with acute ischaemic stroke.

Inflammation, involving cytokine/chemokine expression, occurs after stroke and deteriorates its course with leukocyte-mediated brain infarct progression. Chemokines are cytokines attracting selective leukocyte subsets and subgrouping into the four major subfamilies, CC, CXC, C, and CX3C. The CC subfamily preferentially acts on mononuclears. The study aimed to define serum CCL2, CCL3 and CCL5 levels in stroke patients and their relationship to the extent of disease severity and outcome. 27 ischaemic stroke patients and 20 controls were studied. Blood sampling for the determination of chemokines was performed at days 1, 2 and 3 of stroke, while neurological and functional deficits were estimated, respectively, with the Scandinavian Stroke Scale (SSS) and Barthel Index (BI) at the same time points and at days 14 and 28. Serum CCL3 levels at days 1, 2 and 3 of stroke were significantly higher than in controls. Serum CCL2 and CCL5 levels in stroke patients did not differ from those in controls at any of the time points examined. Serum chemokine levels in stroke studied separately did not differ between each other at any time point studied and demonstrated considerable variability. No correlation between serum chemokine levels and SSS scores was observed. Serum CCL2 and CCL3 levels at days 1, 2 and 3 of stroke correlated with BI scores at day 28. Serum CCL2 levels at days 2 and 3 of stroke also correlated with BI scores at day 14. Serum CCL5 levels at day 2 of stroke correlated with BI scores at day 28. The early and sustained increase in serum CCL3 levels in stroke patients along with correlation between them and short-term poststroke functional disability could indicate that the chemokine response may predispose to poor stroke outcome. The relationship between non-increased serum CCL2 and CCL5 levels and worse stroke outcome seems to be coincidental. Overall, as a result of large interindividual variability, CCL2, CCL3 and CCL5 are not reliable candidates for surrogate markers in stroke.

Interleukin-12 in acute ischemic stroke patients.

Cytokines are important mediators of stroke-induced immunological/inflammatory reaction which contributes to brain infarct progression as well as to the disease severity and outcome. The aim of the study was to evaluate the levels of the proinflammatory and immunomodulatory cytokine interleukin-12 (IL-12) in serum of acute ischemic stroke patients, and to investigate the relation between these levels and demographic, laboratory, neuroimaging, and clinical data. The study comprised 23 first-ever ischemic stroke patients and 15 age- and sex-matched controls. Blood sampling for the determination of IL-12 and such peripheral markers of inflammation as erythrocyte sedimentation rate (ESR) and leukocyte count, together with cranial CT were performed within 24 h of stroke, while neurological and functional deficits were estimated, respectively, with the Scandinavian Stroke Scale (SSS) and Barthel Index (BI) within the same period and two weeks later. Stroke patients displayed significantly higher serum IL-12 levels in comparison with controls. The serum IL-12 levels in stroke patients correlated significantly with the ESR values, the volume of early brain CT hypodense areas, and with the SSS and BI scores calculated within both studied times. The results indirectly suggest that IL-12 may play a role in the pathophysiology of ischemic stroke.

CXCL1 (GRO-alpha) chemokine in acute ischaemic stroke patients.

The inflammation accompanies and exacerbates cerebral ischaemia. The infiltrated leucocytes are thought to contribute to tissue injury in stroke patients. GRO-alpha (CXCL1) is a potent neutrophil chemoattractant which may play an important role in pathophysiology of stroke. 23 ischaemic stroke patients and 15 controls have been studied. CSF and blood sampling together with cranial CT were performed within first 24 hours of stroke. CXCL1 levels were determined by ELISA, and volume of stroke-related brain CT hypodense areas was calculated. Stroke patients displayed significantly higher CSF CXCL1 level than controls (65.6+/-22.3 vs 43.8+/-2.3 pg/ml; p<0.01). Serum CXCL1 levels in stroke patients did not differ from controls. CSF CXCL1 level correlated positively with volume of brain CT hypodense areas (p<0.001). The results suggest that CXCL1 may be involved in inflammatory reaction during an early phase of ischaemic stroke.

Hyperthermia in ischemic stroke.

Hyperthermia following ischemic stroke is a common but undesirable event whose pathophysiology and clinical importance are not fully recognized. Hyperthermia in ischemic stroke may result from the brain infarct itself; however, the progress of biochemical and inflammatory mechanisms associated with cerebral ischemia is also relevant. Consequently, the presence of hyperthermia accentuates ischemic mechanisms within the penumbra, an area of reversibly impaired neuronal function surrounding the infarct, contributing to conversion of the penumbra into an irreversible lesion. Therefore, hyperthermia following ischemic stroke seems to be an event both induced by and inducing brain infarct progression. Both clinical and experimental studies show hyperthermia-dependent exacerbation of ischemic brain damage and stroke outcome. The detrimental effects of hyperthermia in human stroke are associated in particular with increased body temperature within the first 24 hours of the disease. The common occurrence of superimposed infections in stroke patients may be an important peripheral cause of poststroke hyperthermia. Pharmacological antipyretic medication is recommended in every case of hyperthermia following ischaemic stroke, regardless of its cause, as any hyperthermia may worsen stroke outcome. There is currently no evidence from randomized trials to support the routine use of chemical or physical cooling therapy in acute stroke Further understanding of the mechanisms inducing hyperthermia and its contribution to an increase in the degree of injury during stroke may lead to new and important therapeutic approaches.

[Cytokines in clinical and experimental ischemic stroke]. / Cytokiny w klinicznym i doswiadczalnym udarze niedokrwiennym mózgu.

Inflammatory reaction following acute cerebral ischaemia exacerbates infarct size and neurological deficit. Brain resident cells localised within ischaemic region rapidly synthesise cytokines, proteins involved in cellular communication. The cytokines become important mediators of endothelial-leukocyte interactions leading to the influx of haematogenous inflammatory cells into the brain ischaemic region. Proinflammatory cytokines: tumour necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) initiate inflammatory reaction and induce expression of other cytokines and inflammatory mediators. The presence of cytokines in brain infarct region has been shown in human and animal autopsy studies. Suppression of proinflammatory cytokines expression reduces brain infarct size in animal models of stroke. Increased levels of proinflammatory cytokines in cerebrospinal fluid and/or in serum of acute ischaemic stroke patients correlate with brain infarct volume and stroke severity and may have a predictive value for stroke outcome. This review presents cytokines studied in clinical and experimental strokes documenting that the molecules may exert not only detrimental but also neuroprotective effect on ischaemic brain.

Acute ischaemic stroke increases the erythrocyte sedimentation rate, which correlates with early brain damage.

The acute phase response follows tissue injury and contributes to its exacerbation with pro-inflammatory and pro-thrombotic mechanisms. Acute phase proteins promote erythrocyte aggregation and falling, with the result that the erythrocyte sedimentation rate (ESR) is a measure of the acute phase response. As the acute phase response accompanies ischaemic brain damage, we studied ESR values in patients within the first 24 hours of ischaemic stroke and evaluated whether these values may be related to the volume of anatomically relevant single hemispheric brain computed tomography (CT) areas observed at the same period, indicating early stroke-related cerebral changes. We observed an increase in ESR in stroke patients and a positive correlation between the ESR values and the volume of early brain CT hypodense areas. The results suggest that elevation in ESR values is observed soon after a stroke and may reflect the relationship between the degree of acute phase response in the early phase of ischaemic stroke and the extent of local brain damage.

Adhesion molecules of immunoglobulin gene superfamily in stroke.

Stroke-induced inflammatory reaction leads to the accumulation of leukocytes in the brain ischaemic region, where they exert a detrimental effect--promotion and extension of cerebral damage. Intracerebral infiltration of peripheral blood leukocytes requires prior endothelial-leukocyte interactions that are mediated by such cell surface proteins as adhesion molecules. Among adhesion molecules, it is the immunoglobulin gene superfamily (IgSF) that is responsible for strong attachment and transendothelial migration of leukocytes. The principal members of IgSF are: intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and platelet endothelial cell adhesion molecule-1 (PECAM-1). In this review the following issues were described and discussed: an increased expression of ICAM-1 and VCAM-1 in ischaemic brain as well as a detection of their soluble(s) forms in sera of stroke victims. The presented data suggest the involvement of both ICAM-1 and VCAM-1 in the sequence and timing of the infiltration of leukocytes into the brain ischaemic zone after stroke. They have also revealed changes in serum concentrations of sICAM-1 and sVCAM-1 that are characteristic for stroke. Recently, increase in sPECAM-1 levels in serum and cerebrospinal fluid (CSF) has been shown within 24 h of the onset of stroke, having indirectly suggested involvement of the molecule in the inflammatory events during the early phase of stroke.

IL-15 is elevated in sera of patients with relapsing-remitting multiple sclerosis.

Interleukin-15 is a novel cytokine produced by monocytes/macrophages and sharing several biological activities with IL-2. IL-15 induces T cell proliferation, enhances natural killer (NK) cell cytotoxicity and also stimulates B cells to proliferate and secrete immunoglobulins. The purpose of our study was to measure IL-15 levels in the serum and CSF of 21 patients with relapsing-remitting form of MS, 9 with active gadolinium enhancing lesions in MRI, 12 without enhancing MRI lesions and to compare the results with the control group. IL-15 levels were measured by ELISA. We found a significant increase of IL-15 in the sera of patients with MS in comparison with the control group consisting of 8 patients with tension headache. IL-15 serum levels were highest in patients with active, gadolinium enhancing lesions. IL-15 CSF levels were low and there was no difference between studied groups. The results may suggest the contribution of IL-15 in the immunopathogenesis of multiple sclerosis.