Secondary injury and inflammation after intracerebral haemorrhage: a systematic review and meta-analysis of molecular markers in patient brain tissue

Loan, James J M; Kirby, Caoimhe; Emelianova, Katherine; Dando, Owen; Poon, Michael T C; Pimenova, Leisan; Hardingham, Giles E.; McColl, Barry W.; Klijn, Catharina J.M.; Salman, Rustam Al-Shahi; Schreuder, Floris H.B.M.; Samarasekera, Neshika

doi:10.1136/jnnp-2021-327098

Cited by 17 publications

(11 citation statements)

References 33 publications

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“…Inflammation, which is the main pathological feature of ICH and the leading factor of HE, plays a key role in the development of hemorrhage-induced brain injury and perihematomal edema. 16 A number of studies have shown that inflammatory markers such as interleukin 6 (IL-6), neutrophils count and CRP were significantly associated with a short-term poor prognosis of ICH. 8,17,18 The neutrophils, as the biomarkers of the severity of systemic inflammation, generally promote the production of chemokines, cytokines, reactive oxygen species (ROS), and extracellular proteases in the brain.…”

Section: Discussionmentioning

confidence: 99%

Association between systemic inflammatory response syndrome and hematoma expansion in intracerebral hemorrhage

Zhu¹,

Xie²,

Shen³

et al. 2022

Adv Clin Exp Med

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Background. Hematoma expansion (HE) is a relatively common complication after intracerebral hemorrhage.Objectives. To explore the association between systemic inflammatory response syndrome (SIRS) and HE in patients with intracerebral hemorrhage (ICH). Materials and methods.From June 2013 to October 2020, the sociodemographic data and clinical data of 780 ICH patients were collected. The logistic regression analysis with odd ratios (ORs) and 95% confidence intervals (95% CIs) was performed to analyze the risk factors for HE in patients with ICH.Results. Hematoma expansion occurred in 151 (19.36%) patients with ICH. Significant differences were presented between SIRS and HE (OR = 2.549, 95% CI: [1.497; 4.342], p = 0.0006). After adjusting the covariates, a further analysis showed that the respiratory rate >20 beats/min (OR = 3.436, 95% CI: [1.981; 5.960], p < 0.0001), white blood cell (WBC) > 12×10 9 /L or WBC ≤ 4×10 9 /L (OR = 2.489, 95% CI: [1.494; 4. 149], p = 0.0005) increased the risk for HE in ICH patients. Our study also found that the significant differences between HE and non-HE patients in proportion of patients with history of diabetes mellitus, basal ganglia hemorrhage, hypothalamus hemorrhage and fasting blood glucose (all p < 0.05) (OR = 2.076, 95% CI: [1.274; 3.381], p = 0.0034), basal ganglia hemorrhage (OR = 2.512, 95% CI: [1.496; 4.218], p = 0.0005), hypothalamus hemorrhage (OR = 2. 121, 95% CI: [1.007; 4.466], p = 0.0479), high C-reactive protein (CRP) (OR = 1.013, 95% CI: [1.002; 1.024], p = 0.0184), and hyperglycemia (OR = 1.099, 95% CI: [1.026; 1. 178], p = 0.0074) were associated with an increased risk of HE in ICH patients. Conclusions.The SIRS is closely associated with the risk of HE. Respiratory rate >20 beats/min and WBC count >12(10 9 /L) or ≤4(10 9 /L) increased the risk for HE in ICH patients. These findings can help to achieve the early prevention of HE and improve the prognosis of ICH patients.

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Section: Discussionmentioning

confidence: 99%

Association between systemic inflammatory response syndrome and hematoma expansion in intracerebral hemorrhage

Zhu¹,

Xie²,

Shen³

et al. 2022

Adv Clin Exp Med

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“…There are limited conclusive data to inform our knowledge of the processes of secondary injury after ICH in humans [ 28 , 29 ]. Consequently, our collective understanding is largely derived from animal studies or single studies of human brain tissue.…”

Section: Secondary Injurymentioning

confidence: 99%

“…Initially, perihaematomal microglia and MdCs in rodents express high levels of transcripts for proinflammatory cytokines Tnf, Il1a and Il1b [ 33 , 49 , 59 ]. In patients, high levels of IL1B are also detectible from 6h after injury, potentially representative of this initial myelomononuclear response [ 28 ]. However, although in mice depletion of “classically reactive” Ccr2+ monocytes is initially associated with reduced neurological deficits and neuronal injury, at later time points Ccr2 + MdCs contribute to haematoma resolution and functional recovery by Axl-dependent efferocytosis of eryptotic erythrocytes [ 33 , 49 , 60 ].…”

Section: Immune Responsesmentioning

confidence: 99%

Activation of Nrf2 to Optimise Immune Responses to Intracerebral Haemorrhage

et al. 2022

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Haemorrhage into the brain parenchyma can be devastating. This manifests as spontaneous intracerebral haemorrhage (ICH) after head trauma, and in the context of vascular dementia. Randomised controlled trials have not reliably shown that haemostatic treatments aimed at limiting ICH haematoma expansion and surgical approaches to reducing haematoma volume are effective. Consequently, treatments to modulate the pathophysiological responses to ICH, which may cause secondary brain injury, are appealing. Following ICH, microglia and monocyte derived cells are recruited to the peri-haematomal environment where they phagocytose haematoma breakdown products and secrete inflammatory cytokines, which may trigger both protective and harmful responses. The transcription factor Nrf2, is activated by oxidative stress, is highly expressed by central nervous system microglia and macroglia. When active, Nrf2 induces a transcriptional programme characterised by increased expression of antioxidant, haem and heavy metal detoxification and proteostasis genes, as well as suppression of proinflammatory factors. Therefore, Nrf2 activation may facilitate adaptive-protective immune cell responses to ICH by boosting resistance to oxidative stress and heavy metal toxicity, whilst limiting harmful inflammatory signalling, which can contribute to further blood brain barrier dysfunction and cerebral oedema. In this review, we consider the responses of immune cells to ICH and how these might be modulated by Nrf2 activation. Finally, we propose potential therapeutic strategies to harness Nrf2 to improve the outcomes of patients with ICH.

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“…Nrf2 agonists may, therefore, have therapeutic potential for improving recovery after ICH in humans. However, there are no published studies directly examining the Nrf2 pathway in human brain tissue after ICH 16. This is important to establish the translational relevance of preclinical experimental studies of Nrf2 activation after ICH.…”

Section: Introductionmentioning

confidence: 99%

Nrf2 activation in the human brain after stroke due to supratentorial intracerebral haemorrhage: a case–control study

et al. 2022

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AimsPharmacological activation of the antioxidative transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) improves outcomes in experimental models of intracerebral haemorrhage (ICH). However, the Nrf2 pathway has not been previously studied in humans after ICH. Our study aims to address this gap.MethodsWe selected cases with fatal ICH from a prospective community-based inception cohort study and age-matched and sex-matched controls who died suddenly of non-neurological disease. We used immunohistochemistry to quantify Nrf2 (% total area stained overall and % of nuclei stained) and CD68 expression in controls and perihaematomal, ipsilateral and contralateral brain tissue from cases. We measured downstream haem oxygenase-1 (HMOX1) and NAD(P)H dehydrogenase quinone 1 [NQO1] expression using RNA in situ hybridisation.Results26 ICH cases (median age: 82 (IQR 76–86); 13 (50%) male) and eight controls (median age: 79 (IQR 77–80); 3 (37.5%) male) were included. We found no significant differences in overall % of Nrf2 staining between ICH cases and controls. However, the mean % of nuclei staining for Nrf2 seemed higher in perihaematomal compared with contralateral regions, although this was only statistically significant >60 days after ICH (25% (95% CI 17% to 33%) vs 14% (95% CI 11% to 17%), p=0.029). The percentage of perihaematomal tissue staining for CD68 was higher >60 days after ICH (6.75%, 95% CI 2.78% to 10.73%) compared with contralateral tissue (1.45%, 95% CI 0.93% to 1.96%, p=0.027) and controls (1.08%, 95% CI 0.20% to 1.97%, p=0.0008). RNA in situ hybridisation suggested increased abundance of HMOX1 and NQO1 transcripts in perihaematomal versus distant ipsilateral brain tissue obtained <7 days from onset of ICH.ConclusionsWe found evidence of Nrf2 activation in human brain tissue after ICH. Pharmacological augmentation of Nrf2 activation after ICH might be a promising therapeutic approach.

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Secondary injury and inflammation after intracerebral haemorrhage: a systematic review and meta-analysis of molecular markers in patient brain tissue

Cited by 17 publications

References 33 publications

Association between systemic inflammatory response syndrome and hematoma expansion in intracerebral hemorrhage

Association between systemic inflammatory response syndrome and hematoma expansion in intracerebral hemorrhage

Activation of Nrf2 to Optimise Immune Responses to Intracerebral Haemorrhage

Nrf2 activation in the human brain after stroke due to supratentorial intracerebral haemorrhage: a case–control study

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