Therapeutic Modulation of the Complement Cascade in Stroke

Clarke, Alison R.; Christophe, Brandon R.; Khahera, Anadjeet; Sim, Justin; Connolly, E. Sander

doi:10.3389/fimmu.2019.01723

Cited by 21 publications

(18 citation statements)

References 95 publications

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“…Anaphylatoxin C5a is a strong chemoattractant signal that is involved in the regulation of the innate immune system, playing a key role in host homeostasis, inflammation, and defense against pathogens [15][16][17][18][19]. Upon activation through the cleavage of C5 to C5a and C5b by the C5-convertase, C5a takes part in the recruitment and activation of inflammatory cells like neutrophils, eosinophils, T lymphocytes, and monocytes [19,20]. Recently, in a baboon model of Escherichia coli bacteremia, it was shown that complement-mediated bacteriolysis had a detrimental effect by inducing a release of LPS and fulminant inflammation [21].…”

Section: Introductionmentioning

confidence: 99%

Post-Traumatic Sepsis Is Associated with Increased C5a and Decreased TAFI Levels

Vollrath

Marzi

Herminghaus

et al. 2020

JCM

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Background: Sepsis frequently occurs after major trauma and is closely associated with dysregulations in the inflammatory/complement and coagulation system. Thrombin-activatable fibrinolysis inhibitor (TAFI) plays a dual role as an anti-fibrinolytic and anti-inflammatory factor by downregulating complement anaphylatoxin C5a. The purpose of this study was to investigate the association between TAFI and C5a levels and the development of post-traumatic sepsis. Furthermore, the predictive potential of both TAFI and C5a to indicate sepsis occurrence in polytraumatized patients was assessed. Methods: Upon admission to the emergency department (ED) and daily for the subsequent ten days, circulating levels of TAFI and C5a were determined in 48 severely injured trauma patients (injury severity score (ISS) ≥ 16). Frequency matching according to the ISS in septic vs. non-septic patients was performed. Trauma and physiologic characteristics, as well as outcomes, were assessed. Statistical correlation analyses and cut-off values for predicting sepsis were calculated. Results: Fourteen patients developed sepsis, while 34 patients did not show any signs of sepsis (no sepsis). Overall injury severity, as well as demographic parameters, were comparable between both groups (ISS: 25.78 ± 2.36 no sepsis vs. 23.46 ± 2.79 sepsis). Septic patients had significantly increased C5a levels (21.62 ± 3.14 vs. 13.40 ± 1.29 ng/mL; p < 0.05) and reduced TAFI levels upon admission to the ED (40,951 ± 5637 vs. 61,865 ± 4370 ng/mL; p < 0.05) compared to the no sepsis group. Negative correlations between TAFI and C5a (p = 0.0104) and TAFI and lactate (p = 0.0423) and positive correlations between C5a and lactate (p = 0.0173), as well as C5a and the respiratory rate (p = 0.0266), were found. In addition, correlation analyses of both TAFI and C5a with the sequential (sepsis-related) organ failure assessment (SOFA) score have confirmed their potential as early sepsis biomarkers. Cut-off values for predicting sepsis were 54,857 ng/mL for TAFI with an area under the curve (AUC) of 0.7550 (p = 0.032) and 17 ng/mL for C5a with an AUC of 0.7286 (p = 0.034). Conclusion: The development of sepsis is associated with early decreased TAFI and increased C5a levels after major trauma. Both elevated C5a and decreased TAFI may serve as promising predictive factors for the development of sepsis after polytrauma.

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Section: Introductionmentioning

confidence: 99%

Post-Traumatic Sepsis Is Associated with Increased C5a and Decreased TAFI Levels

Vollrath

Marzi

Herminghaus

et al. 2020

JCM

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“…However, other complement activation products may be the most important. 35 Upstream of TCC, the C3 (complement component 3) has been associated with a worse prognosis after ischemic stroke in humans. 14 By contrast, it also seems to play a part in synaptic plasticity and neurogenesis.…”

Section: Discussionmentioning

confidence: 99%

Plasma Inflammatory Biomarkers Are Associated With Poststroke Cognitive Impairment: The Nor-COAST Study

Sandvig

Aam

Alme

et al. 2023

Stroke

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Background: Inflammation is proposed to be involved in the pathogenesis of poststroke cognitive impairment. The aim of this study was to investigate associations between concentrations of systemic inflammatory biomarkers after ischemic stroke and poststroke cognitive impairment. Methods: The Nor-COAST study (Norwegian Cognitive Impairment After Stroke) is a prospective observational multicenter cohort study, including patients hospitalized with acute stroke between 2015 and 2017. Inflammatory biomarkers, including the TCC (terminal C5b-9 complement complex) and 20 cytokines, were analyzed in plasma, collected at baseline, 3-, and 18 months poststroke, using ELISA and a multiplex assay. Global cognitive outcome was assessed with the Montreal Cognitive Assessment (MoCA) scale. We investigated the associations between plasma inflammatory biomarkers at baseline and MoCA score at 3-, 18-, and 36-month follow-ups; the associations between inflammatory biomarkers at 3 months and MoCA score at 18- and 36-month follow-ups; and the association between these biomarkers at 18 months and MoCA score at 36-month follow-up. We used mixed linear regression adjusted for age and sex. Results: We included 455 survivors of ischemic stroke. Higher concentrations of 7 baseline biomarkers were significantly associated with lower MoCA score at 36 months; TCC, IL (interleukin)-6, and MIP (macrophage inflammatory protein)-1α were associated with MoCA at 3, 18, and 36 months ( P <0.01). No biomarker at 3 months was significantly associated with MoCA score at either 18 or 36 months, whereas higher concentrations of 3 biomarkers at 18 months were associated with lower MoCA score at 36 months ( P <0.01). TCC at baseline and IL-6 and MIP-1α measured both at baseline and 18 months were particularly strongly associated with MoCA ( P <0.01). Conclusions: Higher concentrations of plasma inflammatory biomarkers were associated with lower MoCA scores up to 36 months poststroke. This was most pronounced for inflammatory biomarkers measured in the acute phase following stroke. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02650531.

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“…Previous in vitro studies using cultured neurons have reported increased C5a expression with oxygen glucose deprivation (OGD) and stress (53), while C5aR1 deletion prevented OGD-induced neuronal apoptosis. Inhibition of C5aR1 has been shown to attenuate apoptotic neuronal cell death in vitro (61), reduces infarct volume in in vivo stroke models (62,63), and improves recovery in a spinal cord injury model (64). Here, we tested whether IAIP treatment alters C5aR1 expression on neutrophils and whether IAIP-induced neuroprotection is mediated via C5aR1 using C5aR1-knockout mice.…”

Section: Discussionmentioning

confidence: 99%

Exogenous inter-α inhibitor proteins prevent cell death and improve ischemic stroke outcomes in mice

McCullough¹,

Roy-O’Reilly²,

Lai³

et al. 2021

Journal of Clinical Investigation

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Therapeutic Modulation of the Complement Cascade in Stroke

Cited by 21 publications

References 95 publications

Post-Traumatic Sepsis Is Associated with Increased C5a and Decreased TAFI Levels

Post-Traumatic Sepsis Is Associated with Increased C5a and Decreased TAFI Levels

Plasma Inflammatory Biomarkers Are Associated With Poststroke Cognitive Impairment: The Nor-COAST Study

Exogenous inter-α inhibitor proteins prevent cell death and improve ischemic stroke outcomes in mice

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