TNFRSF6 induces mitochondrial dysfunction and microglia activation in the in vivo and in vitro models of sepsis-associated encephalopathy.

Sepsis-associated encephalopathy (SAE) is a serious complication of sepsis. The tumour necrosis factor receptor superfamily member 6 (TNFRSF6) gene encodes the Fas protein, and it participates in apoptosis induced in different cell types. This study aimed to explore TNFRSF6 function in SAE. The SAE mouse model was established by intraperitoneal injection of LPS in TNFRSF6-/- mice and C57BL/6J mice. Microglia were treated with LPS to establish the cell model. The learning, memory and cognitive functions in mice were tested by behavioral tests. Nissl staining was utilized for determining neuronal injury. Microglial activation was tested by immunofluorescence assay. ELISA was utilized for determining TNF-α, IL-1ß, IL-6, and IL-10 contents. Mitochondrial dysfunction was measured by mitochondrial oxygen consumption, ATP content, ROS production, and JC-1 assay. TNFRSF6 was upregulated in the LPS-induced mouse model and cell model. TNFRSF6 deficiency notably alleviated the impaired learning, memory and cognitive functions in SAE mice. Furthermore, we found that TNFRSF6 deficiency could alleviate neuronal injury, microglial activation, and inflammation in SAE mice. Additionally, mitochondrial dysfunction in the SAE mice was improved by TNFRSF6 depletion. In the LPS-induced microglia, we also proved that TNFRSF6 knockdown reduced inflammatory response inhibited ROS production, and alleviated mitochondrial dysfunction. TNFRSF6 induced mitochondrial dysfunction and microglia activation in the in vivo and in vitro models of SAE.

Elevated sTREM2 and NFL levels in patients with sepsis associated encephalopathy.

PURPOSE: Sepsis-associated encephalopathy (SAE) is a common manifestation of sepsis that may lead to cognitive decline. Our aim was to investigate whether the neurofilament light chain (NFL) and soluble triggering receptor expressed on myeloid cells 2 (sTREM2) could be utilized as prognostic biomarkers in SAE. MATERIALS AND METHODS: In this prospective observational study, baseline serum levels of sTREM2 and cerebrospinal fluid (CSF) levels of sTREM2 and NFL were measured by ELISA in 11 SAE patients and controls. Patients underwent daily neurological examination. Brain magnetic resonance imaging (MRI) and standard electroencephalography (EEG) were performed. Cognitive dysfunction was longitudinally assessed after discharge in 4 SAE patients using the Mini-Mental State Examination (MMSE) and Addenbrooke's Cognitive Examination-Revised (ACE-R) tests. RESULTS: SAE patients showed higher CSF sTREM2 and NFL levels than controls. sTREM2 and NFL levels were not correlated with the severity measures of sepsis. Three months after discharge, 2 SAE patients displayed ACE-R scores congruent with mild cognitive impairment (MCI), persisting in one patient 12 months after discharge. SAE patients with MCI showed higher CSF NFL levels, bacteremia, and abnormal brain MRI. Patients with increased serum/CSF sTREM2 levels showed trends towards displaying poorer attention/orientation and visuo-spatial skills. CONCLUSIONS: sTREM2 and NFL levels may serve as a prognostic biomarker for cognitive decline in SAE. These results lend further support for the involvement of glial activation and neuroaxonal degeneration in the physiopathology of SAE.

Metabolic Reprogramming of Microglia in Sepsis-Associated Encephalopathy: Insights from Neuroinflammation.

Sepsis-associated encephalopathy (SAE) is a diffuse brain dysfunction caused by sepsis that manifests as a range of brain dysfunctions from delirium to coma. It is a relatively common complication of sepsis associated with poor patient prognosis and mortality. The pathogenesis of SAE involves neuroinflammatory responses, neurotransmitter dysfunction, blood-brain barrier (BBB) disruption, abnormal blood flow regulation, etc. Neuroinflammation caused by hyperactivation of microglia is considered to be a key factor in disease development, which can cause a series of chain reactions, including BBB disruption and oxidative stress. Metabolic reprogramming has been found to play a central role in microglial activation and executive functions. In this review, we describe the pivotal role of energy metabolism in microglial activation and functional execution and demonstrate that the regulation of microglial metabolic reprogramming might be crucial in the development of clinical therapeutics for neuroinflammatory diseases like SAE.

Effect of molecular hydrogen treatment on Sepsis-Associated encephalopathy in mice based on gut microbiota.

INTRODUCTION: In our experiments, male wild-type mice were randomly divided into four groups: the sham, SAE, SAE + 2% hydrogen gas inhalation (H2 ), and SAE + hydrogen-rich water (HW) groups. The feces of the mice were collected for 16 S rDNA analysis 24 h after the models were established, and the serum and brain tissue of the mice were collected for nontargeted metabolomics analysis. AIM: Destruction of the intestinal microbiota is a risk factor for sepsis and subsequent organ dysfunction, and up to 70% of severely ill patients with sepsis exhibit varying degrees of sepsis-associated encephalopathy (SAE). The pathogenesis of SAE remains unclear. We aimed to explore the changes in gut microbiota in SAE and the regulatory mechanism of molecular hydrogen. RESULTS: Molecular hydrogen treatment significantly improved the functional outcome of SAE and downregulated inflammatory reactions in both the brain and the gut. In addition, molecular hydrogen treatment improved gut microbiota dysbiosis and partially amended metabolic disorder after SAE. CONCLUSIONS: Molecular hydrogen treatment promotes functional outcomes after SAE in mice, which may be attributable to increasing beneficial bacteria, repressing harmful bacteria, and metabolic disorder, and reducing inflammation.

Central role of microglia in sepsis-associated encephalopathy: From mechanism to therapy.

Sepsis-associated encephalopathy (SAE) is a cognitive impairment associated with sepsis that occurs in the absence of direct infection in the central nervous system or structural brain damage. Microglia are thought to be macrophages of the central nervous system, devouring bits of neuronal cells and dead cells in the brain. They are activated in various ways, and microglia-mediated neuroinflammation is characteristic of central nervous system diseases, including SAE. Here, we systematically described the pathogenesis of SAE and demonstrated that microglia are closely related to the occurrence and development of SAE. Furthermore, we comprehensively discussed the function and phenotype of microglia and summarized their activation mechanism and role in SAE pathogenesis. Finally, this review summarizes recent studies on treating cognitive impairment in SAE by blocking microglial activation and toxic factors produced after activation. We suggest that targeting microglial activation may be a putative treatment for SAE.

Metformin Improves the Prognosis of Adult Mice with Sepsis-Associated Encephalopathy Better than That of Aged Mice.

Sepsis-associated encephalopathy (SAE) is often associated with increased ICU occupancy and hospital mortality and poor long-term outcomes, with currently no specific treatment. Pathophysiological mechanisms of SAE are complex and may involve activation of microglia, multiple intracranial inflammatory factors, and inflammatory pathways. We hypothesized that metformin may have an effect on microglia, which affects the prognosis of SAE. In this study, metformin treatment of mice with SAE induced by lipopolysaccharide (LPS) reduced the expression of microglia protein and related inflammatory factors. Poor prognosis of SAE is related to increased expression of tumor necrosis factor-α (TNF-α) and interleukin-1 beta (IL-1ß) in brain tissues. Levels of inflammatory cytokines produced by LPS-induced SAE mouse microglia were significantly increased compared with those in the sham group. In addition, ionized calcium-binding adapter molecule 1 (Iba-1) was significantly reduced in metformin-treated SAE mice compared with untreated SAE mice, suggesting that metformin can reduce microgliosis and inhibit central nervous system inflammation, thereby improving patient outcomes. In conclusion, our results stipulate that metformin inhibits inflammation through the adenosine 5'-monophosphate (AMP-) activated protein kinase pathway by inhibiting nuclear factor kappa beta (NF-κB). Metformin can partially reverse the severe prognosis caused by sepsis by blocking microglial proliferation and inhibiting the production of inflammatory factors.

Sepsis-Associated Encephalopathy and Blood-Brain Barrier Dysfunction.

Sepsis is a life-threatening clinical condition caused by a dysregulated host response to infection. Sepsis-associated encephalopathy (SAE) is a common but poorly understood neurological complication of sepsis, which is associated with increased morbidity and mortality. SAE clinical presentation may range from mild confusion and delirium to severe cognitive impairment and deep coma. Important mechanisms associated with SAE include excessive microglial activation, impaired endothelial barrier function, and blood-brain barrier (BBB) dysfunction. Endotoxemia and pro-inflammatory cytokines produced systemically during sepsis lead to microglial and brain endothelial cell activation, tight junction downregulation, and increased leukocyte recruitment. The resulting neuroinflammation and BBB dysfunction exacerbate SAE pathology and aggravate sepsis-induced brain dysfunction. In this mini-review, recent literature surrounding some of the mediators of BBB dysfunction during sepsis is summarized. Modulation of microglial activation, endothelial cell dysfunction, and the consequent prevention of BBB permeability represent relevant therapeutic targets that may significantly impact SAE outcomes.

Senkyunolide I Protects against Sepsis-Associated Encephalopathy by Attenuating Sleep Deprivation in a Murine Model of Cecal Ligation and Puncture.

Sepsis may lead to sleep deprivation, which will promote the development of neuroinflammation and mediate the progression of sepsis-associated encephalopathy (SAE). Senkyunolide I, an active component derived from an herb medicine, has been shown to provide a sedative effect to improve sleep. However, its role in sepsis is unclear. The present study was performed to investigate whether Senkyunolide I protected against SAE in a murine model of cecal ligation and puncture (CLP). Here, we showed that Senkyunolide I treatment improved the 7-day survival rate and reduced the excessive release of cytokines including TNF-α, IL-6, and IL-1ß. A fear conditioning test was performed, and the results showed that Senkyunolide I attenuated CLP-induced cognitive dysfunction. Senkyunolide I treatment also decreased the phosphorylation levels of inflammatory signaling proteins, including p-ERK, p-JNK, p-P38, and p-P65, and the level of inflammatory cytokines, including TNF-α, IL-6, and IL-1ß, in the hippocampus homogenate. Sleep deprivation was attenuated by Senkyunolide I administration, as demonstrated by the modification of the BDNF and c-FOS expression. When sleep deprivation was induced manually, the protective effect of Senkyunolide I against inflammatory responses and cognitive dysfunction was reversed. Our data demonstrated that Senkyunolide I could protect against sepsis-associated encephalopathy in a murine model of sepsis via relieving sleep deprivation.

Sepsis-Associated Encephalopathy: from Pathophysiology to Progress in Experimental Studies.

Sepsis is an organ dysfunction caused by an uncontrolled inflammatory response from the host to an infection. Sepsis is the main cause of morbidity and mortality in intensive care units (ICU) worldwide. One of the first organs to suffer from injuries resulting from sepsis is the brain. The central nervous system (CNS) is particularly vulnerable to damage, mediated by inflammatory and oxidative processes, which can cause the sepsis-associated encephalopathy (SAE), being reported in up to 70% of septic patients. This review aims to bring a summary of the main pathophysiological changes and dysfunctions in SAE, and the main focuses of current experimental studies for new treatments and therapies. The pathophysiology of SAE is complex and multifactorial, combining intertwined processes, and is promoted by countless alterations and dysfunctions resulting from sepsis, such as inflammation, neuroinflammation, oxidative stress, reduced brain metabolism, and injuries to the integrity of the blood-brain barrier (BBB). The treatment is limited once its cause is not completely understood. The patient's sedation is far to provide an adequate treatment to this complex condition. Studies and experimental advances are important for a better understanding of its pathophysiology and for the development of new treatments, medicines, and therapies for the treatment of SAE and to reduce its effects during and after sepsis.

Sepsis promotes gliogenesis and depletes the pool of radial glia like stem cells in the hippocampus.

Sepsis associated encephalopathy (SAE) is a major complication of patients surviving sepsis with a prevalence up to 70%. Although the initial pathophysiological events of SAE are considered to arise during the acute phase of sepsis, there is increasing evidence that SAE leads to persistent brain dysfunction with severe cognitive decline in later life. Previous studies suggest that the hippocampal formation is particularly involved leading to atrophy in later stages. Thereby, the underlying cellular mechanisms are only poorly understood. Here, we hypothesized that endogenous neural stems cells and adult neurogenesis in the hippocampus are impaired following sepsis and that these changes may contribute to persistent cognitive dysfunction when the animals have physically fully recovered. We used the murine sepsis model of peritoneal contamination and infection (PCI) and combined different labeling methods of precursor cells with confocal microscopy studies to assess the neurogenic niche in the dentate gyrus at day 42 postsepsis. We found that following sepsis i) gliogenesis is increased, ii) the absolute number of radial glia-like cells (type 1 cells), which are considered the putative stem cells, is significantly reduced, iii) the generation of new neurons is not significantly altered, while iv) the synaptic spine maturation of new neurons is impaired with a shift to expression of more immature and less mature spines. In conclusion, sepsis mainly leads to depletion of the neural stem cell pool and enhanced gliogenesis in the dentate gyrus which points towards an accelerated aging of the hippocampus due to septic insult.

Serial blood cytokine and chemokine mRNA and microRNA over 48 h are insult specific in a piglet model of inflammation-sensitized hypoxia-ischaemia.

BACKGROUND: Exposure to inflammation exacerbates injury in neonatal encephalopathy (NE). We hypothesized that brain biomarker mRNA, cytokine mRNA and microRNA differentiate inflammation (E. coli LPS), hypoxia (Hypoxia), and inflammation-sensitized hypoxia (LPS+Hypoxia) in an NE piglet model. METHODS: Sixteen piglets were randomized: (i) LPS 2 µg/kg bolus; 1 µg/kg infusion (LPS; n = 5), (ii) Saline with hypoxia (Hypoxia; n = 6), (iii) LPS commencing 4 h pre-hypoxia (LPS+Hypoxia; n = 5). Total RNA was acquired at baseline, 4 h after LPS and 1, 3, 6, 12, 24, 48 h post-insult (animals euthanized at 48 h). Quantitative PCR was performed for cytokines (IL1A, IL6, CXCL8, IL10, TNFA) and brain biomarkers (ENO2, UCHL1, S100B, GFAP, CRP, BDNF, MAPT). MicroRNA was detected using GeneChip (Affymetrix) microarrays. Fold changes from baseline were compared between groups and correlated with cell death (TUNEL) at 48 h. RESULTS: Within 6 h post-insult, we observed increased IL1A, CXCL8, CCL2 and ENO2 mRNA in LPS+Hypoxia and LPS compared to Hypoxia. IL10 mRNA differentiated all groups. Four microRNAs differentiated LPS+Hypoxia and Hypoxia: hsa-miR-23a, 27a, 31-5p, 193-5p. Cell death correlated with TNFA (R = 0.69; p < 0.01) at 1-3 h and ENO2 (R = -0.69; p = 0.01) at 48 h. CONCLUSIONS: mRNA and miRNA differentiated hypoxia from inflammation-sensitized hypoxia within 6 h in a piglet model. This information may inform human studies to enable triage for tailored neuroprotection in NE. IMPACT: Early stratification of infants with neonatal encephalopathy is key to providing tailored neuroprotection. IL1A, CXCL8, IL10, CCL2 and NSE mRNA are promising biomarkers of inflammation-sensitized hypoxia. IL10 mRNA levels differentiated all three pathological states; fold changes from baseline was the highest in LPS+Hypoxia animals, followed by LPS and Hypoxia at 6 h. miR-23, -27, -31-5p and -193-5p were significantly upregulated within 6 h of a hypoxia insult. Functional analysis highlighted the diverse roles of miRNA in cellular processes.

Sepsis-Associated Encephalopathy: Insight into Injury and Pathogenesis.

Sepsis-associated encephalopathy causes long-term health problems in patients with sepsis. This review explores the pathogenesis of sepsis-associated encephalopathy, including its effects on the blood-brain barrier, microglia activation, mitochondrial dysfunction, the inflammatory medium and neurotransmitters and its roles in amino acid balance disorders, hyperammonemia, and intestinal flora imbalance. Understanding the etiology of sepsis-associated encephalopathy may allow the development of adjunctive therapies targeting its underlying mechanism and help develop preventative strategies.

Isoflurane reduces septic neuron injury by HO­1­mediated abatement of inflammation and apoptosis.

Sepsis­associated encephalopathy (SAE) frequently occurs in critically ill patients with severe systemic infections. Subanesthetic isoflurane (0.7% ISO) possesses anti­inflammatory, antioxidant and anti­apoptotic properties against a number of human diseases, including brain injury. The activation of heme oxygenase­1 (HO­1) impedes inflammation, oxidation and apoptosis, thus alleviating sepsis­induced brain damage. However, whether 0.7% ISO affords protection against septic neuronal injury involving HO­1 activation is unclear. The present study aimed to investigate the neuroprotective effects of 0.7% ISO and its potential underlying mechanisms in SAE using a mouse model established by cecal ligation and puncture (CLP). The results indicated that the expression and activity of HO­1 in the mouse hippocampus were increased by CLP, and further enhanced by ISO. ISO reduced the death rate, brain water content and blood­brain barrier disruption, but improved the learning and memory functions of CLP­treated mice. ISO significantly decreased the production of pro­inflammatory cytokines and the levels of oxidative indictors in the serum and hippocampus, as well as the number of apoptotic neurons and the expression of pro­apoptotic proteins in the hippocampus. Inversely, anti­inflammatory factors, antioxidative enzymes and anti­apoptotic proteins were markedly increased by ISO administration. However, the neuroprotective effects of ISO were abolished by a HO­1 inhibitor. Overall, these findings suggested that 0.7% ISO alleviated SAE via its anti­inflammatory, antioxidative and anti­apoptotic properties, which involved the activated form of HO­1.

Electroacupuncture Improves Cognition in Rats With Sepsis-Associated Encephalopathy.

BACKGROUND: Sepsis-associated encephalopathy (SAE) is a common complication of sepsis. Although sepsis is effectively managed with the administration of antibiotics and source control, which may include surgical intervention, SAE usually leads to prolonged cognitive dysfunction affecting the quality of life of the patients. In this study, we investigated the possible effect of electroacupuncture (EA) on cognition in a model of SAE induced by cecal ligation and puncture (CLP). MATERIALS AND METHODS: The rats were randomly divided into four groups: the control group, the CLP group, the CLP with EA treatment group (CLP + EA), and the CLP with sham EA treatment group (CLP + sham EA). EA at DU20, LI11, and ST36 or sham EA was performed 30 min daily for 10 consecutive days starting from 2 days before CLP. Then cognitive function was examined by the Morris water maze test. On day 14 after CLP surgery, the synaptic injury, neuron loss, and oxidative stress were studied. RESULTS: Rats with EA treatment showed improved survival rate, spatial learning, and memory abilities. The dendritic spine density, the synaptic proteins, and the hippocampal neuron number were also increased after EA treatment. Furthermore, EA suppressed oxidative stress through regulating the level of malondialdehyde and superoxide dismutase and enhanced the expression of antioxidant nuclear factor erythroid-2-related factor-2 and hemeoxygenase-1. But sham EA did not have the same effect. CONCLUSIONS: EA may protect against SAE-induced cognitive dysfunction by inhibiting synaptic injury, neuronal loss, and oxidative stress, and the nuclear factor erythroid-2-related factor-2/hemeoxygenase-1 signaling pathway may be involved in this effect.

iTRAQ-based quantitative proteomic analysis of the therapeutic effects of 2% hydrogen gas inhalation on brain injury in septic mice.

Sepsis encephalopathy (SAE) has a high incidence and mortality rate in patients with sepsis; however, there is currently no effective treatment. Our previous studies have reported that 2% hydrogen (H2) gas inhalation had a protective effect on sepsis and SAE; however, the specific mechanism have not been fully elucidated. In the current study, male Institute of Cancer Research mice were either used to create the cecal ligation and puncture (CLP) model or for sham surgery, followed by 2% H2 gas inhalation for 60 min beginning at 1 and 6 h following sham or CLP surgeries. The isobaric tags for relative and absolute quantitation (iTRAQ)-based quantitative proteomics combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis, hematoxylin and eosin (H&E) staining, Nissl staining, and western blot analysis were used to investigate the effects of H2 on brain injury in mice with sepsis. The results of the H&E, and Nissl staining indicated that the CLP mice had a significant brain injury, which was characterized by aggravated pathological damage and was alleviated by 2% H2 inhalation. Quantitative proteomics based on iTRAQ combined with LC-MS/MS analysis quantified a total of 5317 proteins, of which 39 were connected with the protective mechanism of H2. In addition, H2 could regulate the immune and the coagulation systems. Furthermore, western blot analysis revealed that H2 decreased SAE in septic mice by downregulating the protein expression levels of SMAD4, DPYS, PTGDS and upregulating the expression level of CUL4A. These results provide insights into the mechanism of the positive effect of H2 on SAE and contribute to the clinical application of H2 in patients with sepsis.

Sestrin 2 attenuates sepsis-associated encephalopathy through the promotion of autophagy in hippocampal neurons.

Sepsis-associated encephalopathy (SAE) has typically been associated with a poor prognosis. Although sestrin 2 (SESN2) plays a crucial role in metabolic regulation and the stress response, its expression and functional roles in SAE are still unclear. In the present study, SAE was established in mice through caecal ligation and puncture (CLP). The adeno-associated virus 2 (AAV2)-mediated SESN2 expression (ie overexpression and knockdown) system was injected into the hippocampi of mice with SAE, and subsequently followed by electron microscopic analysis, the Morris water maze task and pathological examination. Our results demonstrated an increase of SESN2 in the hippocampal neurons of mice with SAE, 2-16 hours following CLP. AAV2-mediated ectopic expression of SESN2 attenuated brain damage and loss of learning and memory functions in mice with SAE, and these effects were associated with lower pro-inflammatory cytokines in the hippocampus. Mechanistically, SESN2 promoted unc-51-like kinase 1 (ULK1)-dependent autophagy in hippocampal neurons through the activation of the AMPK/mTOR signalling pathway. Finally, AMPK inhibition by SBI-0206965 blocked SESN2-mediated attenuation of SAE in mice. In conclusion, our findings demonstrated that SESN2 might be a novel pharmacological intervention strategy for SAE treatment through promotion of ULK1-dependent autophagy in hippocampal neurons.

The dynamic change of serum S100B levels from day 1 to day 3 is more associated with sepsis-associated encephalopathy.

We investigated the role of dynamic changes of serum levels S100B protein in brain injury and poor outcome of sepsis. This is a prospective cohort study designed to include 104 adult patients with sepsis who are admitted to ICU from Jan 2015 to Aug 2016. Sepsis was defined as sepsis 3.0. Patients with a GCS score of <15, or at least one positive CAM-ICU score were thought to have brain dysfunction. 59 patients were diagnosed with SAE and the rest 45 patients were diagnosed with non-SAE. Serum S100B was measured on day 1 and 3 after ICU admission. Primary outcomes included brain dysfunction and 28-day/180-day mortality. The SAE group showed a significantly higher APACHE II score, SOFA scores, length of ICU stay, 28-day and 180-day mortality, serum S100B levels on day 1 and day 3. S100B levels on day 1 of 0.226 µg/L were diagnostic for SAE with 80.0% specificity and 66.1% sensitivity, and the area under (AUC) the curve was 0.728, S100B levels on day 3 of 0.144 µg/L were diagnostic for SAE with 84.44% specificity and 69.49% sensitivity, and the AUC was 0.819. In addition, the AUC for S100B on day 3 for predicting 180-day mortality was larger than for S100B on day 1 (0.731 vs. 0.611). Multiple logistic regression analysis showed that S100B3 (p = 0.001) but not S100B1 (p = 0.927) were independently correlated with SAE. Kaplan-Meier survival analysis showed that patients with S100B levels higher than 0.144 µg/L had a lower probability of survival at day 180. There were more patients with encephalopathy and a higher 28-day or 180-day mortality in the ΔS100B + group than in the ΔS100B- group. Multiple logistic regression analysis showed that SAE and IL-6 on day 3 were independently correlated with S100B dynamic increase. These findings suggest that elevated serum S100B levels on day 3 and the dynamic changes of serum S100B levels from day three to one were more associated with brain dysfunction and mortality than that on day 1 in patients with sepsis.

Hydrogen attenuates sepsis-associated encephalopathy by NRF2 mediated NLRP3 pathway inactivation.

OBJECTIVE: Sepsis-associated encephalopathy (SAE) is a major cause of mortality worldwide. Oxidative stress, inflammatory response and apoptosis participate in the pathogenesis of SAE. Nuclear factor erythroid 2-related factor 2 (Nrf2) and nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) pathway is involved in oxidative stress and inflammatory response. We reported that hydrogen gas protected against sepsis in wild-type (WT) but not Nrf2 knockout (KO) mice. Therefore, it is vital to identify the underlying cause of hydrogen gas treatment of sepsis-associated encephalopathy. METHODS: SAE was induced in WT and Nrf2 KO mice by cecal ligation and puncture (CLP). As a NLRP3 inflammasome inhibitor, MCC950 (50 mg/kg) was administered by intraperitoneal (i.p.) injection before operation. Hydrogen gas (H2)-rich saline solution (5 mL/kg) was administered by i.p. injection at 1 h and 6 h after sham and CLP operations. Brain tissue was collected to assess the NLRP3 and Nrf2 pathways by western blotting, reverse transcription-polymerase chain reaction (RT-PCR) and immunofluorescence. RESULTS: SAE increased NLRP3 and Nrf2 expression in microglia. MCC950 inhibited SAE-induced NLRP3 expression, interleukin (IL)-1ß and IL-18 cytokine release, neuronal apoptosis and mitochondrial dysfunction. SAE increased NLRP3 and caspase-1 expression in WT mice compared to Nrf2 KO mice. Hydrogen increased Nrf2 expression and inhibited the SAE-induced expression of NLRP3, caspase-1, cytokines IL-1ß and IL-18, neuronal apoptosis, and mitochondrial dysfunction in WT mice but not Nrf2 KO mice. CONCLUSION: SAE increased NLRP3 and Nrf2 expression in microglia. Hydrogen alleviated inflammation, neuronal apoptosis and mitochondrial dysfunction via inhibiting Nrf2-mediated NLRP3 pathway.

Fulminant encephalopathy in a child with hyperferritinemic sepsis: a case report.

BACKGROUND: Sepsis-associated encephalopathy (SAE) is epidemic in intensive care units and recognized as a fatal complication of sepsis. SAE is characterized by diffuse brain dysfunction and the correct diagnosis of SAE requires ruling out direct central nervous system (CNS) infection or other types of encephalopathy, such as hepatic encephalopathy, pulmonary encephalopathy, and other encephalopathy. CASE PRESENTATION: We reported a rare case of a 5-year-old girl who presented with abdominal pain, vomiting, recurrent seizures, and coma. Brain magnetic resonance imaging (MRI) showed diffuse white matter abnormalities in the brain on day 1. Cerebrospinal fluid (CSF) tests revealed that protein levels and glucose levels were normal without pleocytosis. CSF PCRs for pathogens were all negative. The electroencephalography examination demonstrated diffuse, generalized and slow background activity. The patient showed the symptom of hyperferritinemic sepsis with multiple organ dysfunction syndrome (MODS). SAE was also diagnosed by ruling out other encephalitis or encephalopathy. The patient made marked improvements of clinical symptoms and the lesions on brain imaging disappeared completely within two months after appropriate treatment including antibiotic treatments, methylprednisolone, intravenous immunoglobulin, membrane-based therapeutic plasma exchange (TPE), and continuous renal replacement therapy (CRRT). CONCLUSIONS: SAE can be a fatal complication of sepsis which asks for immediate diagnosis and treatment. Few reports have focus on MRI imaging findings on the early onset of hyperferritinemic sepsis with MODS since these children were too ill to undergo an MRI scan. However, SAE might appear before other systemic features of sepsis are obvious, and MRI could show abnormal lesion in the brain during the early course. Therefore, MRI should be performed early to diagnose this fatal complication which would play important roles in improving the clinical outcomes by early initiation with appropriate treatments.

Astroglia in Sepsis Associated Encephalopathy.

Cellular pathophysiology of sepsis associated encephalopathy (SAE) remains poorly characterised. Brain pathology in SAE, which is manifested by impaired perception, consciousness and cognition, results from multifactorial events, including high levels of systemic cytokines, microbial components and endotoxins, which all damage the brain barriers, instigate neuroinflammation and cause homeostatic failure. Astrocytes, being the principal homeostatic cells of the central nervous system contribute to the brain defence against infection. Forming multifunctional anatomical barriers, astroglial cells maintain brain-systemic interfaces and restrict the damage to the nervous tissue. Astrocytes detect, produce and integrate inflammatory signals between immune cells and cells of brain parenchyma, thus regulating brain immune response. In SAE astrocytes are present in both reactive and astrogliopathic states; balance between these states define evolution of pathology and neurological outcomes. In humans pathophysiology of SAE is complicated by frequent presence of comorbidities, as well as age-related remodelling of the brain tissue with senescence of astroglia; these confounding factors further impact upon SAE progression and neurological deficits.