Thromboinflammation in Stroke Brain Damage

Meyer, Simon F. De; Denorme, Frederik; Langhauser, Friederike; Geuß, Eva; Fluri, Felix; Kleinschnitz, Christoph

doi:10.1161/strokeaha.115.011238

Cited by 261 publications

(212 citation statements)

References 96 publications

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“…Because neutrophils are recruited at sites of cerebral ischemia and are important sources of proteases and reactive oxygen species capable of damaging the BBB, they have been previously incriminated as possible culprits contributing to BBB disruption and HT. 14,21 Furthermore, in recent years, neutrophil to lymphocyte ratio has emerged as a predictor of short-and long-term outcomes in ischemic stroke patients and of risk of HT in stroke patients treated with intravenous thrombolysis. 22 In line with this clinical data, we found that HG rats had an increase in neutrophil to lymphocyte ratio compared with NG rats.…”

Section: Discussionmentioning

confidence: 99%

Exacerbation of Thromboinflammation by Hyperglycemia Precipitates Cerebral Infarct Growth and Hemorrhagic Transformation

Desilles

Syvannarath

Ollivier

et al. 2017

Stroke

123

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A cute ischemic stroke (AIS) remains a leading cause of disability, cognitive impairment, and mortality worldwide, despite the development of revascularization therapies. Besides recanalization status, other prognostic factors in AIS patients are associated with clinical outcome. Among them, hyperglycemia has been found to be associated with hemorrhagic transformation (HT) and worsened neurological outcomes. 1,2 Given that 40% to 50% of AIS patients present with hyperglycemia, 3 understanding and reducing hyperglycemia-induced neurovascular injury constitute an important clinical stake. Experimental studies have investigated extensively the relationship between hyperglycemia and poor outcome after AIS. [4][5][6] Notably, these studies have shown that preexisting hyperglycemia, whether acute or prolonged, was an important determinant of brain injury in AIS. In contrast, hyperglycemia induced after the period of ischemia had no effect on experimental stroke outcome.5 Hyperglycemia was further shown to increase cerebral ischemia-reperfusion-induced blood-brain Background and Purpose-Admission hyperglycemia is associated with a poor outcome in acute ischemic stroke. How hyperglycemia impacts the pathophysiology of acute ischemic stroke remains largely unknown. We investigated how preexisting hyperglycemia increases ischemia/reperfusion cerebral injury. Methods-Normoglycemic and streptozotocin-treated hyperglycemic rats were subjected to transient middle cerebral artery occlusion. Infarct growth and brain perfusion were assessed by magnetic resonance imaging. Markers of platelet, coagulation, and neutrophil activation were measured in brain homogenates and plasma. Downstream microvascular thromboinflammation (DMT) was investigated by intravital microscopy. Results-Hyperglycemic rats had an increased infarct volume with an increased blood-brain barrier disruption and hemorrhagic transformation rate compared with normoglycemic rats. Magnetic resonance imaging scans revealed that hyperglycemia enhanced and accelerated lesion growth and was associated with hemorrhagic transformation originating from territories that were still not completely reperfused at 1 hour after middle cerebral artery recanalization. Intravital microscopy and analysis of brain homogenates showed that DMT began immediately after middle cerebral artery occlusion and was exacerbated by hyperglycemia. Measurement of plasma serotonin and matrix metalloproteinase-9 indicated that platelets and neutrophils were preactivated in hyperglycemic rats. Neutrophils from hyperglycemic diabetic patients showed increased adhesion to endothelial cells as compared with neutrophils from normoglycemic donors in flow chamber experiments. Conclusions-We show that hyperglycemia primes the thromboinflammatory cascade, thus, amplifying middle cerebral artery occlusion-induced DMT. DMT exacerbation in hyperglycemic rats impaired reperfusion and precipitated neurovascular damage, blood-brain barrier disruption, and hemorrhagic transformation. Our results designate DMT as a po...

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Section: Discussionmentioning

confidence: 99%

Exacerbation of Thromboinflammation by Hyperglycemia Precipitates Cerebral Infarct Growth and Hemorrhagic Transformation

Desilles

Syvannarath

Ollivier

et al. 2017

Stroke

123

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“…The GPIb binding site on these smaller vWf fragments is encrypted and must first be unmasked through binding of vWf to subendothelial collagen exposed by vascular damage. De Meyer et al 1 have comprehensively reviewed the mechanistic and animal studies done in the past that highlight the importance of ULvWf and the collagen-vWf-GPIb axis.…”

Section: Article See P 2169mentioning

confidence: 99%

“…Inhibitors of the reinforcement, such as the P 2 Y 12 ADP receptor antagonists and acetylsalicylic acid to suppress cyclooxygenase-1-dependent thromboxane generation, are in current clinical use for secondary stroke prevention. In addition, platelet Gαi2 is an essential mediator of thromboinflammatory brain damage in mice, as reviewed in De Meyer et al, 1 and represents an attractive target.…”

Section: Article See P 2169mentioning

confidence: 99%

“…9 NET cleavage, for example, by DNase-1, accordingly provided protection in a mouse stroke model. 1 Interestingly, if the number of involved neutrophils is high, aggregated NETs have been described to actually resolve inflammation by proteolytic cleavage of proinflammatory chemokines and cytokines. 10 The contact-kinin pathway, initiated by coagulation factor XII is also important for thromboinflammation in stroke, as reviewed recently.…”

Section: Article See P 2169mentioning

confidence: 99%

“…Thrombotic and inflammatory processes are highly intertwined factors leading to cerebral vessel occlusion and stroke, which itself in turn elicits local and systemic inflammatory responses. 1 During the past decade, much insight -mainly from animal models -has been gained into the basic mechanisms contributing to stroke or underlying ischemic brain damage. Because a number of these might be new candidate targets to treat cerebral injury after stroke, a résumé is given in Figure 1.…”

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Resolving Thromboinflammation in the Brain After Ischemic Stroke?

Kehrel

Fender

2016

Circulation

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Hyperacute immune responses associate with immediate neuropathology and motor dysfunction in large vessel occlusions

Farooqui

Ortega‐Gutiérrez

Hernandez

et al. 2022

Ann Clin Transl Neurol

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Objective Despite successful endovascular therapy, a proportion of stroke patients exhibit long‐term functional decline, regardless of the cortical reperfusion. Our objective was to evaluate the early activation of the adaptive immune response and its impact on neurological recovery in patients with large vessel occlusion (LVO). Methods Nineteen (13 females, 6 males) patients with acute LVO were enrolled in a single‐arm prospective cohort study. During endovascular therapy (EVT), blood samples were collected from pre and post‐occlusion, distal femoral artery, and median cubital vein (controls). Cytokines, chemokines, cellular and functional profiles were evaluated with immediate and follow‐up clinical and radiographic parameters, including cognitive performance and functional recovery. Results In the hyperacute phase (within hours), adaptive immune activation was observed in the post‐occlusion intra‐arterial environment (post). Ischemic vascular tissue had a significant increase in T‐cell‐related cytokines, including IFN‐γ and MMP‐9, while GM‐CSF, IL‐17, TNF‐α, IL‐6, MIP‐1a, and MIP‐1b were decreased. Cellularity analysis revealed an increase in inflammatory IL‐17+ and GM‐CSF+ helper T‐cells, while natural killer (NK), monocytes and B‐cells were decreased. A correlation was observed between hypoperfused tissue, infarct volume, inflammatory helper, and cytotoxic T‐cells. Moreover, helper and cytotoxic T‐cells were also significantly increased in patients with improved motor function at 3 months. Interpretation We provide evidence of the activation of the inflammatory adaptive immune response during the hyperacute phase and the association of pro‐inflammatory cytokines with greater ischemic tissue and worsening recovery after successful reperfusion. Further characterization of these immune pathways is warranted to test selective immunomodulators during the early stages of stroke rehabilitation.

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Thromboinflammation in Stroke Brain Damage

Cited by 261 publications

References 96 publications

Exacerbation of Thromboinflammation by Hyperglycemia Precipitates Cerebral Infarct Growth and Hemorrhagic Transformation

Exacerbation of Thromboinflammation by Hyperglycemia Precipitates Cerebral Infarct Growth and Hemorrhagic Transformation

Resolving Thromboinflammation in the Brain After Ischemic Stroke?

Hyperacute immune responses associate with immediate neuropathology and motor dysfunction in large vessel occlusions

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