The major findings of our pilot study are: 1) consistent inverse correlation between circulating EPC and soluble ICAM-1, 2) correlation of acute DWI lesion volume with day 1 MMP-9 and MMP-9/TIMP-1 ratio, 3) association of admission NIHSS with day 1 IL-6 and MMP-9.
We measured soluble ICAM-1, which is easily assessable in clinical setting. It shown to be proportional to cellular ICAM-1, which is expressed on endothelial cells [
24] and, therefore, soluble ICAM-1 may most likely reflect endothelial function. Up-regulation of ICAM-1 is an essential step mediating transmigration of leukocytes through perturbed endothelium and exacerbating reperfusion injury [
25]. Up-regulation of endothelial expression of ICAM-1 is shown in acute ischemic brain tissue in humans [
26]. Increase of ICAM-1 is linked to stroke-related neurological deterioration [
27], and poor short-term stroke prognosis [
15]. The most important finding in the study is the link between high ICAM-1 and low levels of circulating CD133+CD34+ EPC in early stroke. EPC represent a cumulative index of cerebrovascular function [
7], and are decreased in severe atherosclerosis [
8], in patients with increased cardiovascular risk [
7], and in severe strokes [
5]. The precise mechanism of this association remains to be determined; however, a receptor ICAM-1/CD18 is shown to be expressed on EPC and plays an essential role in their recruitment [
28]. Importantly, this subset CD133
+CD34
+ represents immature population of strongly proliferating progenitor cells, and is co-expressed in hematopoietic progenitors [
29]. Previous experimental studies showed a plateau in expression of ICAM-1 by endothelial cells after TNF-α activation between days 1-3 [
24], and after the stroke onset a persistency in soluble ICAM-1 levels on days 1, 3 and 14 [
17] was detected; our follow-up data on day 3 is in line with these findings. The main impact of our study is an attempt to identify factors, which contribute to the impaired EPC mobilization in stroke. A recent study showed an association between high ET-1 levels and low EPC mobilization after acute myocardial infarction [
30]. Temporal profiles of EPC in acute stroke and AMI share similar patterns [
6,
31]. Both ET-1 and ICAM-1 are considered to be important markers of endothelial dysfunction. We failed to show a correlation between low EPC and high ET-1 in our stroke cohort. However, our study in own way supports the reported observation [
30] emphasizing that endothelial dysfunction can be related to impaired neovascularization carried out by EPC.
In our stroke cohort, day 1 MMP-9 and MMP-9/TIMP-1 ratio correlated with acute DWI lesion volumes. Acute lesion volumes are linked with clinical stroke severity [
32] and widely used for outcome prediction. Our findings are in accordance with numerous clinical studies showing associations of MMP-9, responsible for degradation of basal lamina and extracellular matrix components, with increased hemorrhagic transformation in acute stroke [
33], BBB disruption [
20] and worse outcomes [
19].
Increased levels of pro-inflammatory IL-6 are correlated with acute infarct volume measured on computed tomography (CT) and with stroke outcome measured by modified Rankin scale (mRs) at 3 months [
18]. Increase of IL-6 is associated with early neurological worsening [
34], and with 3 month poor outcome (mRs 3-5, death or dependency)[
35]. Our data is in line with previous findings, although our stroke cohort did not include many severe stroke patients.
Focal ischemia initiates an inflammatory response, which amplifies growth of ischemic lesion in acute phase of stroke [
2,
3,
14]. The detected high ICAM-1 level, an important marker of neuroinflammation, is associated with low levels of EPC in early stroke, which supports our hypothesis that early inflammation inhibits neovascularization. The findings also suggest that combination of both markers may be useful for stroke outcome prediction in clinical setting. However, a larger prospective study is needed to confirm our findings. The major limitation of the study is a small sample size. On the other hand, we carefully selected patient population excluding any indication of underlying inflammatory condition. Other limitations of the study include absence of the age- and sex- matched controls.