Differential Leukocyte and Platelet Profiles in Distinct Models of Traumatic Brain Injury.
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ABSTRACT:
SUBMITTER: Hubbard WB
PROVIDER: S-EPMC7996744 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Time dependent-profiles in the gene expression level following lateral moderate fluid percussion injury in the rat brain We used microarray to elucidate relationship between the alteration of gene expression levels and the progression of brain damages following traumatic brain injury. To examine the levels of gene expression in the early phase of traumatic brain injury, we analyzed the gene expression at 3, 6, 12, and 48 h after trauma using the lateral moderate fluid percussion TBI model. The ratios of the gene expression level were compared between chips corresponding to the 3, 6 and 12 h fluid percussion groups and the sham group chips. On the other hand, the rations of gene expression level after 48 h FPI were compared with 48 h sham chip, because the gene expression levels of 48 h sham chip were distinct from sham group chips (3, 6 and 12 h) in the cluster and principal components analyses.
2010-12-07 | E-GEOD-24047 | biostudies-arrayexpress
Project description:The heterogeneity of traumatic brain injury (TBI) remains a core challenge for the success of interventional clinical trials. Data-driven approaches for patient stratification may help to identify TBI patient phenotypes during the acute injury period as well as facilitate targeted trial patient enrollment and analysis of treatment efficacy. In this study, we implemented an unsupervised machine learning approach to identify TBI subpopulations at injury baseline using data from 1213 TBI patients who participated in the Citicoline Brain Injury Treatment Trial (COBRIT) Trial. A wrapper framework utilizing generalized low-rank models automatically selected relevant clinical features that were subsequently used to cluster patients using a partitioning around medoids clustering algorithm. Using this approach, we identified three patient phenotypes with unique clinical injury profiles based on a subset of acute injury features. Phenotype-specific differences in long-term functional outcome trajectories were respectively observed at 3 and 6 months after injury. In comparison, when patients were grouped by baseline Glasgow Coma Scale (GCS), no differences in baseline clinical feature profiles or long-term outcomes were observed. To test phenotype reproducibility in an external validation data set, we used a K-nearest neighbors algorithm to classify subjects in the Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) Pilot data set into corresponding phenotypes, then measured the Gower's dissimilarities between TRACK-TBI and COBRIT subjects in each phenotype. No significant differences were found between trial subjects within two phenotypes, suggesting that these phenotypes may be generalizable within a broad range of TBI severity. Further, Extended Glasgow Outcome Scale (GOS-E) outcomes in the TRACK-TBI data set similarly demonstrated phenotype-specific differences in long-term outcomes. Our results suggest that unsupervised machine learning is a promising and effective approach for discovery of novel injury subpopulations over the conventional GCS-based method, and may improve patient selection in future TBI clinical trials.
| S-EPMC7249479 | biostudies-literature
Project description:Traumatic brain injury (TBI) leads to major brain anatomopathological damages underlined by neuroinflammation, oxidative stress and progressive neurodegeneration, ultimately leading to motor and cognitive deterioration. The multiple pathological events resulting from TBI can be addressed not by a single therapeutic approach, but rather by a synergistic biotherapy capable of activating a complementary set of signalling pathways and providing synergistic neuroprotective, anti-inflammatory, antioxidative, and neurorestorative activities. Human platelet lysate might fulfil these requirements as it is composed of a plethora of biomolecules readily accessible as a TBI biotherapy. In the present study, we tested the therapeutic potential of human platelet lysate using in vitro and in vivo models of TBI. We first prepared and characterized platelet lysate from clinical-grade human platelet concentrates. Platelets were pelletized, lysed by three freeze-thaw cycles, and centrifuged. The supernatant was purified by 56°C 30 min heat treatment and spun to obtain the heat-treated platelet pellet lysate that was characterized by ELISA and proteomic analyses. Two mouse models were used to investigate platelet lysate neuroprotective potential. The injury was induced by an in-house manual controlled scratching of the animals' cortex or by controlled cortical impact injury. The platelet lysate treatment was performed by topical application of 60 µl in the lesioned area, followed by daily 60 µl intranasal administration from Day 1 to 6 post-injury. Platelet lysate proteomics identified over 1000 proteins including growth factors, neurotrophins, and antioxidants. ELISA detected several neurotrophic and angiogenic factors at ∼1-50 ng/ml levels. We demonstrate, using two mouse models of TBI, that topical application and intranasal platelet lysate consistently improved mouse motor function in the beam and rotarod tests, mitigated cortical neuroinflammation, and oxidative stress in the injury area, as revealed by downregulation of pro-inflammatory genes and the reduction in reactive oxygen species levels. Moreover, platelet lysate treatment reduced the loss of cortical synaptic proteins. Unbiased proteomic analyses revealed that heat-treated platelet pellet lysate reversed several pathways promoted by both controlled cortical impact and cortical brain scratch and related to transport, postsynaptic density, mitochondria or lipid metabolism. The present data strongly support, for the first time, that human platelet lysate is a reliable and effective therapeutic source of neurorestorative factors. Therefore, brain administration of platelet lysate is a therapeutical strategy that deserves serious and urgent consideration for universal brain trauma treatment.
| S-EPMC8634089 | biostudies-literature
Project description:BackgroundTraumatic brain injury (TBI) is a significant cause of death and disability worldwide. The TLR4-NFκB signaling cascade is the critical pro-inflammatory activation pathway of leukocytes after TBI, and modulating this signaling cascade may be an effective therapeutic target for treating TBI. Previous studies indicate that recombinant annexin A2 (rA2) might be an interactive molecule modulating the TLR4-NFκB signaling; however, the role of rA2 in regulating this signaling pathway in leukocytes after TBI and its subsequent effects have not been investigated.MethodsC57BL/6 mice were subjected to TBI and randomly divided into groups that received intraperitoneal rA2 or vehicle at 2 h after TBI. The peripheral leukocyte activation and infiltrating immune cells were examined by flow cytometry, RT-qPCR, and immunostaining. The neutrophilic TLR4 expression on the cell membrane was examined by flow cytometry and confocal microscope, and the interaction of annexin A2 with TLR4 was assessed by co-immunoprecipitation coupled with Western blotting. Neuroinflammation was measured via cytokine proteome profiler array and RT-qPCR. Neurodegeneration was determined by Western blotting and immunostaining. Neurobehavioral assessments were used to monitor motor and cognitive function. Brain tissue loss was assessed via MAP2 staining.ResultsrA2 administration given at 2 h after TBI significantly attenuates neutrophil activation and brain infiltration at 24 h of TBI. In vivo and in vitro data show that rA2 binds to and reduces TLR4 expression on the neutrophil surface and suppresses TLR4/NFκB signaling pathway in neutrophils at 12 h after TBI. Furthermore, rA2 administration also reduces pro-inflammation of brain tissues within 24 h and neurodegeneration at 48 h after TBI. Lastly, rA2 improves long-term sensorimotor ability and cognitive function, and reduces brain tissue loss at 28 days after TBI.ConclusionsSystematic rA2 administration at 2 h after TBI significantly inhibits activation and brain infiltration of peripheral leukocytes, especially neutrophils at the acute phase. Consequently, rA2 reduces the detrimental brain pro-inflammation-associated neurodegeneration and ultimately ameliorates neurological deficits after TBI. The underlying molecular mechanism might be at least in part attributed to rA2 bindings to pro-inflammatory receptor TLR4 in peripheral leukocytes, thereby blocking NFκB signaling activation pathways following TBI.
| S-EPMC8353736 | biostudies-literature
Project description:Traumatic brain injury (TBI) is one of the main causes of death worldwide. It is a complex injury that influences cellular physiology, causes neuronal cell death, and affects molecular pathways in the brain. This in turn can result in sensory, motor, and behavioral alterations that deeply impact the quality of life. Repetitive mild TBI can progress into chronic traumatic encephalopathy (CTE), a neurodegenerative condition linked to severe behavioral changes. While current animal models of TBI and CTE such as rodents, are useful to explore affected pathways, clinical findings therein have rarely translated into clinical applications, possibly because of the many morphofunctional differences between the model animals and humans. It is therefore important to complement these studies with alternative animal models that may better replicate the individuality of human TBI. Comparative studies in animals with naturally evolved brain protection such as bighorn sheep, woodpeckers, and whales, may provide preventive applications in humans. The advantages of an in-depth study of these unconventional animals are threefold. First, to increase knowledge of the often-understudied species in question; second, to improve common animal models based on the study of their extreme counterparts; and finally, to tap into a source of biological inspiration for comparative studies and translational applications in humans.
| S-EPMC8596618 | biostudies-literature
Project description:Time dependent-profiles in the gene expression level following lateral moderate fluid percussion injury in the rat brain We used microarray to elucidate relationship between the alteration of gene expression levels and the progression of brain damages following traumatic brain injury.
2010-12-07 | GSE24047 | GEO
Project description:BackgroundTraumatic brain injury (TBI) is a leading cause of death and disability world-wide. The ability to accurately predict patient outcome after TBI has an important role in clinical practice and research. Prognostic models are statistical models that combine two or more items of patient data to predict clinical outcome. They may improve predictions in TBI patients. Multiple prognostic models for TBI have accumulated for decades but none of them is widely used in clinical practice. The objective of this systematic review is to critically assess existing prognostic models for TBI METHODS: Studies that combine at least two variables to predict any outcome in patients with TBI were searched in PUBMED and EMBASE. Two reviewers independently examined titles, abstracts and assessed whether each met the pre-defined inclusion criteria.ResultsA total of 53 reports including 102 models were identified. Almost half (47%) were derived from adult patients. Three quarters of the models included less than 500 patients. Most of the models (93%) were from high income countries populations. Logistic regression was the most common analytical strategy to derived models (47%). In relation to the quality of the derivation models (n:66), only 15% reported less than 10% pf loss to follow-up, 68% did not justify the rationale to include the predictors, 11% conducted an external validation and only 19% of the logistic models presented the results in a clinically user-friendly wayConclusionPrognostic models are frequently published but they are developed from small samples of patients, their methodological quality is poor and they are rarely validated on external populations. Furthermore, they are not clinically practical as they are not presented to physicians in a user-friendly way. Finally because only a few are developed using populations from low and middle income countries, where most of trauma occurs, the generalizability to these setting is limited.
| S-EPMC1657003 | biostudies-literature
Project description:Traumatic brain injury (TBI) is a major cause of mortality and disability worldwide. We validated the utility of plasma metabolomics analysis in the clinical diagnosis of acute TBI in a rat model of controlled cortical impact (CCI) using gas chromatography/mass spectrometry (GC/MS). Thirty Sprague-Dawley rats were randomly divided into two groups of 15 rats each: the CCI group and sham group. Blood samples were obtained from the rats within the first 24 h after TBI injury. GC/MS measurements were performed to evaluate the profile of acute TBI-induced metabolic changes, resulting in the identification of 45 metabolites in plasma. Principal component analysis, partial least squares-discriminant analysis, orthogonal partial least square discriminant analysis using hierarchical clustering and univariate/multivariate analyses revealed clear differences in the plasma metabolome between the acute CCI group and the sham group. CCI induced distinctive changes in metabolites including linoleic acid metabolism, amino acid metabolism, galactose metabolism, and arachidonic acid metabolism. Specifically, the acute CCI group exhibited significant alterations in proline, phosphoric acid, β-hydroxybutyric acid, galactose, creatinine, L-valine, linoleic acid and arachidonic acid. A receiver operating characteristic curve analysis showed that the above 8 metabolites in plasma could be used as the potential biomarkers for the diagnosis of acute TBI. Furthermore, this study is the first time to identify the galactose as a biomarker candidate for acute TBI. This comprehensive metabolic analysis complements target screening for potential diagnostic biomarkers of acute TBI and enhances predictive value for the therapeutic intervention of acute TBI.
| S-EPMC5542452 | biostudies-literature
Project description:The pathophysiological mechanisms underlying mild traumatic brain injury (mTBI) are not well understood, but likely involve neuroinflammation. Here the controlled cortical impact model of mTBI in rats was used to test this hypothesis. Mild TBI caused a rapid (within 6 h post-mTBI) upregulation of synthesis of TNF-α and IL-1β in the cerebral cortex and hippocampus, followed by an increase in production of neutrophil (CXCL1-3) and monocyte (CCL2) chemoattractants. While astrocytes were not a significant source of CXC chemokines, they highly expressed CCL2. An increase in production of CXC chemokines coincided with the influx of neutrophils into the injured brain. At 6 h post-mTBI, we observed a robust influx of CCL2-expressing neutrophils across pial microvessels into the subarachnoid space (SAS) near the injury site. Mild TBI was not accompanied by any significant influx of neutrophils into the brain parenchyma until 24 h after injury. This was associated with an early induction of expression of intercellular adhesion molecule 1 on the endothelium of the ipsilateral pial, but not intraparenchymal, microvessels. At 6 h post-mTBI, we also observed a robust influx of neutrophils into the ipsilateral cistern of velum interpositum (CVI), a slit-shaped cerebrospinal fluid space located above the 3rd ventricle with highly vascularized pia mater. From SAS and CVI, neutrophils appeared to move along the perivascular spaces to enter the brain parenchyma. The monocyte influx was not observed until 24 h post-mTBI, and these inflammatory cells predominantly entered the ipsilateral SAS and CVI, with a limited invasion of brain parenchyma. These observations indicate that the endothelium of pial microvessels responds to injury differently than that of intraparenchymal microvessels, which may be associated with the lack of astrocytic ensheathment of cerebrovascular endothelium in pial microvessels. These findings also suggest that neuroinflammation represents the potential therapeutic target in mTBI.
| S-EPMC5193324 | biostudies-literature
Project description:Background: Traumatic brain injury (TBI) damages white matter tracts, disrupting brain network structure and communication. There exists a wide heterogeneity in the pattern of structural damage associated with injury, as well as a large heterogeneity in behavioral outcomes. However, little is known about the relationship between changes in network connectivity and clinical outcomes. Materials and Methods: We utilize the rat lateral fluid-percussion injury model of severe TBI to study differences in brain connectivity in 8 animals that received the insult and 11 animals that received only a craniectomy. Diffusion tensor imaging is performed 5 weeks after the injury and network theory is used to investigate changes in white matter connectivity. Results: We find that (1) global network measures are not able to distinguish between healthy and injured animals; (2) injury induced alterations predominantly exist in a subset of connections (subnetworks) distributed throughout the brain; and (3) injured animals can be divided into subgroups based on changes in network motifs-measures of local structural connectivity. In addition, alterations in predicted functional connectivity indicate that the subgroups have different propensities to synchronize brain activity, which could relate to the heterogeneity of clinical outcomes. Discussion: These results suggest that network measures can be used to quantify progressive changes in brain connectivity due to injury and differentiate among subpopulations with similar injuries, but different pathological trajectories.
| S-EPMC9805864 | biostudies-literature