scholarly journals TNF-α Impairs Pericyte-Mediated Cerebral Microcirculation via the NF-κB/iNOS Axis After Experimental Traumatic Brain Injury

2021 ◽  
Author(s):  
Shaorui Zheng ◽  
Cheng Wang ◽  
Long Lin ◽  
Shuwen Mu ◽  
Haibing Liu ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Oxidative Damage ◽  
Laser Speckle ◽  
Immunofluorescent Staining ◽  
Cerebral Microcirculation ◽  
Bv2 Cells ◽  
Tnf Α ◽  
Severity Scores ◽  
The Impact

Abstract Background Secondary structural and functional abnormalities of the neurovascular unit are important pathological mechanisms following traumatic brain injury (TBI). The tumor necrosis factor α (TNF-α)/nuclear factor-κB (NF-κB) pathway regulates neuroinflammation and oxidative damage, which may act as triggers for pathological processes after TBI. However, the role of TNF-α/NF-κB in pericyte-mediated cerebral microcirculation are currently unknown. Methods We assessed the activity and mechanisms of the TNF-α/NF-κB signaling axis on pericyte-mediated microcirculation using the mouse controlled cortical impact model and BV2 cells. Immunofluorescent staining and western blot analysis were used to detect activation of the TNF-α/NF-κB signaling pathway and the expression of inducible nitric oxide synthase (iNOS) to evaluate the effects of the TNF-α specific inhibitor infliximab (IFX). Modified neurological severity scores, Garcia test, Nissl staining, and TUNEL staining were employed to determine the neuroprotective effects of IFX supplementation. The relative blood flow values in the capillary areas surrounding the impinging lesion were observed by Laser speckle contrast imaging. The impact of IFX on pericyte markers was assessed to evaluate whether pericyte damage was dependent on the TNF-α/NF-κB/iNOS axis to gain further insight into the mechanisms underlying the development of the microcirculation disturbance after TBI. Results Microglia were activated after TBI, and the expression of NF-κB, iNOS, a disintegrin and metalloproteinase 17, inflammatory factors, and free radicals increased around the injury areas. After lipopolysaccharide treatment, the expression of TNF-α and downstream NF-κB/iNOS in BV2 cells was significantly upregulated. Pharmacological inhibition of TNF-α via IFX significantly reduced NF-κB p65 phosphorylation and nuclear translocation and downregulated iNOS expression. Meanwhile, we found that specific inhibition of TNF-α reversed pericyte marker loss, and improved pericyte function and cerebral microcirculation perfusion after TBI, which could attenuate inflammation and oxidative damage, reduce neuronal cell damage and apoptosis, and play a neuroprotective role. Conclusion The results of this study suggested that microglia activated and released TNF-α after TBI, which promoted neuroinflammation and oxidative stress by activating downstream NF-κB/iNOS signals, and this led to pericyte-mediated disturbance of the cerebral microcirculation, which may be one of the vital mechanisms of secondary injury in TBI.

scholarly journals FTO Regulates Microglia-Induced Inflammation by Stabilizing ADAM17 Expression After Experimental Traumatic Brain Injury

2022 ◽  
Author(s):  
Xiangrong Chen ◽  
Jieran Yao ◽  
Yue Chen ◽  
Wenqi Lv ◽  
Yuanxiang Lin ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Epigenetic Modification ◽  
Down Regulation ◽  
Neuroinflammatory Response ◽  
Microglial Polarization ◽  
Bv2 Cells ◽  
Tnf Α ◽  
Experimental Traumatic Brain Injury

Abstract Background The neuroinflammatory response mediated by microglial polarization plays an important role in the secondary nerve injury of traumatic brain injury (TBI). The post-transcriptional modification of n6-methyladenosine (m6A) is ubiquitous in the immune response of the central nervous system. The fat mass and obesity (FTO)-related protein can regulate the splicing process of pre-mRNA. However, after experimental traumatic brain injury (TBI), the role of FTO in microglial polarization and the subsequent neuroinflammatory response is still unclear. Methods TBI mice model was established by the Feeney weight-drop method. Neurological severity score, brain water content measurement and Nissl staining were used to detect the role of FTO in microglial polarization and the molecular mechanism of targeted RNA epigenetic modification. In vitro and in vivo experiments were conducted to evaluate microglial polarization and the neuroinflammatory response by down-regulation of FTO expression. The level of m6A modification in M1 activated microglia was detected by qRT-PCR, m6A-MeRIP and m6A high-throughput sequencing. Fluorescent in situ hybridization combined with immunofluorescence imaging were used to detect the epigenetic regulation of ADAM17 mediated by an FTO-m6A-dependent mechanism. Results The expression of FTO was significantly down-regulated in BV2 cells treated with lipopolysaccharide and mice with TBI. Down-regulation of FTO expression increased the level of m6A in M1 microglia at the level of the entire transcriptome. Meanwhile, after FTO interference, M1/M0 phenotype detection experiments revealed the BV2 cells shifted from an M0 to M1 phenotype as the population rate of CD11b+/CD86+ increased and secretion of pro-inflammatory cytokines was enhanced. Methylated RNA immunoprecipitation assay showed that the m6A peaks located in the ADAM17 and TNF-α genes increased. Taken together, the results indicated that FTO can affect the transcription modification of ADAM17 and the expression of the downstream TNF-α/NF-kB pathway. In turn, ADAM17 can block the M1-phenotypic transition of microglia driven by FTO-m6A modification. Conclusions The down-regulation of FTO expression leads to the abnormally high expression of ADAM17 in microglia. The activation of microglia and neuroinflammatory response regulated by FTO-related m6A modification play an important role in the early pro-inflammatory process of TBI secondary injury.

Mechanism of death after early decompressive craniectomy in traumatic brain injury

Trauma ◽  
2016 ◽  
Vol 20 (3) ◽  
pp. 175-182 ◽  
Author(s):  
FA Zeiler ◽  
K Trickey ◽  
L Hornby ◽  
SD Shemie ◽  
BWY Lo ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Decompressive Craniectomy ◽  
Injury Severity ◽  
Circulatory Arrest ◽  
Multivariate Regression Analysis ◽  
Societal Implications ◽  
Severity Scores ◽  
Significant Difference ◽  
The Impact

Background Decompressive craniectomy in devastating traumatic brain injury is controversial. The impact of decompressive craniectomy on mechanism of death is unclear in the literature to date. Our goal was to determine the mechanism of death between those receiving early decompressive craniectomy and those managed medically. Methods We performed an institutional retrospective review, from June 2003 to June 2013, of adult patients with devastating blunt traumatic brain injury undergoing early decompressive craniectomy who subsequently died. We compared this group to a retrospectively matched group based on: age, pre-hospital KPS, Marshall diffuse computed tomography grades, Injury Severity Scores, and admission laboratory values. Results Forty patients were analyzed; 20 with decompressive craniectomy and 20 without. The two groups were similar based on admission demographics, with the only statistically significant difference being platelet levels. Upon analysis, through both univariate and multivariate regression analysis, the mechanism of death was significantly different (p = 0.003; OR: 0.07 (0.01–0.41) and p = 0.04; OR: 0.08 (0.01–0.87)) with the decompressive craniectomy and non-decompressive craniectomy groups displaying neurological death rates of 10.0% versus 60.0%, respectively, with all other patients in both groups dying secondary to circulatory arrest after withdrawal of life-sustaining therapy. Time to death was significantly longer in the decompressive craniectomy group (2.83 vs. 9.21 days, respectively) (p = 0.01; OR: 0.65 (0.46–0.91). Conclusions Progression to neurological death appears to be more common in those devastating blunt traumatic brain injury patients treated medically compared to those undergoing early decompressive craniectomy. Given the implications of end-of-life care and societal implications, the mechanism of death determination and organ donation should be reported as relevant outcomes in devastating traumatic brain injury studies.

scholarly journals iTRAQ-based proteomic profiling reveals protein alterations after traumatic brain injury and supports thyroxine as a potential treatment

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Zhongxiang Zhang ◽  
Jiangtao Yu ◽  
Pengcheng Wang ◽  
Lian Lin ◽  
Ruining Liu ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Large Scale ◽  
Transcriptional Level ◽  
Proteomic Profiling ◽  
Severity Scores ◽  
Itraq Proteomics ◽  
Protein Alterations ◽  
The Impact

AbstractTraumatic brain injury (TBI) is a primary cause of disability and death across the world. Previously, RNA analysis was widely used to study the pathophysiological mechanisms underlying TBI; however, the relatively low correlation between the transcriptome and proteome revealed that RNA transcription abundance does not reliably predict protein abundance, which led to the emergence of proteomic research. In this study, an iTRAQ proteomics approach was applied to detect protein alterations after TBI on a large scale. A total of 3937 proteins were identified, and 146 proteins were significantly changed after TBI. Moreover, 23 upregulated proteins were verified by parallel reaction monitoring (PRM), and fold changes in 16 proteins were consistent with iTRAQ outcomes. Transthyretin (Ttr) upregulation has been demonstrated at the transcriptional level, and this study further confirmed this at the protein level. After treatment with thyroxine (T4), which is transported by Ttr, the effects of T4 on neuronal histopathology and behavioral performance were determined in vivo (TBI + T4 group). Brain edema was alleviated, and the integrity of the blood brain barrier (BBB) improved. Escape latency in the Morris water maze (MWM) declined significantly compared with the group without T4 treatment. Modified neurological severity scores (mNSS) of the TBI + T4 group decreased from day 1 to day 7 post-TBI compared with the TBI + saline group. These results indicate that T4 treatment has potential to alleviate pathologic and behavioral abnormalities post-TBI. Protein alterations after T4 treatment were also detected by iTRAQ proteomics. Upregulation of proteins like Lgals3, Gfap and Apoe after TBI were reversed by T4 treatment. GO enrichment showed T4 mainly affected intermediate filament organization, cholesterol transportation and axonal regeneration. In summary, iTRAQ proteomics provides information about the impact of TBI on protein alterations and yields insight into underlying mechanisms and pathways involved in TBI and T4 treatment. Finally, Ttr and other proteins identified by iTRAQ may become potential novel treatment targets post-TBI.

scholarly journals Brain death rates in severe blunt traumatic brain injury: comparison of decompressive craniectomy to a medically managed cohort

2015 ◽  
Vol 42 (S1) ◽  
pp. S17-S17
Author(s):  
FA Zeiler ◽  
J Teitelbaum
Keyword(s):  
Traumatic Brain Injury ◽  
Cardiac Arrest ◽  
Brain Injury ◽  
Brain Death ◽  
Cause Of Death ◽  
Decompressive Craniectomy ◽  
Matched Cohort ◽  
Severity Scores ◽  
The Mean ◽  
The Impact

Introduction: Decompressive craniectomy (DC) in severe traumatic brain injury (TBI) is controversial. The impact DC on cause of death is unclear in the literature to date. Methods: We performed an institutional retrospective review, from June 2003 to June 2013, of patients with severe blunt TBI undergoing DC whom subsequently died. We compared this group to a retrospectively matched cohort based: age, pre-hospital mRS, Marshall diffuse and TBI grades, Injury Severity Scores, and admission laboratory values. The goal was to determine the cause of death between those receiving DC and those managed medically. Results: Nineteen patients received DC and were compared to 16 retrospectively matched patients. The mean age of the DC and matched cohort were 47.1 and 43.6 years, respectively. The mean admission GCS/Marshall diffuse CT grades were 5.8/3.4 for the DC group, and 4.1/3.1 for the matched medical cohort. Overall, in the DC group 94.7% of the deaths occurred secondary to cardiac arrest after withdrawal of life sustaining treatment (WLST), with only 5.3% progressing to brain death. Alternatively, in the matched cohort 62.5% died of cardiac arrest post WLST, with 37.5% progressing to brain death. Conclusions: Progression to brain death appears to be more common in those severe blunt TBI patients treated medically compared to those undergoing DC.

scholarly journals Outcome Prediction after Traumatic Brain Injury: Comparison of the Performance of Routinely Used Severity Scores and Multivariable Prognostic Models

2017 ◽  
Vol 08 (01) ◽  
pp. 020-029 ◽  
Author(s):  
Marek Majdan ◽  
Alexandra Brazinova ◽  
Martin Rusnak ◽  
Johannes Leitgeb
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Injury Severity ◽  
Performance Outcomes ◽  
Prognostic Models ◽  
Operating Characteristics ◽  
Head Region ◽  
Computed Tomographic ◽  
Severity Scores ◽  
The Impact

ABSTRACT Objectives: Prognosis of outcome after traumatic brain injury (TBI) is important in the assessment of quality of care and can help improve treatment and outcome. The aim of this study was to compare the prognostic value of relatively simple injury severity scores between each other and against a gold standard model – the IMPACT-extended (IMP-E) multivariable prognostic model. Materials and Methods: For this study, 866 patients with moderate/severe TBI from Austria were analyzed. The prognostic performances of the Glasgow coma scale (GCS), GCS motor (GCSM) score, abbreviated injury scale for the head region, Marshall computed tomographic (CT) classification, and Rotterdam CT score were compared side-by-side and against the IMP-E score. The area under the receiver operating characteristics curve (AUC) and Nagelkerke's R 2 were used to assess the prognostic performance. Outcomes at the Intensive Care Unit, at hospital discharge, and at 6 months (mortality and unfavorable outcome) were used as end-points. Results: Comparing AUCs and R 2s of the same model across four outcomes, only little variation was apparent. A similar pattern is observed when comparing the models between each other: Variation of AUCs <±0.09 and R 2s by up to ±0.17 points suggest that all scores perform similarly in predicting outcomes at various points (AUCs: 0.65–0.77; R 2s: 0.09–0.27). All scores performed significantly worse than the IMP-E model (with AUC > 0.83 and R 2 > 0.42 for all outcomes): AUCs were worse by 0.10–0.22 (P < 0.05) and R 2s were worse by 0.22–0.39 points. Conclusions: All tested simple scores can provide reasonably valid prognosis. However, it is confirmed that well-developed multivariable prognostic models outperform these scores significantly and should be used for prognosis in patients after TBI wherever possible.

GCS-Pupil Score Has a Stronger Association with Mortality and Poor Functional Outcome than GCS Alone in Pediatric Severe Traumatic Brain Injury

2021 ◽  
pp. 1-8
Author(s):  
Binod Balakrishnan ◽  
Heather VanDongen-Trimmer ◽  
Irene Kim ◽  
Sheila J. Hanson ◽  
Liyun Zhang ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Functional Outcome ◽  
Cerebral Performance Category ◽  
Regression Tree ◽  
Classification And Regression Tree ◽  
Continuous Variables ◽  
Poor Functional Outcome ◽  
Severity Scores ◽  
Pupil Reactivity

<b><i>Background:</i></b> The Glasgow Coma Scale (GCS), used to classify the severity of traumatic brain injury (TBI), is associated with mortality and functional outcomes. However, GCS can be affected by sedation and neuromuscular blockade. GCS-Pupil (GCS-P) score, calculated as GCS minus Pupil Reactivity Score (PRS), was shown to better predict outcomes in a retrospective cohort of adult TBI patients. We evaluated the applicability of GCS-P to a large retrospective pediatric severe TBI (sTBI) cohort. <b><i>Methods:</i></b> Admissions to pediatric intensive care units in the Virtual Pediatric Systems (VPS, LLC) database from 2010 to 2015 with sTBI were included. We collected GCS, PRS (number of nonreactive pupils), cardiac arrest, abusive head trauma status, illness severity scores, pediatric cerebral performance category (PCPC) score, and mortality. GCS-P was calculated as GCS minus PRS. χ<sup>2</sup> or Fisher’s exact test and Mann-Whitney U test compared categorical and continuous variables, respectively. Classification and regression tree analysis identified thresholds of GCS-P and GCS along with other independent factors which were further examined using multivariable regression analysis to identify factors independently associated with mortality and unfavorable PCPC at PICU discharge. <b><i>Results:</i></b> Among the 2,682 patients included in the study, mortality was 23%, increasing from 4.7% for PRS = 0 to 80% for PRS = 2. GCS-P identified more severely injured patients with GCS-P scores 1 and 2 who had worse outcomes. GCS-P ≤ 2 had higher odds for mortality, OR = 68.4 (95% CI = 50.6–92.4) and unfavorable PCPC, OR = 17.3 (8.1, 37.0) compared to GCS ≤ 5. GCS-P ≤ 2 also had higher specificity and positive predictive value for both mortality and unfavorable PCPC compared to GCS ≤ 5. <b><i>Conclusions:</i></b> GCS-P, by incorporating pupil reactivity to GCS scoring, is more strongly associated with mortality and poor functional outcome at PICU discharge in children with sTBI.

Shenfu injection improves cerebral microcirculation and reduces brain injury in a porcine model of hemorrhagic shock; SFI reduces brain injury after hemorrhagic shock

2021 ◽  
pp. 1-11
Author(s):  
Junyuan Wu ◽  
Zhiwei Li ◽  
Wei Yuan ◽  
Qiang Zhang ◽  
Yong Liang ◽  
...  
Keyword(s):  
Brain Injury ◽  
Hemorrhagic Shock ◽  
Interleukin 6 ◽  
Aquaporin 4 ◽  
Flow Index ◽  
Sham Operation ◽  
Volume Resuscitation ◽  
Cerebral Microcirculation ◽  
Shenfu Injection ◽  
Tnf Α

BACKGROUND: Shenfu injection (SFI) is a traditional Chinese herbal medicine which has been clinically used for treatment of septic shock and cardiac shock. The aim of this study was to clarify effects of SFI on cerebral microcirculation and brain injury after hemorrhagic shock (HS). METHODS: Twenty-one domestic male Beijing Landrace pigs were randomly divided into three groups: SFI group (SFI, n = 8), saline group (SA, n = 8) or sham operation group (SO, n = 5). In the SFI group, animals were induced to HS by rapid bleeding to a mean arterial pressure of 40 mmHg within 10 minutes and maintained at 40±3 mmHg for 60 minutes. Volume resuscitation (shed blood and crystalloid) and SFI were given after 1 hour of HS. In the SA group, animals received the same dose of saline instead of SFI. In the SO group, the same surgical procedure was performed but without inducing HS and volume resuscitation. The cerebral microvascular flow index (MFI), nitric oxide synthase (NOS) expression, aquaporin-4 expression, interleukin-6, tumor necrosis factor-α (TNF-α) and ultrastructural of microvascular endothelia were measured. RESULTS: Compared with the SA group, SFI significantly improved cerebral MFI after HS. SFI up regulated cerebral endothelial NOS expression, but down regulated interleukin-6, TNF-α, inducible NOS and aquaporin-4 expression compared with the SA group. The cerebral microvascular endothelial injury and interstitial edema in the SFI group were lighter than those in the SA group. CONCLUSIONS: Combined application of SFI with volume resuscitation after HS can improve cerebral microcirculation and reduce brain injury.

Impact of routine S100B protein assay on CT scan use in children with mild traumatic brain injury

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Fleur Lorton ◽  
Jeanne Simon-Pimmel ◽  
Damien Masson ◽  
Elise Launay ◽  
Christèle Gras-Le Guen ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Mild Traumatic Brain Injury ◽  
University Hospital ◽  
S100b Protein ◽  
Research Network ◽  
Ct Scans ◽  
Intermediate Risk ◽  
Protein Assay ◽  
The Impact

AbstractObjectivesTo evaluate the impact of implementing a modified Pediatric Emergency Care Applied Research Network (PECARN) rule including the S100B protein assay for managing mild traumatic brain injury (mTBI) in children.MethodsA before-and-after study was conducted in a paediatric emergency department of a French University Hospital from 2013 to 2015. We retrospectively included all consecutive children aged 4 months to 15 years who presented mTBI and were at intermediate risk for clinically important traumatic brain injury (ciTBI). We compared the proportions of CT scans performed and of in-hospital observations before (2013–2014) and after (2014–2015) implementation of a modified PECARN rule including the S100B protein assay.ResultsWe included 1,062 children with mTBI (median age 4.5 years, sex ratio [F/M] 0.73) who were at intermediate risk for ciTBI: 494 (46.5%) during 2013–2014 and 568 (53.5%) during 2014–2015. During 2014–2015, S100B protein was measured in 451 (79.4%) children within 6 h after mTBI. The proportion of CT scans and in-hospital observations significantly decreased between the two periods, from 14.4 to 9.5% (p=0.02) and 73.9–40.5% (p<0.01), respectively. The number of CT scans performed to identify a single ciTBI was reduced by two-thirds, from 18 to 6 CT scans, between 2013–2014 and 2014–2015. All children with ciTBI were identified by the rules.ConclusionsThe implementation of a modified PECARN rule including the S100B protein assay significantly decreased the proportion of CT scans and in-hospital observations for children with mTBI who were at intermediate risk for ciTBI.

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