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Models of the Mucosal Inflammatory and Regulatory Immune Pathways: The Role of Host Response in Microbial Persistence and PathogenesisWendelsdorf, Katherine Veronica 13 December 2011 (has links)
The scientific method requires the creation of a unifying hypothesis that reconciles an observed health outcome of infection with experimental data gathered about the disease process following infection. In this era of unprecedented amounts of data and information for various disease models, the creation and articulation of such hypothesis are often beyond human capacity. Modeling offers a means to generate hypothesis that provide complex mechanisms that reconcile seemingly contradictory data as well as quantitatively assess the relative plausibility of different mechanisms proposed to explain the same data/health outcome association.
Here I explain the modeling approach to hypothesis generation and offer several examples of its implementation to address the role of the natural host immune response in determining outcomes of infection by a specific microbe including pathogenesis and microbial clearance. Such knowledge is key to devising sophisticated disease intervention strategies. The systems studied are i) Inflammatory Bowel Disease, where I explore mechanisms of inflammation regulation and how they break down to give rise to a chronic inflammatory disease, ii)H. pylori infection, in which I explore potential bacterial strategies for persistence as a commensal of the microflora or as a pathogen, and iii) HIV infection, where I explore the role of inflammatory and anti-inflammatory mechanisms in establishing viral infection. I present both mathematical, equation based models as well as agent-based, computational models offering a comparison of each method. / Ph. D.
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The Effects of Low Dose Endotoxin on Glucose HomeostasisStevens, Joseph R. 28 August 2014 (has links)
Obese individuals present with an increased inflammatory tone as compared to healthy, normal-weight individuals, which is associated with insulin resistance. One factor hypothesized to contribute to increased inflammation in obese and diabetic states is elevated blood endotoxin levels, also known as metabolic endotoxemia. In healthy rodents (non-obese and insulin sensitive), there is evidence that blood endotoxin levels fluctuate over the course of the day with elevations in the post-prandial state that return to baseline levels in the post-absorptive state. High-fat feeding in these animals altered these fluctuations causing endotoxin levels to remain high throughout the day. The effects of alterations in endotoxin levels on glucose metabolism are not understood. The goal of this study was to determine the effects of short-term and long-term increases in endotoxin of a low magnitude on insulin signaling in a human primary cell line as well as the effects of short-term endotoxin treatments on glucose homeostasis in a C57/Bl6 mouse model. First, we tested the hypothesis in cell culture that short-term low-dose endotoxin treatments would enhance insulin-signaling and glycogen synthesis while long-term treatments would have inhibitory effects. Under our second hypothesis, we examined whether short-term low-dose treatments of endotoxin would contribute to improvements in glucose tolerance in a mouse model. In contrast to our first hypothesis, short-term endotoxin treatments did not improve insulin signaling or glycogen synthesis although long-term treatments did contribute to decreases in glycogen synthesis. Interestingly, short-term endotoxin treatments resulted in significant improvements in glucose clearance in the mouse model; this is believed to be partly attributed to LPS inhibiting gluconeogenesis. Future studies are necessary to understand the mechanisms responsible for altered glucose metabolism in response to low magnitude changes in LPS levels. / Ph. D.
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Characterization of Biomedical and Incidental Nanoparticles in the Lungs and Their Effects on HealthMcDaniel, Dylan K. 20 November 2018 (has links)
Nanomaterials are defined as any material with at least one external dimension less than 100 nm. Recently, nanomaterials have become more common in medicine, technology, and engineering. One reason for their increased interest is due to nanomaterials having unique properties that allow them to interact effectively with biological systems. In terms of drug delivery, the lungs are a highly desirable site to administer therapeutic nanoparticles. Indeed, inflammatory diseases such as asthma and emphysema could potentially benefit from nanoparticle-mediated delivery. However, the lungs are also in constant contact with airborne particulate matter. Thus, harmful nanoparticles can enter the lungs and cause or even exacerbate inflammatory diseases. Our work focused on characterization of both therapeutic and potentially harmful nanoparticles in the lungs. We found that fluorescently-labeled nanoparticles were phagocytosed by macrophages and did not induce apoptosis or inflammation in the lungs, making them potentially useful as a therapeutic for inflammatory diseases. We also characterized a rare form of titanium-based particles called Magnéli phases, which have been shown to be produced via coal burning. We found that while these particles are non-inflammatory in the lungs of mice, they lead to apoptosis of macrophages as well as a change in gene expression associated with increased fibrosis. Ultimately, this was shown to lead to a decrease in lung function parameters and airway hyperresponsiveness, indicating increased lung stiffness after long-term nanoparticle exposure. Our data adds significant contributions to the field by assessing two nanoparticles with vastly different compositions in the lungs. Overall, we found that the unique properties of both particle types allows for interactions with cells and tissues. These interactions can have important outcomes on health, both in terms of disease treatment and exacerbation. / Ph. D. / Over the years, nanoparticles have become more common in medicine, technology, and engineering due to their unique properties. Many of these properties allow for increased interactions with biological materials. Organs such as the lungs are at increased risk of exposure because they naturally encounter microorganisms and airborne particles on a daily basis. However, the lungs are also a highly desirable site for drug delivery using nanoparticles, due to ease of access. Inflammatory diseases such as asthma and emphysema could potentially benefit from nanoparticle-mediated delivery. Additionally, harmful nanoparticles can enter the lungs and cause or even exacerbate these diseases. Unfortunately, there is a lack of knowledge pertaining to this subject. Our work focused on assessing the interactions of nanoparticles in the lungs. First, we looked at nanoparticles that could be used for drug delivery. We found that fluorescentlylabeled nanoparticles were taken up by phagocytic white blood cells called macrophages. Furthermore, these particles did not induce cell death or inflammation in the lungs. Therefore, we found that these particles could be useful for drug delivery in the lungs. Secondly, we investigated potentially harmful nanoparticles and their effects on the lungs. The titanium-based particles called Magnéli phases, have been shown to be produced through coal burning. We found that while these particles are non-inflammatory in the lungs, they do lead to programmed death of macrophages as well as the increase in genes associated with fibrosis. Ultimately these particles led to a decrease in lung function after long-term exposure.
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Targeting brain inflammation with bioconjugated nanoparticlesHirani, Anjali 26 June 2009 (has links)
Brain inflammation has been implicated with the pathogenesis of neurodegenerative diseases. Activated microglia and endothelial cells induce production of reactive oxygen species (ROS) and overexpress pro-inflammatory mediators that perpetuate tissue damage. Current treatments are not effective against progressive stages of neurodegenerative diseases and more advanced therapies need to be developed. Recently, nanomaterials have been investigated for therapeutic applications. Nanoparticles can increase efficiency of drug delivery due to increased tissue distribution and the ability to modify surface chemistry to increase biocompatibility and incorporate targeting moieties.
In the present study, we established in vitro and in vivo brain inflammation models by administering lipopolysaccharide to mouse brain endothelial cells, microglia, macrophage cells and C57BL/6 male mice. Changes in mRNA expression of pro-inflammatory mediators were analyzed by real-time reverse transcriptase-polymerase chain reaction (RT-PCR). Tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), monocyte chemotactic protein-1 (MCP-1), E-selectin, and intercellular adhesion molecule-1 (ICAM-1) displayed significant overexpression when compared to the control. Additionally, folate receptor-α (FR-α) was also overexpressed, confirming that our model will function appropriately for specific targeting experiments.
Cellulose nanocrystals are rod-like particles, approximately 5 nm wide and 100-150 nm long. The surface area consists of extended hydroxyl groups and the structure is hydrophilic in nature. These characteristics make cellulose nanocrystals ideal for surface modification and ensuring long blood circulation half-life. Cell viability was determined using the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] conversion assay and a Lactate Dehydrogenase (LDH) Cytotoxicity Detection Kit. At each concentration of cellulose nanocrystals (10, 25, 50 μg/mL), both assays showed the nanoparticles to be non-toxic. Binding/uptake experiments utilizing a fluorescence plate reader and fluorescence microscope showed no non-specific uptake of untargeted cellulose nanocrystals. In contrast, when conjugated to folic acid, cellulose nanocrystals were selectively incorporated to folate receptor-overexpressing cells.
These results indicate that both in vitro and in vivo brain inflammation models can be utilized to assess therapeutic efficacy of folate receptor-targeted bioconjugated nanoparticles. / Master of Science
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Analyse des propriétés physico-chimiques et pharmacologiques d'Imidazole [1,2-¯]pyridine : évaluation de l'apport de la RMN HR-MAS pour la compréhension de ces mécanismes / Numerical analysis and geophysical study of the dynamic answer of an unstable rock columnFollot, Sébastien 09 February 2011 (has links)
La MAP kinase p38 régule la transduction du signal en réponse à un stress environnemental. Les inhibiteurs spécifiques de p38, qui sont connus pour bloquer la production de cytokines pro-inflammatoires, mais peuvent également intervenir sur le phénomène d'apoptose. C'est dans cette dernière optique que de nouvelles structures d'inhibiteurs, ont été synthétisées. Ces structures, après caractérisation par RMN, ont été ensuite évaluées en termes de mécanisme d'action et de disponibilité biologique. Outre les méthodes classiques cette évaluation a finalement fait appel aux techniques HR-MAS. Les sept molécules ainsi synthétisées ont été regroupées en trois famille (1a, 2a-c, 3a-c). Quoique les propriétés physico-chimique de ces motifs soient très différentes, il en ressort une potentialité d'action commune en tant qu'inhibiteur de la MAP kinase p38. / P38 MAP Kinase regulates the signal's transduction in response to an environmental stress. The specific p38 inhibitors, which are known to bloc the pro inflammatory (cytokines) production, can intervene on the (apoptosis) phenomenon too. This is in this last perspective that news inhibitors' structures have been synthesized. These structures, after RMN characterization, have been estimated in term of the mechanics of an action and biological ability. As well as the classical methods, this evaluation finally requires HR-MAS technics. The 7 molecules synthesized in this manner have been in 3 families regrouped (1a, 2a-c, 3a-c). Although the physic- chemical properties of these motives are very different, it stands out a common potentiality of action as an MAP Kinase p38 inhibitor
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Effects of an acute bout of moderate intensity exercise on postprandial lipemia and airway inflammationJohnson, Ariel M. January 1900 (has links)
Master of Science / Department of Kinesiology / Craig A. Harms / Obesity and asthma often coexist in the same people. Both are characterized by the presence of low-grade systemic inflammation. A high-fat diet may contribute to concurrent development of both conditions by promoting a pro-inflammatory postprandial environment leading to a transient accumulation of blood lipids (postprandial lipemia; PPL) and acute airway inflammation. Previous results from our lab have shown an ~20% increase in airway inflammation two hours after consuming a high-fat meal (HFM) that was significantly associated with increased plasma triglycerides. While acute exercise has been shown to attenuate PPL, it is unknown whether these protective effects will translate to reduced airway inflammation after a high-fat meal. PURPOSE: To determine the effects of an acute bout of exercise on airway inflammation after a HFM. We tested the hypothesis that an acute bout of exercise 12 hours before a high-fat meal would protect against subsequent airway inflammation in healthy men and would be related to the decreased PPL and systemic inflammatory markers. METHODS: In a randomized cross-over study, 12 healthy college-aged men consumed a HFM (1g fat/1kg body weight) 12 hours following exercise (EX; 60 min at 60% VO2max) or without exercise (CON). Exhaled nitric oxide (eNO; measure of airway inflammation), blood lipid profiles (venous sample; total cholesterol, HDL, LDL, triglycerides, glucose), inflammatory markers (hsCRP, TNF-[alpha], IL-6) and pulmonary function tests (PFT) (forced expiratory volume in 1-s,forced vital capacity, forced expiratory flow at 25-75% of vital capacity) were measured pre-HFM, two hours, and four hours post-HFM. RESULTS: Baseline eNO was not different (p>0.05) between trials. eNO increased (p<0.05) post HFM at two hours in the both CON and EX conditions. eNO between trials was not different (p>0.05). Triglycerides were significantly increased two and four hours post HFM but were not different (p>0.05) between conditions. There was no relationship (p>0.05) between eNO and triglycerides or systemic inflammatory markers for any time point in either condition. Pulmonary function did not differ (p>0.05) between any condition. CONCLUSION: These results demonstrate that an acute bout of moderate intensity exercise 12 hours before a HFM does not attenuate postprandial airway inflammation or lipemia in healthy college-aged men.
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Etude de facteurs influençant la susceptibilité de l'hôte au paludisme : Effet de facteurs génétiques et de l' état inflammatoire / Study of factors influencing host susceptibility malaria : the effect of genetic factors and the stateinflammatoryPommier, Janine 04 February 2014 (has links)
Mon travail de thèse a porté sur l'étude des facteurs influençant le devenir de l'infection palustre. Une étude de liaison génétique basée sur des marqueurs répartis sur l'ensemble du génome nous a permis de mettre en évidence la liaison génétique de la région chromosomique 17p11-p13 avec la parasitémie. Nous avons étudié les variations génétiques des gènes HS3ST3A1 et HS3ST3B1 du chromosome 17p12 humain car ces gènes pourraient influencer l'infection de cellules humaines par le Plasmodium. Nous avons ainsi observé la liaison génétique de certain SNP de ces gènes avec la parasitémie. Les anticorps IgG dirigés contre le parasite P. falciparum sont connus pour jouer un rôle important dans la réponse immunitaire. Certain gènes associés à la résistance au paludisme pourraient également être associés au niveau de production d'IgG. Nous avons montré que certains polymorphismes situés dans les gènes HBB, FcRIIA, et du TNF influencent le niveau de production de différentes sous classes IgG. Ces résultats nous permettent de mieux comprendre le contrôle génétique de la réponse humorale contre la malaria.J'ai aussi caractérisé l'inflammation non infectieuse dans un modèle murin afin de tester l'influence de l'état inflammatoire lors de l'infection par le plasmodium. L'étude transcriptomique de trois organes réalisée sur un modèle de souris injectée avec de l'acide oléique, nous a permis de mettre en évidence une réponse inflammatoire principalement au niveau des poumons et du cerveau. Ces résultats vont nous permettre de tester l'hypothèse qu'une réponse inflammatoire pré-existante favoriserait la survenue de forme sévère du paludisme chez des souris infectées par Plasmodium. / My thesis focused on the study of factors influencing the future of malaria infection. A genetic linkage study based on markers distributed throughout the genome has allowed us to highlight the linkage of 17p11 - p13 chromosome region with parasitaemia. We investigated the genetic variation of genes and HS3ST3A1 HS3ST3B1 human chromosome 17p12 because these genes may influence the infection of human cells by Plasmodium . We observed genetic linkage of some SNPs in these genes with parasitaemia.IgG antibodies against the parasite P. falciparum are known to play an important role in the immune response . Certain genes associated with resistance to malaria could also be associated with the level of IgG production . We have shown that some polymorphisms located in genes HBB , Fc RIIA , and TNF influence the level of production of different IgG subclasses . These results allow us to better understand the genetic control of humoral response against malaria.I also characterized non- infectious inflammation in a mouse model to test the influence of the inflammatory condition during infection by Plasmodium . The transcriptomic study performed on three organs mouse model injected with oleic acid , has allowed us to demonstrate an inflammatory response mainly in the lungs and brain. These results will allow us to test the hypothesis that pre-existing inflammatory response favor the occurrence of severe malaria in mice infected with Plasmodium.
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Systemic Immune-Inflammation Index (SII) Predicts Poor Survival in Pancreatic Cancer Patients Undergoing ResectionJomrich, Gerd, Gruber, Elisabeth S., Winkler, Daniel, Hollenstein, Marlene, Gnant, Michael, Sahora, Klaus, Schindl, Martin January 2019 (has links) (PDF)
Background: The systemic immune-inflammation index based on peripheral neutrophil, lymphocyte, and platelet counts has
shown a prognostic impact in several malignancies. The aim of this study was to determine the prognostic role of systemic immune-inflammation index in patients with pancreatic ductal adenocarcinoma undergoing resection.
Methods: Consecutive patients who underwent surgical resection at the department of surgery at the Medical University of Vienna between 1995 and 2014 were included into this study. The systemic immune-inflammation index was calculated by the formula platelet*neutrophil/lymphocyte. Optimal cutoffs were determined using Youden's index. Uni-and multivariate analyses were calculated by the Cox proportional hazard regression model for overall survival.
Results Three hundred twenty-one patients were included in this study. Clinical data was achieved from a prospective patient database. In univariate survival analysis, elevated systemic immune-inflammation index was found to be significantly associated with shortened patients' overall survival (p = 0.007). In multivariate survival analysis, systemic immune-inflammation index
remained an independent prognostic factor for overall survival (p = 0.004). No statistical significance could be found for platelet
to lymphocyte ratio and neutrophil to lymphocyte ratio in multivariate analysis. Furthermore, area under the curve analysis showed a higher prognostic significance for systemic immune-inflammation index, compared to platelet to lymphocyte ratio and neutrophil to lymphocyte ratio.
Conclusion A high systemic immune-inflammation index is an independent, preoperative available prognostic factor in patients with resectable pancreatic ductal adenocarcinoma and is superior to platelet to lymphocyte ratio and neutrophil to lymphocyte ratio for predicting overall survival in pancreatic ductal adenocarcinoma patients.
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Study on inflammatory responses of neonatal natural killer cells and macrophages upon lipoteichoic acid stimulation. / 脂磷壁酸對新生兒自然殺傷細胞和巨噬細胞免疫反應的影響 / Zhi lin bi suan dui xin sheng er zi ran sha shang xi bao he ju shi xi bao mian yi fan ying de ying xiangJanuary 2011 (has links)
Cheng, Siu Fung. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2011. / Includes bibliographical references (leaves 121-141). / Abstracts in English and Chinese. / Abstract (English) --- p.ii / (Chinese) --- p.V / Acknowledgements --- p.viii / List of Abbreviations --- p.x / Table of Contents --- p.xi / Chapter Chapter 1 --- Introduction and Literature Reviews --- p.1 / Chapter 1.1 --- Bacterial Infection in Neonates --- p.1 / Chapter 1.1.1 --- Overview of Bacterial Infection in Neonates --- p.1 / Chapter 1.1.2 --- Gram-Positive Bacteria and Infection in Newborns --- p.2 / Chapter 1.1.3 --- Lipoteichoic Acid - the Immunostumulatory Component of Gram-Positive Bacteria --- p.5 / Chapter Figure 1.1 --- Schematic Representation of Gram-Positive Bacterial Cell Wall --- p.8 / Chapter Figure 1.2 --- Structure of Lipoteichoic Acid Polymer --- p.9 / Chapter 1.2 --- The Immune System of the Neonate --- p.10 / Chapter 1.2.1 --- Overview of the Human Immune System --- p.10 / Chapter 1.2.2 --- Innate Immune System --- p.10 / Chapter 1.2.3 --- Adaptive immune system --- p.13 / Chapter 1.3 --- Macrophages --- p.15 / Chapter 1.3.1 --- Overview of Macrophages --- p.15 / Chapter 1.3.2 --- Functions of Macrophages --- p.16 / Chapter 1.3.3 --- Macrophages in Gram-Positive Bacterial Infection --- p.19 / Chapter 1.4 --- Natural Killer Cells --- p.21 / Chapter 1.4.1 --- Overview of Natural Killer Cells --- p.21 / Chapter 1.4.2 --- Activation of Natural Killer Cells --- p.23 / Chapter 1.4.3 --- Functions of Natural Killer Cells --- p.24 / Chapter 1.4.4 --- Activation Markers on Natural Killer Cell Surface --- p.27 / Chapter Figure 1.3 --- Schematic Diagram of CD 107a Expression in NK Cells During Degranulation --- p.30 / Chapter 1.5 --- Interactions Between Macrophages and Natural Killer Cells --- p.31 / Chapter 1.6 --- Mitogen-Activated Protein Kinases (MAPKs) and Infection --- p.32 / Chapter 1.7 --- ApolipoproteinA-1 (ApoA-1) and Infection --- p.34 / Chapter 1.8 --- Overall Objectives of the Study --- p.36 / Chapter Chapter 2 --- Materials and Methods --- p.37 / Chapter 2.1 --- Reagents Used --- p.37 / Chapter 2.2 --- Sampling Methods --- p.41 / Chapter 2.3 --- Mononuclear Cell Isolation --- p.41 / Chapter 2.4 --- Mononuclear Cell Cryopreservation --- p.42 / Chapter 2.5 --- Induction of Macrophage from MNC culture --- p.42 / Chapter 2.6 --- Enrichment of Natural Killer (NK) Cells from MNC --- p.43 / Chapter 2.7 --- Culture of NK Cells Using Conditioned Medium Collected From LTA-Stimulated Macrophages --- p.45 / Chapter 2.8 --- Western Blotting --- p.46 / Chapter 2.9 --- Cytokines in Culture Supernatant of Macrophages --- p.50 / Chapter 2.10 --- CD107a Assay --- p.51 / Chapter 2.11 --- CD69 Assay --- p.52 / Chapter 2.12 --- Statistical Analysis --- p.53 / Chapter Figure 2.1 --- A Representative Diagram to Show NK Cell Purity After Enrichment by Immuno-Magnetic Beads --- p.55 / Chapter Figure 2.2 --- A Diagram to Illustrate the Gating Method Used in CD 107a Assay --- p.56 / Chapter Figure 2.3 --- A Diagram to Illustrate the Gating Method Used in CD69 Assay --- p.58 / Chapter Chapter 3 --- Lipoteichoic Acid - Induced Inflammatory Responses of Cord Blood Macrophages in vitro --- p.59 / Chapter 3.1 --- LTA-Stimulated Secretion of Tumor Necrosis Factor-Alpha in Cord Blood Macrophages --- p.60 / Chapter 3.2 --- LTA-Stimulated Secretion of Interleukin-6 in Cord Blood Macrophages --- p.61 / Chapter 3.3 --- LTA-Stimulated Secretion of Interleukin-12 in Cord Blood Macrophages --- p.62 / Chapter 3.4 --- LTA-Stimulated Phosphorylation of P44/42 Mitogen-Activated Protein Kinase (ERK1/2) in Cord Blood Macrophages --- p.63 / Chapter 3.5 --- The Effect of Apolipoprotein A-l Pre-Treatment on LTA-Stimulated P44/42 Mitogen-Activated Protein Kinase (Erkl/2) Phosphorylation --- p.64 / Chapter 3.6 --- Discussion --- p.65 / Chapter Figure 3.1 --- LTA-Induced TNFa Secretion by Cord Blood Macrophages --- p.73 / Chapter Figure 3.2 --- LTA-Induced IL-6 Secretion by Cord Blood Macrophages --- p.74 / Chapter Figure 3.3 --- LTA-Induced IL-12 Secretion by Cord Blood Macrophages --- p.75 / Chapter Figure 3.4 --- Phosphorylation of P44/42 MAPK (ERK1/2) Stimulated by LTA in Cord Blood Macrophages --- p.76 / Chapter Figure 3.5 --- The Effect of ApolipoproteinA-1 on LTA-Stimulated P44/42 MAPK Phosphorylation --- p.78 / Chapter Chapter 4 --- Lipoteichoic Acid - Induced Inflammatory Responses of Natural Killer Cells in vitro --- p.80 / Chapter 4.1 --- Dose-Dependent Effect of IL-15 on CD69 Expression --- p.80 / Chapter 4.2 --- Effects of LTA on CD69 Surface Expression in NK Cells --- p.82 / Chapter 4.3 --- Effects of LTA on CD 107a Surface Expression in NK Cells --- p.84 / Chapter 4.4 --- Discussion --- p.87 / Chapter Figure 4.1 --- Dose-Dependent Effect of IL-15 on Cord Blood NK Cells CD69 Surface Expression --- p.93 / Chapter Figure 4.2 --- Effects of LTA and IL-15 on CD69 surface Expression in NK Cells --- p.95 / Chapter Figure 4.3 --- Effects of LTA and IL-15 on CD 107a surface Expression in NK Cells --- p.97 / Chapter Chapter 5 --- Effects of LTA-Primed Macrophage-Conditioned Medium on Autologous Natural Killer Cell Activation --- p.99 / Chapter 5.1 --- Effects of Macrophage-Conditioned Medium on Autologous NK Cell CD 107a Expression --- p.100 / Chapter 5.2 --- Effects of LTA-Stimulated Macrophages on Autologous NK cells CD69 Expression --- p.102 / Chapter 5.3 --- Discussion --- p.105 / Chapter Figure 5.1 --- Flow Chart of the Experiment Design --- p.110 / Chapter Figure 5.2 --- Effects of Macrophage-Conditioned Medium on Autologous NK CD 107a Expression --- p.111 / Chapter Figure 5.3 --- Effects of Macrophage-Conditioned Medium on Autologous NK CD69 Expression --- p.113 / Chapter Chapter 6 --- Conclusion and General Discussion --- p.115 / Chapter 6.1 --- Conclusion --- p.115 / Chapter 6.2 --- Potential Applications of the Findings --- p.117 / Chapter 6.3 --- Limitations --- p.118 / Chapter 6.4 --- Further Studies --- p.119 / References --- p.121
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Rôle de GILZ (Glucocorticoid-induced leucine zipper) dans l’apoptose du polynucléaire neutrophile et la résolution de l’inflammation / GILZ (Glucocorticoid-induced leucine zipper) role in polymorphonuclear neutrophil and inflammation resolutionEspinasse, Marie-Alix 03 February 2014 (has links)
L’élimination des polynucléaires neutrophiles (PN) du site inflammatoire est nécessaire à la résolution de l’inflammation. Lors de cette phase, les PN s’engagent massivement vers l’apoptose et sont phagocytés par les macrophages. Dans certaines pathologies inflammatoires comme le syndrome de détresse respiratoire aiguë (SDRA), un défaut des mécanismes d’apoptose des PN est associé à la persistance de l’inflammation et à un mauvais pronostic. GILZ (Glucocorticoid-induced leucine zipper) est une protéine possédant des propriétés anti-inflammatoires, basées principalement sur l’inhibition des facteurs de transcription, comme NF-кB (nuclear factor-kappa B) et AP-1 (activator protein-1). GILZ module également la survie des cellules hématopoïétiques, en favorisant ou retardant l’apoptose selon le type cellulaire étudié. L’objectif de ce travail a été d’évaluer le rôle de GILZ dans les fonctions et l’apoptose du PN lors de l’inflammation. Dans un premier temps, nous nous sommes intéressés aux situations physiopathologiques dans lesquelles GILZ pouvait être exprimé et plus spécifiquement dans le syndrome de détresse respiratoire aiguë (SDRA). Cette pathologie a retenu notre attention pour le caractère systémique de l’inflammation et surtout pour le rôle prépondérant que jouent les neutrophiles dans ce syndrome. Dans le cadre d’une étude clinique prospective menée à l’hôpital Bichat, nous avons pu montrer une plus forte expression de GILZ au niveau transcriptionnel et protéique dans des neutrophiles circulants de patients souffrant de SDRA.Dans la deuxième partie du travail, nous avons évalué le rôle de GILZ dans les fonctions et le phénotype des PN. En utilisant la lignée PLB-985 différenciée en neutrophiles par addition d’acide rétinoïque (ATRA) et de diméthylformamide (DMF), nous avons mis en évidence in vitro que la surexpression de GILZ dans ce modèle de polynucléaires neutrophiles favorisait l’apoptose de ces cellules. Cette apoptose est dépendante des caspases, implique la voie mitochondriale et s’explique notamment par une diminution de l’expression de Mcl-1 (myeloid cell leukemia-1), alors que l’expression des ARNm de mcl-1 n’est pas affectée. Une activation prolongée de JNK (c-JUN N-terminal kinase) serait impliquée et entraînerait la phosphorylation de Mcl-1 et sa dégradation par le protéasome. Ces deux résultats laissent entrevoir un rôle potentiel de GILZ dans la résolution de l’inflammation in vivo. Pour adresser cette question, nous mettons en place le modèle de l’ALI (Acute Lung Injury) ou inflammation pulmonaire aiguë induite par le LPS (lipopolysaccharide), qui est un modèle murin du SDRA. Nous utilisons des souris dans lesquelles l’expression de GILZ a été invalidée spécifiquement dans les neutrophiles. Cette approche nous permettra de mieux comprendre le rôle de GILZ dans la résolution de l’inflammation. GILZ pourrait ainsi représenter une cible thérapeutique dans les pathologies inflammatoires impliquant le PN. / Elimination of polymorphonuclear neutrophils (PN) from inflammatory site is a necessary step in the resolution of inflammation, where PN undergo massive apoptosis and are phagocyted by macrophages. In some inflammatory disorders, such as acute respiratory distress syndrome (ARDS), defective apoptosis of neutrophils was described and related to persistent inflammation and poor prognosis. GILZ (Glucocorticoid-induced leucine zipper) is a potent anti-inflammatory protein, mainly through inhibition of NF-кB (nuclear factor-kappa B) and AP-1 (activator protein-1) transcription factors. Moreover, GILZ modulates hematopoietic cells survival, either by preventing or inducing their apoptosis. The overall objective of this work has been to evaluate the role of GILZ in neutrophils functions and apoptosis during inflammation. First, we sought pathophysiological situations where GILZ could be expressed. ARDS caught our attention because of the systemic nature of inflammation and the prominent role of neutrophils. A prospective clinical study was conducted at Bichat hospital and showed a higher GILZ expression at protein and transcriptional levels in blood neutrophils of ARDS patients.Secondly, we evaluated the role of GILZ in neutrophils functions and phenotypes. Using the PLB-985 cell line induced towards the neutrophil lineage using all trans retinoic acid (ATRA) and dimethylformamid (DMF), we evidenced that GILZ over-expression promoted exacerbated apoptosis of these cells. This apoptosis was caspase-dependent, involved the mitochondrial pathway and was explained, at least in part, by a diminution of myeloid cell leukemia-1 (Mcl-1) expression, whereas mcl-1 mRNA levels were not affected. A sustained activation of c-Jun N-terminal kinases (JNK) could be involved and lead to Mcl-1 phosphorylation and subsequent degradation by the proteasome machinery.Altogether, these results suggest a potential role of GILZ in the resolution of inflammation in vivo. To address this question, we currently develop an acute lung injury (ALI) model induced by lipopolysaccharides, which mimics the septic component of ARDS. This model will be implemented in mice invalidated for GILZ specifically in neutrophils. This approach should allow a better understanding of the role of GILZ in the resolution of inflammation. In the future, GILZ could represent a therapeutical target in inflammatory diseases involving neutrophils.
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