Sepsis-associated encephalopathy: a vicious cycle of immunosuppression

Ren, Chao; Yao, Ren-qi; Zhang, Hui; Feng, Yang; Yao, Yong‐Ming

doi:10.1186/s12974-020-1701-3

Cited by 177 publications

(149 citation statements)

References 149 publications

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“…The occurrence of SAE is one of the main manifestations of organ dysfunction caused by sepsis, excluding clinical or laboratory evidence of a central nervous system infection, a structural abnormality, or another encephalopathy (such as hepatic encephalopathy or uraemic encephalopathy); SAE refers to a diffuse brain dysfunction resulting from sepsis and is mainly exhibited as delirium, cognitive impairment, decreased learning and memory ability, coma, twitch and so on [3,6]. The mechanism may involve the dysfunction of cerebral microvascular cells, the loss of blood-brain barrier integrity, mitochondria dysfunction, the activation of microglia and astrocytes, and neuronal death [7,8]. Currently, the diagnostic criteria and potential risk factors for SAE remain incompletely understood, with no reliable means of clinically evaluating sepsis-associated neurological dysfunction [9].…”

Section: Discussionmentioning

confidence: 99%

A retrospective study of sepsis-associated encephalopathy: epidemiology, clinical features and adverse outcomes

et al. 2020

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Background Sepsis-associated encephalopathy (SAE) is a common complication of sepsis that may result in worse outcomes. This study was designed to determine the epidemiology, clinical features, and risk factors of SAE. Methods This was a retrospective study of all patients with sepsis who were admitted to the Critical Care Medicine Department of Hangzhou First People’s Hospital Affiliated with Zhejiang University School of Medicine from January 2015 to December 2019. Results A total of 291 sepsis patients were screened, and 127 (43.6%) were diagnosed with SAE. There were significant differences in median age, proportion of underlying diseases such as hypertension, Sequential Organ Failure Assessment (SOFA) score, Acute Physiology and Chronic Health Evaluation II (APACHE II) score, gastrointestinal infections, detection rate of Enterococcus, and 28-day mortality between the SAE and non-SAE groups. Both the SOFA score and APACHE II score were independent risk factors for SAE in patients with sepsis. All 127 SAE patients were divided into survival and non-survival groups. The age, SOFA score, and APACHE II score were independently associated with 28-day mortality in SAE patients. Conclusion In the present retrospective study, nearly half of patients with sepsis developed SAE, which was closely related to poor outcomes. Both the SOFA score and APACHE II score were independent risk factors for predicting the occurrence and adverse outcome of SAE.

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Section: Discussionmentioning

confidence: 99%

A retrospective study of sepsis-associated encephalopathy: epidemiology, clinical features and adverse outcomes

et al. 2020

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“…The mortality rate of SAE patients has been reported to be from 26 to 49% higher than that of septic patients without neurological manifestations [4]. Several mechanisms have been proposed regarding the pathogenesis of SAE, these include the dysfunction of blood-brain barrier, the effect of endotoxins, the effect of inflammatory mediators [5,6], neurovascular coupling [7], regulation of vagus nerve [8], and the vicious cycle between brain injury and a progressively aberrant immune response [9]. Nonetheless, there is a lack of effective clinical intervention for SAE currently.…”

Section: Introductionmentioning

confidence: 99%

ProBDNF promotes sepsis-associated encephalopathy in mice by dampening the immune activity of meningeal CD4+ T cells

Luo

Zhong

et al. 2020

J Neuroinflammation

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Background: Sepsis-associated encephalopathy (SAE) increases the mortality of septic patients, but its mechanism remains unclear. The present study aimed to investigate the roles of T lymphocytes, proBDNF, and their interaction in the pathogenesis of SAE. Methods: Fear conditioning tests were conducted for cognitive assessment in the lipopolysaccharide (LPS, 5 mg kg −1)-induced septic mice. Meninges and peripheral blood were harvested for flow cytometry or qPCR. FTY720 and monoclonal anti-proBDNF antibody (McAb-proB) were used to investigate the effect of lymphocyte depletion and blocking proBDNF on the impaired cognitive functions in the septic mice. Results: In the septic mice, cognitive function was impaired, the percentage of CD4 + T cells were decreased in the meninges (P = 0.0021) and circulation (P = 0.0222), and pro-inflammatory cytokines were upregulated, but the antiinflammatory cytokines interleukin (IL)-4 (P < 0.0001) and IL-13 (P = 0.0350) were downregulated in the meninges. Lymphocyte depletion by intragastrically treated FTY720 (1 mg kg −1) for 1 week ameliorated LPS-induced learning deficit. In addition, proBDNF was increased in the meningeal (P = 0.0042) and peripheral (P = 0.0090) CD4 + T cells. Intraperitoneal injection of McAb-proB (100 μg) before LPS treatment significantly alleviated cognitive dysfunction, inhibited the downregulation of meningeal (P = 0.0264) and peripheral (P = 0.0080) CD4 + T cells, and normalized the gene expression of cytokines in the meninges. However, intra-cerebroventricular McAb-proB injection (1 μg) did not have such effect. Finally, exogenous proBDNF downregulated the percentage of CD4 + T cells in cultured splenocytes from septic mice (P = 0.0021). Conclusion: Upregulated proBDNF in immune system promoted the pathogenesis of SAE through downregulating the circulating CD4 + T cells, limiting its infiltration into the meninges and perturbing the meningeal pro-/antiinflammatory homeostasis.

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“…In ammatory cytokines, BBB destruction, ischemic processes, neurotransmitter changes, and mitochondrial dysfunction may be involved in this complex process, but its speci c mechanisms have not yet been established [34]. However, uncontrolled neuroin ammation and ischemic injury are closely related to brain injury after sepsis [35]. Neuroin ammation is a major component of the pathology and progression of many neurological and neurodegenerative diseases [36].…”

Section: Discussionmentioning

confidence: 99%

INT-777 Improves Cognitive Impairment after Sepsis by Attenuating Neuroinflammation Through the TGR5/cAMP/PKA/CREB Signaling Axis in Rats

Jin

Deng

Tian

et al. 2020

Preprint

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Background: Sepsis survivors are left with significant cognitive and behavioral impairments after discharge, but research on the relevant mechanisms and interventions remains lacking. TGR5 plays a neuroprotective role in many neurologic disease models through different mechanisms. To date, no studies have assessed the effects of TGR5 on neuroinflammation or cognitive or behavioral changes in sepsis models.Methods: A total of 267 eight-week-old male Sprague-Dawley rats were used in this study. Sepsis was induced by cecal ligation and puncture (CLP). All animals received volume resuscitation. The rats were given TGR5 CRISPR oligonucleotide intracerebroventricularly 48 hours before CLP surgery. INT-777 was administered intranasally 1 hour after CLP, and the cAMP inhibitor SQ22536 was administered intracerebroventricularly 1 hour after CLP. Survival rate, bodyweight change, clinical score, neurobehavioral tests, western blot, and immunofluorescence staining were performed. The cognitive function of rats was measured by Morris water maze during 15-20 days after CLP.Results: The expression of TGR5 in the rat hippocampus was upregulated and peaked at 3 days after CLP. The survival rate of rats after CLP was less than 50%, and the growth rate in terms of weight was significantly decreased, while these changes were not improved by INT-777 treatment. However, INT-777 treatment reduced the clinical scores of rats at 24 hours after CLP. On day 15 and later, the surviving mice completed a series of behavioral tests. CLP rats showed spatial and memory deficits and anxiety-like behaviors, and INT-777 treatment significantly improved these effects. Mechanistically, immunofluorescence analysis showed that INT-777 treatment reduced the number of microglia in the hippocampus, neutrophil infiltration and the expression of inflammatory factors after CLP in rats. Moreover, INT-777 treatment significantly increased the expression of TGR5, cAMP, p-PKA, and p-CREB and downregulated the expression of IL-1β, IL-6 and TNF-α. CRISPR-mediated TGR5 knockdown and SQ22536 treatment abolished the neuroprotective effects of TGR5 activation after CLP.Conclusion: This study demonstrates that INT-777 treatment reduced neuroinflammation and microglial cell activation, and then improved cognitive impairment in the experimental sepsis rats. TGR5 has translational potential as a therapeutic target to improve neurological outcomes in sepsis survivors.

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Sepsis-associated encephalopathy: a vicious cycle of immunosuppression

Cited by 177 publications

References 149 publications

A retrospective study of sepsis-associated encephalopathy: epidemiology, clinical features and adverse outcomes

A retrospective study of sepsis-associated encephalopathy: epidemiology, clinical features and adverse outcomes

ProBDNF promotes sepsis-associated encephalopathy in mice by dampening the immune activity of meningeal CD4+ T cells

INT-777 Improves Cognitive Impairment after Sepsis by Attenuating Neuroinflammation Through the TGR5/cAMP/PKA/CREB Signaling Axis in Rats

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