Matching Items (13)
Description
Approximately 2.8 million Americans seek medical care for traumatic brain injury (TBI) each year. Of this population, the majority are sufferers of diffuse TBI, or concussion. It is unknown how many more individuals decline to seek medical care following mild TBI. This likely sizeable population of un- or self-treated individuals combined with a lack of definitive biomarkers or objective post-injury diagnostics creates a unique need for practical therapies among diffuse TBI sufferers. Practical therapies stand to decrease the burden of TBI among those who would otherwise not seek treatment or do not meet clinical diagnostic criteria upon examination. For this unique treatment niche, practical therapies for TBI are defined as having one or more of the following qualities: common availability, easy administration, excellent safety profile, and cost-effectiveness. This dissertation identifies and critically examines the efficacy of four classes of practical treatments in improving rodent outcome from experimental diffuse traumatic brain injury.
Over-the-counter (OTC) analgesics, omega-3 fatty acids, specialized pro-resolving mediators (SPMs), and remote ischemic conditioning (RIC) were administered before or following midline fluid percussion injury. Behavioral, histological, and molecular analyses were used to assess treatment effects on functional outcome and secondary injury progression. Acute administration of common OTC analgesics had little effect on post-injury outcome in mice. Dietary supplementation with omega-3 fatty acid docosahexaenoic acid (DHA) prior to or following diffuse TBI significantly reduced injury-induced sensory sensitivity and markers of neuroinflammation with no effect on spatial learning. Intraperitoneal administration of omega-3 fatty acid-derived SPM resolvin E1 significantly increased post-injury sleep and suppressed microglial activation. Aspirin-triggered (AT) resolvin D1 administration improved both motor and cognitive outcome following diffuse TBI. RIC treatment in mice demonstrated little effect on functional outcome from diffuse TBI. Untargeted proteomic analysis of plasma samples from RIC-treated mice was used to identify candidate molecular correlates of RIC. Identification of these candidates represents a vital first step in elucidating the neuroprotective mechanisms underlying RIC. The overall findings suggest that omega-3 fatty acid supplementation, SPM administration, and RIC may serve as effective practical therapies to reduce the somatic, cognitive, and neurological burden of diffuse TBI felt by millions of Americans.
Over-the-counter (OTC) analgesics, omega-3 fatty acids, specialized pro-resolving mediators (SPMs), and remote ischemic conditioning (RIC) were administered before or following midline fluid percussion injury. Behavioral, histological, and molecular analyses were used to assess treatment effects on functional outcome and secondary injury progression. Acute administration of common OTC analgesics had little effect on post-injury outcome in mice. Dietary supplementation with omega-3 fatty acid docosahexaenoic acid (DHA) prior to or following diffuse TBI significantly reduced injury-induced sensory sensitivity and markers of neuroinflammation with no effect on spatial learning. Intraperitoneal administration of omega-3 fatty acid-derived SPM resolvin E1 significantly increased post-injury sleep and suppressed microglial activation. Aspirin-triggered (AT) resolvin D1 administration improved both motor and cognitive outcome following diffuse TBI. RIC treatment in mice demonstrated little effect on functional outcome from diffuse TBI. Untargeted proteomic analysis of plasma samples from RIC-treated mice was used to identify candidate molecular correlates of RIC. Identification of these candidates represents a vital first step in elucidating the neuroprotective mechanisms underlying RIC. The overall findings suggest that omega-3 fatty acid supplementation, SPM administration, and RIC may serve as effective practical therapies to reduce the somatic, cognitive, and neurological burden of diffuse TBI felt by millions of Americans.
ContributorsHarrison, Jordan L (Author) / Lifshitz, Jonathan (Thesis advisor) / Neisewander, Janet (Thesis advisor) / Stabenfeldt, Sarah (Committee member) / Willyerd, Frederick A (Committee member) / Pirrotte, Patrick (Committee member) / Arizona State University (Publisher)
Created2017
Description
Traumatic brain injury (TBI) is a leading cause of disability worldwide with 1.7 million TBIs reported annually in the United States. Broadly, TBI can be classified into focal injury, associated with cerebral contusion, and diffuse injury, a widespread injury pathology. TBI results in a host of pathological alterations and may lead to a transient blood-brain-barrier (BBB) breakdown. Although the BBB dysfunction after TBI may provide a window for therapeutic delivery, the current drug delivery approaches remains largely inefficient due to rapid clearance, inactivation and degradation. One potential strategy to address the current therapeutic limitations is to employ nanoparticle (NP)-based technology to archive greater efficacy and reduced clearance compared to standard drug administration. However, NP application for TBI is challenging not only due to the transient temporal resolution of the BBB breakdown, but also due to the heterogeneous (focal/diffuse) aspect of the disease itself. Furthermore, recent literature suggests sex of the animal influences neuroinflammation/outcome after TBI; yet, the influence of sex on BBB integrity following TBI and subsequent NP delivery has not been previously investigated. The overarching hypothesis for this thesis is that TBI-induced compromised BBB and leaky vasculature will enable delivery of systemically injected NPs to the injury penumbra. This study specifically explored the feasibility and the temporal accumulation of NPs in preclinical mouse models of focal and diffuse TBI. Key findings from these studies include the following. (1) After focal TBI, NPs ranging from 20-500nm exhibited peak accumulation within the injury penumbra acutely (1h) post-injury. (2) A smaller delayed peak of NP accumulation (40nm) was observed sub-acutely (3d) after focal brain injury. (3) Mild diffuse TBI simulated with a mild closed head injury model did not display any measurable NP accumulation after 1h post-injury. (4) In contrast, a moderate diffuse model (fluid percussion injury) demonstrated peak accumulation at 3h post-injury with up to 500 nm size NPs accumulating in cortical tissue. (5) Robust NP accumulation (40nm) was found in female mice compared to the males at 24h and 3d following focal brain injury. Taken together, these results demonstrate the potential for NP delivery at acute and sub-acute time points after TBI by exploiting the compromised BBB. Results also reveal a potential sex dependent component of BBB disruption leading to altered NP accumulation. The applications of this research are far-reaching ranging from theranostic delivery to personalized NP delivery for effective therapeutic outcome.
ContributorsBharadwaj, Vimala Nagabhushana (Author) / Stabenfeldt, Sarah E (Thesis advisor) / Kodibagkar, Vikram D (Thesis advisor) / Kleim, Jeffrey (Committee member) / Tian, Yanqing (Committee member) / Lifshitz, Jonathan (Committee member) / Anderson, Trent R (Committee member) / Arizona State University (Publisher)
Created2018
Description
Traumatic brain injury (TBI) is a significant public health concern in the U.S., where approximately 1.7 million Americans sustain a TBI annually, an estimated 52,000 of which lead to death. Almost half (43%) of all TBI patients report experiencing long-term cognitive and/or motor dysfunction. These long-term deficits are largely due to the expansive biochemical injury that underlies the mechanical injury traditionally associated with TBI. Despite this, there are currently no clinically available therapies that directly address these underlying pathologies. Preclinical studies have looked at stem cell transplantation as a means to mitigate the effects of the biochemical injury with moderate success; however, transplants suffer very low retention and engraftment rates (2-4%). Therefore, transplants need better tools to dynamically respond to the injury microenvironment.
One approach to develop new tools for stem cell transplants may be to look towards the endogenous repair response for inspiration. Specifically, activated cell types surrounding the injury secrete the chemokine stromal cell-derived factor-1α (SDF-1α), which has been shown to play a critical role in recruiting endogenous neural progenitor/stem cells (NPSCs) to the site of injury. Therefore, it was hypothesized that improving NPSC response to SDF-1α may be a viable mechanism for improving NPSC transplant retention and migration into the surrounding host tissue. To this end, work presented here has 1. identified critical extracellular signals that mediate the NPSC response to SDF-1α, 2. incorporated these findings into the development of a transplantation platform that increases NPSC responsiveness to SDF-1α and 3. observed increased NPSC responsiveness to local exogenous SDF-1α signaling following transplantation within our novel system. Future work will include studies investigating NSPC response to endogenous, injury-induced SDF-1α and the application of this work to understanding differences between stem cell sources and their implications in cell therapies.
One approach to develop new tools for stem cell transplants may be to look towards the endogenous repair response for inspiration. Specifically, activated cell types surrounding the injury secrete the chemokine stromal cell-derived factor-1α (SDF-1α), which has been shown to play a critical role in recruiting endogenous neural progenitor/stem cells (NPSCs) to the site of injury. Therefore, it was hypothesized that improving NPSC response to SDF-1α may be a viable mechanism for improving NPSC transplant retention and migration into the surrounding host tissue. To this end, work presented here has 1. identified critical extracellular signals that mediate the NPSC response to SDF-1α, 2. incorporated these findings into the development of a transplantation platform that increases NPSC responsiveness to SDF-1α and 3. observed increased NPSC responsiveness to local exogenous SDF-1α signaling following transplantation within our novel system. Future work will include studies investigating NSPC response to endogenous, injury-induced SDF-1α and the application of this work to understanding differences between stem cell sources and their implications in cell therapies.
ContributorsAddington, Caroline (Author) / Stabenfeldt, Sarah E (Thesis advisor) / Kleim, Jeffrey A (Committee member) / Caplan, Michael R (Committee member) / Lifshitz, Jonathan (Committee member) / Massia, Stephen P (Committee member) / Arizona State University (Publisher)
Created2015
Description
Schizophrenia is considered a multifactorial disorder with complex genetic variants in response to environmental stimuli. However, the specific genetic contribution to schizophrenia risk is largely unknown. The transcription factor early growth response gene 3 (EGR3) can be activated rapidly after stimuli and thus may translate environmental stimuli into gene changes that influence schizophrenia risk. However, the downstream genes that may be regulated by EGR3 are not clear. While the 5-Hydroxytryptamine receptor 2A (5HT2AR) - encoding gene Htr2a has been implicated in the etiology of schizophrenia, the mechanisms by which Htr2a influences susceptibility to this illness are poorly understood. We previously found that in addition to schizophrenia-like abnormalities, Egr3 -/- mice have approximately 70% deduction of 5HT2AR level in the prefrontal cortex, which underlines their resistant to the sedating effect of clozapine. These findings indicate that the two schizophrenia candidate genes are in the same biological pathway that integrates multiple components resulting in schizophrenia. This dissertation is aimed to identify the mechanisms by which Egr3 regulates the expression of Htr2a in response to environmental stimuli like stress.
To determine if Egr3 alters Htr2a transcription under stress, I examined messenger ribonucleic acid (mRNA) levels of these two genes in wildtype (WT) and Egr3 -/- mice after 6hrs of sleep deprivation (SD). I found both genes are increased in WT mice after SD compared with controls. In addition, Egr3 is required for Htr2a induction because SD fails to induce Htr2a expression in Egr3 -/- mice. Next, I performed chromatin immunoprecipitation (ChIP) to determine if EGR3 binds to Htr2a promoter in vivo. I found a significant increase of EGR3 binding to Htr2a distal promoter 2hrs after seizure. To determine the functionality of this binding, I co-transfected the CMV- EGR3 vector or CMV- vector alone with the Htr2a distal promoter reporter clone. I found overexpression of EGR3 activates the Htr2a distal promoter-driven luciferase gene. Although the ChIP assay shows no direct binding of EGR3 to Htr2a proximal promoter, I found EGR3 overexpression activates Htr2a proximal promoter-driven luciferase gene. These findings suggest that EGR3 regulates Htr2a probably through both direct and indirect ways.
To determine if Egr3 alters Htr2a transcription under stress, I examined messenger ribonucleic acid (mRNA) levels of these two genes in wildtype (WT) and Egr3 -/- mice after 6hrs of sleep deprivation (SD). I found both genes are increased in WT mice after SD compared with controls. In addition, Egr3 is required for Htr2a induction because SD fails to induce Htr2a expression in Egr3 -/- mice. Next, I performed chromatin immunoprecipitation (ChIP) to determine if EGR3 binds to Htr2a promoter in vivo. I found a significant increase of EGR3 binding to Htr2a distal promoter 2hrs after seizure. To determine the functionality of this binding, I co-transfected the CMV- EGR3 vector or CMV- vector alone with the Htr2a distal promoter reporter clone. I found overexpression of EGR3 activates the Htr2a distal promoter-driven luciferase gene. Although the ChIP assay shows no direct binding of EGR3 to Htr2a proximal promoter, I found EGR3 overexpression activates Htr2a proximal promoter-driven luciferase gene. These findings suggest that EGR3 regulates Htr2a probably through both direct and indirect ways.
ContributorsZhao, Xiuli (Author) / Gallitano, Amelia (Thesis advisor) / Van Keuren-Jensen, Kendall (Committee member) / Lifshitz, Jonathan (Committee member) / Neisewander, Janet (Committee member) / Arizona State University (Publisher)
Created2017
Description
Traumatic brain injury involves a primary mechanical injury that is followed by a secondary<br/>inflammatory cascade. The inflammatory cascade in the CNS releases cytokines which are<br/>associated with leukocytosis and a systemic immune response. Acute changes to peripheral<br/>immune cell populations post-TBI include a 4.5-fold increase of neutrophils 3 hours post-injury,<br/>and 2.7-fold or higher increase of monocytes 24 hours post-injury. Flow Cytometry is a<br/>technique that integrates fluidics, optics, and electronics to characterize cells based on their light<br/>scatter and antigen expression via monoclonal antibodies conjugated to fluorochromes. Flow<br/>cytometry is a valuable tool in cell characterization however the standard technique for data<br/>analysis, manual gating, is associated with inefficiency, subjectivity, and irreproducibility.<br/>Unsupervised analysis that uses algorithms packaged as plug-ins for flow cytometry analysis<br/>software has been discussed as a solution to the limits of manual gating and as an alternative<br/>method of data visualization and exploration. This investigation evaluated the use of tSNE<br/>(dimensionality reduction algorithm) and FlowSOM (population clustering algorithm)<br/>unsupervised flow cytometry analysis of immune cell population changes in female mice that<br/>have been exposed to a LPS-induced systemic inflammatory challenge, results were compared to<br/>those of manual gating. Flow cytometry data was obtained from blood samples taken prior to and<br/>24 hours after LPS injection. Unsupervised analysis was able to identify populations of<br/>neutrophils and pro-inflammatory/anti-inflammatory monocytes, it also identified several more<br/>populations however further inquiry with a more specific fluorescent panel would be required to<br/>establish the specificity and validity of these populations. Unsupervised analysis with tSNE and<br/>FlowSOM demonstrated the efficient and intuitive nature of the technique, however it also<br/>illustrated the importance of the investigator in preparing data and modulating plug-in settings.
ContributorsDudic, Ahmed (Author) / Stabenfeldt, Sarah (Thesis director) / Lifshitz, Jonathan (Committee member) / Rojas, Luisa (Committee member) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2021-05
Description
Traumatic brain injury (TBI) affects an estimated 1.7 million people in the United States each year and is a leading cause of death and disability for children and young adults in industrialized countries. Unfortunately, the molecular and cellular mechanisms of injury progression have yet to be fully elucidated. Consequently, this complexity impacts the development of accurate diagnosis and treatment options. Biomarkers, objective signatures of injury, can inform and facilitate development of sensitive and specific theranostic devices. Discovery techniques that take advantage of mining the temporal complexity of TBI are critical for the identification of high specificity biomarkers.
Domain antibody fragment (dAb) phage display, a powerful screening technique to uncover protein-protein interactions, has been applied to biomarker discovery in various cancers and more recently, neurological conditions such as Alzheimer’s Disease and stroke. The small size of dAbs (12-15 kDa) and ability to screen against brain vasculature make them ideal for interacting with the neural milieu in vivo. Despite these characteristics, implementation of dAb phage display to elucidate temporal mechanisms of TBI has yet to reach its full potential.
My dissertation employs a unique target identification pipeline that entails in vivo dAb phage display and next generation sequencing (NGS) analysis to screen for temporal biomarkers of TBI. Using a mouse model of controlled cortical impact (CCI) injury, targeting motifs were designed based on the heavy complementarity determining region (HCDR3) structure of dAbs with preferential binding to acute (1 day) and subacute (7 days) post-injury timepoints. Bioreactivity for these two constructs was validated via immunohistochemistry. Further, immunoprecipitation-mass spectrometry analysis identified temporally distinct candidate biological targets in brain tissue lysate.
The pipeline of phage display followed by NGS analysis demonstrated a unique approach to discover motifs that are sensitive to the heterogeneous and diverse pathology caused by neural injury. This strategy successfully achieves 1) target motif identification for TBI at distinct timepoints and 2) characterization of their spatiotemporal specificity.
Domain antibody fragment (dAb) phage display, a powerful screening technique to uncover protein-protein interactions, has been applied to biomarker discovery in various cancers and more recently, neurological conditions such as Alzheimer’s Disease and stroke. The small size of dAbs (12-15 kDa) and ability to screen against brain vasculature make them ideal for interacting with the neural milieu in vivo. Despite these characteristics, implementation of dAb phage display to elucidate temporal mechanisms of TBI has yet to reach its full potential.
My dissertation employs a unique target identification pipeline that entails in vivo dAb phage display and next generation sequencing (NGS) analysis to screen for temporal biomarkers of TBI. Using a mouse model of controlled cortical impact (CCI) injury, targeting motifs were designed based on the heavy complementarity determining region (HCDR3) structure of dAbs with preferential binding to acute (1 day) and subacute (7 days) post-injury timepoints. Bioreactivity for these two constructs was validated via immunohistochemistry. Further, immunoprecipitation-mass spectrometry analysis identified temporally distinct candidate biological targets in brain tissue lysate.
The pipeline of phage display followed by NGS analysis demonstrated a unique approach to discover motifs that are sensitive to the heterogeneous and diverse pathology caused by neural injury. This strategy successfully achieves 1) target motif identification for TBI at distinct timepoints and 2) characterization of their spatiotemporal specificity.
ContributorsMartinez, Briana Isabella (Author) / Stabenfeldt, Sarah E (Thesis advisor) / Lifshitz, Jonathan (Committee member) / Sierks, Michael (Committee member) / Kleim, Jeffrey (Committee member) / Arizona State University (Publisher)
Created2020
Description
Traumatic brain injury (TBI) consists of the primary mechanical forces to the head followed by secondary inflammatory cascades. This inflammatory cascade consists of neuroinflammation characterized by microglial activation as the first line of defense. Another component of secondary inflammation comprises of activation of peripheral immune cells that can infiltrate the compromised blood brain barrier and susceptible organs such as the lungs. Acute inflammatory processes in the lungs include a disruption of the epithelial barriers allowing infiltration of neutrophils, and edema build up in the alveoli. This is known as acute lung injury (ALI) and it dampens respiratory function in approximately 20-25% of TBI patients necessitating an intervention. Remote ischemic conditioning (RIC) is an intervention consisting of repeated intervals of cessation and reperfusion of blood flow to a distal limb and has treated ALI, myocardial infarction, and neurological injury. TBI was hypothesized to induce ALI through degradation of alveolar-capillary membrane and infiltration of peripheral leukocytes. Furthermore, RIC was hypothesized to protect the integrity of the alveolar-capillary membrane, reduce infiltration of peripheral immune cells, and reduce microglial activation in the brain through myokine recruitment. Male CD1 mice were subject to either midline fluid percussion or sham injury and further randomized into 4 groups: sham, sham RIC, TBI, TBI RIC. RIC was administered on proximal thigh for 4x5 minutes, with 5-minute reperfusion one hour prior to TBI. One-hour post-injury, brain, lung, BAL fluid, and blood were collected. Lung histopathology showed RIC reduced hydrostatic edema in the alveoli by protecting the alveolar capillary membrane. BAL findings revealed TBI mice had increased neutrophil counts, RIC lowered neutrophil counts. In the brain, RIC increased cortex microglial endpoints were observed with no other significant differences in microglial morphology as well as plasma myokine levels across all sham, sham RIC, TBI, and TBI RIC animals. While underlying mechanisms still have to be further studied, this current study provides evidence that RIC can be used as a therapeutic intervention to ameliorate TBI-induce ALI.
ContributorsChristie, Immaculate (Author) / Newbern, Jason (Thesis director) / Lifshitz, Jonathan (Committee member) / Saber, Maha (Committee member) / School of Life Sciences (Contributor, Contributor) / Barrett, The Honors College (Contributor)
Created2020-05
Time-Lapse Visualization of Microglia Cell Processes using Fluorescent Miniature (Miniscope) Imaging
Description
In the United States, an estimated 2 million cases of traumatic brain injury (TBI) resulting in more than 50,000 deaths occur every year. TBI induces an immediate primary injury resulting in local or diffuse cell death in the brain. Then a secondary injury occurs through neuroinflammation from immune cells in response to primary injury. Microglia, the resident immune cell of the central nervous system, play a critical role in neuroinflammation following TBI. Microglia make up 10% of all cells in the nervous system and are the fastest moving cells in the brain, scanning the entire parenchyma every several hours. Microglia have roles in both the healthy and injured brain. In the healthy brain, microglia can produce neuroprotective factors, clear cellular debris, and organize neurorestorative processes to recover from TBI. However, microglia mediated neuroinflammation during secondary injury produces pro-inflammatory and cytotoxic mediators contributing to neuronal dysfunction, inhibition of CNS repair, and cell death. Furthermore, neuroinflammation is a prominent feature in many neurodegenerative diseases such as Alzheimer’s, and Parkinson’s disease, of which include overactive microglia function. Microglia cell morphology, activation, and response to TBI is poorly understood. Currently, imaging microglia can only be performed while the animal is stationary and under anesthesia. The Miniscope technology allows for real-time visualization of microglia in awake behaving animals. The Miniscope is a miniature fluorescent microscope that can be implanted over a craniectomy to image microglia. Currently, the goals of Miniscope imaging are to improve image quality and develop time-lapse imaging capabilities. There were five main sub-projects that focused on these goals including surgical nose cone design, surgical holder design, improved GRIN lens setup, improved magnification through achromatic lenses, and time-lapse imaging hardware development. Completing these goals would allow for the visualization of microglia function in the healthy and injured brain, elucidating important immune functions that could provide new strategies for treating brain diseases.
ContributorsNelson, Andrew Frederick (Author) / Stabenfeldt, Sarah (Thesis director) / Lifshitz, Jonathan (Committee member) / Harrington Bioengineering Program (Contributor) / Barrett, The Honors College (Contributor)
Created2019-05
Description
Synaptosomes are isolated nerve terminals that contain pre- and post-synapticproteins and can be used to model functionally intact synapses. While the quantification and characterization of synaptosomes have been used to study neurological conditions and diseases, relatively few studies have included the use of flow cytometry in the quantification and analytical processes. As such, this study highlights the use of flow cytometry in the synaptosomal quantification process and describes the adaptation of a previously performed synaptic flow protocol to find the optimal concentrations, protein- to-antibody ratios and gating strategies that meet the goals of this and future studies. To validate the protocol, three independent experiments measuring different treatments – traumatic brain injury (TBI), neurodevelopment, and ketamine - on synaptosomal quantity were conducted and compared to pre-existing literature. Despite the high standard deviation values between certain sample replicates, the synaptic flow protocol was validated by the right-skewed nature of the frequency distribution of the standard deviations between sample replicates and that most of the deviations fell below 40% of the maximum variance value. Further analysis showed significant differences (p < 0.05) between the ketamine and TBI groups compared to the control group while no significant differences were observed between the neurodevelopment (P30) group. This study validates the use of flow cytometry in synaptosomal quantification while providing insight to the potential of the synaptic flow protocol in future TBI and psychoplastogen studies.
ContributorsChua, Wan Rong (Author) / Lifshitz, Jonathan (Thesis advisor) / Balmer, Timothy (Thesis advisor) / Velazquez, Ramon (Committee member) / Arizona State University (Publisher)
Created2023
Description
Background: Nociceptive and neuropathic pain occurs as part of the disease process after traumatic brain injury (TBI) in humans. Central and peripheral inflammation, a major secondary injury process initiated by the traumatic brain injury event, has been implicated in the potentiation of peripheral nociceptive pain. We hypothesized that the inflammatory response to diffuse traumatic brain injury potentiates persistent pain through prolonged immune dysregulation.
Results: To test this, adult, male C57BL/6 mice were subjected to midline fluid percussion brain injury or to sham procedure. One cohort of mice was analyzed for inflammation-related cytokine levels in cortical biopsies and serum along an acute time course. In a second cohort, peripheral inflammation was induced seven days after surgery/injury with an intraplantar injection of carrageenan. This was followed by measurement of mechanical hyperalgesia, glial fibrillary acidic protein and Iba1 immunohistochemical analysis of neuroinflammation in the brain, and flow cytometric analysis of T-cell differentiation in mucosal lymph. Traumatic brain injury increased interleukin-6 and chemokine ligand 1 levels in the cortex and serum that peaked within 1–9 h and then resolved. Intraplantar carrageenan produced mechanical hyperalgesia that was potentiated by traumatic brain injury. Further, mucosal T cells from brain-injured mice showed a distinct deficiency in the ability to differentiate into inflammation-suppressing regulatory T cells (Tregs).
Conclusions: We conclude that traumatic brain injury increased the inflammatory pain associated with cutaneous inflammation by contributing to systemic immune dysregulation. Regulatory T cells are immune suppressors and failure of T cells to differentiate into regulatory T cells leads to unregulated cytokine production which may contribute to the potentiation of peripheral pain through the excitation of peripheral sensory neurons. In addition, regulatory T cells are identified as a potential target for therapeutic rebalancing of peripheral immune homeostasis to improve functional outcome and decrease the incidence of peripheral inflammatory pain following traumatic brain injury.
ContributorsRowe, Rachel K. (Author) / Ellis, Gavin I. (Author) / Harrison, Jordan (Author) / Bachstetter, Adam D. (Author) / Corder, Gregory F. (Author) / Van Eldik, Linda J. (Author) / Taylor, Bradley K. (Author) / Marti, Francesc (Author) / Lifshitz, Jonathan (Author) / College of Liberal Arts and Sciences (Contributor)
Created2016-05-13