Дисертації з теми "Neutrophils"
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1
Gillis, Caitlin. "Neutrophils in IgG- and endotoxin-induced systemic inflammation : protective or pathological agents ?" Thesis, Paris 6, 2016. http://www.theses.fr/2016PA066279/document.
Анотація:
Les neutrophiles contribuent à l'inflammation protectrice et pathologique. Ce projet de thèse consiste à déterminer le rôle des neutrophiles dans des modèles d'inflammation systémique graves et potentiellement mortelles, induite par le lipopolysaccharide (LPS, endotoxémie) ou par des complexes immuns antigène-anticorps (anaphylaxie). L'anaphylaxie est une réaction allergique qui peut être IgE- et/ou IgG-dépendante. L’endotoxémie est un modèle pertinent de l'inflammation au cours de maladies graves. Pour étudier les neutrophiles in vivo, nous avons utilisé un nouveau modèle murin de neutropénie inductible. Nous montrons que les neutrophiles et la Myélopéroxidase qu’ils produisent ont un rôle protecteur dans le choc endotoxique, indépendamment de l'environnement microbiologique. A l'inverse, les neutrophiles peuvent contribuer à l'anaphylaxie induite par les IgG chez la souris. Comme les récepteurs pour les IgG (FcγR) murins sont très différents des humains, nous avons développé un modèle de souris knock-in dans lequel les FcγR murins a été remplacé par les FcγR humains, activateurs et inhibiteur. Chez ces souris, nous montrons que des IgG humaines peuvent induire une anaphylaxie: le FcγRIIA a un rôle dominant, via l'activation des neutrophiles, et les médiateurs PAF et histamine. En parallèle, nous développons un modèle murin d’anaphylaxie à un curare, le Rocuronium, utilisé en clinique. Au même temps, dans une étude clinique, les résultats d’analyses des échantillons sanguins des patients suspectés d’avoir subi une anaphylaxie au curare soutien notre hypothèse de travail: que l’activation des neutrophiles par des IgG spécifiques est impliquée dans l'anaphylaxie humaineNeutrophils are agents of protective and pathological inflammation. This thesis work aimed to determine the role of neutrophils during severe, potentially fatal models of systemic inflammation induced by lipopolysaccharide (LPS, endotoxemia) or by IgG immune complexes (anaphylaxis). Anaphylaxis is a severe allergic reaction that may proceed via IgE- or IgG-dependant pathways. Endotoxemia is a model relevant to inflammation during critical illness. To study neutrophils in vivo, we employed a new mouse model of inducible neutropenia. We found, surprisingly, that neutrophils and neutrophil-derived MPO protect against the severity of endotoxic shock, independently of the microbiological environment, suggesting that neutrophils limit inflammation during endotoxemia. Conversely, neutrophils can contribute to IgG-induced anaphylaxis in mice. As mice and human IgG receptors (FcγR) are very different, we developed a novel mouse strain in which targeted insertion of human FcγR into the murine loci recapitulated hFcγR expression. Herein, using these mice, this work demonstrates that anaphylaxis induced by hIgG proceeds within a native context of activating and inhibitory hFcγRs, and that neutrophil activation via FcγRIIA is a dominant pathological pathway, involving the mediators PAF and histamine. Finally, we describe ongoing development of a mouse model of anaphylaxis in response to Rocuronium, a curare-based neuromuscular blocking agent (NMBA). In addition, as part of a collaborative clinical study we analysed blood samples from patients suspected of NMBA-induced anaphylaxis, finding evidence for the activation of a neutrophil- and IgG-dependent axis during human anaphylaxis
2
Mawhin, Marie-Anne. "Role of neutrophils and leukotrienes in atherosclerotic plaque destabilisation : implication of endotoxemia." Thesis, Strasbourg, 2017. http://www.theses.fr/2017STRAJ034/document.
Анотація:
La déstabilisation de la plaque d’athérosclérose reste de nos jours un problème majeur, malgré les progrès récents dans sa compréhension. Les neutrophiles sont des acteurs puissants de l’immunité innée capables d’altérer les plaques. Un chimio-attractant majeur des neutrophiles, le leucotriène B4, pourrait être un des contributeurs potentiels de la déstabilisation des plaques en particulier dans l’endotoxémie, elle-même associée aux accidents cardiovasculaires. L’objectif de ce travail a été de définir le rôle du leucotriène B4 dans l’attraction des neutrophiles dans la plaque au cours de l’endotoxémie et de déterminer si les neutrophiles peuvent basculer l’équilibre qui maintient les plaques stables. Nous avons montré que le recrutement des neutrophiles médié par le leucotriène B4 a un impact délétère sur la stabilité des plaques au cours de l’endotoxémie en favorisant l’apoptose et la dégradation de fibres matricielles. En conclusion, cette étude ouvre la voie vers de nouvelles approches thérapeutiques visant à cibler l’axe leucotriène-neutrophiles dans la maladie athérosclérotiqueAtherosclerotic plaque destabilisation remains an important issue, in spite of the recent advances in its comprehension. Neutrophils are powerful innate immune actors capable of altering plaques. In this context, the leukotriene B4, one of the main chemoattractants of neutrophils, has been proposed as a potential contributor to plaque destabilisation. A particular context in which these two actors are closely linked is endotoxemia, itself associated with plaque destabilisation This work was aimed at determining whether leukotriene B4 plays a role in the chemoattraction of neutrophils in plaques during endotoxemia and at assessing whether neutrophils can tip the balance which maintains plaques stable. We have herein evidenced that the recruitment of neutrophils mediated by leukotriene B4 has a deleterious impact upon plaque stability during endotoxemia by promoting apoptosis and degrading matrix fibres. In conclusion, this study paves the way to novel therapeutic approaches aimed at targeting the axis leukotriene-neutrophil in atherosclerotic disease
3
Yao, Yi. "Sequential Priming of Neutrophils." University of Toledo Health Science Campus / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=mco1389612809.
4
Manriquez, Rojas Valeria. "Role of the innate immune response in vascular damage caused by Neisseria meningitidis infection Vascular colonization by Neisseria meningitidis triggers a delayed and inefficient neutrophil response Intermittent pili-mediated forces fluidize Neisseria meningitidis aggregates promoting vascular colonization Adhesion to nanofibers drives cell membrane remodeling through 1D wetting." Thesis, Sorbonne Paris Cité, 2018. http://www.theses.fr/2018USPCB076.
Анотація:
Neisseria meningitidis est un diplocoque à Gram négatif responsable de méningite et de choc septique. Alors que la méningite est la forme d'infection la plus fréquente, la septicémie fulminante est responsable de 90% de la mortalité imputable à N. meningitidis. La septicémie méningococcique est caractérisée par une éruption purpurique due à des lésions vasculaires. Les observations au niveau histologique révèlent des méningocoques associés aux cellules endothéliales, des thromboses, des hémorragies périvasculaires et des infiltrations de cellules inflammatoires. Les mécanismes conduisant à ces lésions vasculaires ainsi que les raisons pour lesquelles le système immunitaire inné est incapable de contrôler l'infection avant l'atteinte de ce stade pathologique sont inconnus. Dans ce travail de doctorat, nous abordons ces questions en utilisant un modèle murin humanisée par xénogreffe de peau humaine chez des animaux immunodéficients. Nous rapportons que la prolifération bactérienne dans les capillaires est rapide et mène à l'occlusion des vaisseaux en moins de 3 heures post-infection. Dans ce contexte, les macrophages périvasculaires jouent un rôle de sentinelles car ils phagocytent efficacement les bactéries intraluminales adhérentes, aux stades précoces de l'infection et sont essentiels pour recruter les neutrophiles au site d'infection. L'imagerie intravitale et les expériences de déplétion des neutrophiles indiquent que ceux-ci jouent un rôle important dans la destruction des bactéries adhérentes par un processus de migration inverse c'est à dire de l'extérieur vers l'intérieur des vaisseaux et, par conséquent, diminuent les dommages vasculaires induits par les bactéries. L'analyse de la cinétique de recrutement des neutrophiles montre que ceux-ci atteignent un pic de recrutement entre 16h et 24h post-infection chez la souris infectée par voie intravasculaire, comme c'est le cas lors d'une infection naturelle alors que cela ne prend seulement 3h lorsque les bactéries sont injectées par voie intradermique. Ces résultats montrent que la détection intraluminale des bactéries par les macrophages périvasculaires conduit finalement au recrutement des neutrophiles et au contrôle des lésions vasculaires, mais cette réponse dépendante des macrophages périvasculaires est initiée trop tard pour être pleinement efficaceNeisseria meningitidis is a gram-negative diplococcus responsible for meningitis and septic shock. While meningitidis is the most frequent form of infection, fulminant septicemia is responsible for 90% of the mortality imputable to N. meningitidis. Meningococcal sepsis is characterized by a purpuric rash due to vascular damages. Observations at the histological level reveal meningococci associated to endothelial cells, thrombosis, perivascular hemorrhage and inflammatory cells infiltrates. The mechanisms leading to this vascular damage and the reasons for which the innate immune system is unable to control the infection before reaching this pathological stage are unknown. In this doctoral work, we address these questions using a humanized skin xenograft mouse model of Neisseria meningitidis infection. We report that bacterial proliferation inside capillaries is rapid leading to vessel occlusion in less than 3 hours post-infection. In this context, perivascular macrophages play a role of sentinels as they efficiently phagocytose adhering intraluminal bacteria at early stages of infection and are essential to recruit neutrophils to the site of infection. Intravital imaging and neutrophils depletion experiments indicate that neutrophils play an important role in killing adherent bacterial through a reverse migration process and as a consequence decrease the vascular damages induced by the bacteria. Interestingly, detailed analysis of the kinetics of neutrophil recruitment show that while neutrophil numbers reach a peak between 16h and 24h post-infection in mice challenged by the intravascular route as during the natural infection, this takes only 3h when bacteria are injected intra-dermally. These results show that intraluminal detection of bacteria by perivascular macrophages eventually leads to neutrophil recruitment and vascular damage control but this perivascular macrophage-dependent response is initiated too late to be fully efficient
5
Fischer, Steven Harold. "Interactions of Neisseria gonorrhoeae with human neutrophils: Gonococcal outer membrane protein II modulates neutrophil responses." Diss., The University of Arizona, 1988. http://hdl.handle.net/10150/184364.
Анотація:
The disease gonorrhea has plagued mankind at least as long as written records have been kept (Black and Sparling, 1985). N. gonorrhoeae is still an important cause of suffering, infertility, and occasional mortality despite the fact that treatment with antibiotics is relatively easy and highly effective, even with the recent increase in penicillin-resistant isolates (Jephcott, 1986). The continued existence of this public health problem is partly the result of a reservoir of asymptomatic carriers within the community who normally don't seek treatment and continue their usual sexual practices (Handsfield, 1983; Kavli et al., 1984). Asymptomatic carriers do not have the purulent discharge characteristic of gonococcal urethritis and cervicitis in which the neutrophil is such a prominent element. Since IgM is present in only trace amounts on genital mucosa (Schumacher, 1973), and this is the "naturally occurring" antibody against gonococci (Rich and Kasper, 1982); it is not unreasonable to assume that non-opsonic chemotaxis and non-opsonic phagocytosis by PMN may play important roles in initiating the inflammatory response and symptomatology seen with gonorrhea. Further, non-opsonic phagocytic killing may be important in eventually clearing gonococcal infection since the role of specific humoral immunity is limited by the ability of gonococcus to constantly vary its antigenic facade (Zak et al., 1984). I have found that three different gonococcal strains express certain outer membrane proteins of the protein II (P.II) family which stimulate neutrophil phagocytic killing and oxidative metabolism in a highly efficient, dose-dependent manner. Other P.IIs expressed by two of the strains are non-stimulatory. Since all P.IIs have very similar physicochemical properties, these results suggest that a specific receptor-ligand interaction occurs between the gonococcal P.II and some element of the neutrophil plasma membrane. The presence or absence of pili on the gonococcal surface has no apparent effect on the ability of certain P.IIs to stimulate neutrophils. Changes in gonococcal outer membrane protein I and lipopolysaccharide, which are thought to confer serum resistance, also have no apparent effect on P.II stimulation of human PMN. Therefore, gonococcal outer membrane P.II may be an important mediator in the inflammatory response to gonococcal infection. Once gonococci are phagocytized by human PMN killing occurs rapidly and there is no evidence of significant intracellular survival. Non-oxidative killing by human chronic granulomatous disease neutrophils is as effective as the killing seen with normal PMN. Extracellular killing of gonococci does not occur to any appreciable extent.
6
GRIMOLIZZI, FRANCO. "Neutrophils alter placental glucose metabolism in gestational diabetes mellitus via neutrophil elastase mediated IRS1 degradation." Doctoral thesis, Università Politecnica delle Marche, 2017. http://hdl.handle.net/11566/245194.
Анотація:
La gravidanza è da considerarsi una condizione pro-inflammatoria dove si osserva un’attivazione dei neutrofili circolanti. Con l'avanzare della gravidanza la concentrazione nel sangue di nucleosomi e mieloperossidasi aumenta e riflette la produzione delle trappole extracellulari dei neutrofili (NETs). Abbiamo dimostrato che in corso di diabete mellito gestazionale (GDM) tale produzione è aumentata in confronto ad una gravidanza fisiologica. Elevati livelli di glucosio e TNF-a, segni tipici presenti in corso di GDM, in vitro agiscono in modo sinergico e sono in grado di pre-attivare i neutrofili ed indurre il rilascio delle NETs. Abbiamo ipotizzato che, lo stato di iperattivazione osservato a livello sistemico possa essere associato ad una aumentata attività leucocitaria a livello placentare. A sostegno della nostra ipotesi, si osserva nei villi coriali isolati da placente GDM un’aumentata infiltrazione di PMNs pro-NETotici in associazione ad un accumulo della neutrofili elastasi (NE). Per valutare un possibile effetto pro-infiammatorio del glucosio a livello placentare, abbiamo incubato cellule di trofoblasto (BeWo) in presenza di un’elevata concentrazione di glucosio e successivamente valutato la produzione di TNF-a. È stato interessante rilevare un aumento nel rilascio di TNF- a tale da indurre un effetto pro-NETotico sui PMN con consequente rilascio della NE. Da recenti ricerche è emerso come in corso di diabete e tumore la NE possa essere internalizzata dalle cellule ed alterare la trasduzione del segnale insulinico attraverso la degradazione del substrato 1 del recettore insulinico (IRS1). Esperimenti in vitro hanno dimostrato che in presenza della NE si osserva una riduzione di IRS1 nelle cellule BeWo ed una diminuzione dell’internalizzazione del glucosio. Poichè l’espressione di IRS1 risulta ridotta nelle placente GDM é verosimile ipotizzare che la massiva presenza di NE ne può essere la causa. In conclusione, i nostri dati suggeriscono che in corso di GDM si verifica un’elevata produzione di NETs ed una massiva infiltrazione di pro-NETotici PMN nella placenta. Queste scoperte dimostrano come la NETosi abbia una significativa utilità diagnostica in corso di GDM e la NE un nuovo potenziale bersaglio terapeutico.Human pregnancy is associated with a mild pro-inflammatory state characterized by activation of circulatory neutrophils (PMNs). Skewing of PMNs responses toward to neutrophil extracellular traps generation (NETs) is reflected in an increased of circulating nucleosomes and myeloperoxidase with advancing gestational age. Our data indicated that this pro-NETotic profile is enhanced in women with gestational diabetes mellitus (GDM). Maternal hyperglycemia and increased levels of TNF-a are a hallmark of GDM and we show a synergistic effect of both factors on the priming and release of NETs. Moreover, we hypothesized that systemic activation was associated with activated PMN in placenta. Indeed, we observed a massive infiltration of pro-NETotic PMNs and neutrophil elastase (NE) accumulation along chorionic villi of GDM placentas. To further explore whether hyperglycemia predisposes to exaggerated inflammatory response in placenta we incubated trophoblast BeWo cells in high glucose conditions and we next tested the TNF-a production capacity. Interestingly, TNF-a level was incresed and exert a pro-NETotic effect on PMN with consequent NE release. Recent studies in cancer tissues and diabetes models have described that released NE induce profound changes in the surrounding cells, altering the signal transducing cascade and promoting insulin resistance via degradation of insulin receptor substrate 1 (IRS1). Our in-vitro data indicate that addition of NE to trophoblast cell line BeWo causes degradation of IRS1 with consequent glucose uptake impairment. IRS1 is reduced in GDM placentas when compared to control placentas, suggesting that the presence of NE might be the causal factor. Taken together, our data showed that GDM is characterized by excessive NET formation and by a massive influx of pro-NETotic PMN into placentas. These findings underline the competence of NETs as a highly relevant diagnostic biomarker for GDM and NE as a new potential therapeutic target.
7
Darbousset, Roxane. "Roles of polymorphonuclear neutrophils in thrombosis." Thesis, Aix-Marseille, 2013. http://www.theses.fr/2013AIXM5071.
Анотація:
L’hémostase est un processus physiologique permettant de préserver l’intégrité du système vasculaire et de prévenir une perte de sang en réponse à une blessure. En situation pathologique, comme dans le cas de cancers, d’infections ou de maladies cardiovasculaires, il peut y avoir activation de la cascade de coagulation entraînant la formation d’un thrombus.Dans cette étude, nous avons utilisé la microscopie intravitale dans un modèle de blessure au rayon laser pour comprendre les mécanismes cellulaires et moléculaires mis en jeu dans la formation d’un thrombus plaquettaire en conditions physiologiques et pathologiques lors du développement d’un cancer. La première partie de ce travail a consisté à décrire l’implication des polynucléaires neutrophiles dans la formation d’un thrombus. Nous montrons que les neutrophiles sont les premières cellules à s’accumuler au niveau du site de blessure et représentent la principale source de facteur tissulaire menant à la génération de fibrine et à la formation du thrombus. Ces neutrophiles sont nécessaires au recrutement de cellules endothéliales progénitrices (Endothelial colony- forming cells, ECFCs), qui sont des cellules capables de jouer un rôle important dans la réparation vasculaire. Dans une seconde partie, nous avons déterminé, dans des modèles murins adaptés, l’implication de l’activation du FT et des plaquettes dans la thrombose associée au cancer. En conclusion, notre travail donne de nouvelles perspectives dans la compréhension du rôle pathophysiologique des neutrophiles, des cellules progénitrices endothéliales et des plaquettesHemostasis is a physiological process to preserve the integrity of the vascular system and to prevent blood loss in response to injury. In pathological conditions, such as cancers, infections or cardiovascular diseases, the blood coagulation cascade can be activated, leading to the formation of a platelet thrombus.Using a laser-injury model coupled with a high-definition, high-speed camera, we explored the cellular and molecular mechanisms involved in thrombus formation in physiological and in pathological conditions associated with the development of a cancer. The first part of this work describes the role of polymorphonuclear neutrophils (PMNs) in thrombus formation. We show that PMNs are the first cells to accumulate at the site of injury and represent the main source of blood-borne tissue factor (TF), leading to the generation of fibrin and thrombus formation. We also show that once present at the site of injury, PMNs recruit Endothelial Progenitor Cells (endothelial colony-forming cells, ECFCs), which play a key role in vascular repair. The second part of this work we determined, in dedicated mouse models, the involvement of TF and platelet activation in thrombosis associated with cancer. Together, our findings provide new perspectives in the understanding of the pathophysiological role of polymorphonuclear neutrophils, Endothelial Progenitor Cells and platelets
8
Haynes, Andrew Paul. "Metabolic abnormalities in uraemic neutrophils." Thesis, University of Nottingham, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.305133.
9
Cross, Andrew. "Molecular properties of inflammatory neutrophils." Thesis, University of Liverpool, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.250467.
10
MacLeod, Ronald. "Gene expression in human neutrophils." Thesis, University of Liverpool, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.317206.
11
Savill, John Stewart. "Macrophage recognition of senescent neutrophils." Thesis, Imperial College London, 1989. http://hdl.handle.net/10044/1/47641.
12
Liu, Li. "Complement and neutrophil activation on protein coated solid surfaces." Göteborg : Dept. of General and Marine Microbiology and Dept of medical Microbiology and Immunology, University of Göteborg, 1997. http://catalog.hathitrust.org/api/volumes/oclc/38986844.html.
13
Bordignon, Milena. "Relationship between AOPP (Advanced Oxidation Protein Products) and bovine neutrophils "in vitro": AOPP production by neutrophils and AOPP effects on neutrophils ROS production and viability." Doctoral thesis, Università degli studi di Padova, 2013. http://hdl.handle.net/11577/3422657.
Анотація:
The aim of the present study was to evaluate the relationship between AOPP (Advanced oxidation protein products) and bovine neutrophils 'in vitro'. For this purpose AOPP were produced "in vitro" by oxidizing bovine serum albumin with HOCl (hypochlorous acid) and bovine neutrophils were isolated from whole blood of dairy cattles. AOPP-BSA were incubated with freshly isolated bovine neutrophils, unstimulated and stimulated with PMA a strong activator of the respiratory burst. Neutrophils ROS production and viability were measured by luminol-amplified chemiluminescence and by MTT and lactate dehydrogenase assays (LDH), respectively. Results obtained have shown that AOPP-BSA are able to reduce significantly ROS production of PMA stimulated neutrophil and their viability measured by MTT assay, no cell lysis was detected by LDH assay. On the basis of these results, our work has studied if AOPP are able to trigger apoptotic events. For this purpose, caspase 8-9-3 and DNA laddering were used as markers in order to discriminate between the 'intrinsic' and the 'extrinsic' pathway of apoptosis. The results obtained showed that un-stimulated bovine neutrophils incubated with AOPP-BSA show a higher but not significant production of active caspase 8 in comparison with the incubation with BSA. Also caspase 3 display an increase, but not significant, in un-stimulated neutrophils after 6 hours of incubation with AOPP-BSA, respects the incubation with BSA. No differences were obtained for caspase 9 and for DNA laddering. Therefore, in these experimental conditions is possible to conclude that the 'intrinsic' pathway of apoptosis was not involved in the reduced functionality of neutrophils or in their reduced viability, but bovine neutrophils incubated with AOPP-BSA seem to be "accompanied" to the early phases of the 'extrinsic' pathways of apoptosis.
In addition, the present work wanted to evaluate the capacity of triggered neutrophils to generate AOPP in vitro. BSA was incubated with un-stimulated and PMA-stimulated bovine neutrophils for 1-2-3 hours and the production of specific markers of protein oxidation such as AOPP, dityrosines and carbonyls was assessed. BSA incubated with stimulated neutrophils presents a significant higher level of AOPP and dityrosines respects the incubation with un-stimulated neutrophils. Carbonyls don't seem to be produced in these condition, at least at the beginning of the incubation. In parallel, BSA incubated with the same concentration of HOCl produced by PMA-stimulated neutrophils, for 1-2-3 hours, presents a higher level of AOPP, dityrosines and carbonyls. Therefore, it's possible to conclude that bovine neutrophils are able to oxidize BSA in vitro and generate chemical and structural modification such as AOPP and dityrosines, in the experimental condition used. However, carbonyls seem to be a non-specific indicator of neutrophils-mediated protein oxidation. The direct exposure of BSA to HOCl couldn't fully mimic the complex events leading to BSA oxidation and AOPP production by activated neutrophils.Lo scopo del presente studio è stato quello di valutare le relazioni tra AOPP (prodotti avanzati di ossidazione proteica) e i neutrofili di bovino "in vitro". A questo scopo le AOPP sono state generate "in vitro", ossidando l'albumina sierica bovina con HOCl (acido ipocloroso) mentre i neutrofili di bovino sono stati isolati da sangue intero di bovine da latte. Le AOPP-BSA sono state incubate con i neutrofili di bovino appena isolati in condizioni di assenza di stimolo o stimolati con PMA un forte attivatore del "burst" respiratorio. La produzione di ROS da parte dei neutrofili e la loro vitalità , sono state misurate rispettivamente mediante chemiluminescenza amplificata dal luminolo e dai saggi MTT e lattato deidrogenasi (LDH). I risultati ottenuti hanno mostrato che le AOPP-BSA sono in grado di ridurre significativamente la produzione di ROS da parte dei neutrofili stimolati con PMA e la loro vitalità , misurata con il saggio MTT mentre non è stata rilevata lisi cellulare mediante saggio LDH. Sulla base di questi risultati il presente lavoro si è proposto di studiare se le AOPP sono in grado di scatenare eventi apopotici. A questo scopo le caspasi 3, 8 , 9 e la frammentazione del DNA sono stati utilizzati come marker con l'obiettivo di discriminare tra la via intrinseca e quella estrinseca di apoptosi. I risultati ottenuti hanno mostrato che i neutrofili di bovino non stimolati e incubati con AOPP-BSA per 1 ora e 6 ore, presentano una maggiore ma non significativa produzione di caspasi 8 attiva, se comparati con l'incubazione con BSA. Anche la caspasi 3 mosta un incremento, non significativo in neutrofili non stimolati incubati con AOPP-BSA per 6 ore, rispetto all'incubazione con BSA. Non è stata ottenuta alcuna differenza per quanto riguarda la caspasi 9 e la frammentazione del DNA. Tuttavia, in queste condizioni sperimentali è possibile concludere che la via intrinseca dell'apoptosi non è coinvolta nella riduszione della funzionalità dei neutrofili di bovino o nella loro vitalità ma i neutrofili di bovino incubati con AOPP-BSA sembrano piuttosto essere 'accompagnati' verso le fasi precoci della via estrinseca dell'apoptosi. Inoltre, il seguente studio ha voluto valutare la capacità dei neutrofili di bovino attivati di generare AOPP 'in vitro'. La BSA è stata incubata con neutrofili di bovino non stimolati e stimolati con PMA per 1-2-3 ore, ed è stata misurata la formazione di specifici marcatori di ossidazione proteica come le AOPP le ditirosine e i carbonili. La BSA incubata con neutrofili stimolati con PMA, presenta un livello significativamente alto di AOPP e ditirosine rispetto all'incubazione con neutrofili non stimolati. I carbonili invece sembrano non essere prodotti in queste condizioni, almeno nelle fasi inziali dell'incubazione. In parallelo, la BSA incubata con la stessa concentrazione di HOCl prodotta dai neutrofili stimolati, per 1-2-3 ore, presenta livelli più elevato di AOPP, ditirosine e carbonili. Tuttavia è possibile concludere che i neutrofili di bovino sono in grado di ossidare la BSA e generare modificazioni chimiche e strutturali come AOPP e ditirosine nelle condizioni sperimentate. I carbonili invece sembrano non essere un marcatore specifico di ossidazione proteica mediata dai neutrofili. In aggiunta la diretta esposizione della BSA all'HOCl non è in grado di mimare completamente la complessità degli eventi che portano all'ossidazione della BSA e alla produzione di AOPP da parte dei neutrofili attivati.
14
Koch, Crystal C. "Effects of azithromycin on human neutrophils." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp03/MQ48018.pdf.
15
Naylor, Emma J. "Interactions of neutrophils with Haemophilus influenzae." Thesis, University of Liverpool, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.427016.
16
Medeiros, Kyle Andrew. "Hypoxia and the activity of neutrophils." Thesis, Boston University, 2012. https://hdl.handle.net/2144/12516.
Анотація:
Thesis (M.A.)--Boston University
PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you.Polymorphonuclear leukocytes (neutrophils) play a major role in fighting off invading bacteria. They are the first of the inflammatory cells to migrate to sites of inflammation through a process known as chemotaxis. Neutrophils eliminate invading organisms is by phagocytosis. Each phagocytic event results in the accumulation of reactive oxygen species such as the superoxide. Under hypoxic conditions associated with inflammation at local tissues, a set of transcription factors known as hypoxia-inducible factors are activated. This family of transcription factors consists primarily of two members, hypoxia inducible factor-1 (HIF-1) and hypoxia inducible factor-2 (HIF-2). HIF-1 is a heterodimer composed of alpha and beta subsets. In this study, we examined the expression of HIF-1α, HIF-1β and HIF-2 in neutrophils under hypoxic conditions at different time intervals. Expression of HIF -1α significantly increased under hypoxic conditions as compared to the normoxia. The results provide evidence suggesting that HIF-1α is the primary factor in mediating oxygen homeostasis under hypoxic conditions by regulating superoxide generation in neutrophils.
17
Lowe, David. "The roles of neutrophils in tuberculosis." Thesis, Imperial College London, 2013. http://hdl.handle.net/10044/1/24828.
Анотація:
This thesis explores the potential roles of neutrophils in the host response to tuberculosis. First, a review of literature identifies the capacity of neutrophils to phagocytose and kill mycobacteria as well as their ability to influence the development of acquired immune responses. The effect of HIV infection on neutrophil function is also explored. Novel assays are presented to assess phagocytosis of mycobacteria (flow cytometry) and restriction of mycobacterial metabolism (bio-luminescence) by human neutrophils. Subsequently neutrophil function is investigated in HIV-infected antiretroviral-naïve patients and control participants from the same community. Results show that HIV-infected patients' neutrophils restrict mycobacterial metabolism less effectively and undergo more rapid cell death than those of controls. The HIV-infected cohort is followed over 6 months of antiretroviral therapy; during this time all studied functions improve towards the levels of HIV-uninfected participants. In vitro studies on other modifiers of neutrophil antimycobacterial function are inconsistent but there is some evidence for an effect of zinc chloride in arresting neutrophil cell death. Augmentation of human blood with live or dead neutrophils before infection with M.tuberculosis significantly impacts on both mycobacterial control and supernatant cytokine responses. In particular, necrotic neutrophils facilitate more growth of M.tuberculosis and reduce Th1 cytokine responses while increasing IL-10 release. Further investigation into the influence of neutrophils on the development of antimycobacterial immune responses utilises a mouse model to study BCG vaccination. Macrophage Inflammatory Protein-2 (MIP-2)-mediated recruitment of additional neutrophils to the vaccination site significantly increases release of interferon-γ from restimulated splenocytes versus controls three weeks after vaccination, while 1A8 anti-Ly6G antibody-mediated neutrophil depletion pre-vaccination significantly decreases downstream interferon-γ release versus controls. Finally the prognostic significance of neutrophilia in active tuberculosis is investigated. This analysis on 1236 patients finds that neutrophilia, itself predicted by pulmonary disease and white ethnicity, is an independent risk factor for fatality.
18
Wan, Shek-kong Thomas. "Neutrophil function tests in Chinese newborn infants." Hong Kong : University of Hong Kong, 1991. http://sunzi.lib.hku.hk/hkuto/record.jsp?B13186292.
19
McColl, Shaun Reuss. "Factors affecting the regulation of leukotriene production by neutrophils." Title page, contents and summary only, 1987. http://web4.library.adelaide.edu.au/theses/09PH/09phm1288.pdf.
20
Romanelli, Raquel G. "Activation of neutrophil collagenase in periodontitis." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape11/PQDD_0022/MQ40756.pdf.
21
Rigby, David Andrew. "Inflammation-induced migration of neutrophils across the lymphatic endothelium." Thesis, University of Oxford, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.561107.
Анотація:
The lymphatic system provides a conduit for the trafficking of immune cells from the periphery to draining lymph nodes, both for constitutive immune surveillance and during inflammation. Thus, leucocyte migration into the lymphatics represents an important step in the initiation of a primary immune response, which occurs within lymph nodes. Traditionally, it has been considered that neutrophils are absent from the afferent lymph, having a finite lifespan in the periphery after extravasation from the blood. However, recent research has reported the presence of neutrophils in lymph nodes, in animal models of infection, where neutrophil trafficking was found to occur through afferent lymphatic vessels. This thesis examines the mechanisms regulating neutrophil migration, both by the lymphatic endothelium and neutrophils themselves, under resting and inflammatory conditions. Primary human dermal lymphatic endothelial cells (HDLECs) respond to the pro- inflammatory cytokine, TNF-α by instigating a distinct expression programme, characterised by the up-regulation of various adhesion molecules (ICAM-1, VCAM-1, E-selectin), and CXC- chemokines (ENA-78, GROβ, IL-8), as well as other potential regulators of neutrophil entry such as constitutively expressed adhesion molecules, CD99 and ESAM. Moreover, neutrophils possess counter-receptors for these adhesion molecules and contain basement membrane-specific proteases (elastase) and matrix metalloproteinases (MMPs) such as MMPs -8 and -9, localised in intracellular granules, ready to be exocytosed upon inflammatory stimuli. In vitro data presented in this thesis demonstrate that neutrophil adhesion and transmigration of the lymphatic endothelium is entirely dependent on prior activation of the monolayer with TNF-a. Furthermore, the aforementioned lymphatic-expressed adhesion molecules and chemokines, as well as neutrophil-derived proteases and MMPs are shown to play critical roles in neutrophil adhesion and transmigration of the lymphatic endothelium. Subsequent in vivo experiments confirmed that neutrophil trafficking to lymph nodes across lymphatic vessels is wholly dependent on prior vaccination with Mycobacterium bovis Bacillus Calmette-Guerin (BCG) Tokyo-172. Moreover, neutrophils trafficking to lymph nodes across lymphatic vessels are shown to require ICAM-1. The results described in this thesis provide the first evidence that both the lymphatic endothelium and neutrophils act in concert to regulate entry to lymph nodes and determine the outcome of infection, or vaccination.
22
De, Chiara Alessia. "Molecular analysis of the prosurvival effect of cytosolic Proliferating Cell Nuclear Antigen (PCNA) in neutrophils." Thesis, Paris 5, 2014. http://www.theses.fr/2014PA05S002.
Анотація:
Le polynucléaire neutrophile (PMN), cellule clé de l’immunité innée, est la première cellule à être recrutée sur le site inflammatoire. Après avoir détruit l’agent pathogène, il entre en apoptose puis est éliminé par les macrophages pour éviter le déversement de son contenu lytique, dangereux pour l’environnement. La régulation de la balance survie/apoptose du neutrophile est donc une étape cruciale de la résolution de l’inflammation. Notre laboratoire a mis en évidence la présence du Proliferating Cell Nuclear Antigen (PCNA) dans le neutrophile mature. PCNA est exprimé dans le noyau des cellules proliférantes, où il est impliqué dans la réplication/réparation de l’ADN et dans le contrôle du cycle cellulaire. PCNA est une protéine trimérique conservée au cours de l’évolution dépourvue d’activité enzymatique. En effet, PCNA constitue une “plateforme” qui interagit avec différents partenaires protéiques et orchestre leurs fonctions. De plus, pour assurer sa fonction, PCNA doit être obligatoirement sous forme trimérique. Dans le neutrophile mature, il a été démontré que PCNA avait une localisation exclusivement cytosolique et qu’il contrôlait spécifiquement la survie du neutrophile. La translocation de PCNA du noyau au cytosol a lieu pendant la différenciation granulocytaire. Elle est dépendante d'une séquence d'export nucléaire (NES) accessible et fonctionnelle que lorsque PCNA est monomérique. Le but de ma thèse a été d’étudier la plateforme de PCNA dans le cytosol du neutrophile afin d'identifier les protéines associées à PCNA afin de comprendre sa fonction dans les neutrophiles. Nous avons montré la présence de la forme monomérique et de la forme trimérique de PCNA dans le cytosol du neutrophile mature. Nous avons démontré une activité anti-apoptotique de la forme monomérique dans des cellules PLB985 différenciées en neutrophiles. De plus, nous avons identifié des peptides exposés sur la surface monomérique de PCNA qui sont utilisé comme des compétiteurs pour déplacer les interactions entre PCNA et ses partenaires dans le cytosol des neutrophiles. Ces peptides modulent la survie des neutrophiles. Grâce à des analyses de Spectrométrie de Masse, nous avons identifié des nouveaux partenaires de PCNA dans le cytosol du neutrophile impliqués dans plusieurs voies métaboliques. Cela suggère que PCNA régule la survie du neutrophile en interagissant avec différents protéines cytosoliques. Parmi les partenaires identifiés, nous avons trouvé les sous-unités cytosoliques de la NADPH oxydase, enzyme responsable de la production de formes réactives de l’oxygène, à la base de l’activité microbicide du neutrophile. Nous avons montré en particulier l’interaction entre p47phox et PCNA. Nous avons enfin étudié l’implication fonctionnelle de l’interaction de PCNA avec la NADPH oxydase dans des cellules PLB985 et également dans des neutrophiles humains. L’ensemble des résultats suggère que PCNA cytoplasmique maintient le neutrophile dans un état de repos, et aide l’assemblage de la NADPH oxydase lors de son activation. Le réseau protéique associé à PCNA régule l’activité et la survie du neutrophile en modulant différentes voies de signalisationPolymorphonuclear neutrophils (PMN), key cells of innate immunity are the first cell recruited to the inflammatory site. After destroying the pathogen, neutrophils undergo apoptosis and are cleared by macrophages to prevent the spillage of their lytic content that is dangerous for the environment. The regulation of the survival/apoptosis balance of neutrophil is a crucial step in the inflammation resolution. Our laboratory has shown the presence of Proliferating Cell Nuclear Antigen (PCNA) in mature neutrophils. PCNA is expressed in the nucleus of proliferating cells, where it is involved in DNA replication/repair and in cell cycle control. PCNA is a trimeric protein conserved during evolution and deprived of enzymatic activity. Indeed, PCNA is a “platform” that interacts with different partner proteins and orchestrates their functions. Furthermore, PCNA must be in trimeric form to play its role. In mature neutrophils, PCNA has an exclusively cytosolic localization where it specifically controls their survival. The PCNA translocation from nucleus to the cytosol happened during the granulocytic differentiation. This nuclear-to-cytosol relocalisation is dependent on a nuclear export sequence (NES), which is accessible and functional when PCNA is monomeric. The aim of my thesis was to study the PCNA platform in the neutrophil cytosol to identify the proteins associated with PCNA in order to understand its function in neutrophils. We have shown the expression of monomeric and trimeric forms of PCNA in the cytosol of mature neutrophils. We have demonstrated the anti-apoptotic activity of the monomeric form in PLB985 cells differentiated in neutrophils. Moreover, we have identified the surface-exposed peptides from the monomeric PCNA which are used as competitors of interactions between PCNA and its partner in the cytosol of neutrophils. These peptides modulate neutrophils survival. Thanks to the analysis of Mass Spectrometry, we have identified new partners of PCNA in the neutrophil cytosol involved in several metabolic pathways. This suggests that PCNA regulates neutrophil survival by interacting with different cytosolic proteins. Among the identified partners, we have found the cytosolic subunits of the NADPH oxidase, the enzyme responsible of the reactive oxygen species production, at the base of the neutrophil microbicidal activity. We have shown especially the interaction between p47phox and PCNA. Finally, we have investigated the functional implication of the interaction of PCNA with the NADPH oxidase in PLB985 cells and also in human neutrophils. Taken altogether, results suggest that the cytosolic PCNA maintains the resting state of neutrophils, and it helps the assembly of the NADPH oxidase when activated. The protein network associated with PCNA regulates the activity and the survival of neutrophil by modulating several pathways
23
Lawson, Roderick A. "Neutrophils in bacterial pneumonia : influx and clearance." Thesis, University of Edinburgh, 1997. http://hdl.handle.net/1842/28407.
Анотація:
A rabbit model of pneumonia was used. Bacteria were instilled bronchoscopically into a localised area, allowing strict timing of pneumonia onset, and study of subsequent evolving processes. Two organisms were used: 1) Streptococcus pneumoniae, an organism characteristic of pneumonia CAP and; 2) Escherichia coli, an organism characteristic of NP. It was hypothesised that in pneumonia due to the former (PneuS), the usual remarkably complete recovery witnessed clinically is due to the tissue load of neutrophils being carefully controlled. By contrast, pneumonia due to the latter (PneuE), is clinically much more severe and lung-damaging, due to a larger lung neutrophil burden. Radiolabelled neutrophils from donor animals were injected at intervals after induction of pneumonia to assess the magnitude of ongoing neutrophil recruitment. In PneuS, neutrophil influx was significantly elevated above control levels at 6 hour but not 30 hour or subsequent time points. In PneuE, neutrophil influx was at least as high at 30 hours as at 6 hours. This confirms the hypothesis that neutrophil influx is more prolonged in PneuE than in PneuS. The animal model demonstrated that neutrophil influx was more prolonged in PneuE than in PneuS. It is suggested this contributes to the more severe clinical manifestations of the former. CD18 was important to the influx of neutrophils in PneuE late as well as early in the disease. Anti-IL-8 antibody failed to inhibit neutrophil influx in either type of pneumonia. Evidence that neutrophil apoptosis is involved in their clearance during pneumonia was obtained, together with evidence that a factor is released to promote neutrophil apoptosis and thus provide negative feedback control of inflammation during pneumonia. The control may differ in PneuS and PneuE, affecting outcome.
24
Brumell, John H. "Phosphorylation-dependent signalling mechanisms in human neutrophils." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/tape16/PQDD_0018/NQ27612.pdf.
25
Reinhardt, P. Hans. "The function of VLA-4 on neutrophils." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk2/tape17/PQDD_0024/MQ31370.pdf.
26
Perskvist, Nasrin. "Interaction between Mycobacterium tuberculosis and human neutrophils /." Linköping : Univ, 2001. http://www.bibl.liu.se/liupubl/disp/disp2001/med679s.pdf.
27
Harris, Fiona Elizabeth. "The role of neutrophils in experimental vasculitis." Thesis, St George's, University of London, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.407971.
28
Prigmore, Elena. "Rho family binding proteins in human neutrophils." Thesis, University College London (University of London), 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.314081.
29
Perry, Frances. "Oxidative responses of neutrophils to Streptococcus pneumoniae." Thesis, University of Bristol, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.335509.
30
Freitas, Marisa Andreia Carvalho de. "The Effect of Metals on Human Neutrophils." Doctoral thesis, Faculdade de Farmácia da Universidade do Porto, 2009. http://hdl.handle.net/10216/63815.
31
Corleis, Bjoern. "Interaction of human neutrophils with mycobacterium tuberculosis." Thesis, London School of Hygiene and Tropical Medicine (University of London), 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.549780.
32
Cropp, Amy Rena. "Interaction of Bovine Seminal Proteins with Neutrophils." Thesis, The University of Arizona, 2006. http://hdl.handle.net/10150/193318.
Анотація:
Neutrophils ordinarily infiltrate the female reproductive tract subsequent to mating or artificial insemination, resulting in reduced fertility. Recently, it was demonstrated that equine neutrophil extracellular traps (NETs) entangled sperm in these DNA-rich structures, interfering with their normal transport through the female reproductive tract. Seminal plasma (SP) or proteinaceous extracts from SP inhibited sperm-neutrophil binding and specifically degraded sperm-activated NETs, without suppressing bactericidal activity of neutrophils. Fertility-associated antigen (FAA), a 31 kDa naturally occurring heparin-binding protein (HBP) produced by the accessory sex glands, has been shown to bind to sperm and potentiate heparin-induced capacitation. FAA shares 87% identity with DNase I-like family members, and contains two internal DNase-I-like peptide motifs. The purpose of this study was to determine if a recombinant form of FAA displayed capacitating effects associated with the native protein and to determine whether rFAA displayed DNase activity similar to SP or SP protein extracts to inhibit sperm-neutrophil binding.
33
Laight, David W. "Neutrophils and vascular reactivity in ischaemia/reperfusion." Thesis, University of Bath, 1994. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.385291.
34
Freitas, Marisa Andreia Carvalho de. "The Effect of Metals on Human Neutrophils." Tese, Faculdade de Farmácia da Universidade do Porto, 2009. http://hdl.handle.net/10216/63815.
35
Kalupov, Timofey. "Protéases à serine du neutrophile et inflammations pulmonaires : 1. L’air exhalé condensé est-il un matériel adapté pour les mesures d’activités protéolytiques ? : 2. La spécificité des protéases neutrophiliques valide-t-elle l’utilisation du modèle souris de Broncho-Pneumopathie Chronique Obstructive (BPCO) ?" Thesis, Tours, 2009. http://www.theses.fr/2009TOUR3301/document.
Анотація:
Le recrutement des neutrophiles qui caractérise l’inflammation observée lors de différentes pathologies pulmonaires conduit à la libération dans le milieu extracellulaire de protéases à sérine qui sont en partie responsables de la dégradation du tissu pulmonaire et/ou de la chronicité de l’inflammation. L’objectif initial de cette thèse était de développer une méthode de quantification de ces protéases, à partir des condensats d’air exhalé. En dépit de la sensibilité de la technique nous n’avons pas été en mesure de détecter des quantités significatives de protéases actives dans ces condensats. Ces résultats négatifs ont néanmoins permis de confirmer des hypothèses sur la distribution des protéases dans le milieu extracellulaire. La deuxième partie des travaux a été consacrée à la validation du modèle souris exposée à la fumée de cigarette comme modèle animal de bronchopneumopathie chronique obstructive. Nous avons purifié les trois protéases à sérine du neutrophile murin et avons construit des nouveaux substrats sensibles et spécifiques à partir des informations fournies par des études de modélisation moléculaire. Ces nouveaux outils permettent de valider l’utilisation du modèle souris pour comprendre le rôle des protéases à sérine dans la génération de peptides chimiotactiques au cours de la BPCONeutrophils recruitment is a hallmark of the inflammation associated with different lung diseases. This recruitment leads to the release in the extracellular matrix of serine proteases that are responsible at least in part, of the degradation of the pulmonary tissue and/or of the chronicity of inflammation. The initial objective of this thesis was to develop a method of quantification of these proteases, based on the analysis of exhaled air condensate. But in spite of the sensitivity of the methods, we have not been able to detect any significant activity of neutrophil serine proteases in these condensates. This negative result however gave support a hypothesis we formulated on the extracellular biodistribution of proteases in lung secretions. The second part of this thesis was devoted to the validation of an animal model of chronic obstructive pulmonary disease, i.e. the mouse exposed to cigarette smoke. We have purified three murine serine neutrophil proteases and developed new sensitive and specific FRET substrates which were designed starting from molecular modeling studies. These new tools that validate the use of the mouse model of human COPD, will be of great help to understand the role of serine proteases for generating chemotactic peptides during this chronic disease
36
Schroder, Angie Lisa. "A Role for Neutrophil Extracellular Traps in the Pathogenesis of Inflammatory Bowel Disease." Thesis, The University of Sydney, 2022. https://hdl.handle.net/2123/28779.
Анотація:
Neutrophil influx is a distinctive feature of inflammatory bowel disease (IBD), correlated with disease severity. Formation of neutrophil extracellular traps (NETs) is mediated by enzymes neutrophil elastase (NE), and myeloperoxidase (MPO) and its product hypochlorous acid (HOCl). Release of MPO in NETs results in extracellular HOCl production, causing tissue damage.
To investigate NET formation in clinical IBD, ileal biopsies were retrieved from Crohn’s disease (CD) patients, allocated an endoscopic assignment of healthy, transitional or diseased, and corresponding histopathological score. A significant linear correlation was observed between pathological score and cell viability evaluated with terminal deoxynucleotidyl transferase biotin-dUTP nick end labelling (TUNEL). Immunofluorescence analysis demonstrated distribution of NET markers MPO, NE and specific NET marker citrullinated histone (CitH3). Staining intensity of all markers increased according to assigned groupings, and pathological score where all showed a significant linear correlation. Multiplex immunofluorescence staining exhibited colocalisation of MPO, NE, CitH3 and a nuclear marker, confirming presence of NETs.
To evaluate viability of developing an MPO detection assay using MPO inhibitor AZD3241, biopsies taken from adult IBD patients were histologically evaluated and assigned a pathological score. A luminol assay validated efficacy of AZD3241 in homogenised tissue, however a time-course indicated no correlation between pathological score and luminescence. A commercial assay of MPO also found no positive correlation with pathological score.
The combined data is a novel example of positive correlations between NET formation and CD tissue damage, and of NET-specific marker CitH3 being measured in CD tissue. As this study is correlative, no causality can be inferred thus further studies are warranted.
37
Koehl, Bérengère. "Implication de l'endotheline-1 dans l'adhérence et l'activation des polynucléaires neutrophiles dans la drépanocytose." Thesis, Sorbonne Paris Cité, 2017. http://www.theses.fr/2017USPCC112/document.
Анотація:
La drépanocytose est une maladie génétique du globule rouge, due à une mutation ponctuelle du gène β de la chaine de l’hémoglobine. Néanmoins, la physiopathologie de la maladie va bien au-delà des anomalies érythrocytaires, avec notamment un dysfonctionnement vasculaire et leucocytaire qui font toute la complexité de la maladie. Au cours de ce travail, nous avons étudié le rôle de l’endothéline-1, peptide vaso-constricteur impliqué de nombreuses pathologies notamment vasculaires, sur l’activation et l’adhérence des polynucléaires neutrophiles dans la drépanocytose. Nous avons travaillé à la fois sur un modèle murin de drépanocytose (les souris SAD) et sur des échantillons sanguins de patients. Sur le modèle animal, nous avons réalisé des expériences de microscopie intravitale, permettant de tester in vivo l’effet des antagonistes des récepteurs ETA et ETB à l’endothéline sur le recrutement des polynucléaires neutrophiles. Sur les échantillons de sang de patients drépanocytaires, nous avons testé in vitro l’adhérence en flux des neutrophiles à l’endothélium vasculaire en réponse au blocage des récepteurs ETA et ETB. Nous avons enfin étudié l’expression des récepteurs ETA et ETB à la surface des neutrophiles et les voies de signalisations découlant de leur activation.Sur le modèle de souris drépanocytaire, l’inhibition des récepteurs ETA, mais surtout ETB permet de limiter le recrutement leucocytaire important provoqué par un stimulus inflammatoire. Ces résultats confirment le rôle d’ETA et celui, plus inattendu, d’ETB dans toutes les étapes d’adhérence des polynucléaires neutrophiles et dans leur transmigration tissulaire en contexte drépanocytaire.Sur des échantillons humains, nous avons confirmé le rôle crucial d’ETB dans l’adhérence des polynucléaires neutrophiles. Nous avons également confirmé la présence de récepteurs ETA et ETB à la surface des neutrophiles. Le récepteur ETB active une voie de signalisation responsable d’une mobilisation du calcium intra cytoplasmique, mais indépendante de l’activation de la phospho-inositide 3-kinase. Enfin, nous avons montré la capacité de ces cellules à synthétiser et excréter elles-mêmes de l’endothéline-1, pérennisant ainsi probablement la réponse inflammatoire et le recrutement leucocytaire. En conclusion, notre travail a permis de mettre en évidence le rôle important du récepteur ETB dans le recrutement des polynucléaires neutrophiles dans la drépanocytose. Ces données suggèrent que les antagonistes des récepteurs à l’endothéline pourraient être bénéfiques en prévention des phénomènes vaso-occlusifs chez les patients drépanocytairesSickle cell disease is a genetic disorder affecting red blood cells, due to a point mutation in the β chain of the hemoglobin gene. However, the pathophysiology of the disease goes well beyond the erythrocyte abnormalities, including vascular and white blood cell dysfunctions that contribute to the complexity of the disease. In this project, we investigated the role of endothelin-1, a powerful vasoconstrictor peptide involved in many vascular diseases, on activation and adhesion of neutrophil in sickle cell disease.We worked on both a mouse model of sickle cell disease (SAD mice) and blood samples from patients. In mice, we performed intravital microscopy experiments, to test the in vivo effect of endothelin receptor antagonists ETA and ETB on neutrophils recruitment. On blood samples from patients with sickle cell disease, we tested in vitro adhesion of neutrophils to vascular endothelium in response to the blocking of ETA and ETB receptors. Finally, we studied the expression of ETA and ETB receptors on neutrophils and the signaling pathways resulting in their activation.In our mouse model of sickle cell disease, the inhibition of both endothelin receptors ETA and ETB limits the major leukocyte recruitment caused by an inflammatory stimulus. These results confirm the role of ETA and the more unexpected important role of ETB in all stages of neutrophil adhesion and transmigration in sickle cell context.On human samples, we demonstrated the crucial role of ETB in neutrophils adhesion. We also confirmed the expression of ETA and ETB receptors on neutrophils. ETB receptor activates a signaling pathway responsible for intracytoplasmic calcium mobilization, but not involving the activation of phosphoinositide 3-kinase. Finally, we have shown the ability of neutrophils to synthesize and secrete endothelin-1, which can contribute to sustain the inflammatory stimulation and increased leukocyte recruitment.In conclusion, our work has highlighted the important role of ETB receptor in the recruitment of neutrophils in sickle cell disease. These data suggest that the antagonists of endothelin could be beneficial in prevention of vaso-occlusive events in sickle cell patients
38
Tam, Wai-kin, and 譚偉健. "A small scale study evaluating allelic frequencies of human neutrophil antigens in Hong Kong Chinese population." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2014. http://hdl.handle.net/10722/206588.
Анотація:
Background:
Human neutrophil antigens (HNA) are involved in a variety of clinical conditions such as transfusion related acute lung injury (TRALI), alloimmune neutropenia (ANN), autoimmune neutropenia (AIN). There are a total of five HNA systems, namely HNA-1, HNA-2, HNA-3, HNA-4 and HNA-5. In this decade, the allelic and genotypic frequencies of HNA were gradually evaluated in Europe, America and East Asia. [1] Despite HNA system being less polymorphic than HLA antigens, genotypic and allelic frequencies differences can still be observed in different geographical locations even of close proximity. For instance, studies in Thailand and China displayed genotypic and allelic frequencies differences. [2] These data highlights the fact that HNA genotypic and allelic frequencies vary among different populations even within the same region, however, the degree of variation remains to be elucidated. However, there is no information on HNA genotypic and allelic frequencies of Hong Kong population. Commercial genotyping kit has been available in the market but given its high reagent cost, it is not very popular in clinical laboratory. For this reason, a comparative affordable and economical in-house PCR-SSP assay was developed in this study.
Aim
The aim of this study is to evaluate the HNA genotyping and allelic frequencies in Hong Kong Chinese population by the development of an economical in-house PCR-SSP assay.
Methods
A commercial HNA typing kit was tested with reference samples to ensure this project has a standard and clinical compliance method for HNA genotyping prior to adopting in-house genotyping method. After reference protocol was established, in-house primers were designed and tested in parallel with the commercial method for validation purpose. After in-house method has been validated, 113 local samples were tested to calculate the genotype and allele frequencies in Hong Kong Chinese population using the developed in-house assay.
Results
A total of 113 Hong Kong Chinese samples were typed for HNA genotyping and results shown that: HNA-1a was 0.664; HNA-1b was 0.336; whereas HNA-1c allele was not detected. HNA-3a was 0.735 and HNA-3b was 0.265. HNA-4a was 0.991 and HNA-4b was 0.009. HNA-5a was 0.845 and HNA-5b was 0.155. Overall, results echoed with an earlier study performed on Han Chinese. [3] The genotyping frequency distribution for HNA-1, 3, 4 and 5 were: HNA-1a/a was 0.451, HNA-1 b/b was 0.124 and HNA-1 a/b was 0.425; HNA-3 a/a was 0.549, HNA-3a/b was 0.372 and HNA-3b/b was 0.08; HNA-4a/a was 0.982, HNA-4a/b was 0.018; HNA-5a/a was 0.708, HNA-5a/b was 0.274 and HNA-5b/b was 0.018.
Conclusion
This is the first study attempted to define HNA genotype and allelic frequencies by the self-developed in-house PCR-SSP method in Hong Kong Chinese population. The obtained results were comparable to those of gene frequencies in previous Xia’s study in Guangzhou Chinese population but significant difference from earliest reported European frequencies, confirming geographical difference exist. [3-5] However, due to small sample size in this study, further examination in larger sample may allow more representative frequencies for the Hong Kong population.published_or_final_version
Pathology
Master
Master of Medical Sciences
39
Summers, Charlotte. "Neutrophil priming : effects on pulmonary transit time and bio-distribution in vivo." Thesis, University of Cambridge, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.609579.
40
ROCK, JOHN PATRICK. "MOLECULAR BIOLOGY OF GONOCOCCAL DEATH FOLLOWING EXPOSURE TO THE GRANULE EXTRACTS OF HUMAN NEUTROPHILS (NEISSERIA GONORRHOEAE, PEPTIDOGLYCAN, MEMBRANE DAMAGE)." Diss., The University of Arizona, 1986. http://hdl.handle.net/10150/183844.
Анотація:
Gonococci that have been phagocytized by human neutrophils are killed very effectively. While much research has focused on defining the microbicidal mechanisms of the neutrophil arsenal, substantially less is known regarding why phagocytized bacteria die. Gonococci were examined, at the molecular level, following exposure to human neutrophil granule extracts (GE) in an effort to discover the "lethal lesion", that injury to the bacterial cell which results in its death. The cytoplasm-based metabolism of GE-treated gonococci continues to function normally for at least 30 minutes, although these same cells have lost the ability to divide and are reproductively dead. GE-treated gonococci were found to utilize less oxygen than control cells, indicative of damage to the cytoplasmic membrane. Visual examination of GE-treated gonococci by light microscopy revealed that the cells undergo very minimal division once exposed to GE. GE-treated gonococci visualized by transmission electron microscopy had outer membranes which suffered time-related disorganization and disruption; the effects began immediately upon contact with GE. GE-treatment was also observed to cause aberrant structure and orientation of forming bacterial septa. Investigation of gonococcal peptidoglycan, the structural component of the bacterial membrane, yielded interesting results when the effects of GE were scrutinized. GE caused subnormal incorporation of peptidoglycan precursors, and also induced a twofold higher rate of release of peptidoglycan turnover fragments than was seen from control cells. After analysis of peptidoglycan fragments released into culture supernatants by thin-layer chromatography and high-pressure liquid chromatography, it was found that the small amount of high-molecular-weight fragments exhausted by control cells was not present with treated cells. Investigation of the cell-associated peptidoglycan, by the above methods, after exposure to GE revealed differences in the digestion products. There was a distinct reduction in the amount of penicillin bound by the penicillin-binding proteins of GE-treated cells. There was, however, no observed change in the electrophoretic mobility between the PBPs of control and treated cells.
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Ishak, Reezal. "Calpain-1 : investigating its role in murine neutrophils." Thesis, Cardiff University, 2012. http://orca.cf.ac.uk/37448/.
Анотація:
Neutrophils are phagocytic white blood cells which act as the first line of defence against entry of foreign microorganisms. Neutrophils are recruited to their target site through the process of spreading, extravasation and phagocytosis involving complex signal transduction within the cells, which might include the activation of the cytosolic Ca2+ activated protease, calpain-1. The work described here investigates the role of calpain-1 in regulating neutrophil functions such as spreading, trans-endothelial migration, chemotaxis, phagocytosis and Ca2+ signalling. Through the work done at European Mutant Mouse Archive (EMMA), Oxford, and by using intracellular sperm injection (ICSI) of calpain-1 deleted gene from mice generated in the USA, and with a selective genotype breeding programme, a colony of homozygous calpain-1 KO mouse has been generated in Cardiff. Homozygous calpain-1 KO neutrophils appeared to have a smaller surface spreading area and their recruitment into the peritoneal cavity of the mouse in vivo was disrupted. In vitro experiments showed significant defects in their ability to cross the ICAM-1 expressing endothelial cells in trans-endothelial migration assay. Disruption in this transmigration was only evident with ICAM-1 upregulated (TNF-treated) endothelial cells, suggesting a specific defect in the β2 integrin-ICAM-1 signalling process. Calpain-1 absence did not affect signal transduction as neutrophils were able to signal cytosolic Ca2+ in response to β2 integrin engagement (C3bi-opsonised zymosan) and also to release intracellular Ca2+ store upon IP3 uncaging. This showed that the IP3 pathway in the cells was not affected by knocking-out calpain-1 and continued to be functional. The key signalling mechanisms from β2 integrin also remained intact and this is consistent with calpain-1 activation by Ca2+ being an important event in trans-endothelial migration. In conclusion, calpain-1 absence has significantly affected the ability of neutrophils to undergo trans-endothelial migration and this effect is directed towards the event which happens downstream to the increase in cytosolic free Ca2+ concentration.
42
Morton, Jonathan. "Modulation of vascular tone by neutrophils in vivo." Thesis, Cardiff University, 2007. http://orca.cf.ac.uk/55681/.
Анотація:
The vascular endothelium regulates vasomotor tone and blood fluidity through the release of paracrine factors, such as nitric oxide (NO). Acutely activated neutrophils have been shown to consume vasodilatory NO in vitro through the NAD(P)H oxidase-dependent generation of superoxide. As such, neutrophils may contribute to the endothelial dysfunction and increased vascular tone commonly observed in inflammatory vascular diseases. Herein, the experiments in this thesis set out to examine a role for neutrophils in the regulation of vascular tone. Initial experiments aimed to assess the capacity of inflammatory-primed neutrophils to consume NO in vitro. Inflammatory priming of human neutrophils resulted in significantly accelerated rates of NO disappearance from aerobic buffer in vitro in an NAD(P)H oxidase-dependent manner. Thus, neutrophil priming may have a detrimental effect on vascular homeostasis in vivo. With this in mind, subsequent chapters aimed to elucidate a role for neutrophils in regulating vascular tone in vivo using immunodepletion techniques. Following neutrophil depletion, mice exhibited a gradual fall in systolic blood pressure over 3 days, and phenylephrine-induced vasoconstriction was significantly attenuated in thoracic aortae isolated from neutropenic animals compared to controls. There effects were due, at least in-part, to the interferon-y-dependent upregulation of inducible nitric oxide synthase (iNOS) bioactivity in the thoracic aortae of neutropenic mice. Thus, under physiological conditions, neutrophils may modulate vascular tone by negatively regulating the bioactivity of pro-inflammatory enzymes, such as iNOS. Finally, the effect of acute neutropenia on angiotensin (Ang) II-induced hypertension in vivo was examined. Neutrophil depletion prevented the onset of Ang II-induced hypertension, indicating that neutrophils may be directly involved in the development of hypertension associated with this octapeptide in vivo. In conclusion, the data described in this thesis highlight the diversity of neutrophil activities in vivo and in vitro and how changes in neutrophil phenotype may impact upon vascular physiology.
43
Adams, Susan. "Activated gene expression by neutrophils in rheumatoid arthritis." Thesis, University of Liverpool, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.386829.
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Stringer, Rebecca Elizabeth. "Endogenous and activated protein synthesis in human neutrophils." Thesis, University of Liverpool, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.386847.
45
Ellis, J. A. "Studies of the NADPH-oxidase of human neutrophils." Thesis, University of Bristol, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.233765.
46
Rodriguez, Jairo Antonio. "Functional activities of C-reactive protein on neutrophils." Thesis, London School of Hygiene and Tropical Medicine (University of London), 2004. http://researchonline.lshtm.ac.uk/682313/.
Анотація:
C-reactive protein (CRP) is a member of the pentraxin family which opsonises S. pneumoniae through its binding to phosphorylcholine. In addition, CRP binds to Fcγ receptors: FcγRI with high affinity and, probably, FcγRIIA with lower affinity. Binding to FcγRIIA was suggested to depend on a polymorphism at residue 131 of the receptor, HH individuals being poorer binders compared to RR. To clarify the role of CRP binding to FcγRIIA and functional activities upon interaction, neutrophils from HH and RR individuals were incubated with CRP in the presence or absence of pneumococci type 3. No difference in activation as determined by IL-8 synthesis, respiratory burst and phagocytosis were seen between HH and RR donors. Since CRP increases its serum concentration up to 1000 fold above the normal level, we also compared acute-phase concentrations of CRP with normal levels for neutrophil functions. Normal (≤10 μg/ml) and acute-phase (10 - 100 μg/ml) levels increased IL-8 production in the presence or absence of pneumococci. A similar pattern was seen for extracellular reactive oxygen. There was a five-fold increase in DHR oxidation in neutrophils when CRP at 10 μg/ml was used, although this was reduced when CRP at 50 and 100 μg/ml was used in both HH and RR donors. Recombinant CRP also gave a similar pattern in which higher MFIs for DHR oxidation were obtained for CRP at 10 μg/ml. On average a two-fold increase in phagocytosis of pneumococci serotype 3 was obtained for both type of donors for CRP at 10 μg/ml. This effect was also reduced at acute-phase levels of CRP. The down-regulatory effects of CRP are thus selective for certain responses but do not require phagocytosis since CRP at 50 - 100 μg/ml could also inhibit PMA activation. The ability of CRP to bind to Fcγ-receptors using surface plasmon resonance was evaluated, but there was no evidence of CRP binding to FcγRIIA, RIIB or RIII Serum amyloid P component showed strong binding to FcγRIII and weak binding to FcγRIIA and RIIB. A glycosylated form of the Fc receptor may be required for binding
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Rowe, John Christopher. "Targeting Neutrophils to Improve Protection by Sublingual Vaccines." The Ohio State University, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=osu1612190976457585.
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Lingadahalli, Shreyas Vaman. "ACTIVATED NEUTROPHILS MEDIATE KIM-1 SHEDDING AND RENALREMODELLING." Cleveland State University / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=csu1368404728.
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Chi, Maoyen. "C-Reactive protein (CRP) induced signaling in Neutrophils /." The Ohio State University, 2001. http://rave.ohiolink.edu/etdc/view?acc_num=osu1486400446372631.
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Roth, Daniel R. "The chemotactic competence of neutrophils from neonatal calves /." [S.l : s.n.], 1988. http://www.ub.unibe.ch/content/bibliotheken_sammlungen/sondersammlungen/dissen_bestellformular/index_ger.html.