Tesis: "Peripheral challenges and inflammation"

1

Chapman, Katie. "Peripheral inflammation after experimental stroke". Thesis, University of Manchester, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.518434.

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2

McColl, Alison. "The brain response to peripheral inflammation". Thesis, University of Glasgow, 2015. http://theses.gla.ac.uk/6764/.

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Communication between the immune system and the central nervous system (CNS) is becoming increasingly topical as evidence suggests the two systems are intricately linked. Although the brain is considered an ‘immune-specialised’ tissue, it is not free from the influences of the periphery. Recent data indicate that peripheral immune stimulation can significantly affect the CNS, and patients with chronic inflammatory diseases, including rheumatoid arthritis (RA) and psoriasis, are often further burdened by the onset of neuropsychiatric conditions such as major depressive disorder (MDD), schizophrenia and anxiety. However, despite increases in our understanding, the precise mechanisms underpinning this relationship remain unclear. Therefore, the aim of this thesis is to investigate the communication pathways that exist between the immune system and the nervous system and to enhance our understanding of this bidirectional relationship. Using a well-characterised animal model of psoriasis-like skin inflammation, I have investigated the effects of cutaneous, peripheral inflammation on the brain. Psoriasis-like skin inflammation was induced in female C57BL/6 mice via the repeated application of Aldara cream to the shaved dorsal skin. Twenty-four hours after the fifth application, the transcriptional response in the brain was assessed and compared with mice treated with an aqueous control cream, using Affymetrix GeneChip arrays. The induction of target genes, identified using microarray analysis, was confirmed in an independent model using QPCR and was compared to the gene induction following a number of other inflammatory models, including a sterile model of cutaneous inflammation. Transcriptional profiling techniques allowed me to identify a number of differentially expressed genes in the brains of Aldara- and Imiquimod (IMQ)- treated mice when compared with the brains of control mice. This response included a range of interferon-stimulated genes (ISGs) and chemokines that were not induced in the peripheral blood leukocytes (PBL), and occurred independently of an overt cytokine response in the PBL. The brain ISG and chemokine response was not detected following a sterile model of cutaneous inflammation or following the intraperitoneal administration of Imiquimod. The central induction of a number of chemokines prompted the evaluation of immune cell infiltration into the brain parenchyma. In addition, the functional consequences of topical Aldara treatment, and the involvement of inflammatory chemokines, were determined by assessing dentate neurogenesis and burrowing behaviour in wild-type and ACKR2-deficient mice. The transcriptional response following cutaneous IMQ-induced inflammation is indicative of a peripherally triggered inflammatory response in the brain. In addition, the data described in this thesis demonstrate a functional consequence of peripheral immune stimulation and suggest that cutaneous inflammation could modulate the recruitment of leukocytes to the brain. These data highlight a potential mechanism of TLR-dependent communication between the periphery and the brain that could be mediated through the activation of the afferent vagus nerve.

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3

Adeoye, Opeolu M. D. "Peripheral Leukocytes and Intracerebral Hemorrhage". University of Cincinnati / OhioLINK, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1353100438.

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4

Jiang, Yanyan. "The role of peripheral TNF in acute brain inflammation". Thesis, University of Oxford, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.496980.

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5

Gherhes, Cristian. "The challenges of entrepreneurship in peripheral post-industrial places". Thesis, University of Sheffield, 2018. http://etheses.whiterose.ac.uk/20317/.

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The UK has a long history of spatial disparity in economic prosperity across its regions which, despite periodic shifts in its geographies of economic development governance, have persisted. As such, a key question that continues to preoccupy economic geographers is why some local and regional economies are more capable of renewal and transformation than others which remain locked in decline or underperformance. Research has hitherto highlighted the importance of ‘place’ and institutional context in shaping the outcomes of economic development. At the same time, the role of entrepreneurship as an engine of economic development is widely acknowledged, yet there is significant heterogeneity in the nature and level of entrepreneurial activity across places, with previous research highlighting the key role of institutions in shaping its outcomes. The thesis addresses these debates through a focus on entrepreneurship in peripheral post-industrial places (PPIPs), with the aim of examining the institutional challenges to fostering more entrepreneurial and resilient PPIPs.

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6

Barr, Laura Caroline. "Peripheral blood mononuclear cell depletion for experimental human lung inflammation". Thesis, University of Edinburgh, 2014. http://hdl.handle.net/1842/23705.

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Acute lung injury (ALI) affects a significant proportion of patients requiring critical care and is associated with high morbidity and mortality. Treatment is currently only supportive, with no pharmacological treatment yet shown to definitively improve outcome. There is evidence from murine models of ALI that monocytes play a key role in the development of the neutrophilic lung infiltration characteristic of ALI. Depletion of blood monocytes in mice given intra-tracheal lipopolysaccharide (LPS) significantly reduces pulmonary neutrophil influx, systemic neutrophilia and other markers of lung injury. In humans, monocyte-like cells have been documented in the bronchoalveolar lavage (BAL) fluid of patients with a variety of inflammatory lung conditions, including ALI. This thesis describes novel work performed in healthy human subjects to test whether, in an experimental model of human lung inflammation, depletion of circulating blood monocytes can ameliorate systemic and pulmonary inflammation. LPS inhalation is an established method of modelling ALI in healthy human subjects as it safely and consistently induces mild and self-limiting systemic and pulmonary inflammation. A preliminary study in a group of 12 healthy subjects confirmed the safety and efficacy of LPS inhalation compared to saline placebo. LPS inhalation induced a marked blood neutrophilia together with a rise in body temperature and heart rate and elevated BAL neutrophil and pro-inflammatory cytokine concentrations. This study also used flow cytometry to confirm the presence of pulmonary monocyte-like cells (PMLCs) in BAL fluid, which, although distinct from blood monocytes, could be clearly divided into two separate sub-types according to CD14/CD16 expression. LPS inhalation caused a rise in the number of circulating classical monocytes in blood and an expansion in the CD14++CD16- 'inducible' iPMLC subtype (reminiscent of classical blood monocytes), compared to the CD14++CD16+ 'resident' rPMLC subtype. This may represent transmigration of classical monocytes from blood across the pulmonary endothelium. In humans, mononuclear cell (MNC) leukapheresis provides a readily available method of depleting circulating blood monocytes. A second preliminary study, performed in a separate group of 6 healthy subjects, demonstrated that leukapheresis of four total blood volumes could be safely employed to deplete large numbers of circulating blood monocytes. Active recruitment of monocytes into circulating blood during leukapheresis did, however, limit the reduction in total circulating blood monocyte counts. This study also investigated, for the first time, the potential pulmonary effects of leukapheresis. Despite a relative prominence of iPMLCs in BAL fluid after leukapheresis, there was no evidence of significant neutrophil influx or a clinically important pro-inflammatory effect in the alveolar space. A randomised, double blind, placebo-controlled trial was then performed in a third group of 30 healthy human subjects who all inhaled LPS at baseline. There was no evidence that MNC leukapheresis (depletion group, n=15), compared to a sham procedure (sham group, n=15), attenuated the systemic and pulmonary inflammation induced by LPS inhalation, as measured by: blood neutrophil and plasma C-reactive protein (CRP) levels; by the neutrophil, protein and pro-inflammatory cytokine content of BAL fluid; and by [18F]fluorodeoxyglucose positron emission tomography ([18F]FDG PET)-derived measures of global lung inflammation. MNC leukapheresis temporarily prevented the LPS-induced rise in circulating classical monocytes and was also associated with a small reduction in the estimated numbers of MNCs in BAL fluid. It did not, however, appear to affect the LPS-induced expansion in the iPMLC subtype. Further characterisation of the PMLC subtypes by flow cytometry/sorting and cell culture demonstrated that the iPMLC subtype was more pro-inflammatory but less mature and with a lower proliferation potential than the rPMLC subtype. In summary, this work did not support a role for circulating blood monocytes in the evolution of LPS-induced systemic or pulmonary neutrophilia in man. The rise in circulating levels of classical blood monocytes and the dramatic expansion of pro-inflammatory, immature iPMLCs in BAL fluid after LPS inhalation do, however, suggest that monocytes migrate to the lung and are to some extent involved in the pathogenesis of lung inflammation. Compared to murine methods of monocyte depletion, leukapheresis could not achieve such an extensive or sustained reduction in circulating blood monocyte counts, nor was it likely to have influenced other (specifically patrolling or splenic) monocyte pools. Future work in the drive to find treatments for ALI should therefore investigate the potential of pre-emptive leukapheresis or the efficacy and safety of other methods of human monocyte depletion in experimental lung inflammation.

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7

Karim, Salman. "Peripheral and central markers of inflammation in mild cognitive impairment". Thesis, University of Manchester, 2011. https://www.research.manchester.ac.uk/portal/en/theses/peripheral-and-central-markers-of-inflammation-in-mild-cognitive-impairment(bd21dafe-65c1-42c9-949b-733abfc71037).html.

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There has been accumulating scientific evidence, over the last three decades, of the role of inflammatory processes in the development of Alzheimer's disease (AD). Population based studies suggest that plasma levels of inflammatory markers are raised in peripheral blood of people with AD. People on long term use of non-steroidal anti-inflammatory drugs have a lower prevalence of AD. Moreover, both animal and human histopathology studies have reported localization of inflammation in brain areas primarily affected by AD pathology. Areas of increased inflammation can be visualized in vivo by Positron Emission Tomography (PET) scans using the PK11195 ligand that binds with the benzodiazepine receptor sites of activated microglial cells. Cognitive decline in AD has been shown to correlate with levels of microglial activation using PK11195 PET scans. People with amnestic mild cognitive impairment (MCI) are known to be at high risk of developing AD.We aimed to investigate the association between peripheral and central markers of inflammation and cognitive decline in a group of people with amnestic MCI.MCI subjects (n=70) underwent cognitive testing, IL-6 and CRP in peripheral blood were measured and repeated after 1 year. A sub group (n=15) was followed up for another year and central brain microglial activation was measured by PET using PK11195 along with cognitive and peripheral inflammatory marker measurement. The mean CRP and IL-6 levels of the cohort increased over one year but the rise was only significant for CRP. No association was detected between inflammatory markers levels and cognition as measured by a battery of cognitive instruments. Group comparisons of the PET cohort with healthy controls (n=5) showed increased PK11195 binding (mean binding potential) in frontal lobe, temporal lobe, parietal lobe, putamen, occipital lobes and significantly increased binding in posterior cingulate gyrus. This study, to our knowledge, is unique in studying makers of inflammation in amnestic MCI participants both in peripheral blood and brain. The results of this study, in the light of current literature, add to the importance of recognition of inflammatory processes in people at risk of developing AD. The results suggest that CRP levels rise significantly over time and are detectable in peripheral blood by using practically simple laboratory techniques. The results also suggest that activated microglia in amnestic MCI patients can be visualized in vivo by using PK11195 PET scans and show higher levels of activation as compared to healthy controls. These finding could be useful in identifying people with malactivated (pro-inflammatory) microglia as potential targets for prevention/early treatment strategies. Further studies with larger samples sizes and long term follow-up are needed to investigate whether these peripheral and central inflammatory markers could shed light on the aetiology of AD and be useful in monitoring disease progression.

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8

Thomson, Carolyn. "Peripheral inflammation remotely triggers global gene expression changes in the brain". Thesis, University of Glasgow, 2014. http://theses.gla.ac.uk/5390/.

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Although the central nervous system (CNS) was once considered an immunologically privileged site, in recent years it has become increasingly evident that cross talk between the immune system and the CNS does occur. As a result, patients with chronic inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease or psoriasis are often further burdened with neuropsychiatric symptoms such as depression, anxiety and fatigue. Despite the recent advances in our understanding of neuroimmune communication pathways, the precise effect peripheral immune activation has on neural circuitry remains unclear. Therefore, the primary aim of this thesis was to develop a better understanding of the bidirectional relationship, and communication pathways, that exist between the immune system and the nervous system. By utilising transcriptomics in a well-characterised murine model of systemic inflammation, I have investigated the molecular mechanisms by which inflammation originating in the periphery can induce transcriptional modulation in the brain. Systemic inflammation was induced in male C57BL/6 mice via intraperitoneal injection of lipopolysaccharide (LPS). After 48 hours, whole brain transcriptional profiles were assessed, and compared to that of a vehicle- treated control group, using Affymetrix GeneChip microarrays. Target gene induction, identified by microarray analysis was validated independently using QPCR. Expression of the same panel of target genes was then investigated, in the brains of mice, following the induction of different sterile, and TLR- dependent, models of peripheral inflammation. Microarray analysis of whole brains collected 48hr after LPS challenge revealed increased transcription of a range of interferon-stimulated genes (ISGs) in the brain, including a significant upregulation of the classic interferon-induced chemokine CXCL10. This transcriptional profile could not be reproduced by the systemic administration of TNFα, or following lipoteichoic acid-induced systemic inflammation. However, target genes remained induced in the brain following daily LPS injections, in the absence of a detectable inflammatory cytokine response in the periphery. 1 The central induction of CXCL10 suggests that acute exposure to LPS in the periphery may prime the brain for T cell infiltration. This prompted an investigation into whether leukocytes infiltrated the brain following daily systemic LPS injections. First, the inflammatory chemokine repertoire in the brains of LPS treated mice was systematically characterised. In addition to Cxcl10, repeated injection of LPS in the periphery triggered a transient increase in the transcription of a number of other inflammatory chemokines in the brain. Chemokine induction was associated with an influx of leukocytes from the periphery, and an increase in mRNA encoding the relevant chemokine receptors. Therefore, chemokine induction in the brain following daily systemic LPS injections may mediate the recruitment of leukocytes from the periphery. The transcriptional response in the brain following systemic LPS challenge is indicative of a peripherally triggered inflammatory response in the brain. The data described in this thesis highlight a potential mechanism of gene modulation in the brain which may be dependent on a TLR-induced type I interferon response. Considerable evidence links type I interferons to psychiatric disorders, and consequently, interferon production in the brain could represent an important mechanism linking peripheral TLR-induced inflammation with behavioural changes. In addition, the data described in this thesis demonstrate that chronic exposure to LPS in the periphery may remotely modulate the recruitment of leukocytes to the brain. This highlights a potential protective mechanism that could prevent a chronic bacterial infection from spreading from the periphery to the brain.

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9

Tzoulaki, Ioanna. "Inflammation and haemostasis in the development and progression of peripheral atherosclerotic disease". Thesis, University of Edinburgh, 2007. http://hdl.handle.net/1842/2148.

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Peripheral arterial disease (PAD) defines atherosclerotic disease of the arteries to the legs. PAD begins early in life and remains asymptomatic over long periods. The ankle brachial index (ABI) is an important diagnostic test which can identify asymptomatic individuals and serve as a good marker of the underlying peripheral and systemic atherosclerosis. Recent advances in vascular biology proposed a role of inflammatory and haemostatic mechanisms in atherosclerotic disease. Although inflammatory and haemostatic markers have been associated with coronary atherosclerosis in large scale epidemiological studies their role in PAD development is not well established and for many markers unknown. Also, their relationship with the progression of early asymptomatic disease has not been studied before. The aim of this thesis was to examine 12 markers of inflammation and haemostasis in relation to peripheral atherosclerotic progression and incident PAD. The Edinburgh Artery Study was used for this analysis. This is a population based cohort study of 1,592 men and women recruited in 1987. ABI was measured at baseline and at two follow up examinations which were conducted after 5 and after 12 years. Also, subjects were followed up for cardiovascular events for 17 years. Conventional cardiovascular risk factors, C-reactive protein (CRP), interleukin-6 (IL-6), intercellular adhesion molecule 1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), E-selectin, fibrinogen, D-dimer, tissue plasminogen activator (t-PA), vonWillebrand factor (vWF), factor VII, fibrinopeptide A (FpA) and prothrombin fragments 1+2 (F1+2) were measured at baseline. Valid ABI measurements were available for 1,582 subjects at baseline, for 1,081 subjects at the 5 year follow up and for 816 subjects at the 12 year follow up. The population showed a progression in atherosclerotic disease assessed by the mean ABI decline over time. The mean change in ABI was -0.04 (0.18) after 5 years and -0.06 (0.19) after 12 years. From inflammatory markers, CRP (p <0.01), IL-6 (p <0.001) and ICAM-1 (p <0.01) were associated with atherosclerotic progression after 12 years, independently of baseline ABI and of conventional cardiovascular risk factors. Also, from haemostatic markers, fibrinogen (p =0.05) and D-dimer (p ≤ 0.05) were significantly associated with atherosclerotic progression independently of baseline ABI and cardiovascular risk factors. Moreover, subjects with higher levels of both D-dimer and IL-6 at baseline had the greatest ABI decline. Also, IL-6 showed the stronger independent effect on atherosclerotic progression and retained statistical significance after adjustments for all inflammatory markers and for fibrinogen and D-dimer. Approximately 26% of the baseline population developed at least one event of major CVD and 14% of the baseline population developed symptomatic PAD after 17 years of follow up. Inflammatory markers, CRP and IL-6 showed modest associations with PAD which lost statistical significance in the multivariable model. On the other hand, these markers were associated with incident major CVD with hazard ratios (95% CI) 1.6 (1.2, 2.3) and 1.8 (1.3, 2.6) respectively (top vs. bottom tertile) in the multivariable model. ICAM-1 showed weak associations with incident CVD, however, was significantly associated with PAD with hazard ratio (95% CI) 1.8 (1.2, 2.7) (top vs. bottom tertile) after adjustments for cardiovascular risk factors and CVD at baseline. Haemostatic markers, fibrinogen and D-dimer were associated with 2.2 (95% CI: 1.5, 3.2) and 1.7 (1.2, 2.6) increase in the risk of PAD development and 1.8 (1.3, 2.3) and 1.6 (1.2, 2.1) increase in the risk of CVD independently of cardiovascular risk factors and history of CVD at baseline, respectively. This analysis showed a major role of inflammatory markers, CRP, IL-6 and ICAM-1 in atherosclerotic development and progression. In addition, fibrinogen and D-dimer, but not other haemostatic factors, were associated with progressive and incident peripheral atherosclerosis. Since D-dimer and fibrinogen are acute phase reactants, these data support the hypothesis that inflammation is more related to atherosclerosis than is hypercoagulation. Most importantly, the majority of the reported associations were not explained by increased levels of cardiovascular risk factors or pre-existing clinical or subclinical arterial disease. Thus these markers are more likely to have a causal than a consequential role in atherosclerotic disease.

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10

Parmar, Jiteshkumar H. "The role of inflammation in ischaemia reperfusion injury due to peripheral arterial revascularisation". Thesis, University of Manchester, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.509840.

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11

Hau, Vincent Sinh. "EFFECT OF PERIPHERAL INFLAMMATORY PAIN ON THE BLOOD-BRAIN BARRIER". Diss., Tucson, Arizona : University of Arizona, 2005. http://etd.library.arizona.edu/etd/GetFileServlet?file=file:///data1/pdf/etd/azu%5Fetd%5F1071%5F1%5Fm.pdf&type=application/pdf.

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12

RUSCONI, MICHELA. "Activation state and functionality of dendritic cells from peripheral blood of amyotrophic lateral sclerosis patients". Doctoral thesis, Università degli Studi di Milano-Bicocca, 2017. http://hdl.handle.net/10281/153236.

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Molti dati pubblicati sottolineano l’importanza dell’infiammazione per la neurodegenerazione nella sclerosi laterale amiotrofica (SLA) con un aumento del reclutamento al midollo spinale dei monociti periferici, delle cellule dendritiche (DCs) e delle cellule T in modelli murini e nell’uomo. Ad oggi non ci sono dati circa lo stato funzionale delle DCs nel sangue periferico dei pazienti SLA. Lo scopo dello studio è esaminare le DCs circolanti in una coorte di pazienti SLA prendendo in considerazione la loro storia clinica, per capire come queste cellule contribuiscano alla progressione della patologia. Per fare questo abbiamo analizzato la frequenza di espressione delle molecole costimolatorie, migratorie e delle MHC delle DCs CD1c+ e abbiamo indagato la capacità di DCs purificate di produrre spontaneamente e in risposta ad agonisti dei TLR (lipopolisaccaride LPS) citochine infiammatorie. Abbiamo incluso nello studio 72 pazienti SLA, 47 donatori sani e 25 pazienti affetti da disordini neurologici non correlati con la SLA, stratificati per sesso ed età. Il numero di DCs circolanti ed il loro fenotipo sono stati analizzati con analisi citofluorimetriche. Abbiamo trovato che i pazienti SLA hanno un numero minore di DCs circolanti rispetto a donatori sani e che queste DCs esprimono più bassi livelli di ntegrina CD62L. Questa integrina è necessaria per il reclutamento dei leucociti agli organi linfoidi secondari o ai siti infiammatori quindi la nostra osservazione conferma il fatto che nei pazienti SLA le DCs sono reclutate attivamente al sistema nervoso centrale con un meccanismo che coinvolge, presumibilmente, CD62L. Abbiamo poi analizzato la produzione spontanea o indotta da LPS di citochine infiammatorie quali TNFα, IL1β, IL6, IL8, IL10 eCCL2. Abbiamo individuato una sottopopolazione di pazienti con una produzione spontanea di IL8 più alta che mostrano anche una più alta efficienza di secrezione di CCL2. Nonostante non sia stato possibile dimostrare una correlazione tra questa più alta efficienza di secrezione di citochine e la progressione della patologia, alti livelli di CCL2 sono presenti nel midollo spinale di topi SOD, un modello murino per una sottoclasse di pazienti SLA, e in alcuni pazienti. Questa osservazione suggerisce che delle semplici analisi del sangue periferico potrebbero essere sufficienti ad identificare un sottogruppo di pazienti. Abbiamo inoltre analizzato la correlazione tra i livelli di ogni singolo citochina, prima e dopo l’esposizione ad LPS, ed alcuni parametri di malattia. Abbiamo così evidenziato una correlazione inversa tra l’intervallo di tempo tra l’insorgenza e la diagnosi e i livelli di ΔIL6, suggerendo che l’efficienza di produzione di IL6 possa accelerare le fasi iniziale della patologia. In conclusione possiamo dire che le DCs sono il subset cellulare maggiormente reclutato al sistema nervoso centrale. Nonostante la maggior parte delle DCs attivate migrino al sistema nervoso centrale, alcune differenze posso essere osservate a livello del sangue periferico. Sulla base dei nostri risultati le analisi sul sangue periferico potrebbero essere utili a stratificare i pazienti dividendo chi ha un’alta risposta infiammatoria da chi invece non ha alterazioni. Data l’elevata eterogeneità della SLA non è stato possibile, per il momento, osservare correlazioni significative con i parametri di malattia, anche se analisi più raffinate basate su specifici criteri potrebbero essere informative su alcuni particolari aspetti della patologia. L’elevato livello di espressione di CD62L da parte delle DCs periferiche suggerisce che questa molecola possa essere un target per un trattamento in vivo. A questo proposito abbiamo in programma di mettere a punto uno studio preclinico in topi SOD per verificare se un trattamento con un anticorpo bloccante CD62L possa interferire con la progressione della patologia.
Several published data highlight the importance of inflammation for neurodegeneration in Amyotrophic lateral sclerosis (ALS) with an increased spinal cord recruitment of peripheral proinflammatory monocytes, dendritic cells (DCs) and T cells found in patients and animal models. To date no clear data are available regarding the functional state of DCs in peripheral blood of ALS patients.The aim of the present study was to examine circulating DCs in a large cohort of ALS patients taking into account their clinical phase in order to lay the basis to understand how these cells contribute to disease progression. To do this, we performed ex vivo analyses of the frequency and expression of costimulatory, MHC and migratory mole¬cules of CD1c+ DC subsets and we investigated the capacity of purified DCs to spontaneously produce inflammatory cytokines and to respond to the TLR agonist, lipopolysaccharide (LPS). We enrolled 72 ALS patients, 47 healthy donors and 25 Patients affected by neurological disorders unrelated with ALS stratified for age and sex. DC numbers and their phenotype were investigated by cytofluorimetric analyses. We found that ALS patients have much lower number of circulating DCs (identified as CD1c+ and CD19-) compared with healthy donor, and their DCs show an increased expression of the integrin CD62L. Since this integrin is required for the recruitment of leukocytes to secondary lymphoid organs or to inflammatory sites, these observations confirmed that in ALS patients DCs are actively recruited in the central nervous system with a mechanism presumably involving the CD62L molecule. We then analysed the spontaneous o LPS-induced production of inflammatory cytokines such as TNFα, IL1β, IL6, IL8, IL10 and CCL2. We noticed a subpopulation of ALS patients with a higher spontaneous and LPS-induced IL8 production. These patients, interestingly, also showed higher efficiency of CCL2 secretion. Although we could not define a correlation between the higher efficiency of these inflammatory cytokine production and disease progression, high levels of CCL2 have been shown in the spinal cord of SOD mice, a mouse model of a subclass of ALS disease, and in some ALS patients. According to our results, DCs can be a source of CCL2 in the spinal cord in a subpopulation of ALS patients. This observation suggests that a simple peripheral blood analysis can be sufficient to identify subgroups of ALS patients. We, thus, analysed the correlation between the levels of any single cytokines in ALS patients before and after LPS exposure and some disease parameters.We observed a significant inverse correlation between the time from onset to diagnosis and the ΔIL6 levels, suggesting that an increased efficiency of IL-6 production in ALS patients may accelerate the initial phases of the disease.In conclusion, DCs are one of the major cell subset recruited to the central nervous system at least in some ALS patients. Although the majority of activated DCs may migrate to the central nervous system, some differences are still observable in the peripheral blood. Based on our results, peripheral blood DC analyses can be useful to stratify patients in those that have a high inflammatory response versus those that do not show an altered inflammatory pathway.Given the high heterogeneity of ALS disease we could not observe for the moment significant correlations with disease parameters, nevertheless a more refined analysis based on specific criteria is likely to be informative on some particular disease aspects.The high levels of CD62L expression by peripheral blood DCs suggest that this molecule could be a possible target for in vivo treatment. To this regard, we are planning to perform a preclinical study in SOD mice to verify if a treatment with a blocking anti-CD62L antibody could interfere with disease progression.

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13

Araújo, Lucas Guilherme de. "On cholecystokinin-opioid interaction in the spinal dorsal horn following peripheral nerve injury and inflammation /". Stockholm, 1999. http://diss.kib.ki.se/1999/91-628-3560-2/.

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14

Lavinskienė, Simona. "Peripheral blood neutrophil and eosinophil activity during allergen-induced late-phase airway inflammation in asthma". Doctoral thesis, Lithuanian Academic Libraries Network (LABT), 2015. http://vddb.library.lt/obj/LT-eLABa-0001:E.02~2014~D_20150106_083713-90371.

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There is no doubt that eosinophils and neutrophils are important cells participating in asthma pathogenesis. The most prominent feature reflecting asthma pathogenesis is late-phase airway inflammation, which occurs a few hours after allergen inhalation. The worldwide published studies on asthma show that most attention is paid to individual, not complex, functions of neutrophils and eosinophils in the airways. Moreover, associations between peripheral blood neutrophil and eosinophil activity and infiltration of these cells in the airways during asthma have not been com¬pletely elucidated yet. There are no data about peripheral blood neutrophil and eosinophil activity during allergen-induced late-phase airway inflam¬mation in asthma patients. Therefore, the aim of this study was to evaluate peripheral blood neutrophil and eosinophil functional activity during allergen-induced late-phase airway inflammation in asthma. We found that an inhaled allergen activates peripheral blood neutrophil and eosinophil chemotaxis, phagocytosis, generation of reactive oxygen species and also reduces apoptosis during late-phase airway inflammation in asthma. Furthermore, altered peripheral blood neutrophil and eosinophil functional activity is related with airway neutrophilia and eosinophilia. Our findings provide new evidence about neutrophil and eosinophil functional activity during allergen-induced late-phase airway inflammation in asthma patients.
Mokslininkai neabejoja, jog eozinofilai ir neutrofilai yra vienos svarbiausių ląstelių, dalyvaujančių astmos patogenezėje, kurią labiausiai atspindi vėlyva kvėpavimo takų uždegimo fazė, išsivystanti praėjus kelioms valandoms po alergeno įkvėpimo. Pasaulinėje literatūroje publikuojami darbai, nagrinėja atskirus kvė¬pavimo takų neutrofilų ir eozinofilų aktyvumo pokyčius. Ypač mažai darbų apie periferinio kraujo neutrofilų ir eozinofilų funkcijas bei jų ryšį su šių ląstelių pagausėjimu kvėpavimo takuose, sergant astma. Taip pat nėra tyrimų, vertinančių periferinio kraujo uždegimo ląstelių (neutrofilų ir eozi¬nofilų) funkcijų alergeno sukeltos vėlyvos fazės kvėpavimo takų uždegimo metu. Todėl šio tyrimo tikslas buvo įvertinti periferinio kraujo neutrofilų ir eozinofilų funkcinį aktyvumą alergeno sukeltos vėlyvos fazės kvėpavimo takų uždegimo metu sergant astma. Tyrimo metu nustatėme, kad įkvėptas alergenas aktyvina periferinio kraujo neutrofilų ir eozinofilų funkcijas - chemotaksį, fagocitozę, reaktyvių deguonies formų susidarymą, degranuliaciją bei silpnina apoptozę vėlyvos fazės kvėpavimo takų uždegimo metu. O šių ląstelių aktyvumo pokyčiai yra susiję su kvėpavimo takų neutrofilija ir eozinofilija. Moksliniame darbe pateikiami rezultatai suteikia naujų duomenų apie sergančiųjų alergine astma periferinio kraujo neutrofilų ir eozinofilų funkcinių savybių ypatumus ir parodo jų pokyčius alergeno sukeltos vėlyvos fazes kvėpavimo takų uždegimo metu.

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15

Komla, Essie S. "Antinociceptive tolerance to morphine is driven by colonic inflammation and mediated by peripheral opioid receptors". VCU Scholars Compass, 2019. https://scholarscompass.vcu.edu/etd/5818.

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Opioids are powerful analgesics. Despite their high efficacy for the management of moderate to severe pain, their clinical utility is limited due to the occurrence of adverse effects. The main problem associated with opioid use is the differential rate of tolerance development to the various pharmacological effects of opioids, with tolerance to respiratory depression occurring at a slower rate than analgesic and euphoric effects. The development of analgesic tolerance, where the efficacy of the drug progressively diminishes with repeated administration, requires higher doses of the drug to achieve a maximum effect. Reports have implicated inflammation as a major driver of analgesic tolerance development. With surmounting evidence that the prototypical opioid, morphine induces pro-inflammatory cytokine release in the brain, spinal cord, and gastrointestinal tract, a question arises of whether pro-inflammatory cytokine release in the gut as a result of chronic morphine treatment is paralleled with the development of morphine antinociceptive tolerance. This dissertation investigated the rate at which antinociceptive tolerance to various doses of morphine developed to a different degree in the presence of colonic inflammation. Using a mouse model, colonic inflammation was induced with 2,4,6-Trinitrobenzenesulfonic acid (TNBS) and then the mice were pelleted with 25 mg, 50 mg (2x25), or 75 mg morphine pellet. Antinociceptive tolerance to morphine was determined in a warm-water tail-immersion assay upon an administration of a morphine challenge dose (10 mg/kg). Inflammatory cytokine expressions and protein levels were measured from whole colon using qPCR and ELISA, respectively. Morphine antinociceptive tolerance was significantly enhanced in the presence of colonic inflammation in a dose and time dependent manner. With a daily injection of 0.5 mg/kg peripheral opioid receptor antagonist 6β-N-heterocyclic substituted naltrexamine derivative (NAP), mice pelleted with 25 mg, 50 mg (2x25), or 75 mg morphine pellets were tested on day 5, 4, or 3, respectively. Tolerance to morphine as well as the enhanced tolerance observed in the presence of colonic inflammation was prevented with daily NAP treatment. However, NAP did not block morphine-induced or TNBS-induced inflammation. Collectively, our findings indicate that inflammation is a major modulator of morphine antinociceptive tolerance and peripheral opioid receptors may be responsible for mediating antinociceptive tolerance.

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16

Burdess, Anne. "Role of inflammation and platelet activation in the adverse cardiovascular outcomes of patients undergoing surgery for critical limb ischaemia". Thesis, University of Edinburgh, 2014. http://hdl.handle.net/1842/9539.

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Increased platelet activation and inflammation play a key role in atherothrombosis. Patients with peripheral arterial disease are at increased risk of adverse cardiovascular events, particularly at the time of surgery. We postulated that the increase in peri-operative cardiovascular events is mediated by increased platelet activation and inflammation. We hypothesized that peri-operative dual anti-platelet therapy would improve biomarkers of atherothrombosis without causing unacceptable bleeding in patients undergoing surgery for critical limb ischaemia (CLI). Prior to interventional study, I validated a sensitive flow cytometric technique for the reproducible assessment of in vivo platelet activation in patients with peripheral arterial disease. Thirty patients with stable claudication, attended on two occasions to permit within-day and between-day comparisons. A variety of platelet activation markers were compared to the gold standard of platelet–monocyte aggregation. Platelet-monocyte aggregation demonstrated comparable within-day (mean difference ± co-efficient of reproducibility; 0.9±15.4%) and between-day reproducibility (2.0±12.4%). Plateletmonocyte aggregates correlated well with other platelet activation markers (P selectin r=0.30; Platelet CD40L r=0.41; Platelet microparticles r=0.27; P≤0.026) and monocyte activation markers (monocyte CD40 r=0.27;monocyte CD11b r=0.47; P≤0.026). In a cross sectional study, I demonstrated that resting in vivo platelet activation and inflammation was increased in patients with CLI in comparison to healthy controls, patients with stable claudication and those undergoing treatment for acute coronary syndromes. In addition, platelet activation and inflammation throughout the peri-operative period was markedly increased in CLI patients compared with non-vascular patients undergoing arthroplasty, and exceeded the rise attributable to the stress of surgery itself. In a prospective double-blind randomised controlled trial, 108 patients undergoing infra-inguinal revascularisation or amputation for CLI were maintained on aspirin (75 mg daily) and randomised to clopidogrel (600 mg prior to surgery, and 75 mg daily for 3 days; n=50) or matched placebo (n=58). Peri-operative in vivo platelet activation and inflammation, cardiac-Troponin I (c-TnI) release and bleeding outcomes were recorded. Clopidogrel reduced markers of platelet activation and inflammation before surgery and throughout the post-operative period. Overall, there were 18 troponin-positive events (16.7%), with half of the troponin rises (9) occurring prior to surgery. Patients with postoperative elevations in c-Tn I had significantly greater levels of pre-operative platelet-monocyte aggregation, monocyte CD40, IL-6 and hsCRP. However, despite reducing platelet and inflammatory markers, clopidogrel did not have a direct effect on peri-operative c-Tn I. There was no increase in major life-threatening or minor bleeding, although blood transfusions and wound haematomas were significantly increased. Using sensitive and validated methodologies, I have provided a detailed examination of in vivo platelet activation and inflammation in high-risk vascular surgical patients. This approach has provided the first objective assessment of the risks and benefits of intensive peri-operative anti-platelet therapy in this patient group. Dual anti-platelet therapy reduced biomarkers of atherothrombosis without causing unacceptable bleeding. However, large-scale clinical trials would be required to confirm whether these reductions translate into improvements in clinical outcome.

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17

Hernández, Aguilera Anna. "Peripheral Artery Disease: The search for a biological marker". Doctoral thesis, Universitat Rovira i Virgili, 2017. http://hdl.handle.net/10803/442958.

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La malaltia arterial perifèria (MAP) és una manifestació comuna de l'aterosclerosi sistèmica que afecta les artèries perifèriques. Tot i la seva elevada prevalença, la MAP està infradiagnosticada perquè els primers estadis de la malaltia són asimptomàtics. Tot i les seves limitacions, l’índex turmell-braç és el test usat per al diagnòstic. Hi ha altres biomarcadors circulants però són per a l’aterosclerosi en general. La inflamació, l’oxidació, la remodelació vascular i la disfunció mitocondrial tenen un paper clau en el desenvolupament de l’aterosclerosi. Creiem que un millor coneixement d’aquests processos ens pot proporcionar marcadors circulants per la malaltia i també possibles dianes terapèutiques. A l’estudi 1 vam investigar l’expressió immunohistoquímica de les paraoxonases (PON) i quimiocines en artèries de pacients amb MAP. Els resultats van mostrar que PON1, PON3, la quimiocina (CCL2) i els seus receptors atípics (ACKRs) DARC i D6 estaven incrementats en artèries ateroscleròtiques, suggerint que paraoxonases i quimiocines juguen un paper clau en el desenvolupament de l’aterosclerosi. El recanvi de la matriu extracel·lular (ECM) també està involucrat en la remodelació vascular. A l’estudi 2, combinant histologia i proteòmica, vam observar que les artèries ateroscleròtiques tenien un perfil proteic on els components de l’ECM estaven menys expressats. D’entre un conjunt de neo-epítops, els fragments de degradació de versican i col·làgen tipus IV mostraven potencial com a biomarcador per a segregar patients amb diferents graus de MAP. L’alteració del metabolisme i la disfunció mitocondrial també poden predisposar a la malaltia. A l’estudi 3, vam utilitzar tècniques de metabolòmica en plasma de pacients amb MAP. La major part dels metabòlits mesurats es relacionaven amb les comorbiditats associades a la MAP. D’entre els metabòlits restants, l’(iso)citrat i el glutamat van resultar útils per al diagnòstic de la MAP i també per a una detecció primerenca de la malaltia.
La enfermedad arterial periférica (EAP) es una manifestación común de aterosclerosis sistémica que afecta a las arterias periféricas. Aunque su prevalencia es elevada, está infradiagnosticada porque los primero estadíos de la enfermedad son asintomáticos. El índice tobillo-brazo es el test más usado para el diagnóstico, aunque presenta limitaciones. Existen otros marcadores circulantes pero son para aterosclerosis en general. La inflamación, oxidación, remodelación vascular y disfunción mitocondrial tienen un papel clave en el desarrollo de la aterosclerosis. Creemos que un mejor conocimiento de estos procesos puede proporcionar marcadores circulantes de enfermedad y también posibles dianas terapéuticas. En el estudio 1, investigamos la expresión inmunohistoquímica de las paraoxonasas (PON) y quimiocinas en arterias de pacientes con EAP. Los resultados mostraron que PON1, PON3, la quimiocina CCL2 y los receptores inespecíficos (ACKRs) DARC y D6 estaban incrementados en arterias ateroscleróticas, sugiriendo que paraoxonasas y quimiocinas tienen un papel clave en el desarrollo de la enfermedad. El recambio de la matriz extracelular (ECM) también está involucrado en la remodelación vascular. En el estudio 2, combinando histología y proteómica, observamos que las arterias ateroscleróticas tenían un perfil proteico donde los componentes de la ECM estaban menos expresados. De entre un conjunto de neo-epítopos, los fragmentos de degradación de versican y colágeno IV mostraron potencial como biomarcadores para segregar pacientes con diferentes grados de EAP. La alteración del metabolismo y la disfunción mitocondrial también pueden predisponer a la enfermedad. En el estudio 3, utilizamos técnicas metabolómicas en el plasma de pacientes con EAP. La mayoría de metabolitos cuantificados se relacionaron con las comorbilidades asociadas a la EAP. De entre los metabolitos restantes, el (iso)citrato y glutamato resultaron útiles para el diagnóstico de la EAP, y también para una detección precoz de la enfermedad.
Peripheral artery disease (PAD) is a common manifestation of systemic atherosclerosis affecting peripheral arteries. Despite its high prevalence, PAD is often underdiagnosed because first stages of the disease are asymptomatic. The ankle-brachial index (ABI) is the most used test for PAD diagnosis although its limitations. There are additional circulating biomarkers of diagnosis not exclusively for PAD but for atherosclerosis in general. Inflammation, oxidation, vascular remodeling and mitochondrial dysfunction play an important role in the development of atherosclerosis. We hypothesized that an increased knowledge on these processes may provide circulating biomarkers for the disease as well as possible therapeutic strategies. In Study 1, we investigated the immunohistochemical expression of paraoxonases (PON) and chemokines in arteries of PAD patients. Results showed that PON1, PON3, chemokine (C-C motif) ligand 2 (CCL2) and atypical chemokine receptors (ACKR) DARC and D6 were increased in atherosclerotic arteries, suggesting that both paraoxonases and chemokines play a key role in the development of atherosclerosis. Extracellular matrix (ECM) turnover is also involved in vascular remodeling. In Study 2, by combining histological and proteomics approaches, we observed that atherosclerotic arteries had a specific protein profile in which ECM-related components were underexpressed, suggesting a possible degradation of the ECM. Among a measured a panel of neo-epitopes, Versican and type IV collagen degradation fragments showed potential as biomarkers to segregate patients across the spectrum of PAD. Impaired metabolism and mitochondrial dysfunction may also predispose to disease. In Study 3, we used a targeted metabolomics methodology to assess the plasma metabolome of PAD patients. Many of measured metabolites were connected not with PAD, but with associated comorbidities, age or body mass index. Among remaining metabolites, (Iso)citrate and glutamate were useful for PAD diagnosis and also for an early detection of the disease.

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18

Cristante, Enrico. "Impact of peripheral inflammation in the brain : new roles for the anti-inflammatory molecule Annexin A1". Thesis, Imperial College London, 2013. http://hdl.handle.net/10044/1/14415.

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Growing evidence has shown that peripheral inflammation can trigger a central nervous system response, sometimes worsening pre-existing neurological conditions, breaking down the concept of brain as an immune-privileged organ. Understanding which components contribute to periphery-to-brain communication may help identify molecules exploitable for therapeutic intervention. Usually, inflammation is followed by resolution: one of the main effectors in this process during peripheral inflammation is Annexin A1, while its implications in the CNS are still unclear. This thesis provides evidence for a new face for the molecule: we observed a well-defined expression at blood brain barrier (BBB) at endothelial level and we detected, in vivo, significantly higher BBB permeability in the AnxA1 null mice due to disrupted inter-endothelial cell tight junctions, essentially as a consequence to changes in the actin cytoskeleton. Such changes are reminiscent of early MS pathology, a relationship confirmed by detecting a selective loss of ANXA1 in the plasma and cerebrovascular endothelium of MS patients. Under peripheral inflammatory conditions (i.p. lipopolysaccharide, LPS), in vivo data suggested an inherent sex difference in BBB response, while in vitro studies confirmed the protective action of sex hormone 17β-Estradiol on the endothelium through ANXA1 modulation. Within the CNS, we detected a constitutively higher microglial density and pro-inflammatory environment in the Anxa1 null mouse, which worsened upon peripheral inflammation. In a neurodegeneration model (6-hydroxydopamine), genotype-related differences in microglial invasion occurred, while subsequent peripheral inflammatory challenges synergised and caused worse dopaminergic neuronal loss only in the knock-out model. These original data unveil a novel functional paradigm for ANXA1 as a “translator” between peripheral immune system and CNS through novel pathways compared to its well-characterized peripheral role. In addition, this study opens up a novel path to find therapeutic applications against disorders characterized by central and peripheral inflammation.

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19

Jäger, Amelie [Verfasser] y Christine [Akademischer Betreuer] Dierks. "JAK Pathway inhibition as a novel therapeutic strategy in peripheral t-cell lymphomas with associated inflammation". Freiburg : Universität, 2018. http://d-nb.info/1216826420/34.

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Riester, Karin Dorota [Verfasser]. "The effect of peripheral inflammation on in vivo functional properties of cortical networks / Karin Dorota Riester". Tübingen : Universitätsbibliothek Tübingen, 2020. http://d-nb.info/1217249265/34.

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21

Annisius, Daniel Chandrachur. "Managing Seasonality in Tourism : Challenges and Opportunities for the Tourism Industry in Húsavík, Iceland". Thesis, Högskolan Dalarna, Turismvetenskap, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:du-14307.

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Seasonality is a common phenomenon in the tourism industry around the world. Húsavík, a town on the northern coast of Iceland, has experienced tremendous growth in tourism in recent years and is sometimes recognised as the „Whale Watching Capital of Europe‟. However, Húsavík faces extreme seasonality with high demand mainly during the summer months and limited or no demand at other times of the year. As is emphasised in the tourism literature and widely in practice, seasonality is frequently seen as a problem for the tourism industry which has to be tackled. Academic research has never before been done on seasonality in Húsavík and the aim of this thesis is to understand the nature of seasonality within the tourism industry in Húsavík and discover potential ways to reduce seasonality in Húsavík tourism. In order to fulfil the aim, qualitative semi-structured interviews were undertaken with six tourism managers in Húsavík to investigate their perceptions of seasonality and if and how it could be managed. The results confirmed that the peripheral location of the destination stimulates seasonality and it poses major economic challenges for tourism businesses in Húsavík. Managers would prefer a longer tourism season. Several recommendations were provided for how to reduce seasonality such as develop other attractions than whale watching, improve accessibility, focus marketing on seasons outside the summer, and offer winter packages for foreign and domestic tourists.

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22

Marimuthu, Rekha. "Study of Monocytes in Diabetic Foot Ulcer (DFU) patients with Peripheral Arterial Disease (PAD)". Thesis, The University of Sydney, 2018. https://hdl.handle.net/2123/21374.

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Diabetic foot ulcers (DFUs) are one common and severe complication of diabetes, showing impaired wound healing. Peripheral arterial disease (PAD), which is common in diabetes, increases the severity of DFUs leading to delayed or unsuccessful healing. Prolonged inflammation is one of the likely contributors to this, with an imbalance in macrophage phenotypes seen in diabetes. Monocytes, precursors to macrophages, express M1/M2 macrophage markers indicating monocyte skewing to a particular macrophage phenotype begins in the circulation. Whether the presence of DFU is associated with monocyte M1-skewing and the presence of PAD further influences this is not known. The main aim of this study was to investigate the effect of PAD on the inflammatory profile of circulating monocytes and ulcer macrophages in DFU patients, as well as determining whether monocyte/macrophage profile relates to healing parameters. Blood and ulcer biopsy samples were collected from DFU patients with and without PAD. Whole blood flow cytometry was used to determine monocyte subset proportions and M1-skewing, which was also compared with historical data from healthy controls. Immunohistochemistry was used to detect M1/M2 ulcer macrophages. DFU patients in general had a higher proportion of intermediate monocytes than controls (p=0.042) and DFU/PAD had more intermediates than DFU/NoPAD (p=0.02), suggesting PAD worsens this imbalance. M1-skewing of monocytes was higher in DFU/PAD patients than DFU/NoPAD group (p=0.046) in addition to strong M1 skewing in DFU patients in general (p<0.001). DFU/PAD patients had more M1 macrophages in their ulcers than DFU/NoPAD patients (p=0.04) and their M1/M2 ratio correlated positively with ulcer cross-sectional area (p=0.01). This study highlighted the enhanced inflammatory profile in DFU patients, particularly those complicated with PAD. These monocyte and macrophage alterations, may contribute to the delay in wound healing typical of this group.

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23

Bernards, Nicholas. "PET molecular imaging of peripheral and central inflammatory processes targeting the TSPO 18 kDa". Thesis, Paris 11, 2014. http://www.theses.fr/2014PA112211/document.

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L’objectif de la thèse: À ce jour, il est admis que la TSPO joue un rôle important dans le processus inflammatoire, et qu’il est possible de suivre sa présence à l’aide d’une variété de radiotraceurs adaptés. Les impacts de l’inflammation touchent un grand nombre de personnes à travers le monde pour diverses raisons ; c’est pourquoi, quoique le [ ¹ ⁸F]DPA-714 est très prometteur, il est nécessaire d’aller plus loin pour explorer ses capacités et ses applications possibles. L’inflammation a une forte incidence sur différentes maladies, par conséquent, à impact social élevé (comme la maladie inflammatoire de l’intestin (IBD), la neuroinflammation, et le choc septique). Dans ces modèles nous analyserons et quantifierons les niveaux de d’expression de TSPO 18kDa par imagerie TEP que nous comparerons au niveau exprimé trouvés chez des sujets contrôles. L’objectif étant de déterminer si la TSPO peut constituer une cible biologique d’intérêt pour l’évaluation et la quantification d’un état inflammatoire chez l’individu en utilisant l’imagerie TEP avec le radioligand [ ¹ ⁸F]DPA-714.Aperçu sur le travail de recherche : L’étude entreprise dans cette thèse a fourni des informations conduisant à la conclusion suivante : la TSPO 18kDa peut en effet être utile comme biomarqueur pour l’évaluation d’un état inflammatoire dans plusieurs maladies. Nous avons pu illustrer par l’intermédiaire de deux modèles de la maladie inflammatoire de l’intestin, un modèle de la neuroinflammation et un modèle de choc septique, que la TSPO est un indicateur du niveau de l’inflammation dans la zone affectée. De plus, nous avons pu suivre, mesurer et quantifier l’évolution d’une zone inflammée en fonction du temps.Bien que le [ ¹ ⁸F]DPA-714 est le traceur utilisé pour déterminer la présence et le niveau de l’inflammation, d’autres traceurs sont constamment en cours de développement. Cela est démontré par le travail de collaboration effectuée avec l’équipe de radiochimie, dans lequel nous avons illustré le potentiel d’un nouveau radioligand de TSPO, le [ ¹ ⁸F]DPA-C5yne
Purpose : The purpose of this study was to determine the in vivo potential of the TSPO 18 kDa as a biomarker of inflammation, with the use of its radioligand [ ¹ ⁸F]DPA-714, to non-invasively quantify the inflammatory state within the scope of various pathologies. Procedure : Multiple animal models of various inflammatory diseases, to include : inflammatory bowel disease, neuroinflammation, and septic shock, were developed and put in place by adapted measures. The animals well-being and the subsequent inflammation was evaluated. The inflammatory state was measured using quantitative PET imaging with the TSPO radioligand [ ¹ ⁸F]DPA-714 and correlated to the expression of conventional inflammatory markers using microscopy. Results : Based on the observed data, we were able to distinguish control groups from treated groups when using [ ¹ ⁸F]DPA-714. This TSPO radioligand permitted us to quantify the inflammatory level and to observe evolutionary changes in the inflammatory state of the disease in multiple models. The PET results, using the [ ¹ ⁸F]DPA-714 signal was correlated with an increased TSPO expression at cellular level. Conclusion : Results indicate that [ ¹ ⁸F]DPA-714 is a suitable tracer for studying inflammation of multiple diseases.[ ¹ ⁸F]DPA-714 could be a good molecular probe to non-invasively evaluate the level and localization of inflammation. Moreover, in vivo imaging using this TSPO ligand is potentially a powerful tool to stage and certainly to follow the evolution and therapeutic efficiency at molecular level in inflammatory diseases

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24

Doak, Gregory J. "Peripheral mechanisms of adenosine and 5-hydroxytryptamine contributing to nociception and inflammation in the rat formalin model". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/nq24735.pdf.

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Pitcher, Mark Henry. "Role of the NKCC1 co-transporter in spinal nociceptive mechanisms in a rodent model of peripheral inflammation". Thesis, McGill University, 2011. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=96700.

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The Gate Control Theory describes a spinal circuit whereby activity in low threshold mechano-sensitive fibers attenuates activity in nociceptive fibers, such that innocuous touch eases pain. Paradoxically, for many chronic pain sufferers, lightly touching the injured (primary) region or adjacent uninjured (secondary) region may evoke pain rather than ease pain, phenomena referred to as primary and secondary allodynia, respectively. We hypothesize that enhanced activity of the NKCC1 chloride co-transporter in persistent pain states may underlie this effect. NKCC1 is the main chloride accumulator in primary sensory fibers; by setting the intracellular chloride concentration, NKCC1 determines the magnitude of primary afferent depolarization (PAD) and, consequently, whether or not low intensity mechanical input inhibits or produces activity in nociceptive afferent fibers. In this thesis, we use multiple research techniques to determine the role of NKCC1 in capsaicin-induced allodynia. Capsaicin, the active ingredient in hot chili peppers, produces action potentials in nociceptive afferent fibers by activating TRPV1 receptors in the peripheral terminals. First, we demonstrate that spinal NKCC1 blockade as well as spinal TRPV1 blockade reduces intracolonic capsaicin-evoked secondary allodynia as well as TRPV1-mediated allodynia. Next, we determined that AMPA/kainate but not TRPV1 receptor blockade attenuates capsaicin-evoked increases of NKCC1 expression, suggesting a role for pre-synaptic AMPA/kainate receptors as regulators of NKCC1 expression. Spinal NKCC1 blockade also reduces intracolonic capsaicin-induced increase of FOS labeling in the spinal cord. Interestingly, NKCC1 blockade also partially prevents further enhanced FOS labeling following low intensity stimulation of the region of secondary allodynia. Finally, spinal NKCC1 blockade prevents capsaicin-evoked sensitization of spinal dorsal horn nociceptive neurons, illustrating for the first time that enhanced NKCC1 activity plays a critical role in central nervous system processing of nociceptive input. Together, these studies provide comprehensive support for NKCC1's role in persistent pain as well as evidence that NKCC1 may be a useful therapeutic target.
La théorie du portillon décrit un circuit spinal dans lequel l'activation des fibres mécano-sensitives de bas seuil atténue l'activité des fibres nociceptives, de tel sorte que le toucher léger réduit la douleur. Paradoxalement, pour plusieurs personnes souffrant de douleur chronique, la stimulation tactile de la région affectée (région primaire) ou la région adjacente à la lésion (région secondaire) provoque de la douleur au lieu de la réduire, phénomène respectivement nommé allodynie primaire et allodynie secondaire. Nous suggérons que dans les cas de douleur persistante, l'augmentation de l'activité du co-transporteur de chlore, NKCC1, pourait expliquer ce phénomène. NKCC1 est le principal responsable de l'accumulation intracellulaire de chlore au niveau des fibres sensitives primaires; en ajustant la concentration intracellulaire de chlore, NKCC1 détermine la magnitide de la dépolarisation afférente primaire et, par conséquant, déterminera si une stimulation mécanique de basse intensité activera ou inhibera les fibres nociceptives afférentes. Dans cette thèse, plusieurs techniques de recherche sont utilisées pour déterminer le rôle de NKCC1 dans l'allodynie induite par capsaicine. La capsaicine, la molécule active des piments forts, produit des potentiels d'action au niveau des fibres nociceptives afférentes en activant les récepteurs TRPV1 dans les terminaisons périfériques. Premièrement, nous démontrons que lorsque NKCC1 ou TRPV1 sont bloqués au niveau spinal, il y a une réduction de l'allodynie induite par la capsaicine intracolonique ainsi que de l'allodynie induite par l'administration spinal d'un agoniste de TRPV1. Ensuite, nous démontrons que le blocage des récepteurs AMPA/kainate atténuent l'augmentation de l'expression de NKCC1 par la capsaicine, alors que le blocage des récepteurs TRPV1 n'ont pas d'effet. Cela suggère un rôle des récepteurs pre-synaptiques AMPA/kainate comme régulateur de l'expression d'NKCC1. Dans la moelle épinière, le blocage de NKCC1 réduit aussi l'augmentation de l'expression de FOS induite par la capsaicine intracolonique. Il est aussi intéressant de noté que le blocage de NKCC1 prévient partiellement l'augmentation de l'expression de FOS suivant une stimulation de faible intensité de la région d'allodynie secondaire. Finalement, le blocage de NKCC1 prévient la sensibilisation par la capsaicine des neurones nociceptives de la corne dorsal de la moelle épinière. Cela illustre que l'augmentation de l'activité de NKCC1 joue un rôle modulateur sur les signaux nociceptif afférant. L'ensemble de ces études soutiennent le rôle d'NKCC1 dans la persistance de la douleur et démontre que NKCC1 est une cible thérapeutique prometteuse.

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26

Wendeln, Ann-Christin [Verfasser]. "Long-lasting epigenetic microglial memory of peripheral inflammation modulates hallmarks of Alzheimer's disease pathology / Ann-Christin Wendeln". Tübingen : Universitätsbibliothek Tübingen, 2020. http://d-nb.info/1217249214/34.

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27

Rankin, Gregory. "Investigation of the role of IgE-dependent cytokine release from human peripheral lung tissue in allergic lung inflammation". Thesis, University of Southampton, 2011. https://eprints.soton.ac.uk/378565/.

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Parkinson, Sarah. "Neuroinflammation, Peripheral Inflammation and Gut Microbiome Profiles in Male Mice from Two Proposed Mouse Models of Social Behavior Deficits". Digital Commons @ East Tennessee State University, 2021. https://dc.etsu.edu/etd/3972.

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Autism spectrum disorder (ASD) is a neurodevelopmental disorder marked by social deficits and repetitive actions. A communication pathway exists between the brain and gut called the gut-brain axis. It is thought that gut bacteria can secrete signaling molecules, triggering inflammation across the body. These studies attempt to determine if markers are expressed in two mouse models of ASD behaviors, BTBR and a valproic acid model. Immunohistochemistry of ionized calcium binding adaptor molecule 1 from male mouse brain tissue showed no microglial activation in any group. Cytokine analysis did exhibit an increase in interleukin 1 (IL-1) in male adult mice only. Sequencing of bacterial profiles demonstrated differences between groups. Altogether, it appears that microbiome differences do not trigger robust differences in inflammatory pathways in these animals in this study. It is imperative that a reliable animal model of behaviors be identified for novel studies that can impact the development of the disorder.

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Pitcher, Mark H. "The effects of persistent peripheral inflammation on the ultrastructural localization of spinal cord dorsal horn group I metabotropic glutamate receptors /". Thesis, McGill University, 2005. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=98770.

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Persistent peripheral inflammation is thought to induce functional plasticity of spinal dorsal horn neurons, and may produce changes in glutamate receptor expression. Alterations in expression and cellular localization of group I metabotropic glutamate receptors (mGluR1alpha and mGIuR5) is important in various neuronal systems, and these receptors are also known to modulate nociceptive neurotransmission in the spinal dorsal horn. The aim of the present study is to determine whether persistent inflammation produces alterations in ultrastructural localization of mGluR1alpha and mGluR5 in the dorsal horn of the spinal cord. Persistent inflammation was induced in rats by an intraplantar hindpaw injection of complete Freund's adjuvant (CFA). Three days after the CFA injection, rats were perfused with fixatives, and spinal cords were removed and the lumbar segments L3-L5 were sectioned using a vibratome. Using pre-embedding immunocytochemical protocols for electron microscopy, we quantified immunogold-labeled mGluR1alpha and mGluR5, in lamina IV-V and I-II, respectively, in the spinal dorsal horn of both CFA-treated rats and untreated control rats. Compared to untreated rats, CFA-treated rats had a significant increase in membrane-associated mGluR5 immunogold-labeled particles in lamina I-II neurons. No change in the ratio of membrane vs. intracellular mGluR1alpha receptors was found in CFA-treated rats, however membrane-bound mGluR1alpha moved closer to the synapse in CFA-treated as compared with untreated rats. These findings suggest that persistent peripheral inflammation elicits increased availability of spinal dorsal horn group I mGluR's for synaptically-released glutamate binding. Thus, trafficking of Group I mGluR's may underlie the development of plastic changes in spinal dorsal horn neurons and associated persistent inflammation-induced chronic pain.

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Gelinas, Jinelle Crystal Marie. "The effects of aerobic exercise training on peripheral vascular structure and function and inflammation in patients with Chronic Obstructive Pulmonary Disease". Thesis, University of British Columbia, 2013. http://hdl.handle.net/2429/45454.

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COPD is associated with chronic systemic inflammation that has been linked to an increased risk of atherosclerosis, ischemic heart disease, and stroke. Endothelial dysfunction, vascular remodeling and arterial stiffness are early processes in the pathogenesis of atherosclerosis and are predictive of future cardiovascular events. Aerobic exercise training can reduce the risk of cardiovascular disease in patients with other chronic conditions. However, little is known about the benefits of exercise for improving vascular health in patients with COPD. Ten non-smoking patients with COPD (mean age=69±9yr, FEV1%pred=67± 3%) and six healthy controls matched for age, sex, BMI and activity level underwent pulmonary function and cardiopulmonary exercise testing. Endothelial function was assessed by flow-mediated dilation (FMD) in response to reactive hyperemia in the brachial artery, and carotid artery intima-medial thickness (IMT) was measured by ultrasound. Central and peripheral pulse wave velocity (PWV), carotid compliance and beta stiffness index were determined by applanation tonometry and ultrasound. A venous blood sample was collected to measure systemic inflammation. Following completion of baseline testing, aerobic exercise was performed on lower and upper extremity cycle ergometers, 3x/week for 8 weeks. All baseline measurements were repeated upon completion of the exercise training. An improvement in peak O2-consumption (VO₂peak, 18.0±4.6 to 19.8±3.6 ml/kg/min, p<0.01) and peripheral PWV (7.6±2.5 to 6.8±1.8 m/sec, p=0.03) occurred with training in patients with COPD. However, there was no significant change in measures of FMD, central arterial stiffness, carotid IMT or biomarkers of systemic inflammation, (p>0.05). There was also an improvement in VO₂peak (19.8±2.6 to 26.0±4.1 ml/kg/min, p=0.03) in controls, with no other significant changes following training. This pilot study demonstrated that 8-weeks of aerobic training improved peak aerobic power and peripheral arterial stiffness but had little effect on other established markers of cardiovascular disease risk in patients with COPD. These findings suggest that a typical 8-week pulmonary rehabilitation program may not be long enough to greatly improve vascular function or structure or reduce the systemic inflammation associated with increased cardiovascular disease risk in patients with COPD. Larger randomized, controlled studies are now needed to confirm these preliminary findings.

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Doenlen, Raphael Aloise. "Fingerprints of neural activity after peripheral immune challenges : an experimental study on the communication between the immune and central nervous systems /". [S.l.] : [s.n.], 2008. http://e-collection.ethbib.ethz.ch/show?type=diss&nr=18084.

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Carroll, Mark. "A stereological study assessing the validity of using endobronchial biopsies to assess mast cell density in the central and peripheral bronchial tree". University of Western Australia. School of Medicine and Pharmacology, 2008. http://theses.library.uwa.edu.au/adt-WU2009.0005.

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[Tuncated abstract] There has been longstanding concern over whether endobronchial biopsies adequately represent inflammation throughout the bronchial tree in diseases such as asthma, despite the endobronchial biopsy technique having been used frequently to assess airway inflammation in research settings. There has also been ongoing debate about whether endobronchial biopsies should be assessed by new, unbiased, three-dimensional (3D) stereological techniques instead of traditional, two-dimensional (2D) non-stereological techniques. Therefore, the aims of this study were: (i) to investigate whether endobronchial biopsies represent the density of mast cells in the large and small airways, in alveolar walls and in the lung as a whole (ii) to use both stereological and non-stereological methods to address this question, and where possible, to compare the results of these two approaches. '...' Mast cell density in biopsies was not related to mast cell density immediately adjacent to the biopsy site or to mast cell density in the total airway wall in the large airways, the inner airway wall in the small airways, the walls of the alveoli or the lung as a whole. In general, measurements of mean mast cell density on biopsies to a depth of 100µm below the basement membrane were poorly related to mean mast cell density in other compartments of the lung. Mean 3D and 2D mast cell densities were strongly correlated (r 0.9, p < 0.005) and where both methods were used, results were similar. The mean height and area profile of a mast cell were approximately 12µm and 68µm2 respectively. In disk-shaped IUR lung samples, percent shrinkage in height due to paraffin processing was systematically greater than percent radial shrinkage by an average of approximately 4 times. Cavalieri lung volumes were systematically smaller than displacement volumes by an average of 14%. Any given endobronchial biopsy is unlikely to represent mast cell density around the airway wall generally in the vicinity of the biopsy site. However, the average of at least 4 biopsies from different sites in the proximal airways can be used to both represent mean mast cell density in the inner airway wall of the large airways, and act as the basis for inter-subject comparisons of mean mast cell density in the total airway wall of the small airways. On biopsies, mast cell counts should be measured over the entire inner airway wall not just to a depth of 100µm or less below the basement membrane. 3D mast cell densities obtained by stereological methods are closely related to 2D mast cell densities obtained by non-stereological methods and are likely to result in similar conclusions. Lung volumes are smaller when measured by the Cavalieri method than when measured by fluid displacement. Shrinkage of isotropic uniform random samples of human lung tissue due to paraffin processing is anisotropic. The mean volume of a mast cell in the human lung is likely to be much smaller than that reported previously for monkey lungs.

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Säther, Jodie Katja. "Automated vehicles on airports : A case study of process challenges and opportunities in developing employee acceptance". Thesis, Uppsala universitet, Företagsekonomiska institutionen, 2021. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-433831.

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This study aims to explore the development of employee acceptance and process challenges and opportunities that surface when new technologies are introduced in a workplace environment. In the case of the implementation of automated vehicles, this study was conducted in close relationship with the organisation. In particular, we investigate employee acceptance and process challenges with an assistance of an analytic model, TAPA, built on the theoretical framework of trust, practice theory and Technology Acceptance Model (TAM), which is supported with trust and practice theory to form a comprehensive framework. The study stands on the philosophy of engaged scholarship and uses qualitative material from an exploratory case study, interviewing 22 respondents in order to cover an extensive part of the processes and practices affected by this implementation. Interestingly, the empirical data suggests that developing employee acceptance and combating process challenges and harnessing opportunities are not separate subjects, but streams in the same river. Therefore, to develop acceptance, the organisation would also need to work through the process challenges the respondents warrants action.

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Raza-Ullah, Tatbeeq y Rizwan Mir. "The “Go-Global” Notion of Entrepreneurs from Non-Metropolitan Regions : Evidence from SMEs located in North Region of Sweden". Thesis, Umeå universitet, Handelshögskolan vid Umeå universitet (USBE), 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-53485.

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Owing to their gigantic participation in global economic growth, the phenomenon of SMEs internationalization has become the centre of attention for numerous researchers. Starting from Uppsala model (1977) to born-global approaches today, scholars have been coming up with several theories and models time to time. An in-depth study of literature concerning SMEs internationalization, however, reveals that extant literature has primarily focused on firms that are operating from metropolitan or core regions of the world. It has largely ignored the vast peripheral and non-metropolitan regions of the world from where a great number of SMEs are operating in foreign markets. Particularly increasing number of small high-tech firms with ‘low to no demand’ in domestic market coupled with higher returns available in global markets are induced to internationalize despite intimidating challenges of periphery. Consequently, internationalization phenomenon from said locations, even in face of daunting challenges that hinder SMEs growth, turns out to be an attention-grabbing area – hence worth-investigating! The purpose of this study is to investigate the phenomenon of internationalization that is being pursued by SMEs located in non-metropolitan regions that offer unique constraints and challenges. More specifically, the objective is to explore the kind of entrepreneurial skills and talent that is required to develop networking relations with key players and to eventually internationalize from a peripheral location. To carry out this research, eight semi-structured interviews were conducted informally with key individuals from five small high-tech international firms located in North region of Sweden – a non-metropolitan region. Based on the findings, a conceptual model is developed which underlines that an entrepreneur in non-metropolitan regions should: possess global mind-set, social and team formation skills, and, industry experience; develop social, business and incessant snowball networks by efficiently utilizing his social skills; understand the peripheral challenges like: lack of financial resources, scarcity of non-tech professionals, being far away from core markets, absence of agglomeration advantage and travelling time and cost; and on the same time exploit the peripheral advantages which include loyal, hardworking, less salaried and easily retained employees, and, easy life and exotic climate that exclusively prevail in non-metropolitan regions. Having possessed skills, developed networks, and exploited the opportunities, the entrepreneur is now able to build a pool of potential and strength which minimizes the effect of constraints that he has already understood . As a result he can successfully pursue internationalization from a non-metropolitan region. We believe that this study has contributed both theoretically and practically and will inspire future empirical or conceptual research regarding this important topic.
CiiR(Centre for Interorganizational Innovation Research)

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Tarkowski, M. S. "ANALYSIS OF THE FREQUENCIES OF CD235A+CD71+ PRE-ERYTHROID CELLS IN PERIPHERAL BLOOD AND THEIR FUNCTION IN HIV INFECTED PEOPLE". Doctoral thesis, Università degli Studi di Milano, 2017. http://hdl.handle.net/2434/487852.

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Le cellule pre-eritroidi, caratterizzate dall’espressione di glicoforina A (CD235a) e recettore della transferrina (CD71) sono state precedentemente indicate in grado di modulare la risposta immunitaria e inibire la reazione infiammatoria. Poiché il processo dell’eritropoiesi è spesso alterato nel corso dell’infezione da HIV, è stato ipotizzato che le cellule pre-eitroidi, assenti in condizioni normali nel circolo periferico di adulti sani, possano essere riscontrate in soggetti con infezione da HIV ed esercitare un’attività immunomodulatoria. Lo scopo di questo studio è stato di investigare la presenza e la funzione di cellule pre-eritroidi riscontrata nel sangue periferico di soggetti adulti HIV positivi e HIV/HCV coinfetti, E’ stato riportato che le cellule pre-eritroidi sono presenti nel sangue periferico di soggetti adulti HIV positivi e HIV/HCV coinfetti, e in particolare in soggetti che sviluppano anemia. Le cellule pre-eritroidi di questi individui hanno mostrato essere una fonte significativa di espressione di Arg 1, e l’attività plasmatica di questo enzima è stata trovata significativamente più elevata in entrambi i gruppi di pazienti con infezione da HIV in confronto con il gruppo di soggetti non infetti. Analisi in vitro dell’attività di cellule pre-eritroidi derivate da sangue di cordone ombelicale hanno confermato quanto precedentemente riportato e hanno mostrato che tali cellule sono in grado di diminuire i processi dell’attivazione immunitaria. Sebbene queste osservazioni possano essere confermate in alcuni casi di pazienti con infezione da HIV, l’effetto immunosoppressivo esercitato dalle loro cellule pre-eritroidi è meno marcato. Nonostante l’evidenza di un aumentato numero di cellule pre-eritroidi con potenziale attività immunosoppressiva, i pazienti anemici con infezione da HIV e coinfezione HIV/HCV, hanno mostrato valori di attivazione immunitaria o infiammatoria simili o addirittura più elevati rispetto ai pazienti infetti non anemici. La discrepanza di queste osservazioni può indicare che nonostante il potenziale carattere immunosoppressivo delle cellule pre-eritroidi la loro limitata permanenza nel distretto sanguigno periferico può non essere sufficientemente significativa nei confronti di reazioni pro-infiammatorie maggiormente sostenute. E’ inoltre necessario considerare che in questo studio sono stati esplorati un numero limitato di marcatori di attivazione immunitarie e infiammatoria. La spiegazione di un potenziale effetto delle cellule pre-eritroidi durante il processo di anemizzazione in soggetti con infezione da HIV e HIV/HCV coinfetti richiede ulteriori studi e potrebbe essere di aiuto nella comprensione l’associazione tra anemia e aumento della mortalità, aumento della progressione di malattia e ridotta qualità della vita in questi gruppi di pazienti.
Pre-erythroid cells, characterized by expression of glycophorin A (CD235a) and transferrin receptor (CD71) were demonstrated before to modulate immune responses and to suppress inflammatory reactions. As the process of erythropoiesis is often disturbed during HIV infection it was assumed that pre-erythroid cells, normally not present in peripheral blood of healthy adults, may be found in this tissue of HIV infected people and exert immunomodulatory activity. The purpose of the study was to investigate the presence and function of pre-erythroid cells found in peripheral blood of HIV and HIV/HCV co-infected adults. It was found that pre-erythroid cells are present in peripheral blood of HIV and HIV/HCV co-infected adults, especially those who developed anemia. Pre-erythroid cells of these people were found to be a significant source of Arg1 expression, and plasma activity of this enzyme was significantly higher in both groups of HIV infected patients in comparison to healthy group. In vitro analyses of activity of cord blood derived pre-erythroid cells confirmed previously reported findings and showed that these cells diminish the processes of immune activation. Although these observations could be confirmed in some cases of HIV infected patients, the immunosuppressive effect exerted by their pre-erythroid cells was less evident. Despite the findings of increased number pre-erythroid cells with potentially immunosuppressive activity, anemic HIV infected and HIV/HCV co-infected demonstrated similar or for some parameters even higher values of immune activation or inflammation than not anemic, infected people. The discrepancy between these observations can indicate that despite potential immunosuppressive character of the pre-erythroid cells their short term presence in peripheral blood may not be significant enough to affect more sustained pro-inflammatory reactions. It needs also to be considered that in this study limited number of immune activation and inflammation markers were studied. Explanation of the potential effect of pre-erythroid cells during the course of anemia in HIV and HIV/HCV co-infected people requires further studies as it can help to better understand the association between anemia and increased mortality, increased disease progression, and reduced quality of life in these groups of patients.

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Quinteiro, Mariana da Silva 1982. "Evaluation of peripheral effect of 15d-PGJ2 on inflammatory process induced by rheumatoid arthritis into rats' temporomandibular joint = Avaliação do efeito periférico da 15d-PGJ2 no processo inflamatório induzido pela artrite reumatoide na articulação temporomandibular de ratos". [s.n.], 2014. http://repositorio.unicamp.br/jspui/handle/REPOSIP/289486.

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Orientador: Juliana Trindade Clemente Napimoga
Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba
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Resumo: O processo inflamatório induzido pela Artrite Reumatoide (AR) na articulação temporomandibular (ATM) resulta em uma dor persistente causando estresse em muitos pacientes. ... Observação: O resumo, na íntegra, poderá ser visualizado no texto completo da tese digital
Abstract: Inflammation of the temporomandibular joint (TMJ) induced by Rheumatoid Arthritis (RA) have often resulted in persistent pain and caused distress to many patients... Note: The complete abstract is available with the full electronic digital thesis or dissertations
Doutorado
Fisiologia Oral
Doutora em Odontologia

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Pisi, Paula Carolina Bezzan. "Influência da perda de peso induzida por cirurgia bariátrica na resposta imune em paciente com obesidade grau III". Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/17/17138/tde-06062017-163504/.

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A inflamação associada à obesidade é caracterizada por uma ativação crônica e de baixa intensidade do sistema imune. Diversos autores demonstraram mudanças em parâmetros inflamatórios após perda de peso. A cirurgia bariátrica é um método para tratar obesidade com alta eficiência e menor risco de recidiva. Os mononucleares de sangue periférico (MNSP) constituem um material biológico interessante para pesquisa, visto a capacidade de refletir alterações de expressão gênica de diferentes tecidos e o fácil acesso para análise. O presente estudo teve por objetivo avaliar os efeitos da obesidade e da perda de peso induzida por cirurgia bariátrica sobre a atividade imunológica, por meio de cultura primária de MNSP de pacientes com obesidade grau III (IMC >= 40 kg/m2). Foram coletadas amostras de sangue de veia periférica de 10 voluntários com peso normal (grupo controle) e antes e após a cirurgia de 20 voluntários com obesidade grau III. Após a separação dos mononucleares pelo gradiente de Ficoll-HyPaque, as células foram estimuladas por lipopolissacarídeo (LPS) ou concanavalina A (Con-A) e os sobrenadantes das culturas coletados para dosagem de IL-1?, IL-6, TNF-?, IFN-?, IL-10 e IL-17 por teste ELISA. As amostras de sangue também foram utilizadas para exames bioquímicos, dosagens de adiponectina, leptina e citocinas séricas. Os resultados evidenciaram maiores concentrações de IL-6, TNF-?, IL-1? e IL-10 nos sobrenadantes das culturas de MNSP do grupo com obesidade em relação ao grupo controle. Na comparação entre dosagens de citocinas do grupo com obesidade, observamos redução de TNF-?, IL-1? e IL-10 após 6 meses da cirurgia, a qual não foi observada após 1 ano, e aumento de IL-17 após 1 ano de tratamento. Não houve diferença significativa nas concentrações de citocinas séricas na comparação entre os grupos com obesidade e controle ou pré e pós-operatório. Observamos correlações das citocinas de sobrenadante das culturas de MNSP e séricas com resultados laboratoriais relacionados à homeostase glicêmica em pacientes com obesidade antes e após a cirurgia bariátrica, além da correlação entre citocinas do sobrenadante e o estado de adiposidade no pós-operatório. Concluímos que a obesidade grau III está associada a modificações da produção de citocinas por MNSP e a perda de peso induzida por cirurgia bariátrica influencia esta produção no primeiro ano de tratamento.
The obesity-associated inflammation is characterized by a chronic and low intensity activation of the immune system. Several authors have shown changes in inflammatory parameters after weight loss. Bariatric surgery is a method for treating obesity with high efficiency and less risk of recurrence. Peripheral blood mononuclear cells (PBMC) are an interesting biological material for research, due to the ability to reflect changes in gene expression in different tissues and easy access to analysis. This study aimed to evaluate the effects of obesity and weight loss induced by bariatric surgery on immune activity through PBMC culture of morbidly obese patients (BMI >= 40 kg/m2). Peripheral vein blood samples were collected from 10 volunteers with normal weight (control group) and before and after the surgery in 20 volunteers with morbid obesity. After separation of the mononuclear cells by Ficoll-Hypaque gradient centrifugation, cells were stimulated with lipopolysaccharide (LPS) and concanavalin A (Con-A) and culture supernatants collected for IL-1?, IL-6, TNF-?, IFN-?, IL-10 and IL-17 dosage by ELISA. Blood samples were also used for biochemical examinations and adiponectin, leptin and serum cytokine dosage. The results showed higher concentrations of IL-6, TNF-?, IL-1? and IL-10 in the supernatants of the MNSP cultures of the obesity group in relation to the control group. In the comparison between cytokine dosages of the obesity group, we observed reduction of TNF-?, IL-1? and IL-10 after 6 months of surgery, which was not observed after 1 year, and IL-17 increased after 1 year of treatment. There was no significant difference in serum cytokine concentrations in the comparison between obesity and control groups or operated group. We observed correlations of cytokines obtained in PBMC culture supernatant and serum with laboratory results related to glucose homeostasis in patients with obesity before and after bariatric surgery, as well as correlation between cytokines of the supernatant and the state of adiposity postoperatively. We conclude that morbid obesity is associated with changes in cytokine production by PMNC and weight loss induced by bariatric surgery influences cytokine production in the first year of treatment.

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Wachtel, Nikolaus Constantin [Verfasser]. "Polyunsaturated fatty acids, colorectal cancer, and inflammation: Effects of three major polyunsaturated fatty acids on the lipid metabolism of colorectal adenocarcinoma HT-29 cells and on the cytokine secretion by peripheral blood mononuclear cells / Nikolaus Constantin Wachtel". Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2020. http://d-nb.info/1218076240/34.

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Martinez, Caroline Silveira. "Efeitos da exposição ao alumínio sobre parâmetros neurológicos, reprodutores, cardiovasculares e bioquímicos em ratos". Universidade Federal do Pampa, 2017. http://dspace.unipampa.edu.br:8080/jspui/handle/riu/3363.

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O Alumínio (Al) é o metal de maior exposição humana, no entanto os efeitos do metal em nível de exposição humana ainda são pouco conhecidos. Assim, o objetivo desse estudo foi investigar os efeitos da exposição ao Al por 60 dias em dose equivalente a exposição humana ao metal através da dieta sobre o Sistema Nervoso Central (SNC), Sistema Nervoso Periférico (SNP), sistema reprodutor masculino e sistema cardiovascular e, comparar com os efeitos de uma exposição alta ao metal com efeitos tóxicos conhecidos. Para isso, ratos Wistar com 3 meses de idade foram divididos em: 1) Grupo 1: baixas doses de Al, onde durante 60 dias os ratos receberam por água de beber: a) Controle – água ultrapura; b) Al na dose de 1,5 mg/kg de peso corporal e, c) Al na dose de 8,3 mg/kg de peso corporal e, 2) Grupo 2: alta dose de Al, onde durante 42 dias os ratos receberam por gavagem: a) Controle – água ultrapura; b) Al na dose de 100 mg/kg de peso corporal. O tratamento com Al mesmo em baixas doses prejudicou a memória de reconhecimento de objetos e promoveu o desenvolvimento de catalepsia nos ratos. Somado a isso, a exposição ao Al aumentou os níveis de espécies reativas de oxigênio (EROs) e de peroxidação lipídica, reduziu a capacidade antioxidante e inibiu a atividade da acetilcolinesterase no hipocampo dos animais. No SNP, o Al promoveu o desenvolvimento de alodínea mecânica, aumentou o estresse oxidativo sistêmico, induziu inflamação com recrutamento de macrófagos e, o metal foi capaz de depositar-se entre as fibras do nervo ciático. Já no sistema reprodutor masculino, a exposição ao Al reduziu a contagem espermática, a motilidade e a produção diária de espermatozides, aumentou a porcentagem de espermatozoides com anormalidades morfológicas, alterou a estrutura testicular, aumentou os níveis de estresse 14 oxidativo e a inflamação testicular, demonstrando que uma baixa concentração do metal nos testículos (3.35 μg/g) é o suficiente para comprometer a espermatogênese e a qualidade dos gametas masculinos. No sistema cardiovascular, o Al aumentou a pressão arterial sistólica, reduziu a resposta vasodilatadora a acetilcolina, aumentou a resposta vasoconstritora a fenilefrina, reduziu a modulação endotelial na resposta vasoconstritora, reduziu a biodisponibilidade de óxido nítrico, o envolvimento dos canais de potássio nas respostas vasculares e aumentou a produção de EROs principalmente via NAD(P)H oxidase e de prostanóides contráteis da via da COX-2. A exposição ao Al aumentou o estresse oxidativo em artérias aorta e mesentérica, reduziu a expressão de mRNA de eNOS e SOD1 e aumentou a expressão da isoforma da NAD(P)H oxidase 1, COX-2 e a expressão de TXA-2 R. Tomados em conjunto, nossos dados demonstram que a exposição subcrônica ao Al por 60 dias em baixa dose, que reflete a exposição humana ao metal através da dieta, alcança um limiar tóxico suficiente para promover efeitos adversos no SNC, SNP, sistema reprodutor masculino e sistema cardiovascular. Além disso, os efeitos de uma exposição em baixa dose são praticamente os mesmos de uma exposição alta ao metal.
Aluminum (Al) is the most important environmental and human contaminant. While a good deal of research has been conducted on the acute toxic effects of Al, little is known about the effects of longer-term exposure at human dietary Al levels. Therefore, the purpose of this study was to investigate the effects of 60-day Al exposure at low doses on Central Nervous System (CNS), Peripheral Nervous System (PNS), male reproductive system and cardiovascular system for comparison with a model of exposure known to produce toxicity in rats. Three-month-old male Wistar rats were divided into two major groups: 1) Grou 1, low aluminum levels - rats were treated orally by drinking water for 60 days as follows: a) Control – received ultrapure drinking water; b) Aluminum at 1.5 mg/kg b.w. and c) Aluminum at 8.3 mg/kg b.w. and 2) Group 2, high aluminum level - rats were treated through oral gavages for 42 days as follows: a) Control – received ultrapure water; b) Aluminum at 100 mg/kg b.w. Al treatment even at low doses promoted recognition memory impairment seen in object recognition memory testing and catalepsy behavior in rats. Moreover, Al increased hippocampal reactive oxygen species (ROS) and lipid peroxidation levels, reduced antioxidant capacity and decreased acetylcholinesterase activity. On PNS, Al promoted the development of mechanical allodynia, increased inflammation in the sciatic nerve, systemic oxidative stress and, is able to be retained in the sciatic nerve. Regarding the male reproductive system, Al decreased sperm count, daily sperm production, sperm motility, normal morphological sperm, impaired testis histology; increased oxidative stress in reproductive organs and inflammation in testis, showing that low concentrations of Al in testes (3.35 μg/g) are sufficient to impair 16 spermatogenesis and sperm quality. On cardiovascular system, Al increased systolic blood pressure, decreased acetylcholine-induced relaxation, increased response to phenylephrine, decreased endothelial modulation of vasoconstrictor responses, the bioavailability of nitric oxide, the involvement of potassium channels on vascular responses, as well as increased ROS production from NAD(P)H oxidase and contractile prostanoids mainly from COX-2 in both aorta and mesenteric resistance arteries (MRA). Al exposure increased vascular ROS production and lipid peroxidation as well as altered the antioxidant status in aorta and MRA. Al decreased vascular eNOS and SOD1 mRNA levels and increased the NAD(P)H oxidase 1, COX-2 and TXA-2 R mRNA levels. Taken together, our data demonstrate that 60-day subchronic exposure to low doses of Al from feed and added to the water, which reflect human dietary Al intake, reaches a threshold sufficient to promote adverse effects on SNC, PNS, male reproductive system and cardiovascular system. Moreover, these effects were almost the same as Al exposure at much higher levels.

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KASSA, Roman Mehari. "The role of peripheral challenges and inflammation in motoneuron degeneration caused by nerve trauma and disease". Doctoral thesis, 2007. http://hdl.handle.net/11562/338054.

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Gli esperimenti presentati e discussi estesamente nelle sezioni 2,3 e 4 della Tesi si sono focalizzati sullo studio del motoneurone, un neurone con caratteristiche peculiari poiché il corpo cellulare risiede nel sistema nervoso centrale (SNC) ed ha come bersaglio il muscolo, al di fuori dell’SNC, che raggiunge tramite un lungo assone. Le caratteristiche peculiari del motoneurone, ed in particolare la sua relazione con il bersaglio periferico, sono state prese in considerazione in riferimento ad alterazioni degenerative che possono colpire tale cellula, quali la sclerosi laterale amiotrofica (SLA). Inoltre, è stato preso in esame lo studio del micro-ambiente del motoneurone e, in particolare, le relazioni di tale cellula con le cellule gliali circostanti, di grande rilevanza durante fenomeni infiammatori che sembrano svolgere un ruolo fondamentale nel determinare la sopravvivenza o la morte del motoneurone.
The experiments presented in sections 2, 3 and 4 focused on the motor circuit implying crosstalk between neurons, as well as between motoneurons and target muscles, between a neural circuit and the environment. The experiments also focused on the motor circuit as a model of neurodegenerative motoneuron disease.

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41

Marques, Fernanda Cristina Gomes de Sousa. "The choroid plexus as a sensor of peripheral inflammation". Doctoral thesis, 2008. http://hdl.handle.net/1822/8942.

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Tese de Doutoramento Ciências da Saúde - Ciências Biológicas e Biomédicas
Particular interest has been raised in the last few years, regarding the contribution of the immune system in neurological and psychiatric diseases. It is recognized that an inflammatory component underlies disorders such as Alzheimer’s disease and multiple sclerosis. However, whether these are a consequence, a cause, or just a trigger of disease progression remains to be clarified. In this context, understanding how peripheral inflammatory stimulus reach the brain may contribute to better understand the mechanisms involved in such conditions. Most studies on the communication between the periphery and the central nervous system (CNS) focus on the bloodbrain barrier, which is composed by the endothelial cells of the brain capillaries. However, the blood-cerebrospinal fluid barrier (BCSFB) may as well convey signals from the periphery into the CSF and backwards. The BCSFB is formed by the choroid plexus (CP) epithelial cells. Given its role as the major producer of the CSF, and the presence of several receptors and transporters both in the apical and in the basolateral membranes, the CP is ideally positioned to transmit signals between the immune and the CNS. In the present study we address the CP response to inflammatory stimuli induced in the periphery. We show that the CP displays a specific, rapid and transient response to an acute inflammatory stimulus induced by the intraperitoneal administration of the Gram negative bacteria cell wall lipopolysaccharide (LPS). As soon as 1h after the injection, the CP responds by altering the expression of several genes. This response reaches a maximum at 3h, in which the level of 324 (out of 24 000 studied) transcripts are altered, and returns to the basal profile for most of the transcripts at 72h. Most of the up-regulated genes belong to immune-mediated cascades while those down-regulated encode for proteins involved in the maintenance of the CP barrier function. When LPS is administered repetitively every 2 weeks for 3 months, the CP response persists for longer periods but is attenuated. The biological pathway with higher up-regulation includes genes encoding for proteins that facilitate cells entry into the CSF, which may be particularly relevant in diseases such as multiple sclerosis. Of notice, in both conditions of acute and sustained inflammatory response, we observed altered expression of genes that participate in the innate immune response to infection by microorganisms, and that are related to iron homeostasis. In both conditions, the CP responds by decreasing iron availability for bacterial growth. Specifically, lipocalin 2, a sequester for bacteria iron-loaded siderophores is rapidly secreted into the CSF, persisting in the sustained inflammatory conditions. In addition, the CP is here suggested to play an identical role of that played by the liver, in regulating iron uptake and release, through the synthesis and secretion of hepcidin. Of interest, iron deregulation has been implicated in neurodegenerative diseases including Alzheimer’s disease and multiple sclerosis. Taken together, the data presented here highlights the role of the CP in mediating immune signals into the brain. How, this ultimately corresponds to neuroprotective or deleterious consequences for the brain and how this may relate to diseases of the CNS needs to be further investigated.
Nos últimos anos tem aumentado o interesse no estudo da participação do sistema imunológico em doenças neurológicas e psiquiátricas. A inflamação é hoje aceite com estando presente em doenças como a de Alzheimer e a esclerose múltipla. No entanto, ainda está por esclarecer se esta é uma causa, consequência ou estímulo de progressão e agravamento da doença. Neste contexto, a compreensão do modo como estímulos inflamatórios periféricos influenciam o cérebro pode contribuir para a compreensão dos mecanismos envolvidos nestas doenças. A maioria dos estudos sobre a comunicação entre a periferia e o sistema nervoso central têm incidido na barreira hemato-encefálica, que é constituída pelas células endoteliais dos capilares sanguíneos. No entanto, a barreira sangue-líquido céfalo-raquidiano (BCSFB) pode, igualmente, participar na transmissão de sinais entre a periferia e o CSF. A BCSFB é formada pelas células epiteliais dos plexus coroideus (CP). Tendo como função principal a produção de CSF, e uma vez que possuem vários receptores e transportadores, tanto na membrana apical como na basolateral, os CP estão idealmente posicionados para facilitar a interacção entre os sistemas imunológico e nervoso central. O trabalho desenvolvido nesta tese avalia a resposta dos CP a estímulos inflamatórios periféricos induzido pela administração intraperitoneal do lipopolissacarídeo (LPS) da parede de bactérias de Gram negativo. Quando este estímulo é agudo, observa-se uma resposta específica, rápida e transitória nos níveis de expressão de vários genes. Esta resposta é evidente 1h após a injecção, atinge um máximo às 3h, com a expressão diferencial de 324 (num total de 24 000 estudados) transcritos, e volta ao estado basal para a maioria dos transcritos ao fim de 72h. De entre os genes cuja expressão se encontra alterada os que têm expressão mais aumentada codificam moléculas envolvidas em cascatas imunológicas, enquanto que aqueles com expressão mais diminuída incluem genes que codificam proteínas que participam na manutenção da função de barreira do CP. Quando o LPS é administrado a cada 2 semanas durante 3 meses, a resposta dos CP persiste mais tempo e é de pequena amplitude. A via metabólica com maior aumento na expressão inclui genes que codificam proteínas que facilitam a migração de células para o CSF, o que pode ser relevante em doenças como a esclerose múltipla. De realçar, tanto na resposta inflamatória aguda como na continuada, observa-se expressão alterada de genes que participam na resposta imunológica inata à infecção por microorganismos, e que estão relacionados com o metabolismo do ferro. Em ambos os casos, o CP responde diminuindo a disponibilidade de ferro necessário para o crescimento bacteriano. Especificamente, a lipocalina 2, uma proteína que sequestra sideroforos bacterianos que ligam ferro, é rapidamente segregada para o CSF; uma resposta que persiste na inflamação continuada. Para além disso os resultados obtidos sugerem que o CP desempenha uma função idêntica à do fígado na regulação da captação e libertação de ferro, através da regulação da síntese e segregação de hepcidina. É de notar que alterações no metabolismo do ferro têm sido implicadas em doenças neurodegenerativas como a doença de Alzheimer e a esclerose múltipla. No seu conjunto, os resultados desta tese apontam para uma função clara do CP na transmissão da resposta inflamatória periférica para o cérebro. Se a consequência final desta resposta é benéfica ou deletéria para o cérebro, ou se contribui para doenças do sistema nervoso central fica ainda por esclarecer.

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42

Arioli, Jessica. "TIM-1 glycoprotein mediates neutrophil peripheral recruitment during inflammation". Doctoral thesis, 2020. http://hdl.handle.net/11562/1017959.

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In the last decade, the T cell immunoglobulin and mucin domain 1 (TIM-1) has emerged as a key regulator of innate and adaptive immune responses, representing a promising therapeutic target to be investigated. TIM-1 is widely distributed across immune cells, such as T, B and dendritic cells, where it exerts multiple functions. Despite being well investigated in cancer, transplantation, atopic and autoimmune diseases, several functional aspects of TIM-1 are still unclear. Recently, we have shown a novel function for TIM-1 as adhesion receptor for T helper (Th) 1 and Th17 cells, controlling their recruitment during inflammatory conditions. Neutrophils represent the first leukocyte population recruited to the injured site and several adhesion molecules are implicated in this process. Although neutrophils are classically associated with acute inflammatory processes, they are now emerging as crucial players also in chronic inflammatory diseases, including Alzheimer’s disease (AD). However, the potential involvement of TIM-1 in neutrophil biology has never been investigated. The main goal of this project was to investigate neutrophil TIM-1 expression and its role in neutrophil recruitment during inflammation. By using flow cytometry and immunofluorescence staining, we demonstrated for the first time, that TIM-1 was expressed in mouse and human neutrophils, mainly stored in the cytoplasm under resting conditions. However, neutrophil activation after exposure to different inflammatory stimuli, including chemokines, fMLP, C5a, PMA and toll-like receptor (TLR) ligands rapidly triggered TIM-1 translocation to the cell surface. In the light of previous studies describing TIM-1 as an adhesion molecule and our results showing rapid translocation on neutrophil plasma membrane in response to chemotactic signals, we next tested the involvement of TIM-1 in neutrophil adhesion during inflammatory responses. By using a model of sterile thioglycolate-induced peritonitis, we demonstrated that the systemic blockade of TIM-1 or injection of exogenous neutrophils lacking a TIM- 1 functional domain, strongly reduced neutrophil accumulation in the inflamed peritoneum, indicating that TIM-1 had a role in neutrophil recruitment during acute inflammation. 4 We also found that the oligomeric form of amyloid b 1-42 (Ab1-42) peptide, a potent inflammatory mediator and pivotal key player in the development and progression of AD, strongly upregulated TIM-1 expression on neutrophil surface, suggesting a potential TIM-1 contribution in neutrophil responses during neuroinflammation. By flow cytometry, we demonstrated that TIM-1 expression increases on circulating neutrophils of 3xTg-AD mice, an animal model of AD, compared to sex- and agematched WT controls. Moreover, in 3XTg-AD mice, TIM-1-positive neutrophils accumulated in the meninges and in the choroid plexus, which are main access sites of leukocytes to the inflamed brain. Since a soluble form of TIM-1 (sTIM-1) was detected in several pathological diseases, we also measured sTIM-1 levels in the serum of 3xTg-AD mice. Interestingly, sTIM-1 significantly accumulated in the serum during disease progression, while it remained stable in the controls during aging, indicating TIM-1 as a new potential biomarker for AD. We also investigated the impact of TIM-1 on memory decline and neuropathological changes in 3xTg- AD mice crossed with TIM-1Δmucin mice lacking functional TIM-1. By using different behavioral tests we observed a significant restoration of spatial and associative memory in 3xTg-AD/Tim-1Δmucin mice when compared to 3xTg-AD control animals. Moreover, TIM-1 deficiency led to a drastic reduction of neutrophil accumulation in the brain during early disease and reduced neuropathological features, such as amyloid deposition, microglial activation and tau hyperphosphorylation, suggesting a role for TIM-1 in the induction of brain inflammation and neuropathological changes in an animal model of AD. Collectively, our findings shed a new light on the role of TIM-1 as a novel trafficking receptor for neutrophils suggesting that TIM-1 blockade may have a beneficial effect on the development of acute and chronic inflammatory responses.

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43

Vale, Ana Margarida Gonçalves Candeias do. "Impact of Peripheral Inflammation on the Susceptibility to Neurodegenerative Diseases". Master's thesis, 2021. http://hdl.handle.net/10400.6/11501.

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Lipopolysaccharide (LPS) is an inflammatory agent widely used to induce peripheral inflammatory responses in animal models. When administered at low concentrations and over a short time interval, it has the ability to induce neuroprotection in animal models of Alzheimer’s Disease and stroke. This neuroprotective effect is due to the activation of the peripheral immune system and subsequently activation and induction of innate immune memory in microglial cells. Thus, the main objective of this work was to understand the effects of LPS and histamine, a biogenic amine also involved in peripheral inflammatory reactions, in the ability to induce innate immune memory and, consequently, to promote neuroprotection of dopaminergic neurons in an animal model of Parkinson’s Disease (PD). For this, C57BL/6J mice were subjected to intraperitoneal administration with LPS or histamine and, after 3 weeks, were exposed to intrastriatal injury with 6-hydroxydopamine (6-OHDA) to mimetize PD. The inflammatory response was evaluated by the expression of proinflammatory cytokines (TNF-a and IL-1ß) and anti-inflammatory cytokines (IL-10) in the blood, and by the expression of the ionised calcium binding adapter molecule 1 (Iba-1), a cell marker of microglia and macrophage cells, in the brain. To evaluate dopaminergic survival and motor behavior, immunohistochemistry for tyrosine hydroxylase (TH) and apomorphine test were use, respectively. The results suggest that LPS and histamine induce activation of the peripheral inflammatory response with consequent activation of microglia, triggering innate immune memory. In the long term, it is verified that these inflammatory stimuli protect dopaminergic neurons in a PD model, as well as motor recovery, resulting in a new mechanism of prevention and cellular and functional improvement of PD.
O lipopolissacarídeo (LPS) é um agente inflamatório amplamente utilizado para induzir respostas inflamatórias periféricas em modelos animais. Quando administrado a baixas concentrações e durante um curto intervalo temporal, tem a capacidade de induzir neuroproteção em modelos animais da Doença de Alzheimer e de Acidente Vascular Cerebral. Este efeito neuroprotetor deve-se à ativação do sistema imunitário periférico e, subsequentemente, ativação e indução da memória imunitária inata nas células da microglia. Assim, o principal objetivo deste trabalho foi compreender os efeitos do LPS e da histamina, uma amina biogénica também envolvida em reações inflamatórias periféricas, na capacidade de induzir memória imunitária inata e, consequentemente, promover neuroproteção dos neurónios dopaminérgicos num modelo animal da Doença de Parkinson (DP). Para tal, murganhos C57BL/6J foram sujeitos à administração intraperitoneal com LPS ou histamina e, após 3 semanas, foram expostos à lesão intraestriatal com 6-hidroxidopamina (6-OHDA) para mimetizar a DP. A resposta inflamatória foi avaliada através da expressão de citocinas pro-inflamatórias (TNF-a e IL-1ß) e anti-inflamatórias (IL-10) no plasma sanguíneo, e da expressão da molécula adaptadora de ligação ao cálcio ionizado 1 (Iba-1), marcador celular de células de microglia e macrófagos, no cérebro. Para avaliar a sobrevivência dopaminérgica e o comportamento motor, recorreu-se às técnicas de imunohistoquímica para tirosina hidroxilase (TH) e ao teste da apomorfina, respetivamente. Os resultados obtidos sugerem que o LPS e a histamina induzem ativação da resposta inflamatória periférica com consequente ativação da microglia, desencadeando memória imunitária inata. A longo prazo, verifica-se que estes estímulos inflamatórios protegem os neurónios dopaminérgicos num modelo da DP, bem como a recuperação motora, traduzindo-se num novo mecanismo de prevenção e melhoria celular e funcional da DP.

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44

Fang-YiKo y 柯芳宜. "Brain region-specific microglial activation in response to peripheral LPS-induced inflammation". Thesis, 2010. http://ndltd.ncl.edu.tw/handle/27222561195714367804.

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碩士
國立成功大學
細胞生物及解剖學研究所
98
Microglia, one of three glial cell types in the central nervous system (CNS), play an important role as resident immunocompetent and phagocytic cells in the CNS in the event of injury and disease. Numerous studies indicated that peripheral inflammation may induce CNS inflammation and microglia activation. Activation of microglia is associated with cell transformation to phagocytes, capable of releasing potentially cytotoxic substances such as oxygen radicals, proteases, and proinflammatory cytokines. Recent studies indicated that CNS in?ammation and microglial activation is a common component of the pathogenesis for multiple neurodegenerative diseases, including Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, etc. It has been shown that the densities of microglia are unevenly distributed across different brain regions. However, whether the uneven distribution of microglia has any effect on peripheral inflammation-induced microglia activation remains unknown. The objective of this study is to investigate the temporal and spatial profiles of microglia activation after the peripheral inflammation in male C57BL/6 mice. Microglia morphological changes and densities of microglial cells in various brain regions were visualized using an immunohistochemical method with a polyclonal antibody recognizing the mouse ionized calcium binding adaptor protein-1 (Iba-1). Our results showed that substantia nigra (SN) had the highest microglia densities among the brain regions, followed by (in a high to low order) cortex, limbic system, basal nucleus, midbrain, thalamus, hypothalamus, brain stem, and the lowest in cerebellum. Microglia activation (soma enlargement, Iba-1-positive cell area and cell density) were observed after intraperitoneal LPS injection, with the highest degree of change in SN. I hypothesize that the integrity of blood-brain barrier (BBB) is involved in the transmission of inflammatory responses from the periphery to the CNS. The results showed that the BBB leakage was most pronounced in the SN among other brain regions. . Previously, it has been shown that TNFα/TNFα receptor 1 (TNFR1) play critical role in transmitting the inflammation signal from periphery into CNS. Therefore, we also investigated the expression of TNFR1 one day after LPS injection. The results showed that the highest LPS-induced TNFR1 levels was in the SN. Furthermore, activated microglia is capable of release cytokines and chemokines; among them monocyte chemoattractant protein (MCP-1) is vital in attracting peripheral monocytes into CNS. Hence, the levels of MCP-1 were measured. The results showed that the expressions of MCP-1 were elevated in all brain regions, with the highest in the SN. Furthermore, we used the Ly6C, a surface marker for monocytes but not microglia, to distinguish peripheral monocytes from residual microglia and found that the number of Ly6C-positve cells was highest in the SN. In conclusion, this study indicates that SN has the highest microglia density in the CNS. Upon peripheral inflammation stimulation, the degree of microglia activation was most prominent in the SN. This phenomenon may be due to the higher TNFR1 expression in the SN after the stimulation of inflammation, leading to larger leakage of BBB, higher expression of MCP-1 and more monocyte infiltration into the SN. Therefore, the SN is the most susceptible brain region in response to systemic immunological insults.

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45

Rosenkranz, Melissa A. "Reciprocal modulation of peripheral inflammation and affective neural circuitry in health and disease". 2008. http://www.library.wisc.edu/databases/connect/dissertations.html.

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46

Tian, Tin-Yi y 田婷怡. "Peripheral inflammation induces cytokine expression in brain and increases the permeability of blood-brain barrier". Thesis, 1999. http://ndltd.ncl.edu.tw/handle/07223055509356639351.

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碩士
國立成功大學
微生物暨免疫學研究所
87
英文摘要 The CNS (central nervous system) of mammal is considered to be an immunologically privileged site because it lacks lymphatic drainage, the brain is separated from the blood compartment by the blood-brain barrier (BBB). The brain also expresses FasL and TGFβ that can down-modulate the immune response. However, peripheral administration of lipopolysaccharide has been found to stimulate the hypothalamic- pituitary- adrenocortical axis to induce fever and influence behavior. This result showed that communication between peripheral immune system and CNS exists. It is general believed that cytokines produced in peripheral tissue can not cross the BBB because of the unique features of brain microvascular endothelial cells that wrapped by astrocyte. In this study, we reported that the peripheral stimulation with complete Freund’s adjuvant (CFA) induced the cytokine expression in brain. With immunohistochemical staining, TNFα and cyclooxygenase type 2 (COX-2) were detected on brain microvascular vessels post CFA or poly (Glu60 Ala30 Tyr10 , GAT ) in CFA injection. IL-1βwas detected in microvascular vessels only in mice injected with GAT/CFA. On the contrary, the constitutive expression of IL-6 on brain microvascular vessels and IL-1α on brain neuron bundle were found to decrease. The cytokine induction was also confirmed by semiquantitative reverse-transcription polymerase chain reaction, indicating its de novo synthesis. Using the M4 E. coli that constitutive expresses β-galactosidaseas as a tracer to quantitate the increased permeability of BBB, we found that the vasopermeability of BBB increased maximum at 96 h post CFA injection and 48 h post GAT/CFA injection. The increase of BBB permeability was inhibited by either NS398 (COX-2 inhibitor) or anti-TNFα antiserum. Using immunohistochemistry staining, the TNFαexpression was inhibited by NS398 treatment while COX-2 induction was blocked by anti-TNFαadministration. Furthermore, peripheral administration of GAT/CFA were found to induce fever at 48 h. The fever was not inhibited by anti-TNFαantiserum, but could be inhibited by NS398 or indomethacin (COX-1 and COX-2 inhibitor). Based on the above data, we conclude that peripheral inflammation stimulates TNFα or IL-1βexpression on brain microvascular vessels. The TNFαwould further cause COX-2 induction that involved in the increase of BBB permeability. The IL-1βinduction might be responsible for the fever that can be inhibited by COX inhibitor.

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47

Oruebor, Jennifer Nkem. "Peripheral blood biomarkers in youth with bipolar disorder: a systematic review". Thesis, 2019. https://hdl.handle.net/2144/36613.

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Bipolar disorder (BD) is a chronic, progressive illness characterized by fluctuations in mood. It is associated with psychosocial and cognitive impairment that can affect a person’s life at home, at work or school, and in interpersonal relationships. Children and adolescents diagnosed with BD experience similar functional impairments and risk for suicidal thoughts or actions compared to adults. Additionally, they are at an increased risk for poorer prognosis during adulthood given the negative outcomes associated with early illness onset, delayed treatment, misdiagnosis, and longer illness duration. The etiology and pathophysiology of bipolar disorder is incompletely understood. Peripheral blood biomarkers can provide insight into the mechanisms underlying the disease and can aid in identifying at-risk individuals, making an accurate diagnosis, monitoring illness activity and improving therapeutic intervention. A PubMed search was carried out and 12 studies were identified that assessed potential peripheral blood biomarkers in children and adolescents with bipolar disorder. These studies suggest that fatty acid biostatus, markers of lipid and protein oxidation, markers of inflammation and immune disturbance, neurotrophic factors and enzymes related to inflammation may serve as biomarkers of BD. These potential biomarkers of the disorder warrant further study in youth with BD. Current findings support a staging hypothesis of BD wherein cumulative episodes lead to disruptions of the pathways associated with the disorder and thus greater impairment in patients farther from their disease onset. However, these and other biomarkers will need to be evaluated in larger, longitudinal studies to validate their use and expand knowledge in the field.

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48

Ho, Ying-Hao y 何英豪. "Peripheral inflammation increases seizure susceptibility via the induction of neuroinflammation and oxidative stress in the hippocampus". Thesis, 2015. http://ndltd.ncl.edu.tw/handle/52580917089874888255.

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博士
國立中山大學
生物科學系研究所
103
Epilepsy is a common neurological disorder. Neuroinflammation is involved in the pathophysiology of epilepsy. Tissue oxidative stress is another confounding factor in epilepsy. While both neuroinflammation and brain oxidative stress are involved, relationship between these two factors in epileptogenesis, however, is not fully understood. In this study, I investigated the relationship and the underlying molecular mechanism. In aim 1, I established a rodent model of chronic neuroinflammation via peripheral inflammation induced by continuous infusion of E. coli lipopolysaccharide (LPS; 2.5 mg/kg/day) in the peritoneum for 7 or 14 days. Results showed an increased proinflammatory cytokines level, including IL-1β, IL-6 and TNF-α in plasma and various areas of brain (frontal lobe, temporal lobe, hippocampus, striatum, rostral ventrolateral medulla (RVLM), nucleus tractus solitarii (NTS)), increased number of the activated microglia in brain and sensitivity to induction of seizure by KA (KA, 10 mg/kg) injection. Based on these findings, I focused my study on the hippocampus, which is associated with temporal lobe epilepsy, a common form of epilepsy in human. Pharmacological agents were delivered via intracerebroventricular infusion with an osmotic minipump in chronic neuroinflammation model for 7 days. In aim 2, a cycloxygenase-2 inhibitor, NS398 (5 μg/μl/h), was used to study the relationship between neuroinflammation and tissue oxidative stress in seizure susceptibility after the LPS-induced peripheral inflammation. The results showed that NS398 significantly blunted the increase in microglia activation, production of proinflammatory cytokines, and tissue oxidative stress (upregulations of the NADPH oxidase subunits) in the hippocampus. The same treatment also ameliorated the increase in seizure susceptibility in the KA-induced seizure model. In aim 3, a reactive oxygen species scavenger, tempol (2.5 μg/μl/h), was used to study the relationship between neuroinflammation and oxidative stress in the increase in seizure susceptibility under peripheral inflammation. The results showed that tempol did not blunt the increase in activated microglia, production of proinflammatory cytokines, but significantly blunted tissue oxidative stress (upregulations of the NADPH oxidase subunits) in the hippocampus and ameliorated the increase in seizure susceptibility in the KA-induced seizure model. These results indicated that peripheral inflammation evoked neuroinflammation and the subsequent oxidative stress in the hippocampus, resulting in the increase seizure susceptibility. Moreover, protection from neuroinflammation and oxidative stress in the hippocampus exerted beneficial effect on seizure susceptibility following peripheral inflammation.

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49

Cuhlmann, S., W. Gsell, der Heiden K. Van, J. Habib, J. L. Tremoleda, M. Khalil, F. Turkheimer et al. "In vivo mapping of vascular inflammation using the translocator protein tracer 18F-FEDAA1106". 2014. http://hdl.handle.net/10454/10331.

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Yes
Non-invasive imaging methods are required to monitor the inflammatory content of atherosclerotic plaques. FEDAA1106 (N-(5-fluoro-2-phenoxyphenyl)-N-(2-(2-fluoroethoxy)-5- methoxybenzyl) acetamide) is a selective ligand for TSPO-18kDa (also known as peripheral benzodiazepine receptor), which is expressed by activated macrophages. We compared 18F- FEDAA1106 and 18F-FDG (a marker of glucose metabolism) for PET imaging of vascular inflammation. This was tested using a murine model where focal inflammation was induced in the carotid artery via placement of a constrictive cuff. Immunostaining revealed CD68-positive cells (macrophages) at a disturbed flow site located downstream from the cuff. Dynamic PET imaging using 18F-FEDAA1106 or 18F-FDG was registered to anatomical data generated by CT/CT angiography. Standardized uptake values (SUV) were significantly increased at cuffed compared to contralateral arteries using either 18F-FEDAA1106 (p<0.01) or FDG (p<0.05). However, the 18F-FEDAA1106 signal was significantly higher at the inflamed disturbed flow region compared to the non-inflamed uniform flow regions, whereas differences in FDG uptake were less distinct. We conclude that 18F-FEDAA1106 can be used in vivo for detection of vascular inflammation. Moreover, the signal pattern of 18F-FEDAA1106 correlated with vascular inflammation more specifically than FDG uptake.
: This study was funded by the British Heart Foundation and through a grant from the Swiss National Science Foundation (310030_143343/1 to B.R.K.)

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50

Chen, Ying-Ju y 陳映儒. "Increased expression of a proton-sensing G-protein coupled receptor, TDAG8, in DRG neurons after peripheral inflammation". Thesis, 2006. http://ndltd.ncl.edu.tw/handle/32750630763754454077.

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碩士
國立中央大學
生命科學研究所
94
High concentrations of hydrogen ions are usually found in local area surrounding the insulted tissues during several inflammatory responses. The tissue acidosis phenomenon is thought to be associated with inflammatory pain because the proton molecule can activate nociceptors (pain-related neurons) directly through proton-sensing ion channels. Several proton-sensing receptors expressed in dorsal root ganglia neurons. Some of them, such as vallinoid receptor1 and acid-sensing ion channel 3 are thought to be involved in inflammatory hyperalgesia. However, it is still unclear that whether there are any other proton-sensing receptors involved in inflammation. Here we have demonstrated that a proton-sensing G-protein-coupled receptor, mouse T-cell Death Associated gene 8 (mTDAG8), was predominantly expressed in small-diameter neurons, which give rise to the majority of nociceptors. The transcripts of mTDAG8 were increased 24 hours after complete Freund’s Ajuvant (CFA)-induced inflammation, suggesting that the TDAG8 receptors might associate with inflammatory pain. Consistently, data of in situ showed that the total TDAG8-expressing neurons increased approximately 15% in DRG neurons after CFA-inflammation. Most of the increased TDAG8-expressing neurons are large-diameter neurons (9-10%), and the increased small-diameter neurons expressing TDAG8 are restricted in IB4-positive neurons (5-7%). Since the large-diameter neurons can be activated by non-noxious stimulations during inflammation, and the responses of IB4-positive neurons are enhanced after treating with inflammatory mediators, the increased number of neurons expressing TDAD8 receptors may associate with allodynia and hyperalgesia in inflammation. In addition, the mTDAG8-transfected HEK 293 cells accumulated the cAMP in responding to pH 6.0 buffers. Thus the TDAG8 may mediate certain responses through cAMP-pathway in neurons after inflammation.

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