Inflammatory Events Following Subarachnoid Hemorrhage (SAH)

Schneider, Ulf C.; Xu, Rihao; Vajkoczy, Peter

doi:10.2174/1570159x16666180412110919

Cited by 81 publications

(73 citation statements)

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“…Microglia are the primary innate immune effector cells of the central nervous system (CNS) with a similar function to macrophages. Intracerebral and subarachnoid hemorrhages (ICH and SAH, respectively) are associated with activation of microglia and growing evidence suggest that inflammation is the key contributor of secondary brain injury induced by ICH or SAH (108,109). Microglia have an important function in hematoma resolution by phagocytosing RBCs which process is mediated by the class B scavenger receptor CD36 (110,111).…”

Section: Activation Of Microglia By Hb-derived Dampsmentioning

confidence: 99%

Pro-inflammatory Actions of Heme and Other Hemoglobin-Derived DAMPs

2020

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Damage associated molecular patterns (DAMPs) are endogenous molecules originate from damaged cells and tissues with the ability to trigger and/or modify innate immune responses. Upon hemolysis hemoglobin (Hb) is released from red blood cells (RBCs) to the circulation and give a rise to the production of different Hb redox states and heme which can act as DAMPs. Heme is the best characterized Hb-derived DAMP that targets different immune and non-immune cells. Heme is a chemoattractant, activates the complement system, modulates host defense mechanisms through the activation of innate immune receptors and the heme oxygenase-1/ferritin system, and induces innate immune memory. The contribution of oxidized Hb forms is much less studied, but some evidence show that these species might play distinct roles in intravascular hemolysis-associated pathologies independently of heme release. This review aims to summarize our current knowledge about the formation and pro-inflammatory actions of heme and other Hb-derived DAMPs.

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Section: Activation Of Microglia By Hb-derived Dampsmentioning

confidence: 99%

Pro-inflammatory Actions of Heme and Other Hemoglobin-Derived DAMPs

2020

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“…Brain injury after aneurysmal subarachnoid hemorrhage (aSAH) is a multimodal process that includes early brain injury and delayed cerebral ischemia (DCI). The mechanisms that lead to DCI are not fully understood 1 . The pathogenesis of DCI is hypothesized to include cerebral vasospasm (VSP), cortical spreading ischemia, microthrombosis and constriction of the microcirculation 2 .…”

Section: Introductionmentioning

confidence: 99%

Preliminary results in the analysis of the immune response after aneurysmal subarachnoid hemorrhage

Roa

Sarkar

Zanaty

et al. 2020

Sci Rep

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Cerebral vasospasm (VSP) is a common phenomenon after aneurysmal subarachnoid hemorrhage (aSAH) and contributes to neurocognitive decline. The natural history of the pro-inflammatory immune response after aSAH has not been prospectively studied in human cerebrospinal fluid (CSF). In this pilot study, we aimed to identify specific immune mediators of VSP after aSAH. Peripheral blood (PB) and CSF samples from patients with aSAH were prospectively collected at different time-points after hemorrhage: days 0–1 (acute); days 2–4 (pre-VSP); days 5–9 (VSP) and days 10 + (post-VSP peak). Presence and severity of VSP was assessed with computed tomography angiography/perfusion imaging and clinical examination. Cytokine and immune mediators’ levels were quantified using ELISA. Innate and adaptive immune cells were characterized by flow cytometry, and cell counts at different time-points were compared with ANOVA. Confocal immunostaining was used to determine the presence of specific immune cell populations detected in flow cytometry. Thirteen patients/aneurysms were included. Five (38.5%) patients developed VSP after a mean of 6.8 days from hemorrhage. Flow cytometry demonstrated decreased numbers of CD45+ cells during the acute phase in PB of aSAH patients compared with healthy controls. In CSF of VSP patients, NK cells (CD3-CD161 +) were increased during the acute phase and progressively declined, whereas CD8+CD161+ lymphocytes significantly increased at days 5–9. Microglia cells (CD45dimCD11b +) increased over time after SAH. This increase was particularly significant in patients with VSP. Levels of VEGF and MMP-9 were consistently higher in VSP patients, with the highest difference occurring at the acute phase. Confocal immunostaining demonstrated the presence of CD8+CD161+ lymphocytes in the arterial wall of two unruptured intracranial aneurysms. In this preliminary study, human CSF showed active presence of innate and adaptive immune cells after aSAH. CD8+CD161+ lymphocytes may have an important role in the inflammatory response after aneurysmal rupture and were identified in the aneurysmal wall of unruptured brain aneurysms. Microglia activation occurs 6 + days after aSAH.

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“…In conclusion, cerebral NO concentrations are highly elevated within the first 7 days after SAH, predominantly from inflammatory sources based on the literature [14,37]. In vivo elevated NO levels were strongly correlated with cerebral lactate and pyruvate levels (and LPR), as well as with the During the next phase, damaged cells are supposed to release damageassociated molecular patterns (DAMPs), which activate aseptic inflammation in the brain tissue.…”

Section: Discussionmentioning

confidence: 94%

Cerebral nitric oxide and mitochondrial function in patients suffering aneurysmal subarachnoid hemorrhage—a translational approach

et al. 2020

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Background Cerebral ischemia and neuroinflammation following aneurysmal subarachnoid hemorrhage (SAH) are major contributors to poor neurological outcome. Our study set out to investigate in an exploratory approach the interaction between NO and energy metabolism following SAH as both hypoxia and inflammation are known to affect nitric oxide (NO) metabolism and NO in turn affects mitochondria. Methods In seven patients under continuous multimodality neuromonitoring suffering poor-grade aneurysmal SAH, cerebral metabolism and NO levels (determined as a sum of nitrite plus nitrate) were determined in cerebral microdialysate for 14 days following SAH. In additional ex vivo experiments, rat cortex homogenate was subjected to the NO concentrations determined in SAH patients to test whether these NO concentrations impair mitochondrial function (determined by means of high-resolution respirometry). Results NO levels showed biphasic kinetics with drastically increased levels during the first 7 days (74.5 ± 29.9 μM) and significantly lower levels thereafter (47.5 ± 18.7 μM; p = 0.02). Only during the first 7 days, NO levels showed a strong negative correlation with brain tissue oxygen tension (r = − 0.78; p < 0.001) and a positive correlation with cerebral lactate (r = 0.79; p < 0.001), pyruvate (r = 0.68; p < 0.001), glutamate (r = 0.65; p < 0.001), as well as the lactate-pyruvate ratio (r = 0.48; p = 0.01), suggesting mitochondrial dysfunction. Ex vivo experiments confirmed that the increase in NO levels determined in patients during the acute phase is sufficient to impair mitochondrial function (p < 0.001). Mitochondrial respiration was inhibited irrespectively of whether glutamate (substrate of complex I) or succinate (substrate of complex II) was used as mitochondrial substrate suggesting the inhibition of mitochondrial complex IV. The latter was confirmed by direct determination of complex IV activity. Conclusions Exploratory analysis of our data suggests that during the acute phase of SAH, NO plays a key role in the neuronal damage impairing mitochondrial function and facilitating accumulation of mitochondrial substrate; further studies are required to understand mechanisms underlying this observation.

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Inflammatory Events Following Subarachnoid Hemorrhage (SAH)

Cited by 81 publications

References 100 publications

Pro-inflammatory Actions of Heme and Other Hemoglobin-Derived DAMPs

Pro-inflammatory Actions of Heme and Other Hemoglobin-Derived DAMPs

Preliminary results in the analysis of the immune response after aneurysmal subarachnoid hemorrhage

Cerebral nitric oxide and mitochondrial function in patients suffering aneurysmal subarachnoid hemorrhage—a translational approach

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