Abstract
BackgroundA number of data indicate that the lectin pathway of complement activation contributes to the pathophysiology of ischemic stroke. The lectin pathway may be triggered by the binding of mannose-binding lectin (MBL), ficolin-2 or ficolin-3 to different ligands. Although several papers demonstrated the significance of MBL in ischemic stroke, the role of ficolins has not been examined.MethodsSera were obtained within 12 hours after the onset of ischemic stroke (admission samples) and 3-4 days later (follow-up samples) from 65 patients. The control group comprised 100 healthy individuals and 135 patients with significant carotid stenosis (patient controls). The concentrations of ficolin-2 and ficolin-3, initiator molecules of the lectin complement pathway, were measured by ELISA methods. Concentration of C-reactive protein (CRP) was also determined by a particle-enhanced immunturbidimetric assay.ResultsConcentrations of both ficolin-2 and ficolin-3 were significantly (p < 0.001) decreased in both the admission and in the follow-up samples of patients with definite ischemic stroke as compared to healthy subjects. Concentrations of ficolin-2 and ficolin-3 were even higher in patient controls than in healthy subjects, indicating that the decreased levels in sera during the acute phase of stroke are related to the acute ischemic event. Ficolin-3 levels in the follow-up samples inversely correlated with the severity of stroke indicated by NIH scale on admission. In follow-up samples an inverse correlation was observed between ficolin-3 levels and concentration of S100β, an indicator of the size of cerebral infarct. Patients with low ficolin-3 levels and high CRP levels in the follow up samples had a significantly worse outcome (adjusted ORs 5.6 and 3.9, respectively) as measured by the modified Rankin scale compared to patients with higher ficolin-3 and lower CRP concentrations. High CRP concentrations were similarly predictive for worse outcome, and the effects of low ficolin-3 and high CRP were independent.ConclusionsOur findings indicate that ficolin-mediated lectin pathways of complement activation contribute to the pathogenesis of ischemic stroke and may be additive to complement-independent inflammatory processes.
Highlights
A number of data indicate that the lectin pathway of complement activation contributes to the pathophysiology of ischemic stroke
Several studies have demonstrated the essential role of complement activation in brain damage following cerebral ischemia. Such evidence includes (i) an increased expression of complement proteins and complement receptors after permanent middle cerebral artery occlusion (MCAO) [8,9,10,11] (ii) different pathological events in complement-deficient/-sufficient animals after the onset of cerebral ischemia compared to wild-type littermates: complement deficient animals are at least partially protected after transient MCAO [12,13,14,15]. (iii) In rodent experimental models, complement depletion induced using the cobra venom factor (CVF) [16,17], as well as complement inhibition by a plasma-derived C1-inhibitor [18,19], a recombinant C1 inhibitor [20], CR2-Crry [13] and intravenous immunoglobulin administration [14] were proven to exert beneficial, neuroprotective effects, indicating the protective role of complement antagonism and inhibition
The concentrations of the proteins of the lectin pathway and C-reactive protein (CRP) in the sera of patients with ischemic stroke, as compared to healthy controls and patient controls The serum levels of ficolin-2, ficolin-3 and CRP were measured in the samples obtained from 65 stroke patients on admission and 3-4 days later, as well as in the sera of 100 healthy volunteers and 134 patient controls (Figure 1)
Summary
A number of data indicate that the lectin pathway of complement activation contributes to the pathophysiology of ischemic stroke. The group of De Simoni [24] reported on the formation of functional MBL/MASP-2 complexes in plasma in mice after MCAO, and demonstrated that molecules, which strongly bound to MBL, induced significant reduction in neurological deficits and infarct volume, when administered 6 h after transient MCAO. These data support the notion that the lectin pathway plays a crucial role in the development of ischemic stroke
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