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Dissertations / Theses on the topic 'Inflammation of the Bone'
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Bernhold, Brechter Anna. "Kinins : important regulators in inflammation induced bone resorption." Doctoral thesis, Umeå : Univ, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-959.
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Ljunggren, Östen. "Involvement of bradykinin in inflammation induced bone resorption." Umeå : University of Umeå, 1991. http://catalog.hathitrust.org/api/volumes/oclc/24493228.html.
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Song, Hannah. "Endothelial bone morphogenic protein 4 and bone morphogenic protein receptor II expression in inflammation and atherosclerosis." Diss., Atlanta, Ga. : Georgia Institute of Technology, 2007. http://hdl.handle.net/1853/28258.
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Thesis (M. S.)--Biomedical Engineering, Georgia Institute of Technology, 2008.<br>Committee Chair: Hanjoong Jo; Committee Member: Ajit P. Yoganathan; Committee Member: Andrew P. Kowalczyk; Committee Member: David G. Harrison; Committee Member: Kathy K. Griendling
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AL-Hashimi, Najat AL-Sayed. "Experimental studies on effects of orthodontic forces in generation of immune responses : possible roles for immunoregulating molecules in the control of alveolar bone remodeling /." Stockholm, 2004. http://diss.kib.ki.se/2004/91-7349-985-4/.
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Ka, Khady. "Fat and bone metabolism in relation to gingival inflammation in children." Thesis, McGill University, 2014. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=121433.
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Introduction: Epidemiological evidence suggests an association between diseases related to fat and bone metabolism and periodontal health. Despite the extensive evidence showing these associations in adults, only a few studies have been conducted in children. We address a gap in the pediatric literature by examining the extent to which markers of gingival inflammation are associated with i) metabolic syndrome (MetS) and: ii) plasma uncarboxylated osteocalcin (unOC). As a preliminary step, we first explore the extent to which whole-body bone measurements were associated with fat mass after taking into account the effect of lean mass. Methodology: The data used in this project derives from the QUALITY cohort, an ongoing longitudinal study investigating the natural history of obesity in children of Quebec, Canada. The QUALITY cohort includes 630 Caucasian children aged 8-10 years at cohort inception, with at least one obese biological parent. Participants were systematically recruited through schools located within 75 km of Montreal and Quebec City. In this thesis, we present cross-sectional analyses from the baseline visit using multiple linear regression analyses with adjustment for potential confounding variables. Whole-body bone mineral content (BMC, g), bone area (cm2), bone mineral density (BMD, g/cm2), lean mass (kg) and fat mass (kg) were measured by dual-energy X-ray absorptiometry (DXA). MetS was defined according to the International Diabetes Federation recommendations. Plasma unOC levels were determined by enzyme-linked immunosorbent assay. Gingival inflammation was defined by the level of gingival crevicular fluid (GCF) tumour necrosis factor alpha (TNF-α) and the extent of gingival bleeding. Results: Positive associations between fat mass and whole-body DXA bone measurements, including BMC, bone area and BMD, were observed after taking into account the effect of lean mass. Specifically, a 1-kg increase in fat was associated with 9.32 g (95% confidence interval [CI]: 7.26, 11.39), 8.02 cm2 (95%CI: 6.72, 9.32) and 0.002 g/cm2 (95%CI: 0.000, 0.002), increase in whole-body BMC, bone area and BMD respectively. Boys with MetS compared to those without, had a 49.5% (95%CI: 25.72, 73.22) higher GCF TNF-α level and 13.7% (95%CI: 1.1, 26.2) more sites with gingival bleeding. Moreover, for 3 of the 5 components of MetS – waist circumference, fasting plasma triglycerides and systolic blood pressure – an increase was associated with increased GCF TNF-α level in boys. No such findings were seen in girls. A 1-ng/ml increase in plasma unOC was associated with 0.96% decrease (95% CI: -1.69, -0.23) in GCF TNF-α level. Conclusion: Our results provide novel findings showing a clustering of metabolic abnormalities, low plasma unOC and high gingival inflammation among 8-10 Caucasian children. Moreover, they suggest that fat and bone metabolism may be associated with periodontal health as early as in childhood. Documenting the association of conditions related to fat and bone metabolism with periodontal health in children may have public health implications. This may allow identification of individuals at risk of developing several related conditions long before they develop clinically and implementation of early preventive measures.<br>Introduction: Les données épidémiologiques suggèrent une association entre la santé parodontale et les maladies liées au métabolisme des graisses et des os. En dépit des nombreuses études montrant ces associations chez l'adulte, seules quelques études ont été menées chez l'enfant. Dans ce projet, nous avons tenté de combler une lacune dans la littérature pédiatrique en examinant dans quelle mesure des marqueurs de l'inflammation gingivale sont associées : 1) au syndrome métabolique (MetS) et 2) à la concentration plasmatique d'ostéocalcine non carboxylée (unOC). De plus, dans un premier temps, nous avons évalué la relation entre des mesures de santé osseuse et la masse grasse indépendamment de la masse maigre. Méthodologie: Dans ce projet, nous utilisons des données provenant de la cohorte QUALITY, une étude longitudinale portant sur l'histoire naturelle de l'obésité chez les enfants du Québec, au Canada. La cohorte QUALITY inclut 630 enfants de race blanche, âgés de 8-10 ans lors du recrutement, ayant au moins un parent biologique obèse. Les participants ont été recrutés dans les écoles situées à moins de 75 kilomètres de Montréal et de la ville de Québec. Dans cette thèse, nous présentons des analyses transversales de la visite initiale. Nous avons utilisé des régressions linéaires multiples avec ajustement pour les variables de confusion potentielles. La teneur minérale osseuse (BMC, g), la surface osseuse (cm2), la densité minérale osseuse (BMD, g/cm2), la masse maigre (kg) et la masse grasse (kg) ont été mesurées au niveau du corps entier à l'aide de l'absorption bi-photonique à rayons X (DXA). Le MetS a été défini selon les recommandations de la Fédération Internationale du Diabète. La concentration plasmatique en unOC a été déterminée par méthode immuno-enzymatique (ELISA). L'inflammation gingivale a été définie par la concentration de facteur de nécrose tumoral dans le fluide gingival créviculaire (GCF TNF-α) et par le niveau de saignement gingival. Résultats: Nous avons observé des associations positives entre la masse grasse et les mesures de santé osseuse indépendamment de la masse maigre. Plus précisément, une augmentation de 1-kg de masse grasse était associée respectivement avec une augmentation de 9,32 g (95% intervalle de confiance [IC]: 7,26 ; 11,39), 8,02 cm2 (95% IC: 6,72 ; 9,32) et 0,002 g/cm2 (95% IC: 0,000 ; 0,002), en BMC, surface osseuse et BMD.Les garçons présentant le MetS avaient une concentration en GCF TNF-α 49,5% (95% IC: 25,72 ; 73,22) plus élevée et 13,7% (95% IC: 1,1 ; 26,2) plus de sites de saignement gingival comparativement à ceux sans MetS. Par ailleurs, chez les garçons, pour 3 des 5 composantes du MetS - tour de taille, concentration plasmatique de triglycérides, pression artérielle systolique - une augmentation était associée à une concentration en GCF TNF-α plus élevée. Aucun de ces résultats n'a été observé chez les filles.Une augmentation de 1-ng/ml de la concentration plasmatique en unOC était associée à une diminution de 0.96% (95% IC: -1,69 ; -0,23) de la concentration en GCF TNF-α. Conclusion: Nos résultats montrent le regroupement de conditions médicales incluant des anomalies métaboliques, une faible concentration plasmatique en unOC et la présence d'inflammation gingivale chez des enfants de race blanche, âgés de 8-10 ans. Ces résultats suggèrent que le métabolisme des graisses ainsi que celui des os peuvent être associés à la santé parodontale à un jeune âge. Documenter l'association de ces conditions avec la santé parodontale chez l'enfant peut avoir des répercussions en santé publique. En effet, cela pourrait permettre d'identifier les personnes à risque de développer plusieurs conditions inter-reliées bien avant qu'elles ne se développent cliniquement et de mettre en place des mesures préventives.
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George, Estee L. "Quantifying the roles of stimulated osteocytes and inflammation in bone remodeling." University of Akron / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=akron155559673634022.
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Uno, Jennifer Kikue. "Bone Mineralization in a Murine Model of Inflammatory Bowel Disease." Diss., Tucson, Arizona : University of Arizona, 2006. http://etd.library.arizona.edu/etd/GetFileServlet?file=file:///data1/pdf/etd/azu%5Fetd%5F1650%5F1%5Fm.pdf&type=application/pdf.
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Hussein, Hayam. "Cathepsin K Inhibition In Bone And Bone Marrow In Horses." The Ohio State University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=osu1449218489.
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Modugu, Asha. "Inflammatory studies on bone cement." Thesis, Uppsala universitet, Institutionen för teknikvetenskaper, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-187460.
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Simvastatin, a cholesterol lowering drug, has the capacity to stimulate bone formation along with having anti-inflammatory effects. Incorporating simvastatin to the calcium phosphate cement would result in slow release of the drug stimulating bone formation and by preventing a local inflammation and bone resorption. The main aim is to study and examine the inflammatory response towards calcium phosphate cements in vitro and compare it with cements incorporated with simvastatin.
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Madhavan, Shashi D. "Biomechanical signals mediate cellular mechano-transduction and gene regulation." Columbus, Ohio : Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1195234773.
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Platts, Louise Ann Marie. "The L-arginine/nitric oxide pathway in bone (re)modelling and articular inflammation." Thesis, Imperial College London, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.391503.
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Kriel, Muhammed Hashir. "Investigation of the pathogenesis of bone loss associated with inflammation and steroid therapy." Thesis, University of Bristol, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.619137.
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Patients with inflammatory bowel disease (IBO), comprising Crohn's disease (CD) and ulcerative colitis (UC) are at increased risk of osteoporosis with associated fracture and morbidity, particularly at a younger age. Numerous studies in the literature have shown that disease activity and glucocorticoid (GC) use are major contributing factors. Individuals can vary in their response to GC as reflected by their Iymphocyte steroid sensitivity (LSS) in vitro and the sensitivity of bone to effects of GC can vary as well. The observation that rapid bone loss at Ward's triangle occurred in a cohort of CD patients treated for a disease relapse with a single course of glucocorticoid therapy lead to the interventional randomised control trial that formed the basis of this project and the prospective and cross-sectional investigations described in this thesis. The RCT was designed to determine whether risedronate could prevent bone loss in CD and UC patients treated with a short course of GC for a relapse. Patients recruited to the RCT provided serum and urine samples at regular intervals which were used to measure Iymphocyte steroid sensitivity (LSS), bone turnover markers (P1 NP and CTX), cytokine concentrations and 11 hydroxysteroid dehydrogenase (11BHSD1). The aim of the project was to explore mechanisms which determine the extent of bone loss in patients with IBD and to determine whether the degree of bone loss is related to individual steroid sensitivity or the extent of systemic inflammation or both of these mechanisms. Hence skeletal changes measured by DXA and bone turnover markers were related to LSS, cytokines concentrations and disease activity scores. We determined whether 11 BHSD1 could predict change in BMD or bone markers. Risedronate was effective at reducing bone loss at WT shown to our knowledge for the first time during a short course of steroid therapy. 11BHS01 did not predict bone loss but this had not been explored in' the context of IBD previously. The cross-sectional data for LSS revealed some intriguing results but may not predict clinical steroid responsiveness in all patients. Clarifying the pathogenesis of bone loss may inform strategies to minimise bone loss, but there is no clear method of predicting which patients are most susceptible to the deleterious effects of GC.
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Pappalardo, Angela. "Defining the role of γδ cells in bone loss associated with chronic inflammation". Thesis, University of Aberdeen, 2013. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=203414.
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The extensive infiltration of immune cells in the joints of patients affected by rheumatoid arthritis (RA), and the subsequent production of pro-inflammatory cytokines triggers bone erosion through the extensive stimulation of bone resorbing osteoclasts (OCs). The activity of γδ T cells has been implicated to influence the onset and severity of the disease pathology in murine models of human RA. With this study the effects of γδ T cells for influencing OC differentiation and resorptive activity were assessed in vitro. Activated γδ T cells exerted inhibitory effects on OC differentiation and resorptive activity, these effects were mediated by the release of soluble factors, since similar inhibitory effects were obtained using conditioned medium (CM) from activated γδ T cells. The primary mediator of such effects was determined to be IFN, since neutralisation markedly restored OC differentiation and resorptive activity. γδ T cell proliferation, activation and survival following culture with autologous mature OCs were assessed by flow cytometry. Interestingly, OCs and OC-derived CM induced activation of γδ T cells as determined by the expression of the early activation marker CD69. A mediator of this stimulatory effect on T cells was found to be TNF, since neutralisation of TNFα decreased the stimulatory effect of OCs on CD69 expression. Consistently, OCs, but not OC-derived CM, increased the proliferation of IL-2-stimulated γδ T cells and also supported the survival of resting γδ T cells. This study provides new insights into the in vitro interactions between human γδ T cells and OCs, moreover it defines osteoclasts as immune competent cells capable of influencing the activation status and the viability of T lymphocytes, and provide evidence for a novel stimulatory effect of OCs on γδ T cells.
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Donnelly, Jessica M. "Inflammation-Induced Activation of Bone Marrow-Derived Mesenchymal Stem Cells During Gastric Disease." University of Cincinnati / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1380613253.
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Morrison, Matthew Sam. "Osteoclast function : role of extracellular pH and ATP." Thesis, University College London (University of London), 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.369218.
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Kašėta, Vytautas. "Investigation of Bone Marrow Hematopoietic Stem Cell Migration during Inflammation in BALB/c Mice." Doctoral thesis, Lithuanian Academic Libraries Network (LABT), 2011. http://vddb.laba.lt/obj/LT-eLABa-0001:E.02~2011~D_20111102_110918-10945.
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The aim of dissertation work to investigate the anti-inflammatory effect of murine bone marrow hematopoietic stem cells and their migration in the BALB/c mouse contact hypersensitivity model in vivo. It was found that isolated hematopoietic cell populations had a significant anti-inflammatory effect and inhibited the edema. The studies showed that the most efficient (up to 66%) inhibition of foot edema was obtained when using the HSC population. For the first time the HSC population migration kinetics in the BALB/c mouse contact hypersensitivity model in vivo was investigated. We determined that cells of this population can be found in mice paw edema and liver after just one hour. A little bit later they are detected in the spleen. We did the HSC population quantitative migration kinetic studies and found that in case of foot inflammation there is a secondary migration of the transplanted HSC migrating from the bone marrow to the spleen hematopoietic niche. We have shown that these cells selectively migrate into the inflammation areas of the foot edema. Transplanted cells quantity in the samples of foot edema, as compared with the untreated foot, was more than 1000 times higher. A transplanted hematopoietic stem cell migration research during inflammation, carried out in this work, contributes to clarification of stem cell migration patterns in case of pathological processes. This is particularly important in ensuring a safe and effective stem cell application in practice.<br>Šio darbo tikslas ištirti pelių kaulų čiulpų hemopoetinių kamieninių ląstelių priešuždegiminį poveikį bei migraciją BALB/c pelių kontaktinio hiperjautrumo modelyje in vivo. Nustatyta, kad išskirtos hemopoetinės ląstelių populiacijos pasižymėjo efektyviu priešuždegiminiu poveikiu ir slopino edemą. Efektyviausiai (iki 66%) pėdos edemą slopino HKL populiacija. Pirmą kartą buvo ištirta HKL populiacijos migracijos kinetika BALB/c pelių kontaktinio hiperjautrumo modelyje in vivo. Nustatyta, kad šios populiacijos ląstelės jau po 1 val. aptinkamos tiriamų pelių pažeistoje pėdoje ir kepenų histologiniuose preparatuose, kiek vėliau jos aptinkamos blužnyje. Atlikti HKL populiacijos kiekybiniai migracijos kinetikos tyrimai. Nustatyta, kad esant uždegimui pėdoje vyksta transplantuotų HKL antrinė migracija iš kaulų čiulpų į blužnies hemopoetines nišas. Parodyta, kad šios populiacijos ląstelės selektyviai migruoja į uždegimo vietą pažeistoje pėdoje. Transplantuotų ląstelių kiekis pėdos edemos mėginiuose buvo daugiau nei 1000 kartų didesnis lyginant su nepaveikta pėda. Šiame darbe atlikti transplantuotų hemopoetinių kamieninių ląstelių migracijos tyrimai uždegimo metu prisideda prie kamieninių ląstelių migracijos dėsningumų išaiškinimo patologinių procesų metu, kas yra ypač svarbu užtikrinant saugų ir efektyvų kamieninių ląstelių taikymą klinikinėje praktikoje.
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Urbina, Princess. "Bone Morphogenetic Protein-7 Attenuates Inflammation and Apoptosis and Improves Cardiac Function in Diabetes." Master's thesis, University of Central Florida, 2013. http://digital.library.ucf.edu/cdm/ref/collection/ETD/id/5716.
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Bone Morphogenetic Protein-7 (BMP-7) belongs to the transforming growth factor-β (TGFβ) family of cytokines has is known to have potent anti-inflammatory properties. It has been used in patients to treat osteoporosis clinically and has been reported to treat diabetic nephropathy in murine models. Moreover, studies show that inflammation is up-regulated in patients with pre-diabetes (PD). We, therefore, hypothesize that the administration of BMP-7 will attenuate inflammation in the heart of Streptozotocin (STZ)-induced PD mice. In this study, we divided C57Bl/6 mice into three groups: CONTROL, PD, and PD+BMP-7. CONTROL mice received intraperitoneal (i.p.) injections of Sodium Citrate Buffer while PD and PD+BMP-7 groups received i.p. injections of Streptozotocin (STZ) for two days. In addition, PD+BMP-7 mice received intravenous injections (i.v.) of BMP-7 (200µg/kg) on the last day of STZ injection and for the following two days. Animals were sacrificed 21 days post last injection and examined for levels of oxidative stress, inflammatory immune response, apoptosis, fibrosis and cardiac function. Our results indicate significant glucose intolerance in PD mice (p<0.05), which was attenuated in the PD+BMP-7 group
(p<0.05). We also observed increased oxidative stress (p<0.001) and secretion of pro-inflammatory cytokines (p<0.05), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), in PD mice as compared with the controls. PD+BMP-7 mice revealed significant up-regulation of M2 macrophages (p<0.05) and secretion of anti-inflammatory cytokines (p<0.05), interleukin-10 (IL-10) and interleukin-1RA (IL-1RA), as compared to PD mice. This was observed with a concomitant down-regulation of pro-inflammatory cytokines, IL-6 and TNF-α, as compared to the PD group. Moreover, we observed significantly increased cardiac apoptosis and fibrosis in PD mice (p<0.001) as compared to the control group.
These observations, however, were down-regulated upon treatment with BMP-7. Lastly, analysis of echocardiograms revealed significantly depressed cardiac function in PD mice as compared with controls, while the PD+BMP-7 group presented improved cardiac function compared to PD mice. In conclusion, our data suggest that treatment with BMP-7 is effective in alleviating cardiac inflammation, inhibiting apoptosis, blunting cardiac remodeling and improving cardiac function in the hearts of STZ-induced PD mice. This reveals the potential of BMP-7 as a therapy in PD patients who present an increased inflammatory immune response.<br>M.S.<br>Masters<br>Molecular Biology and Microbiology<br>Medicine<br>Molecular and Microbiology
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Redente, Elizabeth Frances. "Macrophage and bone marrow derived monocyte activation during mouse lung tumorigenesis and chronic inflammation /." Connect to full text via ProQuest. Limited to UCD Anschutz Medical Campus, 2008.
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Thesis (Ph.D. in Toxicology) -- University of Colorado Denver, 2008.<br>Typescript. Includes bibliographical references (leaves 224-253). Free to UCD Anschutz Medical Campus. Online version available via ProQuest Digital Dissertations;
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Airila-Månsson, Stella. "Progression of periodontitis and influence of periodontal bacteria on release of inflammatory markers in Swedish adults /." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-622-0/.
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Cox, Allison Jeanne. "Whole exome analysis of individuals and families with chronic recurrent multifocal osteomyelitis (CRMO)." Diss., University of Iowa, 2016. https://ir.uiowa.edu/etd/2199.
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Chronic recurrent multifocal osteomyelitis (CRMO) is a rare, pediatric, autoinflammatory disease characterized by bone pain due to sterile osteomyelitis, and is often accompanied by psoriasis or inflammatory bowel disease. There are two syndromic forms of CRMO, Majeed syndrome and DIRA, for which the genetic cause is known. However, for the majority of cases, the genetic basis is unknown. Via whole-exome sequencing and linkage analysis, we determined the most likely causative mutations in four families. While the mutations are in three different genes – FBLIM1, PLCG2 and PIP; all three genes are involved in Fcγ signaling and osteoclast activation.
In a large cohort of 61 individuals with CRMO, we performed gene and pathway based association analysis using the 1000 genomes participants of European ancestry as controls. One gene from the family-based analyses, ANO6, was significantly enriched for rare variants in our cohort of cases. ANO6 is involved in P2RX7- mediated inflammasome activation and in the regulation of bone mineralization. While no pathways were enriched for rare variants in the CRMO cohort after genome-wide correction, four pathways were significantly enriched for rare variants in the control samples, indicating a protective effect of the variants. The second most significant pathway, activation of chaperone genes by XBP1s, is relevant to CRMO pathogenesis as XBP1s is a transcription factor that attenuates ER stress, and regulates the expression of genes involved in RANKL signaling and bone remodeling.
An association analysis using a larger set of cases followed by functional validation of candidate genes is necessary to confidently declare the mutations isolated in the work presented here to be pathogenic. Our preliminary findings suggest that mutations in genes involved in both the inflammatory response and bone remodeling underlie the pathogenesis of CRMO.
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Wood, Lorna J. "The role of bone marrow progenitor cells in allergen-induced airway hyperresponsiveness and airway inflammation." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape9/PQDD_0028/NQ51023.pdf.
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Stanescu, Claudia Ioana. "RESISTANCE TRAINING AND MEASURES OF INFLAMMATION IN RELATION TO BONE MINERAL DENSITY IN POSTMENOPAUSAL WOMEN." Diss., Tucson, Arizona : University of Arizona, 2005. http://etd.library.arizona.edu/etd/GetFileServlet?file=file:///data1/pdf/etd/azu%5Fetd%5F1230%5F1%5Fm.pdf&type=application/pdf.
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Sidney, Laura E. "Tissue engineering in hostile environments : the effects and control of inflammation in bone tissue engineering." Thesis, University of Nottingham, 2013. http://eprints.nottingham.ac.uk/13499/.
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The potential effects of introducing bone regeneration strategies into environments of disease and damage are often overlooked, despite the fact that many of the signalling pathways in inflammation have effects on bone development and healing. Embryonic stem cells (ESCs) are increasingly being used to develop models of disease and have potential in osteogenic-cell based therapies. Osteogenic differentiation strategies for ESCs are well established, but the response of these cells to tissue damage and inflammation has not yet been investigated, particularly in comparison to primary osteoblasts. Here, proinflammatory cytokines were used as part of an in vitro model to mimic elements of skeletal disease, such as rheumatoid arthritis and non-union fractures. The response of osteogenically differentiated mouse embryonic stem cells (osteo-mESCs) to the proinflammatory cytokines interleukin 1-β (IL-1β), tumour necrosis factor-α (TNF-α) and interferon-γ (IFN-γ), was compared to that of primary mouse calvarial osteoblasts, already well-described in literature and used as a “benchmark” in this study. Although histology, immunocytochemistry and PCR showed similarities in osteogenic differentiation of the osteo-mESCs and the primary calvarial cells, over 21 days in culture, there were marked differences in the response to the proinflammatory cytokines. Viability of the osteo-mESCs was maintained in response to cytokines, whereas viability of primary cells was significantly reduced. There were marked increases in nitric oxide (NO) and prostaglandin E2 (PGE2) production in primary calvarial cells over the entire 21-day culture period, but this was not seen with osteo-mESCs until day 21. The study then went on to look at the effects of proinflammatory signalling on the in vitro bone formation of the two cell types. Significant differences in the effects of proinflammatory cytokines on bone nodule formation and matrix production were seen when comparing the osteo-mESCs and the calvarial cells. This study demonstrates that while osteo-mESCs share phenotypic characteristics with primary osteoblasts, there are some distinct differences in their biochemistry and response to cytokines. This is relevant to understanding differentiation of stem cells, developing in vitro models of disease, testing new drugs and developing cell therapies. An additional objective in this investigation was to look at tissue engineering strategies as a means of controlling inflammation in bone disease. The primary calvarial osteoblasts were utilised as an in vitro inflammation model, and used to study the effects of anti-inflammatory mediators. Anti-inflammatory-releasing porous scaffolds were manufactured from poly(lactic-co-glycolic acid) (PLGA) and poly(ethylene glycol) (PEG). The calvarial osteoblast inflammation model was used successfully to show successful release of diclofenac sodium from the PLGA/PEG scaffolds. This study demonstrates that there is much to consider in the development of regenerative strategies for bone disease, particularly the role that the effect and control of inflammation will play in bone healing.
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Ashhurst, Thomas Myles. "Mobilisation of the murine haematopoietic system in the bone marrow during viral encephalitis." Thesis, The University of Sydney, 2019. https://hdl.handle.net/2123/21393.
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Viral infection of the central nervous system (CNS) with West Nile virus (WNV) or Zika virus (ZIKV) results in a rapid influx of monocyte-derived macrophages, that ultimately induce fatal pathology in the mouse. Whilst these cells are suspected to originate from the bone marrow (BM), little is known about the kinetic and migratory events that might mobilise BM monocytes and their progenitors in response to CNS infection. In this study we conducted comprehensive mapping of the murine central nervous system (CNS) and haematopoietic system in the BM using high-dimensional 29-parameter flow cytometry and 47-parameter mass cytometry (CyTOF). Additionally, we developed and utilized 8-way cell sorting capacities for sorting cells on high-dimensional panels. In order to analyse the resulting datasets, we developed an analysis pipeline for clustering (using the tool ‘FlowSOM’) and dimensionality reduction (using the tool ‘tSNE’) to manage large datasets that we termed ‘Cytometry Analysis Pipeline for large and compleX datasets’ (CAPX, scripts and instructions available at www.sydneycytometry.org.au/capx or www.github.com/sydneycytometry/capx). We used this approach to profile cellular infiltration in virally infected brains, revealing a similar pattern of macrophage-dominated infiltration in WNV and ZIKV (strain MR766) infected brains, but an alternative lymphocyte-dominated infiltration in ZIKV (strain IBH) infected brains. In order to map changes to haematopoiesis during infection, we applied the same approach to the BM during WNV or ZIKV infection. By comprehensively mapping haematopoietic pathways in the BM in steady state and inflammatory conditions, we revealed that viral encephalitis drives a reorganisation of cellular output to favour monocyte production, resulting in activation and expansion of monocytes and monocyte progenitors, with increased proliferation of mature and progenitor populations. In addition, we observed compensatory downregulation of B cell lymphopoiesis, and modification of granulopoiesis in the BM, favouring monocyte expansion. Antibody blockade of various cytokine factors resulted in a reduction of this excessive monocyte proliferation, and in some cases resulted in improved clinical outcomes and reduce cellular infiltration in the brain in WNV-infected mice. In this study we have used high-dimensional cytometry approaches to characterise modifications to the haematopoietic lineage during viral encephalitis that favour production of pathogenic monocytes. Based on these results, we sought to further explore how other models of inflammation might drive alternative changes to different aspects of the haematopoietic system. As such, we examined changes to the haematopoietic system in two models of inflammation. Firstly, we used a mouse model of peripheral infection with lymphocytic choriomeningitis virus (LCMV), resulting in an acute system viral infection. Secondly, we used a mouse model of pulmonary emphysema (PE), which results in chronic, long-term, non-infectious inflammation, with heavy neutrophil and macrophage infiltration into the inflamed lung. In addition to the baseline LCMV model, we were able to utilise a range of genetic knock out mice, which we used to further perturb the haematopoietic system. Whilst monocyte expansion featured prominently in both cases, similar to viral encephalitis, we found notably differences in each model. In the emphysema model, we found differences in monocyte and neutrophil amplification over time, consistent with different phases of disease. Additionally, where B cell lymphopoiesis was severely suppressed in viral encephalitis, B cell proliferation was not suppressed in the emphysema model, despite some modifications to the B cell compartment. Systemic infection with LCMV drove monocyte-dominant changes to the haematopoietic system, as expected. However, mice that had genes related to the IFN system removed exhibit a drastic shift towards granulopoiesis in infected animals only. This dramatic shift also resulted in the appearance of extremely immature granulocytes in infected tissues. Additionally, in stat1 knock out mice, LCMV infection resulted in complete ablation of erythropoiesis in the BM, despite normal numbers of erythrocytes in the blood. In summary, whilst myeloid responses dominated in both scenarios, we found that the re- organisation of haematopoietic priorities was determine both by the severity and acuity of inflammation, as well as on the local signalling environment.
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Baum, Rebecca A. "Cytosolic and Endosomal DNA-Sensing Pathways Differentially Regulate Inflammatory Arthritis, Autoantibody Production, and Bone Remodeling: A Dissertation." eScholarship@UMMS, 2016. http://escholarship.umassmed.edu/gsbs_diss/828.
Full textAbstract:
Autoimmune diseases such as rheumatoid arthritis (RA) are associated with debilitating chronic inflammation, autoantibody production, articular bone erosions and systemic bone loss. The underlying mechanisms and cell types that initiate these diseases are not fully understood, and current therapies mainly address downstream mechanisms and do not fully halt disease progression in all patients. Moreover, previous studies have largely focused on the role of adaptive immunity in driving these diseases, and less attention has been given to the contribution of innate immune pathways such as DNA sensor signaling pathways in initiating and/or perpetuating autoimmunity and erosive inflammatory arthritis.
Detection of microbial nucleic acids by DNA sensors such as endosomal toll-like receptors (TLRs) and cytosolic sensors is an early form of antiviral defense. Upon detection of nucleic acid, TLRs dependent on Unc93B and cytosolic sensors dependent on the adaptor stimulator of interferon genes (STING) orchestrate production of type 1 interferons and pro-inflammatory cytokines to resolve infection. Additionally, the cytosolic DNA sensor absent in melanoma 2 (AIM2), which is not dependent on STING, also recognizes microbial DNA and coordinates the cleavage of pro-IL-1β. Previous studies have largely focused on the role of these DNA sensors in macrophages and dendritic cells in the context of antiviral immunity. In recent years, however, the inappropriate recognition of host nucleic acids by these sensors has been associated with several autoimmune diseases including RA.
This dissertation aims to delineate the mechanisms by which DNA sensors contribute to inflammatory arthritis and bone remodeling in the context of a murine model of autoimmunity. In DNase II deficient mice, excessive accrual of undegraded, endogenous DNA leads to robust production of type 1 interferons (IFNs) and proinflammatory cytokines. The high levels of type 1 IFNs result in anemia and embryonic lethality; therefore, the gene for the type 1 IFN receptor (IFNaR) has also been deleted so that the mice survive. DNase II-/- IFNaR-/- double knockout (DKO) mice develop erosive inflammatory arthritis, anti-nuclear antibodies, and splenomegaly not seen in the DNase II+/- IFNaR-/- (Het) control group. To evaluate whether cytosolic or endosomal DNA sensors contribute to the clinical manifestations of DKO mice, genes involved in TLR or cytosolic sensor signaling were deleted on the DKO background. Genetically altered mice include STING/DNaseII/IFNaR TKO (STING TKO), AIM2/DNase II/IFNaR TKO (AIM2 TKO), and Unc93b/DNase II/IFNaR TKO (Unc93 TKO) mice.
Our hypothesis was that the STING, AIM2, and/or Unc93 pathways would contribute to the autoimmune manifestations in DNase II deficient mice. Rigorous examination of inflammation in these lines revealed important roles for both the STING and AIM2 pathways in arthritis. Despite the substantial effects of the STING and AIM2 pathways on arthritis, STING TKO and AIM2 TKO mice still exhibited prominent autoantibody production. Interestingly, inflammation persisted in Unc93 TKO mice while autoantibody production to nucleic acids was abrogated. Collectively, these data indicate that innate immune pathways contribute to the initiation/perpetuation of inflammatory arthritis and demonstrate that cytosolic and endosomal pathways play distinct roles in the manifestations of autoimmunity. Moreover, they reveal a previously undescribed role for AIM2 as a sensor of endogenous nucleic acids in inflammatory arthritis. Thus, therapeutics that target the STING and AIM2 pathways may be beneficial for the treatment of inflammatory joint diseases.
While the role of hematopoietic cells in driving autoimmunity has been well established, the contribution of stromal elements to disease pathogenesis is less well understood. Therefore, we generated bone marrow chimeras to delineate the contribution of hematopoietic and non-hematopoietic cells to the various autoimmune manifestations in DKO mice. These studies revealed that both donor hematopoietic and host radioresistant cells are required for inflammation in the joint as well as for other features of autoimmunity in DKO mice, including splenomegaly, extramedullary hematopoiesis, and autoantibody production. This data demonstrates that stromal host cells play a major role in DNA-driven autoimmunity. Moreover, these results suggest that targeting not only hematopoietic but also stromal elements may be advantageous in the setting of inflammatory arthritis.
In the final chapter of this thesis, a role for innate immune sensor pathways in bone is described. The majority of inflammatory arthritides have been shown to lead to systemic loss of bone. Surprisingly, however, we found that DKO mice accumulate trabecular bone in the long bones over time as well as ectopic bone in the spleens, both sites of robust DNA accrual. Moreover, deficiency of the STING pathway abrogated this bone accumulation. Collectively, these data demonstrate that DNA accrual promotes dysregulated bone remodeling through innate immune sensing pathways. These findings are the first to reveal a role for the STING pathway in bone and may unveil novel targets for the treatment of diseases associated with bone disorders.
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Dutra, Paula GÃes Pinheiro. "Anti-resorptive effect of Sodium Alendronate and the combination of Alendronate and Atorvastatin in ligature-induced periodontitis in rats. PAULA." Universidade Federal do CearÃ, 2012. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=6953.
Full textAbstract:
FundaÃÃo Cearense de Apoio ao Desenvolvimento Cientifico e TecnolÃgico<br>Periodontal disease is an infectious-inflammatory disease, and drugs have been studied as modulators of this inflammatory process. In this context, this thesis, constituted by 3 articles had by objective: (1) Perform a review about the effect of Bisphosphonates (BPs) on periodontal disease; (2) Investigate the effect of Alendronate (ALD) on Bone-specfic Alkaline Phosphatase (BALP) on alveolar bone loss (ABL) in rats; (3) Evaluate the effect of ALD and Atorvastatin (ATV) combination on ABL in rats. On study 1, we sought in data basis, using the keywords âBisphosphonatesâ and âPeriodontitisâ, pre-clinical and clinical studies, published in English and Portuguese, in the last 10 years. On study 2, 36 Wistar male rats, submitted to ligature-induced periodontitis, received 0.9% Saline (SAL) or ALD on the doses of 0.01; 0.05; 0.25 mg/kg-s.c., 30 min before ligature placement and daily during 11 days. It was evaluated: ABL (morphometry and histology) serum levels of Bone-specific Alkaline Phosphatase (BALP), transaminases, and Total Alkaline Phosphatase (TAP); and leukogram and corporal mass. On study 3, 78 Wistar male rats, submitted to ligature-induced periodontitis, received prophylactically (P): SAL or ALD (0.01; 0.25 mg/kg-s.c) or ATV (0.3; 27 mg/kg-v.o.) or the combination ALD+ATV (0.25+27; 0.01+0.3; 0.25+0.3; 0.01+27 mg/kg), 30 min before ligature and daily for 11 days; or the combination ALD+ATV (0.01+0.3 mg/kg) administered therapeutically (T), from the 5th day after ligature until the sacrifice. It was evaluated: ABL [morphometry, histology, histometry; immunohistochemistry for tartrate resistant acid phosphatase (TRAP); myeloperoxidase (MPO); BALP, transaminases; Leukogram and corporal mass]. The study 1 showed that BPs presented anti-resorptive and anti-inflammatory effects, reduced FAO and Telopeptide N-terminal of type I collagen (NTx) and improved periodontal clinical parameters. On article 2, ALD (0.25 mg/kg) prevented BALP and ABL reduction, and did not alter transaminases serum levels, but reduced TAP serum levels (p<0.05), it reduced neutrophilia and lymphomonocytosis (p<0.05), without causing important loss of weight. On the 3rd study, the isolated treatments in high doses, and all combinations controlled ABL (p<0.05). Low doses combination of ALD+ATV controlled ABL (P [38.96%] or T [53.53%]). The histological, histometric (p<0.05) and immunohistochemical analysis corroborated macroscopical findings. The low dose combination of ALD+ATV reduced MPO activity, prevented BALP reduction, reduced neutrophilia and lymphomonocytosis (p<0.05), without altering transaminases serum levels and without causing loss of weight. In this way, we can conclude that BPs presented anti-resorptive and anti-inflammatory effects reduced levels of biochemical markers of bone metabolism and improved periodontal parameters. ALD, administered isolated prevented BALP and ABL reduction, without causing systemic problems, and the combination of ALD+ATV, in low doses, reduced ABL and periodontal inflammation, without causing important systemic alterations as well.<br>A doenÃa periodontal à uma desordem infecto-inflamatÃria, e fÃrmacos tÃm sido estudados como moduladores deste processo inflamatÃrio. Neste contexto, esta tese, constituÃda por 3 artigos, teve por objetivo: (1) Realizar uma revisÃo sobre o efeito de Bisfosfonatos (BFs) na doenÃa periodontal; (2) Investigar o efeito do Alendronato (ALD) nos nÃveis de Fosfatase Alcalina Ãssea (FAO) na perda Ãssea alveolar (POA) em ratos; (3) Avaliar o efeito da combinaÃÃo entre ALD e Atorvastatina (ATV) na POA em ratos. No estudo 1 buscou-se, em bases de dados, utilizando as palavras chave: âBisphosphonatesâ e âPeriodontitisâ, estudos prÃ-clÃnicos e clÃnicos, publicados em lÃngua Inglesa ou Portuguesa, nos Ãltimos 10 anos. No estudo 2, 36 ratos Wistar machos, submetidos à periodontite induzida por ligadura, receberam soluÃÃo Salina (SAL) 0,9% ou ALD nas doses de 0,01; 0,05; 0,25 mg/kg-s.c, 30 min antes da colocaÃÃo do fio e diariamente por 11 dias. Avaliou-se: POA (morfometria e histologia); nÃveis sÃricos de FAO, transaminases e Fosfatase Alcalina Total (FAT); Leucograma e Peso. No estudo 3, 78 ratos Wistar machos, submetidos à periodontite induzida por ligadura, receberam de forma profilÃtica (P): SAL ou ALD (0,01; 0,25 mg/kg-s.c) ou ATV (0,3; 27 mg/kg-v.o.) ou a combinaÃÃo ALD+ATV (0,25+27; 0,01+0,3; 0,25+0,3; 0,01+27 mg/kg), 30 min antes da ligadura e diariamente por 11 dias; ou ainda a combinaÃÃo ALD+ATV (0,01+0,3 mg/kg) na forma terapÃutica (T), ou seja administrada a partir do 5 dia apÃs ligadura, atà o sacrifÃcio. Avaliou-se: POA [morfometria, histologia, histometria; imunohistoquÃmica para fosfatase Ãcido tÃrtaro resistente (TRAP); mieloperoxidase (MPO); FAO, transaminases; Leucograma e Peso]. O artigo 1 mostrou que BFs apresentaram efeitos antirreabsortivo e anti-inflamatÃrio, reduziram FAO e TelopeptÃdeo N-terminal de colÃgeno tipo I (NTx) e melhoraram os parÃmetros clÃnicos periodontais. No artigo 2, o ALD (0,25 mg/kg) preveniu a reduÃÃo de FAO e POA, nÃo alterou nÃveis de transaminases, mas nÃo preveniu reduÃÃo dos nÃveis de FAT (p<0,05), preveniu neutrofilia e linfomonocitose (p<0,05), sem causar perda de peso importante. No 3 estudo, os tratamentos isolados, em altas doses, e todas as combinaÃÃes avaliadas controlaram POA (p<0,05). A combinaÃÃo de ALD+ATV em baixas doses controlou POA (P [38,96%] ou T [53,53%]). As anÃlises histolÃgicas, histomÃtricas (p<0,05) e imunohistoquÃmicas corroboraram os achados macroscÃpicos. A combinaÃÃo de ALD+ATV em baixas doses reduziu a atividade de MPO, preveniu reduÃÃo de FAO, reduziu neutrofilia e linfomonocitose (p<0,05), sem alterar os nÃveis de transaminases e causar perda de peso. Desta forma conclui-se que os BFs apresentaram efeitos antirreabsortivo e anti-inflamatÃrio, reduziram nÃveis de marcadores bioquÃmicos do metabolismo Ãsseo e melhoraram os parÃmetros clÃnicos periodontais. O ALD, administrado isoladamente, preveniu reduÃÃo de FAO, POA, sem repercussÃes sistÃmicas e a combinaÃÃo de ALD+ATV, em baixas doses, reduziu POA e inflamaÃÃo periodontal, tambÃm sem causar alteraÃÃes sistÃmicas importantes.
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Slocombe, Tom. "Control of plasma cell generation and population dynamics." Thesis, University of Edinburgh, 2012. http://hdl.handle.net/1842/7646.
Full textAbstract:
Plasma cells, the effector stage of the B cell compartment, secrete large amounts of antibody. These cells arise in two waves during T-‐dependent immune responses; an early wave (extrafollicular plasma cells) generate low-‐affinity antibodies that provide a first line of defence against invading pathogens. Later, plasma cells emerge from the germinal centre reaction and secrete high-‐affinity antibodies. These plasma cells have the capacity to migrate to the bone marrow, where they become established as long-‐lived, non-‐dividing plasma cells. Here, I show that plasma cells found in the bone marrow of young (5-‐week-‐old) mice had a turnover comparable to that seen in the spleen. Long-‐lived plasma cells accumulated over the ensuing weeks until they came to dominate the bone marrow plasma cell compartment by 30-‐weeks of age. This accumulation required MHC II, CD40 and a normal B cell receptor repertoire, implying that these cells are generated during T-‐dependent immune responses. Secondly, I determine the signalling pathways required to generate splenic extrafollicular plasma cell responses in the T-‐dependent response to sheep red blood cells (SRBC) and in bacterial infection with Salmonella. While T cell help, antigen recognition through the B cell receptor (BCR) and TLR signalling were required for maximal plasma cell responses to SRBC, in Salmonella infection TLR signalling was required for day 4 IgM plasma cell responses, whereas class-‐ switched responses at day 8 required T cell help. The extrafollicular responses generated in Salmonella persisted for around 35 days, far greater than the 2-‐3 days seen following SRBC immunisation. This was likely due to both antigen persistence causing the generation of new plasma cells, and the induction of cellular populations that produced the plasma cell survival factor APRIL. Thirdly, I document the failure of chronic immune responses to generate long-‐ lived bone marrow plasma cells. This was accomplished by measuring the generation and survival of bone marrow plasma cells in models of rheumatoid arthritis (K/BxN mice), long-‐term infection with Salmonella, and a direct comparison between acute and chronic delivery of the T-‐dependent protein antigen NP-‐KLH. In all cases, chronic immune responses generated few bone marrow plasma cells, ostensibly due to a failure to migrate to the organ. Finally, I show the depletion of bone marrow plasma cell populations caused by inflammatory episodes. This was observed in Salmonella infection, Schistosoma mansoni infection and immunisation with protein antigen plus adjuvants. This depletion mediated a reduction of antigen-‐specific bone marrow plasma cell populations and serum antibody previously established by the secondary response to NP-‐KLH.
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Pickworth, Josephine. "Links between dysfunctional Bone Morphogenetic Protein signalling and Interleukin-1ß mediated inflammation in pulmonary arterial hypertension." Thesis, University of Sheffield, 2017. http://etheses.whiterose.ac.uk/18607/.
Full textAbstract:
Rationale: Bone morphogenetic protein receptor type 2 (BMPR2) mutations are present in up to 70% of patients with heritable and up to 25% with idiopathic pulmonary arterial hypertension, however penetrance within families with the same mutation is low implying the necessity for a ‘second hit’. Inflammatory cytokines are raised in patients with PAH, and in animal models have been shown to play a modulating role in disease pathogenesis. Objective: To determine whether there is a pulmonary specific interplay between BMPR2 deficiency and inflammatory Interleukin 1ß (IL-1ß) signalling that may explain the local manifestation of PAH in the lung. Methods and Results: mRNA microarray analysis of RNA isolated from pulmonary artery (PASMC) and aortic (AoSMC) smooth muscle cells demonstrated reduced inflammatory pathway activation in response to IL-1ß in PASMC compared with AoSMCs. However, further microarray analysis of PASMCs analysis demonstrated an exaggerated inflammatory response to IL-1ß upon loss of BMPR2 signalling. To determine whether IL-1ß supplementation would exacerbate disease phenotype on the background of a BMPR2 mutation, R899X+/- BMPR2 transgenic mice fed western diet for six weeks were given daily injections of IL-1ß. IL-1ß treated mice had higher white blood cell counts, demonstrating effective administration of IL-1ß. Raised serum protein levels of Interleukin-6 and Osteoprotegerin recapitulating in vitro PASMC data. Phenotypically, IL-1ß treated mice demonstrated a significant increase in pulmonary vascular remodelling. Conclusion: IL-1ß induces a pulmonary artery-specific transcriptome that is altered by suppression of BMPR2 signalling in vitro. In vivo and in vitro IL-1ß drives an exaggerated inflammatory response under conditions where BMPR2 signalling is reduced.
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Hyzy, Sharon Leigh. "Adverse effects of bone morphogenic protein-2 during osseointegration." Thesis, Georgia Institute of Technology, 2012. http://hdl.handle.net/1853/44728.
Full textAbstract:
Modifications of biomaterial surface properties are employed to increase osteoblast differentiation and bone formation. Microtextured metallic surfaces promote osteoblast differentiation and high surface energy- achieved by controlling surface hydrocarbon contamination- increases osteoblast differentiation and peri-implant bone formation. Recombinant human bone morphogenic protein 2 (BMP2) is approved to induce bone formation in a number of applications. It is used clinically in combination with biomaterials to improve peri-implant bone formation and osseointegration. The amount of BMP2 that is required is large and inflammatory (swelling/seroma) and bone-related (ectopic bone/bone resorption) complications have been reported after BMP2 treatment. The aim of this study was to examine potential deleterious effects of BMP2 on the inflammatory environment and apoptosis of osteoblasts.
Surface roughness and energy decreased pro-inflammatory interleukins and increased anti-inflammatory interleukins. In contrast, BMP2 abolished the surface effect, increasing pro-inflammatory interleukin (IL) 6, IL8, and IL17 in a surface roughness-dependent fashion and decreasing anti-inflammatory IL10 on rough surfaces. 5Z-7-Oxozeaenol and Dorsomorphin, but not H-8, blocked the effect of BMP2 on IL1A expression. There was an increase in expression of IL6 when treated with BMP2 for the control and H-8 groups, but both 5Z-7-Oxozeaenol and Dorsomorphin blocked the effect. Both 5Z-7-Oxozeaenol and H-8 blocked the effect of BMP2 on IL10 expression.
BMP2 treatment had little effect on apoptosis in human mesenchymal stem cells (MSCs). Exogenous BMP2 had no effect on TUNEL. Caspase-3 activity was increased only at 200ng/ml BMP2. BAX/BCL2 decreased in MSCs treated with 50 and 100ng/ml BMP2. In contrast, BMP2 increased caspase-3 activity and TUNEL at all doses in normal human osteoblasts (NHOst). BAX/BCL2 increased in NHOst treated with BMP2 in a dose-dependent manner. Cells treated with 200 ng/ml BMP2 had an 8-fold increase in BAX/BCL2 expression in comparison with untreated cells. Similarly, BMP2 increased DNA fragmentation in NHOst cells. The BMP2-induced increase in DNA fragmentation was eliminated by 5-Z7-Oxozeaenol and Dorsomorphin.
The results suggest that while surface features modulate an initial controlled inflammatory response, the addition of BMP2 induces a pro-inflammatory response. The effect of BMP2 on apoptosis depends on cell maturation state, inducing apoptosis in committed osteoblasts. BMP2 together with microtextured orthopaedic and dental implants may increase inflammation and possibly delay bone formation. Dose, location, and delivery strategies are important considerations in BMP2 as a therapeutic and must be optimized to minimize complications.
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Leyland, R. J. "Lineage relationship analysis of lymphoid progenitor subsets in the bone marrow of naïve mice and during inflammation." Thesis, University College London (University of London), 2011. http://discovery.ucl.ac.uk/1322960/.
Full textAbstract:
During haematopoiesis multipotent stem cells generate all cellular components of the blood including lymphocytes. Despite great progress in the isolation of lineage restricted progenitors, the exact precursor-product relationship of these subsets remains poorly understood. In particular the exact branch point of T- and B-cell development in the bone marrow has not been unequivocally mapped. The aim of my project was to investigate the developmental relationship of various progenitor subsets in normal mice and during an acute inflammation. In order to permanently identify all cells which emanated from early lymphoid compartments we generated a mouse model in which a Cre recombinase was inserted into the Rag1 locus and functional Cre activity would result in activation of an eYFP reporter. Expression of the reporter was found in all T- and B-cells and in a significant subset of NK-cells and dendritic cells. Furthermore this model allowed the prospective isolation of an ‘ELP analogue’ and two subsets of CLPs on the basis of their reporter expression. Functional analysis of these subsets in vivo demonstrated comparable developmental properties with slightly different kinetics. Furthermore, in vitro analysis of isolated progenitors established that reporter-positive CLPs were significantly more advanced in their commitment to the B-cell lineage. We extended our studies by investigating the impact of an acute systemic inflammation on the size and composition of early haemato-lymphoid subsets. Administration of LPS or heat-inactivated E. coli to mice in vivo resulted in a complete halt of bone marrow lymphopoiesis. In addition, a marked decrease in the number of myeloid progenitors accompanied by upregulation of Sca-1 on haematopoietic progenitors was observed. These inflammation-induced changes were found to be mainly caused by IFNγ and to a lesser extend by TNFα, thus identifying these cytokines as key mediators for the infection-induced regulation of haematopoiesis.
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Wiebe, Edgar [Verfasser]. "The role of endogenous glucocorticoid signaling in osteoblasts on inflammation and bone destruction by autoimmune arthritis / Edgar Wiebe." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2021. http://d-nb.info/1241541612/34.
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Karlsson, Marjam. "Nano-porous Alumina, a Potential Bone Implant Coating." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis, 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-4452.
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Díez, Tercero Leire. "Modulation of the inflammatory response using a guided bone regeneration membrane with dual drug delivery capacity." Doctoral thesis, Universitat Internacional de Catalunya, 2021. http://hdl.handle.net/10803/671867.
Full textAbstract:
Bone is a complex and dynamic tissue that fulfills several critical functions such as
protecting vital organs including the brain, heart and lungs; providing sites of attachment
for muscles to allow movement and maintaining ion homeostasis. Moreover, bone has a
remarkable regenerative capacity which allows the complete healing of the tissue upon
damage. However, this capacity can be exceeded when the size of the defect is too large
due to clinical procedures such as tumor resection or the presence of traumatic fracture
or osteolysis, which constitute a significant clinical challenge nowadays. Autologous grafts,
as well as allografts and xenografts present several limitations to their clinical application
such as limited bone supply, disease transmission and ethical issues. Therefore, tissue
engineering combining biomaterials and stimulatory molecules to guide bone
regeneration presents as an alternative to these methods.
Recent advances in bone biology have shown that osteogenesis occurs due to the
interaction of multiple systems and not only by the actions of the bone tissue. In this
sense, the immune system has gained great importance since the inflammatory response
promoted by either tissue damage or the immune recognition of the implanted
biomaterial can direct the outcome of the bone healing response. More precisely,
macrophages have been described to have a central role in bone regeneration. Their
differentiation to a pro-inflammatory phenotype (M1) phenotype can lead to the
development of chronic inflammation, which impairs bone healing, whereas their
differentiation to an anti-inflammatory phenotype (M2) can lead to enhanced biomaterial
integration and improved bone regeneration. Therefore, the design of biomaterials has
focused on modulating macrophage differentiation to M2 phenotype to improve bone
regeneration.
One of the approaches to modulate macrophage response has been the release of antiinflammatory
modulators such as cytokines, viral vectors or siRNAs. However, their short
half-life and concerns in their efficiency in cellular uptake, as well as long term safety limit
VI
their clinical application. Ions have risen as a promising alternative since they are stable
cues which are present at low concentrations in the body and have already shown
benefits on angiogenesis and bone regeneration when delivered from scaffolds. However,
there are limited evidences showing their immunomodulatory potential.
This thesis is focused on modulating macrophage response by developing a dual drug
delivery system with the ability to release ions, as well as small drugs, to promote the M2
macrophage phenotype. First, an initial screening of three bioactive ions was performed
to determine the cytotoxic and therapeutic concentrations in macrophages. Those
concentrations that induced macrophage differentiation towards the M2 phenotype were
tested in presence of different concentrations of a pro-inflammatory stimulus, which
allowed to determine the anti-inflammatory potential of these ions. Then, the effect of
the ions combined with an anti-inflammatory drug was tested in macrophages to observe
a possible synergistic effect between both molecules, although no major differences were
observed compared to the effect of the drug alone.
Following these assays, the dual drug delivery system was developed, which consisted of a
collagen film with ion loaded microparticles and drug loaded microspheres. The results
showed that these films not only were able to release controlled concentrations of the
ion, but they were also able to perform a sustained release of the drug. Finally,
macrophages and mesenchymal stem cells (MSCs) were exposed to the films, showing
that they were able to induce M2 macrophage differentiation and osteogenesis.
Moreover, treating MSCs with conditioned media from film-induced M2 macrophages
further improved the osteogenic differentiation.<br>El hueso es un tejido complejo y dinámico que cumple varias funciones críticas como la
protección de órganos vitales como el cerebro, el corazón y los pulmones; permite el
movimiento del cuerpo humano proporcionando sitios de unión para los músculos; y el
mantenimiento de la homeostasis iónica. Además, el hueso tiene una notable capacidad
regenerativa que permite la curación completa del tejido en caso de que haya habido
alguna lesión. Sin embargo, la capacidad regenerativa del hueso puede verse sobrepasada
cuando el tamaño del defecto es demasiado grande, lo que ocurre en procedimientos
clínicos como la resección tumoral, ciertas fracturas o en situaciones en las que hay
osteolisis. Los injertos autólogos, así como los aloinjertos y los xenoinjertos presentan
varias limitaciones para su aplicación clínica, entre las que se encuentran la disponibilidad
de suficiente cantidad de hueso, la transmisión de enfermedades y los problemas éticos.
Por tanto, la ingeniería de tejidos se presenta como una alternativa a estos métodos,
combinando biomateriales y moléculas que guíen la regeneración ósea.
Avances recientes en biología ósea han demostrado que la osteogénesis se produce
debido a la interacción de múltiples sistemas y no solo por las acciones del tejido óseo. En
este sentido, el sistema inmune ha ganado una gran importancia, ya que la respuesta
inflamatoria causada por el daño tisular o el reconocimiento del biomaterial implantado
por parte del sistema inmune pueden influenciar el resultado de la regeneración ósea.
Concretamente, se ha descrito que los macrófagos tienen un papel central en la
regeneración ósea. Su diferenciación a un fenotipo pro-inflamatorio (M1) puede conducir
al desarrollo de inflamación crónica, que afecta negativamente a la regeneración ósea,
mientras que su diferenciación a un fenotipo anti-inflamatorio (M2) puede derivar en una
mayor integración del biomaterial y en una mejora de la regeneración ósea. Por tanto, el
diseño de biomateriales se ha centrado en favorecer la diferenciación de macrófagos
hacia el fenotipo M2 con el fin de promover la regeneración ósea.
Una de las estrategias para lograrlo ha sido la liberación de moléculas anti-inflamatorias
como citocinas, vectores virales o siRNA. Sin embargo, su corta vida media, así como las
VIII
dudas en cuanto a la eficiencia en la absorción celular y su seguridad a largo plazo de estos
sistemas, limitan su aplicación clínica. Los iones han surgido como una alternativa
prometedora, ya que son señales estables que están presentes en concentraciones bajas
en el cuerpo y ya han mostrado beneficios en la angiogénesis y la regeneración ósea
cuando se incorporan dentro de biomateriales. Sin embargo, existen evidencias limitadas
que muestran su potencial inmunomodulador.
Esta tesis se centra en el desarrollo de un sistema de administración de fármacos dual con
la capacidad de liberar iones, así como fármacos pequeños, para promover el fenotipo M2
en macrófagos, modulando así la respuesta inmune. En primer lugar, se realizó una
selección inicial de tres iones bioactivos y se determinaron las concentraciones citotóxicas
y terapéuticas en macrófagos. Aquellas concentraciones que indujeron la diferenciación
de macrófagos hacia el fenotipo M2 se probaron en presencia de diferentes intensidades
de un estímulo pro-inflamatorio, lo que permitió determinar el potencial anti-inflamatorio
de estos iones. Luego, se trató de determinar si podría haber un efecto sinérgico en la
diferenciación de los macrófagos cuando estos iones se combinaran con un fármaco
antiinflamatorio, aunque no se observaron diferencias importantes en comparación con el
efecto del fármaco solo.
Después de estos ensayos, se desarrolló el sistema de administración dual de fármacos,
que consistía en una membrana de colágeno con micropartículas cargadas de iones y
microesferas cargadas de fármaco. Los resultados mostraron que estas membranas no
solo pudieron liberar concentraciones controladas del ión, sino que también pudieron
realizar una liberación sostenida del fármaco. Finalmente, se cultivaron macrófagos y
células madre mesenquimales (MSC) en contacto con las membranas, y se pudo
demostrar que eran capaces de inducir la diferenciación de los macrófagos hacia fenotipo
M2 y de promover la osteogénesis. Además, el tratamiento de las MSC con medios
condicionados procedentes de macrófagos M2 mejoró aún más la diferenciación
osteogénica.
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Orr, Yishay Medical Sciences Faculty of Medicine UNSW. "Circulating neutrophil activation and recruitment during the systemic inflammatory response to cardiac surgery with extracorporeal circulation." Publisher:University of New South Wales. Medical Sciences, 2008. http://handle.unsw.edu.au/1959.4/41227.
Full textAbstract:
Circulating neutrophil activation occurs during cardiac surgery with extracorporeal circulation (ECC) and is implicated in the pathophysiology of inflammatory tissue injury and peri-operative organ dysfunction. However, neutrophil directed antiinflammatory strategies have failed to demonstrate consistent therapeutic benefit indicating that the nature and significance of peri-operative circulating neutrophil activation remains incompletely defined. In particular, conformational activation of the b2 integrin Mac-1 (CD11b/CD18), which is required for neutrophil adhesion competence and facilitation of effector functions, has not previously been investigated during cardiac surgery, and the relative contribution of cellular activation and bone marrow neutrophil recruitment to peri-operative changes in circulating neutrophil phenotype and function is unknown. A novel whole blood flow cytometric technique was used to analyze circulating neutrophil phenotype (total Mac-1, conformationally-active CD11b, CD10, CD16, L-selectin and P-selectin glycoprotein ligand-1) and function in cardiac surgery patients to characterize the nature of changes in Mac-1 expression and activation status, and the effects of relative neutrophil immaturity on circulating neutrophil phenotype and function. The effect of heparin, a known CD11b ligand, on Mac-1 epitope expression was also investigated. Circulating neutrophil numbers observed during ECC were mathematically modeled to determine the acute response of the bone marrow neutrophil reserve to an inflammatory stimulus. Plasma cytokine, chemokine and acute phase mediators were measured in cardiac and lung surgery patients to determine potential regulators of systemic neutrophil recruitment. Neutrophils newlyemergent from the bone marrow were characterized as CD10-/CD16low and exhibited distinct changes in cell surface markers and enhanced functional responses, relative to their more mature CD10+ counterparts. Conformational activation of CD11b occurred peri-operatively and provided a more sensitive measure of circulating neutrophil activation status than changes in total Mac-1 or L-selectin expression, although detection of Mac-1 epitopes was reduced in the presence of heparin. Modeling of circulating neutrophil numbers predicted that post-mitotic maturation time was acutely abbreviated by 8.4 hours during 71 minutes of ECC. Systemic chemokine release occurred with cardiac but not non-cardiac thoracic surgery indicating some specificity of the acute inflammatory response. These findings expand the understanding of peri-operative circulating neutrophil activation and recruitment, and identify potential therapeutic targets to limit neutrophil injurious potential during cardiac surgery with ECC.
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Matzelle, Melissa M. "Inflammation Inhibits Osteoblast-Mediated Bone Formation in Rheumatoid Arthritis and Regulates the Wnt and BMP Signaling Pathways: A Dissertation." eScholarship@UMMS, 2012. https://escholarship.umassmed.edu/gsbs_diss/596.
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Osteoclast-mediated focal articular bone erosion is a hallmark of rheumatoid arthritis, a disease of inflammation-induced bone loss. Inflammation in the bone microenvironment enhances osteoclast differentiation leading to bone erosion. Simultaneously, inflammation also inhibits osteoblast-mediated bone formation, further contributing to the net loss of bone. Previous studies have shown a paucity of mature osteoblasts at eroded bone surfaces correlating with suppression of bone formation and upregulation of antagonists of the Wnt pathway, a signaling cascade essential for osteoblast lineage commitment. Despite these observations, the exact pathogenesis of impaired bone formation in the setting of inflammation is not clearly understood.
This dissertation aims to delineate the mechanisms by which inflammation suppresses osteoblast differentiation and activity in inflammatory arthritis. Specifically, this research elucidates how inflammation-induced alterations in the Wnt and bone morphogenetic protein (BMP) osteogenic signaling pathways contribute to bone loss and formation at distinct inflammatory microenvironments within the bone. Secondly, the means by which cellular mediators, including lymphocytes and macrophages, facilitate bone erosion and formation was addressed.
Taken together, the research in this dissertation underscores the relationship between inflammation-induced bone loss and alterations in osteogenic signaling. Using an innovative murine inflammatory arthritis model, this study definitively demonstrates that resolving inflammation promotes osteoblast-mediated bone formation. Repair of erosions correlates with upregulation of synovial expression of Wnt10b, a Wnt agonist, and downregulation of sFRP1 and sFRP2, Wnt antagonists. This work also directly evaluates the contribution of sFRP1 to inflammation-induced bone destruction. Furthermore, this research demonstrates that expression of BMP3, a negative regulator of BMP signaling, is upregulated in osteoblasts by IL-17, a pro-inflammatory cytokine. BMP3-expressing osteoblasts are also observed at erosion sites in murine arthritis. Lastly, evaluation of the mediators of inflammation-induced periosteal bone formation implicates BMP2 as a means by which inflammation may positively regulate osteoblast function.
This dissertation further elucidates the role of T cells and macrophages in the erosion and formation processes, respectively. In the absence of lymphocytes, bone erosion occurred normally, demonstrating that RANKL-expressing lymphocytes are not absolutely required for the bone erosion. Preliminary studies also suggest that M2 macrophages are potential mediators of bone formation via the expression of BMP2.
In conclusion, this dissertation explores the ability of inflammation to act as a rheostat, which controls the fate of bone by modulating not only osteoclast differentiation, but also osteogenic signaling pathways and cellular mediators in the bone microenvironment. The soluble mediators and cell types identified in this research highlight novel mechanisms by which inflammation may regulate osteoblast activity within the bone microenvironment. Collectively, these data imply that strict control of inflammation may be necessary in order to create an anabolic environment that preserves bone architecture in diseases of inflammation-induced bone loss.
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Park, John E. S. "The pulmonary endothelium contributes to inflammation in chronic heart failure : the role of mechanical strain and bone morphogenetic protein-9." Thesis, Imperial College London, 2010. http://hdl.handle.net/10044/1/9069.
Full textAbstract:
Chronic heart failure (CHF) is a debilitating condition with a poor prognosis. Remodelling of the alveolar capillary membrane (ACM) protects against pulmonary oedema, but also results in dyspnoea and a worsened prognosis. Systemic inflammation associated with CHF contributes to the pathophysiology and mortality of the syndrome. Monocyte chemoattractant protein (MCP)-1, a CC chemokine, is elevated in patients with CHF and associated with increased mortality. Also, deficiencies in the bone morphogentic protein receptor (BMPR) signalling contribute to the pathophysiology of vascular remodelling in pulmonary arterial hypertension (PAH), and similar changes are seen in CHF. The mechanisms underlying lung remodelling and inflammation in CHF are not known. This thesis investigated the contribution of the pulmonary endothelium to inflammation and ACM remodelling in CHF. We hypothesised that pulmonary venous hypertension (PVH) in CHF imparts mechanical strain at the ACM stimulating the release of mediators, contributing to lung remodelling. To model PVH cyclic mechanical strain (CMS) was applied to monolayers of human lung microvascular endothelial cells (HLMVEC) and to an endothelial cell line (EaHy 926). MCP-1 was identified as a stretch-induced inflammatory mediator whose induction was dependent on activation of the extracellular signal-related kinase (ERK 1/2) pathway. Supernatants from stretched compared to non-stretched cells increased fibroblast and pulmonary smooth muscle cell proliferation, and fibroblast differentiation. Bone morphogenetic protein (BMP)-9 stimulated pulmonary arterial endothelial cells to release endothelin-1 (ET-1) in a Smad-independent, p38MAPK-dependent, manner. In a rodent heart failure model, animals subjected to left coronary artery ligation had increased levels of MCP-1 in whole lung, serum and bronchoalveolar lavage. Animals treated with gene therapy (SERCA2a) demonstrated functional rescue with attenuated release of MCP-1 and ET-1. These data support a role for pulmonary ECs in inflammation and remodelling in CHF. Increased understanding of lung remodelling may lead to improved management of dyspnoea for CHF sufferers.
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Monteiro, Larice KÃrcia Braz. ""Efeitos anti-inflamatÃrio e antirreabsortivo Ãsseo da Punica granatum l. combinada ou nÃo com laser de baixa intensidade na perda Ãssea induzida por ligadura em ratosâ." Universidade Federal do CearÃ, 2013. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=10787.
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CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior<br>A periodontite à uma doenÃa infecto-inflamatÃria crÃnica caracterizada por intensa perda Ãssea. P. granatum (PNG) e IrradiaÃÃo com Laser de Baixa Intensidade (ILBI) tÃm demonstrado propriedades anti-inflamatÃrias e antioxidantes. O objetivo deste estudo foi avaliar as atividades anti-inflamatÃria e antirreabsortiva Ãssea da PNG combinada ou nÃo com ILBI na periodontite induzida por ligadura em ratos. A periodontite foi induzida em 72 ratos Wistar atravÃs da inserÃÃo de um fio de nylon-3.0 em torno do segundo molar superior esquerdo. A hemimaxila contralateral foi utilizada como controle. Grupos de 6 animais receberam soluÃÃo salina 0,9% (SAL), SAL+ILBI 4 J/cm2, PNG (60, 180, 540) mg/kg ou combinaÃÃo de PNG 540 mg/kg+ILBI 4 J/cm2. O laser de baixa intensidade GaAlAs foi aplicado imediatamente apÃs a cirurgia, enquanto a PNG foi administrada, por gavagem, diariamente, atà o 11 dia, quando, entÃo, os animais foram mortos, suas maxilas removidas e processadas para anÃlises macroscÃpica, histomÃtrica, histolÃgica e marcaÃÃo imunohistoquÃmica para TRAP. Amostras de tecido gengival foram obtidas para avaliaÃÃo da atividade de mieloperoxidase (MPO). Foram coletadas amostras de sangue para dosagem dos nÃveis sÃricos de fosfatase alcalina Ãssea (FAO), leucograma e anÃlise das funÃÃes hepÃtica e renal. Adicionalmente, os Ãndices hepÃtico e renal foram realizados. Os ratos foram pesados diariamente. A induÃÃo da periodontite causou intensa perda Ãssea alveolar (POA), reduÃÃo sÃrica da FAO, destruiÃÃo do ligamento periodontal e do cemento, e intensa infiltraÃÃo leucocitÃria. Sistemicamente, a periodontite induziu leucocitose e nÃo causou alteraÃÃes nos nÃveis sÃricos de transaminases hepÃticas, ureia ou creatinina, bem como nos Ãndices hepÃtico e renal. A POA foi prevenida significantemente por PNG (60= 34%, 180= 34%, 540= 42%), SAL+ILBI= 31% e PNG 540+ILBI= 48% (p<0.05). PNG 540 combinada ou nÃo com ILBI preveniu a perda Ãssea alveolar, a infiltraÃÃo leucocitÃria e preservou o periodonto de maxilas nas quais a periodontite foi induzida. Animais tratados com PNG 540+ILBI mostraram significante reduÃÃo na imunomarcaÃÃo positiva para TRAP (Periodonto NÃo desafiado=0,0  0,0; SAL= 0,016  0,004; SAL+ILBI= 0,01  0,003; PNG 540= 0,011  0,003; PNG 540+ILBI= 0,002  0,0003). O aumento da atividade de MPO foi prevenido por PNG (60= 46%, 180= 49%, 540= 76%), SAL+ILBI= 54% e PNG 540+ILBI= 80% (p<0.05). Embora a reduÃÃo da FAO observada no grupo salina nÃo tenha sido prevenida por PNG ou SAL+ILBI (p>0,05), PNG 540+ILBI causou um aumento significante nos nÃveis sÃricos de FAO (74,2  5,4 U/l), quando comparado ao SAL (44,9  3,0 U/l) (p<0,05). Nenhum grupo apresentou mudanÃas significantes nos nÃveis sÃricos de transaminases hepÃticas, ureia ou creatinina ou nos respectivos Ãndices hepÃtico e renal (p>0,05), e todos os grupos preveniram (p<0,05) a leucocitose quando comparada ao grupo SAL. Em suma, PNG combinada ou nÃo com ILBI reduziu a infiltraÃÃo leucocitÃria e o nÃmero de neutrÃfilos alÃm de reduzir a perda Ãssea alveolar, à custa da inibiÃÃo da ativaÃÃo de osteoclastos, sem causar alteraÃÃes sistÃmicas importantes<br>Periodontitis is a chronic infectious inflammatory disease. P. granatum (PNG) and low level laser irradiation (LLLI) have demonstrated anti-inflammatory properties and antioxidants. The aim of this study was to evaluate the anti-inflammatory and bone antiresorptive activities of PNG combined or not with LLLI in ligature-induced periodontitis in rats. Periodontitis was induced in 72 rats by inserting a nylon-3.0 around the left upper second molar. The contralateral hemimaxila was used as control. Groups of 6 animals received saline 0.9% (SAL), SAL+LLLI 4 J/cm2, PNG [60, 180, 540 (mg/kg)] or PNG 540 mg/kg+LLLI 4 J/cm2. The low intensity laser GaAlAs was applied immediately after surgery, while PNG was administered by gavage daily until day 11, when the animals were killed. The jaws were removed and processed for macroscopic, histometric, histological and immunohistochemical staining for TRAP. Gingival tissue samples were obtained to evaluate the activity of myeloperoxidase (MPO). Blood samples were collected for measurement of serum bone alkaline phosphatase (BALP), leukograms and analysis of liver and kidney function. Additionally, indexes of liver and kidney were performed. Rats were weighted daily. Periodontitis induction caused intense alveolar bone loss (ABL), reduction of BALP, cementum and periodontal ligament destructions, and intense leukocyte infiltration. Systemically, periodontitis induced leukocytosis and and did not alter hepatic transaminases, urea or creatinine serum levels, or liver and kidney indexes. The ABL was prevented by PNG (60= 34%, 180= 34%, 540= 42%), SAL+LLLI= 31% e PNG 540+LLLI= 48% (p<0.05). PNG 540 combined or not with LLLI decreased the alveolar bone resorption, the leukocyte infiltration and preserved the periodontium in the jaws in which the periodontitis was induced. Animals treated with PNG 540+LLLI showed an important decreasing of TRAP positive immunostaining (Periodontium Unchallenged = 0.0  0.0, SAL= 0.016  0.004; SAL+LLLI= 0.01  0.003; PNG 540= 0.011  0.003; PNG 540+LLLI = 0.002  0.0003). The raise of MPO activity was prevented by PNG (60= 46%, 180= 49%, 540= 76%), SAL+LLLI= 54% e PNG 540+LLLI= 80% (p<0.05). In spite the reduction of BALP, seen in SAL group was not prevented by SAL+LLLI or PNG (p>0.05), the combined treatment with PNG 540+LLLI caused an increase on BALP serum levels (74.2  5.4 U/l), when compared to SAL (44.9  3.0 U/l) (p<0.05). No change was seen for hepatic transaminases, urea or creatinine serum levels, or in liver and kidney indexes, in all groups (p>0.05) and all groups prevented (p<0.05) the leukocytosis observed in SAL group. In short, PNG combined or not with LLLI reduced leukocyte infiltration and the number of neutrophils and reduced alveolar bone loss, at the expense of inhibiting osteoclast activation, without causing systemic changes
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Igel, Emily M. "Modulation of Atherosclerosis by Myeloid-derived Human apoE Isoforms or by Mutation of the Proximal Dileucine Motif of LRP1." University of Cincinnati / OhioLINK, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=ucin162766220865364.
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Melo, Bruno José Silva de. "Avaliação do efeito do análogo de glicocorticóide L5 na resposta inflamatória, na estrutura e biomecânica óssea e na composição corporal de camundongos fêmeas adultos." Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/42/42131/tde-06062014-111258/.
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Glicocorticóides são utilizados no tratamento de doenças auto-imunes e inflamatórias. Um novo composto, arilpirazola (L5) exibiu efeito antiinflamatórios e um perfil reduzido de efeitos colaterais. Avaliamos ações antiinflamatórias do L5 in vivo e os efeitos do L5 na estrutura e biomecânica ósseas em camundongos C57BL/6J. Prednisolona (Pred) e L5 reduziram o número de total leucócitos na dose de 2,1 mg/kg.pc/dia e 2,4 mg/kg.pc/dia, respectivamente. A Pred reduziu a massa corporal e o L5. Pred e L5 promoveram aumento na massa do coração. A Pred promoveu redução na massa muscular, enquanto que o L5 não teve efeito. Pred e L5 não alteraram o tecido adiposo. Na análise por microtomografia computadorizada o tratamento com L5 diminuiu BV/TV, Tb/Sp e DA, já a Pred reduziu apenas Tb/Sp. Pred e L5 não promoveram alteração no osso cortical. Pred não alterou parâmetros biomecânicos do fêmur e da tíbia e L5 reduziu energia em quebra da tíbia. Este estudo sugere que o L5 tem o mesmo potencial anti-inflamatório da Pred e que não se mostrou deletério à massa muscular.<br>Glucocorticoids are used to treat autoimmune and inflammatory diseases. A new compound, arilpirazola (L5) exhibited anti-inflammatory effect and reduced side effect profile. We evaluated the anti-inflammatory actions in vivo L5 and L5 on the effects of structure and biomechanical bone in mice C57BL/6J. Prednisone (Pred) and L5 reduced the overall number of leukocytes in a dose of 2.1 mg/kg.pc/day and 2.4 mg/kg.pc/day, respectively. The Pred decreased body mass and not L5. Pred and L5 caused an increase in heart mass. The Pred promoted reduction in muscle mass, while the L5 had no effect. Pred and L5 did not alter adipose tissue. The analysis by computed microtomography treatment with L5 decreased BV/TV, Tb/Sp and DA, since the only Pred reduced Tb/Sp. Pred and L5 did not promote changes in cortical bone. Pred has not altered biomechanical parameters of the femur and tibia and L5 reduced energy breaks the tibia. This study suggests that the L5 have the same potential anti-inflammatory Pred and was not deleterious to the muscle.
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Douat, Estela Sant'Ana Vieira. "Estudo comparativo do efeito do ultra-som terapêutico de 1MHz com frequência de repetição de pulso a 100 Hz e 16 Hz no reparo de osteotomia por escareação em tíbia de rato." Universidade de São Paulo, 2004. http://www.teses.usp.br/teses/disponiveis/82/82131/tde-17012005-110907/.
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O objetivo deste trabalho foi comparar o efeito do ultra-som terapêutico de 1 MHz, nas freqüências de repetição de pulso de 100 Hz e 16 Hz (0,5 W/'CM POT.2' SATA), no processo de reparo de tíbia após osteotomia experimental. Neste trabalho foram utilizados 40 ratos machos albinos Wistar, divididos em 4 grupos experimentais: referência, controle, tratados com ultra-som terapêutico de 100 Hz (UST100) e 16 Hz (UST16). Os animais foram submetidos à fratura cirúrgica por escareação e, após 24 h, iniciou-se o tratamento com ultra-som terapêutico, por 6 dias consecutivos, durante 3 min ao dia. No 7° dia pós-cirúrgico foi realizada coleta de sangue através de punção cardíaca para quantificação dos níveis de fosfatase alcalina, em seguida os animais foram submetidos à eutanásia, a tíbia fraturada foi removida, radiografada e fixada para análise histológica. Para determinar a significância das diferenças observadas foi utilizada análise de variância (ANOVA). Os diâmetros da lesão da tíbia foram significativamente menores nos grupos UST100, UST16, respectivamente, em comparação ao grupo controle. O nível de fosfatase alcalina foi significativamente diferente nos grupos experimentais. A densidade de matriz óssea, fibroblastos, macrófagos, neutrófilos, linfócitos e vasos sangüíneos foram significativamente diferentes entre os grupos, indicando que o tratamento com ultra-som induziu o reparo ósseo. O tratamento com UST acelerou a fase aguda da recuperação óssea, sendo que, o UST com freqüência de repetição de pulso de 100 Hz demonstrou ser mais eficaz<br>The aim of this work was to compare the 1 MHz with pulse frequency repetition of 100 Hz and 16 Hz therapeutic ultrasound effect (0.5 W/'CM POT.2' SATA) in the repair process of the experimental tibia osteotomy. In this work we used 40 male albino Wistar rats divided into 4 experimental groups: reference; control; 100 Hz (UST100) and 16 Hz (UST16) therapeutic ultrasound-treated. The rats undergone bone surgical fracture and the ultrasound treatment started 24 h after the surgery, the treatment lasted for 6 days, during 3 min a day. The blood was sampled by cardiac punction for alkaline phosphatase level quantification at the 7th day after surgery, than the animals were euthanized, the fractured tibia was removed, analyzed by radiography and fixed for histological analysis. The statistical significance of the analyzed parameters was tested with the ANOVA test. The diameter of the tibia lesion decreased significantly in the UST100 and UST16 groups, respectively, as compared to the control group. The blood alkaline phosphatase level was significantly different among experimental groups. The bone matrix, fibroblasts, macrophages, neutrophils, lymphocytes, and blood vessels densities were significantly different among experimental groups, indicating that the ultrasound treatment induced the bone repair. The UST treatment accelerated the acute phase of bone recovery and UST with pulse repetition frequency of 100 Hz was the most effective treatment
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Koufany, Meriem. "Étude de la contribution des récepteurs activés par les proliférateurs de peroxysomes en physiopathologie articulaire." Thesis, Université de Lorraine, 2015. http://www.theses.fr/2015LORR0230/document.
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Les récepteurs activés par les proliférateurs de peroxysomes (PPARs) sont des facteurs de transcription impliqués dans la régulation du métabolisme lipidique et de la tolérance au glucose. Les PPARs contrôlent également l’inflammation associée à de multiples pathologies, dont la polyarthrite rhumatoide. Dans les travaux présentés dans ce manuscrit, nous avons comparé les potentialités anti-arthritiques, dans un modèle expérimental, de deux agonistes synthétiques de haute affinité pour deux isotypes de PPARs, PPARα et PPARγ. Nous avons démontré qu’un traitement avec un agoniste sélectif de PPARγ, la pioglitazone, en plus de diminuer la sévérité de l’arthrite expérimentale, réduisait la perte osseuse inflammatoire en préservant la micro-architecture osseuse. Nous avons mis en évidence que PPARγ, d’une part, régulait l’expression locale et systémique de l’interleukine-17 et de RANKL, et que, d’autre part, il inhibait l’expression du facteur de transcription RORγt, acteur majeur de la voie IL-17/Th17. Les animaux déficients pour PPARγ nous ont permis de confirmer son rôle majeur dans le développement du processus arthritique. En effet, ces animaux présentent tous et de façon spontanée une arthrite associée à une augmentation du nombre de mastocytes capables de produire l’IL-17 et leur propre facteur de différenciation, le SCF dans la synoviale inflammatoire. Enfin, nous avons discuté le lien possible entre l'arthrite inflammatoire et la mastocytose à la lumière de l’étude d’un cas clinique d’un patient atteint de polyarthrite rhumatoïde concomitante à une mastocytose systémique<br>Peroxisome proliferator-activated receptors (PPARs) are transcription factors implicated in lipid metabolism and glucose tolerance. Once activated by specific agonists, PPARs control inflammation associated with numerous diseases, notably Rheumatoid arthritis. The first study presented here aim to compare the anti-arthritic potency of two high-affinity synthetic agonists for PPARα and PPARγ in an experimental model. Then we focused on the effect of pioglitazone, a high-affinity synthetic agonists for PPARγ, and demonstrated that a per os treatment with this agonist not only reduced experimental arthritis but also inhibited partly inflammation-related bone loss by preserving bone microarchitecture. We pointed out that PPARγ, on one hand, regulated local and systemic expression of interleukine-17 (IL-17) and RANKL and on the other hand, inhibited expression of transcription factor RORγt, a main regulator of IL-17/Th17 pathway. Study of mice deficient for PPARγ confirmed its major role in the development of the arthritic process since these mice developed spontaneously arthritis. Of interest arthritis in these mice is associated with increased number of synovial mast cells able to produce IL-17 and their own differenciation factor, the SCF. Finally, we discussed the possible link between inflammatory arthritis and mastocytosis in a case report of a patient suffering from rheumatoid arthritis concomitant to systemic mastocytosis
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Ruiz, Karina Fernandes. "Efeito do DMTI-II, um inibidor de Kunitz isolado das sementes de Dimorphandra molli na resposta inflamatória pulmonar alérgica em ratos." [s.n.], 2010. http://repositorio.unicamp.br/jspui/handle/REPOSIP/308917.
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Orientador: Edson Antunes<br>Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Medicas<br>Made available in DSpace on 2018-08-16T20:02:44Z (GMT). No. of bitstreams: 1
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Previous issue date: 2010<br>Resumo: DMTI-II é um inibidor de serinoproteinase do tipo Kunitz, isolado a partir das sementes de Dimorphandra mollis, uma árvore da família Leguminosae-Mimosoidea, com ampla distribuição nas regiões do cerrado brasileiro e popularmente conhecida por causar toxicidade em gados. Dados preliminares do nosso laboratório mostraram que DMTI-II causa um marcante influxo de eosinófilos após 4 horas de injeção, na cavidade peritoneal de ratos, um tempo no qual este tipo celular não é comumente observado com agentes inflamatórios clássicos. No sentido de ampliar nossos conhecimentos sobre o recrutamento eosinofílico em resposta ao DMTI-II, passamos a usar um modelo experimental no qual esta célula exerce papel fundamental, que é o de sensibilização e desafio com ovalbumina (OVA). O objetivo deste estudo é investigar os efeitos da exposição das vias áreas ao DMTI-II sobre o recrutamento de leucócitos para o pulmão de ratos sensibilizados e desafiados com OVA. Ratos Wistar foram sensibilizados através de injeção subcutânea de
OVA. Quatorze dias após, os ratos sensibilizados foram submetidos a instilações intranasais de DMTI-II (10 µg) ou PBS estéril (grupo controle). Após 2, 4 e 16 h de exposição ao DMTI-II, os animais foram desafiados com OVA. O lavado broncoalveolar (LBA), o sangue e a medula óssea foram coletados 24 horas após o desafio antigênico com OVA. Em grupo separado, os animais foram expostos ao DMTI-II 4 h após o desafio com OVA. De acordo com os resultados, a pré-exposição ao DMTI-II nos tempos de 4 e 16 h aumentou significativamente o recrutamento de eosinófilos no LBA de ratos desafiados com OVA. A pré-exposição de 2 e 4 h ao DMTI-II também promoveu aumento significativo do número de neutrófilos no LBA de ratos desafiados com OVA; entretanto, o número de células mononucleares não foi significativamente alterado. No sangue, a préexposição de 2 e 4 h ao DMTI-II aumentou significativamente o número de eosinófilos em ratos desafiados com OVA. Na medula óssea, a pré-exposição de 4 e 16 h ao DMTI-II, isoladamente, aumentou de forma significativa o número de eosinófilos, sendo esse aumento potencializado em ratos desafiados com OVA no tempo de 4h. A pós-exposição ao DMTI-II aumentou o número de eosinófilos e neutrófilos no LBA e no sangue de ratos desafiados com OVA. Além disso, o número de eosinófilos foi superior quando comparado ao protocolo de pré-exposição. Por outro lado, a pós-exposição ao DMTI-II não afetou o número de eosinófilos na medula óssea de animais desafiados com OVA. No LBA ou soro de ratos desafiados com OVA, notamos uma elevação significativa nos níveis de IgE, IL-4, eotaxina e LTB4. Porém, a exposição ao DMTI-II elevou somente os níveis de IL-4 nos animais desafiados com OVA. A pré- e pós-exposição das vias aéreas ao DMTI-II exacerba a inflamação pulmonar alérgica, com aumento do influxo de células polimorfonucleares. A capacidade do DMTI-II em recrutar eosinófilos está associada, provavelmente àspropriedades alérgicas dos inibidores de proteinases do tipo Kunitz.<br>Abstract: DMTI-II is a Kunitz-type serine proteinase inhibitor isolated from the seeds of Dimorphandra mollis, a widespread Leguminosae-Mimosoidea tree found in the savannahlike ecosystem, popularly known in Brazil to be toxic to cattle. Preliminary date in our laboratory showed that DMTI-II causes a marked eosinophil influx into the rat peritoneal cavity as early as 4 h after injection, a time by which no such cells are usually seen with classical inflammatory agents. In order to further explore our understanding about the eosinophil recruitment in response to DMTI-II we have moved to an experimental model where this cell type exhibits a central role, that is, the sensitization and challenge of rats with ovalbumin (OVA). Therefore, this study aimed to investigate the OVA-induced pulmonary cell recruitment in OVA-sensitized rats exposed to DMTI-II. Male Wistar rats were sensitized by subcutaneous injection of OVA. Fourteen day later, sensitized rats were submitted to intranasal instillations of DMTI-II (10 µg) or sterile PBS buffer (control group). At 2, 4 and 16 h after DMTI-II exposure, animals were challenged with OVA (or instilled with PBS). Bronchoalveolar lavage (BAL) fluid, bone marrow and blood were obtained at 24 h after OVA challenge. In a separate group of animals, rats were exposed to DMTI-II at 4 h after OVA challenge. Pre-exposure to DMTI-II 4 and 16 h prior to OVA-challenged markedly enhanced the eosinophil counts in BAL fluid in OVA-challenged rats. Pre-exposure to DMTI-II at 2 and 4 h prior to OVA-challenged markedly enhanced the neutrophil counts in BAL fluid in OVA-challenged rats, whereas mononuclear cell counts remained unchanged. Pre-exposure to DMTI-II at 2 and 4 h prior to OVA-challenged markedly enhanced the eosinophil counts in circulating blood in OVA-challenged rats. In bone marrow, pre-exposure to DMTI-II alone, 4 and 16 h prior OVA-challenged, significantly increased the number of eosinophils, and that was further increased in OVAchallenged rats 4 h prior to OVA-challenged. Similarly to the pre-exposure protocols, postexposure to DMTI-II elevated the eosinophil e neutrophil counts in BAL fluid and blood when compared with control group. In bone marrow, post-exposure to DMTI-II did not affect the number of eosinophils. In OVA-challenged rats, the levels of IgE in serum and of IL-4, eotaxin and LTB4 in BAL fluid were significantly higher compared with nonchallenged animals. Pre-exposure to DMTI-II alone elevated the IL-4 levels, and further elevated this cytokine levels in OVA-challenged rats. The increased IgE, eotaxin and LTB4 seen in OVA-challenged rats remained unchanged in animals pre-exposed to DMTI-II. In conclusion, the airways exposure to DMTI-II exacerbate the allergic pulmonary polymorphonuclear cell influx. This capacity of DMTI-II to recruit eosinophils is likely to reflect the allergen properties of proteinase inhibitors belonging to the Kunitz family.<br>Mestrado<br>Mestre em Farmacologia
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Castro, Myrella Lessio 1978. "Avaliação da terapia com dose sub-antimicrobiana de doxiciclina como um modulador da resposta imuno-inflamatória do hospedeiro em modelo de doença periodontal e os efeitos dessa terapia sobre a susceptibilidade da Porphyromonas gingivalis." [s.n.], 2012. http://repositorio.unicamp.br/jspui/handle/REPOSIP/288517.
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Orientadores: Pedro Luiz Rosalen, Gilson Cesar Nobre Franco<br>Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba<br>Made available in DSpace on 2018-08-20T03:41:37Z (GMT). No. of bitstreams: 1
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Previous issue date: 2012<br>Resumo: Periodontite é a doença multifatorial que envolvem interações entre algumas espécies bacterianas, como Porphyromonas gingivalis W83 e células do hospedeiro. Levando a uma resposta imuno-inflamatória que causa a destruição do tecido ósseo e gengival Neste contexto, fármacos com a habilidade de modular este processo imuno-inflamatório podem auxiliar no tratamento da doença periodontal (DP). A doxiciclina em dose subantimicrobiana (DDS), apresenta propriedades anti-inflamatórias pela sua atuação em algumas vias da inflamação. No entanto, ainda é discutido o efeito desta terapia dobre a susceptibilidade bacteriana por longo tempo. Assim, o objetivo deste trabalho foi analisar os efeitos da DDS como um modulador da resposta imuno-inflamatória do hospedeiro na DP induzidas em ratos e avaliar a susceptibilidade da P. gingivalis cultivadas com DDS por longo tempo. A DP foi induzida em ratos Wistar machos (SPF) submetidos à colocação de ligadura em torno dos primeiros molares inferiores foram randomizados e divididos em 3 grupos experimentais (n=10 animais/grupo/experimento): 1) grupo controle: ratos sem ligadura e sem tratamento; 2) grupo ligadura: ratos com ligadura e tratados com solução NaCl 0,9 %) e 3) grupo ligadura + DDS: ratos com ligadura e tratados com a DDS (5 mg/kg/dia). No tecido gengival, extraídos de animais tratados por 3 dias, foram avaliadas as expressões gênicas de TNF-'alfa' IL-1' beta', IL-17 e PAR2 através de RTPCR. As mandíbulas dos ratos tratados por 15 dias foram usadas para mensuração da reabsorção óssea alveolar (coradas com Hematoxilina e Eosina) e da quantidade de fibras colágenas (coradas com Picrosirius- Vermelho). Para a análise microbiológica, a P. gingivalis (ATCC BAA-308) foi cultivada por 3 meses (45 gerações) em meio de cultura contendo 0,4 ug/mL de DDS e avaliada por meio de concentração inibitória mínima (CIM) para Amoxiciclina, Doxiciclina e Metronidazol. A DDS inibiu significativamente os níveis de RNAm do tecido gengival para os IL-1' beta', IL-17, TNF-'alfa' e PAR2 (P<0,05, ANOVA, teste Tukey). Além disso, a DDS reduziu a perda óssea quando comparada ao grupo ligadura (P<0,05 ANOVA, teste Tukey) e manteve a porcentagem de fibras colágenas com níveis similares ao grupo controle (P>0,05). Na análise da susceptibilidade de P. gingivalis a DDS não apresentou resistência multi-antibiótica para esta cepa, entretanto, houve uma alteração nos valores de CIM para todos antibióticos testados com a P. gingivalis crescida ao longo do tempo. Em conjunto, os dados demonstram que a DDS diminuiu a resposta inflamatória, a reabsorção óssea e a degradação de colágeno no modelo utilizado de DP, indicando sua atividade como moduladora da resposta do hospedeiro na DP. A alteração microbiana com o uso contínuo e de longo período de DDS modificou a sensibilidade da P. gingivalis, entretanto não desenvolveu resistência antibiótica a doxiciclina<br>Abstract: Periodontitis is a multifactorial disease involving interactions between some bacterial species, as Porphyromonas gingivalis W83, and host cells. Leading to an immune-inflammatory response that causes the destruction of bone and gingival. In this context, drugs with the ability to modulate immuno-inflammatory process that may aid in the treatment of periodontal disease (PD). Doxycycline dose subantimicrobiana (DDS) has anti-inflammatory properties because of its role in some pathways of inflammation. However, it is still discussed the effect of this therapy fold the bacterial susceptibility for a long time. The objective of this study was to analyze the effects of DDS as a modulator of the immune-inflammatory response in the host DP induced in rats and to evaluate the susceptibility of P. gingivalis grown with DDS for a long time. The DP was induced in male Wistar rats (SPF) submitted of ligature around the first molars and divided into three experimental groups (n = 10 animals/group/experiment): 1) control group: rats without ligature and without treatment; 2) ligature group: rats with ligature and treated with 0.9% NaCl solution and 3) ligature + SDD group: rats with ligature and treated with SDD (5 mg/kg/day). In gingival tissue, extracted from animals treated for 3 days, we assessed the gene expression of TNF-'alpha', IL-1'beta', IL-17 and PAR2 by RT-PCR. The jaws of rats treated for 15 days were used for measurement of alveolar bone resorption (stained with Hematoxylin and Eosin) and collagen fibers (stained with Picrosirius-Red). For microbiological analysis, P. gingivalis was grown for 3 months (45 generations) in culture medium containing 0.4 ug/mL of SDD and evaluated by minimum inhibitory concentration (MIC). SDD significantly inhibited mRNA levels of the gingival tissue for IL-1'beta', IL-17, TNF-'alpha' and PAR2 (p<0.05, ANOVA, Tukey test). In addition, SDD has reduced bone loss when compared to the ligature group (p<0.05 ANOVA, Tukey test) and also maintained the percentage of collagen fibers at levels similar to the control group (p> 0.05). In the analysis of susceptibility to P. gingivalis SDD showed no multi-antibiotic resistance for this strain, however, there was a change in the MIC values for all antibiotics tested with P. gingivalis growth to long-time. Together, these data demonstrate that SDD reduced the inflammatory response, bone resorption and collagen degradation in PD, indicating its activity as a modulator of the host response in PD. Furthermore, SDD affected the sensitivity of P. gingivalis, however not developing antibiotic resistance with 3 months therapy<br>Doutorado<br>Farmacologia, Anestesiologia e Terapeutica<br>Doutor em Odontologia
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Galvis, Zambrano Laura Melissa [UNESP]. "Efeito da aplicação local de curcumin nanoparticulado em modelo de doença periodontal experimental induzido por LPS." Universidade Estadual Paulista (UNESP), 2016. http://hdl.handle.net/11449/147068.
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Previous issue date: 2016-12-07<br>Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)<br>Curcumin é a denominação coletiva do composto extraído das raízes da planta herbácea Curcuma longa. A literatura reporta múltiplas atividades biológicas do curcumin, incluindo potente atividade anti-inflamatória. Estudos in vitro e in vivo demonstram que a administração de curcumin reduz a inflamação e destruição tecidual associadas à doença periodontal. No entanto, a maioria dos estudos in vivo administra o curcumin por via oral, o que pode limitar os efeitos deste composto devido à sua hidrofobicidade, baixa absorção no trato gastrointestinal e reduzida meia-vida plasmática. Estas limitações farmacodinâmicas induziram a busca de veículos alternativos para favorecer a biodisponibilidade e atividade biológica do curcumin. O presente estudo foi concebido como um trabalho de prova de princípio visando avaliar o efeito biológico da administração local de curcumin veiculado em nanopartículas, considerando a natureza sítio-específica da doença periodontal e as pobres propriedades farmacodinâmicas do curcumin. Dezesseis ratos Holtzman foram divididos em dois grupos de 8 animais, segundo a indução de doença periodontal experimental por meio de injeções bilaterais de LPS (3 µL, 10 mg/mL) ou do mesmo volume do veículo PBS (pH 7,4) como controle. Estas injeções foram realizadas no tecido gengival palatino adjacente aos primeiros molares superiores 3vezes/semana durante 4 semanas. Injeções de nanopartículas contendo curcumin (50 mg/mL, 3 µL/injeção) ou do mesmo volume do veículo de nanopartículas sem curcumin foram realizadas de forma contra-lateral (lado esquerdo: nanocurcumin, lado direito: veículo) nos mesmos sítios em todos os animais, 2vezes/semana durante as 4 semanas. A administração local do nanocurcumin reduziu a reabsorção óssea inflamatória, avaliada por µCT e por análise macroscópica. Esta redução foi acompanhada por significativa diminuição do número de osteoclastos e de células inflamatórias nos tecidos em que foi injetado LPS e nanocurcumin em comparação aos tecidos em que foi injetado LPS e veículo de nanopartículas. Também observamos marcante atenuação da ativação das vias de sinalização p38 MAPK e NF-kB nos tecidos gengivais injetados com o nanocurcumin. Conclui-se que a administração local de nanocurcumin veiculado em nanopartículas inibe a reabsorção óssea e a inflamação associadas ao modelo de doença periodontal induzido por injeções de LPS.<br>Curcumin is the collective denomination of the compound extracted from the rhizomes of Curcuma longa herbal plant. There is evidence indicating that curcumin has multiple biological activities, including potent anti-inflammatory properties. Both in vitro and in vivo studies demonstrate that curcumin may attenuate inflammation and the connective tissue destruction associated with periodontal disease. However, most of the in vivo studies uses an oral systemic administration route, which is limited by curcumin's hidrophobicity, poor absorption rate in the gastrointestinal tract and reduced half-life in the plasma. These pharmacodynamic limitations prompted the search for alternative vehicles to enhance the bioavailability and biological activity of curcumin. This proof of principle study was designed to assess the biological effect of the local administration of curcumin in a nanoparticle vehicle on experimental periodontal disease, considering the site-specific nature of periodontal disease and also the poor pharmacodynamic properties of curcumin. Sixteen 16 Holtzman rats were divided into two groups of 8 animals according to the induction of experimental periodontal disease by bilateral injections of LPS (3 µL of a 10mg/mL solution) or of the vehicle control (3 µL of PBS, pH 7.4) directly into the gingival tissues adjacent to the palatal aspect of the upper first molars 3time/week for 4 weeks. The same volume of curcumin-loaded nanoparticles (50 mg/mL) or of nanoparticle vehicle were injected into the same sites 2time/week. µCT and macroscopic analysis showed that local administration of curcumin inhibited inflammatory bone resorption. Histomorphometric analysis indicated a significant decrease in the number of osteoclasts and inflammatory cells in the diseased gingival tissues injected with nanocurcumin in comparison with the diseased gingival tissues injected with nanoparticle vehicle. Also, western blot analysis showed a marked attenuation in the activation of p38 MAPK and NF-kB. It is concluded that local administration of curcumin-loaded nanoparticles effectively inhibited inflammation and bone resorption associated with experimental periodontal disease.
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Galvis, Zambrano Laura Melissa. "Efeito da aplicação local de curcumin nanoparticulado em modelo de doença periodontal experimental induzido por LPS /." Araraquara, 2016. http://hdl.handle.net/11449/147068.
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Orientador: Carlos Rossa Junior<br>Resumo: Curcumin é a denominação coletiva do composto extraído das raízes da planta herbácea Curcuma longa. A literatura reporta múltiplas atividades biológicas do curcumin, incluindo potente atividade anti-inflamatória. Estudos in vitro e in vivo demonstram que a administração de curcumin reduz a inflamação e destruição tecidual associadas à doença periodontal. No entanto, a maioria dos estudos in vivo administra o curcumin por via oral, o que pode limitar os efeitos deste composto devido à sua hidrofobicidade, baixa absorção no trato gastrointestinal e reduzida meia-vida plasmática. Estas limitações farmacodinâmicas induziram a busca de veículos alternativos para favorecer a biodisponibilidade e atividade biológica do curcumin. O presente estudo foi concebido como um trabalho de prova de princípio visando avaliar o efeito biológico da administração local de curcumin veiculado em nanopartículas, considerando a natureza sítio-específica da doença periodontal e as pobres propriedades farmacodinâmicas do curcumin. Dezesseis ratos Holtzman foram divididos em dois grupos de 8 animais, segundo a indução de doença periodontal experimental por meio de injeções bilaterais de LPS (3 µL, 10 mg/mL) ou do mesmo volume do veículo PBS (pH 7,4) como controle. Estas injeções foram realizadas no tecido gengival palatino adjacente aos primeiros molares superiores 3vezes/semana durante 4 semanas. Injeções de nanopartículas contendo curcumin (50 mg/mL, 3 µL/injeção) ou do mesmo volume do veículo de nano... (Resumo completo, clicar acesso eletrônico abaixo)<br>Abstract: Curcumin is the collective denomination of the compound extracted from the rhizomes of Curcuma longa herbal plant. There is evidence indicating that curcumin has multiple biological activities, including potent anti-inflammatory properties. Both in vitro and in vivo studies demonstrate that curcumin may attenuate inflammation and the connective tissue destruction associated with periodontal disease. However, most of the in vivo studies uses an oral systemic administration route, which is limited by curcumin's hidrophobicity, poor absorption rate in the gastrointestinal tract and reduced half-life in the plasma. These pharmacodynamic limitations prompted the search for alternative vehicles to enhance the bioavailability and biological activity of curcumin. This proof of principle study was designed to assess the biological effect of the local administration of curcumin in a nanoparticle vehicle on experimental periodontal disease, considering the site-specific nature of periodontal disease and also the poor pharmacodynamic properties of curcumin. Sixteen 16 Holtzman rats were divided into two groups of 8 animals according to the induction of experimental periodontal disease by bilateral injections of LPS (3 µL of a 10mg/mL solution) or of the vehicle control (3 µL of PBS, pH 7.4) directly into the gingival tissues adjacent to the palatal aspect of the upper first molars 3time/week for 4 weeks. The same volume of curcumin-loaded nanoparticles (50 mg/mL) or of nanoparticle vehicle were injected into the same sites 2time/week. µCT and macroscopic analysis showed that local administration of curcumin inhibited inflammatory bone resorption. Histomorphometric analysis indicated a significant decrease in the number of osteoclasts and inflammatory cells in the diseased gingival tissues injected with nanocurcumin in comparison...(Complete abstract electronic access below)<br>Mestre
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Magalhães, Fernando Augusto Cintra. "Efeito protetor da Interleucina-4 na reabsorção óssea periodontal induzida por agonista de TLR2 (Pam2CSK4) /." Araraquara, 2018. http://hdl.handle.net/11449/154085.
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Orientador: Pedro Paulo Chaves de Souza<br>Resumo: A periodontite é resultado do desequilíbrio entre o biofilme bacteriano e a resposta imune do hospedeiro. Componentes bacterianos, como o lipopolissacarídeo (LPS) e as lipoproteínas, são reconhecidos pelo sistema imune e desencadeiam a produção de citocinas que auxiliam no combate à infecção, mas também induzem a destruição tecidual. A participação do LPS na destruição óssea já é bem estabelecida, porém o papel das lipoproteínas na periodontite permanece carente de investigação. Na periodontite, citocinas pró-inflamatórias participam do processo de destruição do tecido ósseo. Neste processo, são secretadas também citocinas osteoprotetoras. Dentre elas, a interleucina 4 (IL-4) é reconhecida pela propriedade de inibir a produção citocinas pró inflamatórias como IL-1, IL-6 e TNF-α. O papel protetor de IL-4 na osteoclastogênese e na doença periodontal induzida por lipoproteína ainda não foi investigado. Nosso estudo foi divido em dois capítulos. No capítulo 1, hipotetizamos que a lipoproteína sintética Pam2CSK4 (PAM2) poderia induzir a reabsorção óssea periodontal. Para isso, foram utilizados camundongos C57bl/6, que receberam injeções a cada 2 dias, por 24 dias, do veículo, LPS de Escherichia. coli ou PAM2, entre o primeiro e segundo molar superior. Após o período experimental, os animais foram eutanasiados e destinados à análise por microCT, análise histológica e imunohistoquímica para marcação dos osteoclastos. A PAM2 apresentou a capacidade de induzir a perda óssea alveolar, ... (Resumo completo, clicar acesso eletrônico abaixo)<br>Abstract: The pathogenesis of periodontitis is a result of imbalance between the bacterial biofilm and the host immune response. Bacterial components such as lipopolysaccharide (LPS) and lipoproteins, activate the immune system leading to periodontal distruction. The participation of LPS in periodontal bone destruction is well established, but there is a lack of information about the role of lipoproteins in periodontitis. In the pathogenesis of periodontitis, these molecular patterns are recognized by host immune system and trigger the production of cytokines that participate of antimicrobial response, but also induce tissue destruction. On the other hand, antinflamatory cytokines produced by Th2 cells, such as IL-4, have an osteoprotective phenotype. The role of IL-4 in lipoprotein-induced periodontitis was not yet investigated. Thus, this thesis was divided in two chapters. In chapter 1, we investigated the role of lipoproteins in the pathogenesis of periodontitis in mice. In this study, we hypothesized that the synthetic lipoprotein Pam2CSK4 (PAM2) can induce periodontal bone resorption. C57bl / 6 mice received bilateral injections every other day for 24 days of: vehicle, Escherichia coli LPS or PAM2, between the first and second upper molars. Twenty-four hours after the last injection, the mice were euthanized and the jaw bones were scanned for micro computed tomography, decalcified and processed for histological analysis and stained for tartrate-resistant acid phosphatase, phenoty... (Complete abstract click electronic access below)<br>Doutor
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BENEFORTI, LINDA. "Role of Bone Marrow-Mesenchymal Stromal Cells and inflammation in the pre-leukemic phase of ETV6-RUNX1-positive childhood Acute Lymphoblastic Leukemia (ALL)." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2019. http://hdl.handle.net/10281/241325.
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La traslocazione t(12;21) è il riarrangiamento cromosomico più frequente nei tumori pediatrici e si associa esclusivamente alla leucemia linfoblastica acuta (LLA) a precursori B. La traslocazione avviene in utero nelle cellule staminali-progenitrici ematopoietiche ma è insufficiente per la leuchemogenesi, poiché il gene di fusione ETV6-RUNX1 (E/R) che ne deriva genera un clone pre-leucemico clinicamente silente; mutazioni secondarie sono quindi necessarie per completare la trasformazione. Queste ultime avvengono nel periodo post-natale verosimilmente in seguito ad una risposta immunitaria disregolata a infezioni /infiammazioni comuni. Le recidive E/R+ non sono molto frequenti ma è plausibile che siano determinate dall’accumulo di nuove mutazioni nel clone pre-leucemico chemioresistente. In passato abbiamo dimostrato che TGFβ, una citochina prodotta durante l’infiammazione, limita la proliferazione delle cellule normali pro-B mentre favorisce il clone pre-leucemico che è insensibile al suo effetto; in più, TGFβ seleziona cellule pre-leucemiche staminali in progenitori CD34+ derivati da sangue cordonale umano. Abbiamo anche precedentemente dimostrato che cellule pro-B murine E/R+ mostrano alterazioni in molecole di adesione e nella migrazione verso CXCL12, suggerendo un loro possibile comportamento anomalo all’interno della nicchia midollare. Le cellule mesenchimali stromali (MSC) sono regolatori chiave sia delle cellule ematopoietiche nella nicchia che dell’infiammazione. È stato inoltre dimostrato che alterazioni delle MSC attivano pathways infiammatori nelle cellule staminali/progenitrici del sangue promuovendo la loro trasformazione a leucemia mieloide acuta in sindromi genetiche predisponenti. Grazie a due modelli cellulari esprimenti E/R (la linea cellulare murina proB Ba/F3 e cellule CD34+ di sangue cordonale umano), il presente studio dimostra che le cellule pre-leucemiche sono avvantaggiate dalla copresenza di MSC e infiammazione in termini di migrazione, sopravvivenza e potenziale progressione. Ba/F3 E/R+ mostrano un profilo di espressione genica pro-infiammatorio, con una particolare signature migratoria e pro-mieloide. Inoltre, sia Ba/F3 che CD34+ esprimenti E/R migrano di più verso i surnatanti di MSC infiammate rispetto alle cellule controllo; nel primo caso, la migrazione dipende dal recettore CXCR2. Molto importante, Ba/F3 E/R+ sono favorite rispetto al controllo quando coltivate su MSC e infiammazione, poiché questa condizione diminuisce molto proliferazione e sopravvivenza delle Ba/F3 normali mentre ha effetti minori o assenti sulle pre-leucemiche. Il vantaggio è mediato da fattori solubili, ma né TGFβ né CXCR2 sono implicati. In aggiunta, MSC e infiammazione aumentano il danno genotossico sia nelle Ba/F3 controllo che E/R+, come indicato dagli aumentati livelli di fosforilazione dell’istone H2AX e di espressione dell’enzima AID, il quale è stato dimostrato favorire la transizione da pre-leucemia a leucemia E/R+. Tuttavia, mentre le Ba/F controllo vanno incontro ad apoptosi, le pre-leucemiche resistono accumulando danni genetici che possono favorirne la trasformazione. Infine, infiammazione e MSC cooperano nel far emergere il compartimento CD34+IL7R+ all’interno della popolazione di CD34+ pre-leucemiche, mentre sfavoriscono quello della popolazione normale. Questa osservazione è particolarmente importante alla luce del fatto che tale compartimento rappresenta lo stadio dell’ematopoiesi fetale che è suscettibile all’azione pre-leucemica di E/R. Concludendo, il presente lavoro dimostra che cellule mesenchimali stromali di midollo osseo e infiammazione cooperano nel favorire la persistenza e la possibile progressione del clone pre-leucemico ETV6-RUNX1+. L’elucidazione dei meccanismi che sottendono tale azione favorente potrebbe fornire strategie innovative per l’eradicazione del clone pre-leucemico chemioresistente.<br>Translocation t(12;21) is the most frequent chromosomal rearrangement in pediatric cancers, exclusively leading to B-cell Precursors Acute Lymphoblastic Leukemia (BCP-ALL). Translocation occurs in utero in stem-progenitor cells (HSPC) but it is insufficient for leukemogenesis, since the consequent ETV6-RUNX1 (E/R) fusion gene only generates a silent B-progenitor pre-leukemic clone; additional mutations are thus required for transformation. These latter occur in the post-natal period likely due to dysregulated immune response to common infections/inflammation. Our published data demonstrated that TGFβ, a cytokine produced during inflammation, limited the proliferation of normal pro-B and cells while favoring the insensitive E/R+ clone; moreover, TGFβ selected putative pre-leukemic stem cells (preLSC) in umbilical cord blood (UCB) CD34+ progenitors transduced with the oncogene. On the other hand, we previously showed that ETV6-RUNX1+ murine B-progenitors were altered in adhesion molecules expression and CXCL12-directed migration, suggesting possible dysregulated interactions within the bone marrow (BM) niche. Mesenchymal Stromal Cells (MSC) are key regulators of both HSPC and inflammation in the niche. Importantly, it has been shown that mesenchymal inflammation promotes secondary myeloid leukemia in predisposing syndromes by increasing DNA damage in HSPC, while MSC/BCP-ALL blasts cross-talk profoundly modifies cytokine and chemokine signalling within the niche excluding normal hematopoiesis in favor of leukemia. Taking advantages from two ETV6-RUNX1-expressing cell models (Ba/F3, a murine pro-B cell line, and ETV6-RUNX1-expressing human UCB-CD34+ progenitors) the present PhD study demonstrates that ETV6-RUNX1-expressing cells take advantage from mesenchymal inflammation in terms of migration, persistence and potential progression. In particular, we have found that pre-leukemic Ba/F3 show a peculiar pro-inflammatory gene expression profile characterized by a marked migratory and myeloid signature. Concordantly, ETV6-RUNX1+ Ba/F3 and CD34+ cells preferentially migrate toward inflamed compared to unstimulated BM-MSC supernatants; in case of the first, migration is CXCR2-dependent. Moreover, ETV6-RUNX1+ Ba/F3 are favored compared to controls in presence of BM-MSC and inflammatory cytokines, as they decrease normal cells proliferation and survival while minimally affecting pre-leukemic cells. The effect is mediated by soluble factors, but neither TGFβ nor CXCR2 axis are implicated. Importantly, the inflamed mesenchymal niche increases genotoxic stress in both control and E/R+ Ba/F3, as indicated by high levels of H2AX phoshorilation, as well as transcription of the activation-induced cytidine deaminase (AID) enzyme (which is implicated in ETV6-RUNX1+ pre-leukemia to leukemia transition). However, while control cells go through apoptosis, pre-leukemic Ba/F3 are resistant to this fail-safe mechanism, increasing chance to accumulate secondary mutations and malignantly transform. Finally, an inflamed MSC favor the emergence of CD34+ILR7+ compartment within ETV6-RUNX1+ UCB-CD34+ population while decreasing its frequency in the normal counterpart; of note, such differential effect doesn’t occur in case of unstimulated MSC. This observation is particularly important as the CD34+ILR+ compartment seems to represent the critical developmental stage during early fetal hematopoiesis for ETV6-RUNX1 pre-leukemic activity. Concluding, our work demonstrated that BM-MSC and inflammation cooperate in favoring the persistence and transformation of ETV6-RUNX1+ pre-leukemic clone. Elucidating mechanisms that underlay such promoting action could provide novel strategies for the pre-leukemic clone eradication.
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Porto, Rodrigo Martins. "Papel dos receptores nucleares ativados por proliferadores de peroxissomos (PPAR) na periodontite induzida em ratos." Universidade de São Paulo, 2012. http://www.teses.usp.br/teses/disponiveis/42/42136/tde-13112012-105538/.
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Este estudo investigou o efeito da Roziglitazona (RTZ) sobre a perda óssea alveolar induzida pela periodontite (POAIP). Durante 3 semanas, ratos receberam sal puro de RTZ (i.p.) ou a formulaço comercial Avandia<font face=\"Symbol\">Ò (v.o.); os grupos controles receberam os repectiovos veículos (DMSO ou CMC). Duas semanas após o inicio do tratamento, a periodontite (P) foi induzida. Após 7 dias da indução da P, as mandíbulas foram removidas para mediço da perda óssea alveolar. Amostras de osso alveolar foram analisadas por qPCR para RUNX2, Osterix, TRAF6, TRAF2, RANKL, óxido nítrico sintases (e, n e iNOS) e PPARs (<font face=\"Symbol\">a, <font face=\"Symbol\">b e <font face=\"Symbol\">g). A farmacocinética da RTZ para cada formulaço foi estudada por HPLC-MS/MS. Tanto o sal puro como a formulaço comercial de RTZ resultou no agravamento da POAIP. Apesar dos resultados similares nas concentrações plasmáticas de RTZ os mecanismos de sinalizaço parecem depender da formulaço administrada a qual pode ser devido a interferência do veículo.<br>This study investigate the effects of rosiglitazone (RTZ) on periodontitis-induced alveolar bone loss (PIABL). Rats received RTZ during 3 weeks, either as the pure maleate salt (i.p.) or the commercial formulation Avandia<font face=\"Symbol\">â (p.o.); control animals received the respective vehicles (DMSO or CMC). Two weeks after the treatments begins, periodontitis (P) were induced. After 7 days after P induction, jaws were removed for ABL measurement. Alveolar bone samples were analyzed by qPCR for RUNX2, Osterix, TRAF6, TRAF2, RANKL, nitric oxide sintase (e, n and iNOS) and PPARs (<font face=\"Symbol\">a, <font face=\"Symbol\">b e <font face=\"Symbol\">g). RTZ pharmacokinetics from each formulation was also studied (HPLC-MS/MS). RTZ, either from the pure maleate salt or the commercial Avandia, resulted in aggravated PIABL. Despite resulting in similar plasma RTZ concentrations, signaling mechanisms seem to depend on the administered formulation which could be due to vehicle related effects interfence.
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Dang, Lei. "Osteoblastic PLEKHO1 contributes to joint inflammation in rheumatoid arthritis." HKBU Institutional Repository, 2019. https://repository.hkbu.edu.hk/etd_oa/687.
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Background: Osteoblasts participating in the inflammation regulation gradually obtain concerns. However, its role in joint inflammation of rheumatoid arthritis (RA) is largely unknown. Here, we investigated the role of osteoblastic pleckstrin homology domain-containing family O member 1 (PLEKHO1), a negative regulator of osteogenic lineage activity, in regulating joint inflammation in RA. Methods: The level of osteoblastic PLEKHO1 in RA patients and collagen-induced arthritis (CIA) mice was examined. The role of osteoblastic PLEKHO1 in joint inflammation was evaluated by a CIA mice model which was induced in osteoblast-specific Plekho1 conditional knockout mice and mice expressing high Plekho1 exclusively in osteoblasts, respectively. The effect of osteoblastic PLEKHO1 inhibition was explored in a CIA mice model. The mechanism of osteoblastic PLEKHO1 in regulating joint inflammation was performed by a series of in vitro studies. Results: PLEKHO1 was highly expressed in osteoblasts from RA patients and CIA mice. Osteoblastic Plekho1 deletion ameliorated joint inflammation, whereas overexpressing Plekho1 only within osteoblasts exacerbated local inflammation in CIA mice. PLEKHO1 was required for TNF receptor-associated factor 2 (TRAF2)-mediated the ubiquitination of receptor-interacting serine/threonine-protein kinase 1 (RIP1) to activate nuclear factor kappa-light-chain-enhancer of activated B (NF-kB) pathway for inducing inflammatory cytokines production in osteoblasts. Moreover, osteoblastic PLEKHO1 inhibition improved joint inflammation and attenuated bone formation reduction in CIA mice. Conclusions: These data strongly suggest that highly expressed PLEKHO1 in osteoblasts mediates joint inflammation in RA. Targeting osteoblastic PLEKHO1 may exert dual therapeutic action of alleviating joint inflammation and promoting bone repair in RA.
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ZEGAIB, SILMEA. "Análise microbiologica em bolsas periodontais infectadas, tratadas pelos métodos de raspagem e alisamento radicular, raspagem ultra-sônica e raspagem e alisamento radicular coadjuvado pelo laser de diodo de alta potência (815nm): estudo in vivo." reponame:Repositório Institucional do IPEN, 2005. http://repositorio.ipen.br:8080/xmlui/handle/123456789/11392.
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11304.pdf: 13648748 bytes, checksum: 23af4545b598a975e256fe0dc5f30c23 (MD5)<br>Dissertacao (Mestrado Profissionalizante em Lasers em Odontologia)<br>IPEN/D-MPLO<br>Instituto de Pesquisas Energeticas e Nucleares, IPEN/CNEN-SP; Faculdade de Odontologia, Universidade de Sao Paulo