Proefschrift Universiteit Maastricht. / Met lit. opg. - Met samenvatting in het Nederlands.

Proefschrift Maastricht. / Met lit. opg. - Met samenvatting in het Nederlands.

Proefschrift Universiteit Maastricht. / Auteursnaam op omslag: Birgit Faber. Met bibliogr., lit. opg. - Met samenvatting in het Nederlands.

Proefschrift Universiteit Maastricht. / Met bibliogr., lit. opg. - Met samenvatting in het Nederlands.

Proefschrift Universiteit Maastricht. / Met bibliogr., lit. opg. - Met samenvatting in het Nederlands.

Thesis (M.S.)--Rochester Institute of Technology, 1993. / Typescript. Includes bibliographical references: p. 90-92.

No description available.

A carotid atherosclerotic plaque represents a nidus of inflammation mere centimetres below the blood-brain barrier. This inflammation, along with associated regions of microcalcification, are histopathological features of atheroma at risk of rupture (so-called “vulnerable plaques”) that trigger thromboembolic stroke. While conventional clinical imaging simply measures the degree of vessel stenosis, it is a crude measure that reveals little of the metabolic processes affecting plaque vulnerability. Our research demonstrates the utility of positron emission tomography (PET) using 18F-fluorodeoxyglucose (FDG) and 18F-sodium fluoride (NaF), measuring inflammation and microcalcification respectively, to identify culprit carotid atheroma in vivo, and establish how these processes influence plaque vulnerability. Furthermore, for stroke care it is the downstream thromboembolic effects upon the brain that are key. While proinflammatory conditions may increase the risk of stroke, the relationship between atheroma inflammation and the peri-infarct inflammatory response following a stroke remains poorly defined. Our work demonstrates how inflammatory activity in symptomatic carotid atheroma, measured using PET, influences both chronic small vessel disease and the evolution of lesion volume in the post-stroke period. Using metabolic imaging we can both identify vulnerable atheroma in vivo and demonstrate how these processes affect infarct evolution. We show that whilst inflammation is a generalised process, microcalcification is a focal process that may represent a point of maximum vulnerability. These results also reveal the complexity of the atheroma-brain interaction that may simultaneously trigger events while also influencing stroke evolution in the early recovery period. This has important implications for understanding pathophysiology of both atherosclerosis and stroke evolution, advancing drug-discovery, and potential clinical applications to minimise the impact from this devastating disease.

Orientadores: Maria Heloísa de Souza Lima Blotta, Rômulo Tadeu Dias de Oliveira / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-23T11:06:38Z (GMT). No. of bitstreams: 1 Mineiro_MarcelaFranco_M.pdf: 3128314 bytes, checksum: 8579ae8081ba0070be37eca4970a0ac6 (MD5) Previous issue date: 2013 / Resumo: A presença de IL-1? e IL-18 em lesões ateroscleróticas e o importante papel dessas citocinas na ativação endotelial, recrutamento celular e na polarização para a resposta TH1 constitui indício indireto do envolvimento dos NLRs na patogênese da aterosclerose. Nesse trabalho investigamos a presença do RNAm e proteína de diversos NLRs, AIM2, caspase-1, proteína adaptadora ASC e IL-1? em placas ateroscleróticas humanas. Observamos que amostras de ateroma de pacientes assintomáticos apresentaram maior expressão relativa do RNAm de NLRP1, 2 e 3, NLRC2, 3, 4 e 5, NAIP e ASC. A presença de fatores de risco não promoveu diferenças na expressão gênica do RNAm para nenhum deles. A marcação por imuno-histoquímica revelou a presença de NLRP1, 3, AIM-2, NLRC2, 3 e 5 e caspase-1, especialmente em macrófagos, células gigantes e células espumosas. Em culturas de monócitos do sangue periférico, macrófagos humanos derivados de monócitos e células da linhagem monocítica THP-1 estimuladas com LPS, a presença de cristais de colesterol teve efeito aditivo na produção de IL-1?. Por outro lado, os inibidores farmacológicos inibiram a produção dessa citocina em células THP-1 após o estímulo com cristais de colesterol. A atividade da citocina IL-1? também foi avaliada pela capacidade de induzir a produção de mediadores inflamatórios por células musculares lisas e células endoteliais. Catepsina S, MMP3, CXCL10, CXCL16 e CX3CL1 foram produzidas apenas por células musculares após o estímulo, mas CCL2, CXCL8 e CCL5 foram produzidos tanto por células musculares quanto por células endoteliais estimuladas. Em conclusão, nosso trabalho mostrou a presença de RNAm e proteína de diversos NLRs em placas de ateroma humano. Além disso, mostramos o papel dos cristais de colesterol na ativação de monócitos e macrófagos produtores de IL-1?, provavelmente via NLRP3, expresso em grande quantidade nas placas analisadas. Finalmente, os experimentos de estimulação de células musculares lisas e endoteliais ressaltaram a importância da IL-1? como agente inflamatório e desestabilizador das lesões, confirmando seu potencial como alvo terapêutico visando a contenção do processo inflamatório que caracteriza a aterosclerose / Abstract: The presence of IL-1? and IL-18 in atherosclerotic lesions and their important role in endothelial activation, cell recruitment and switch to Th1 response, are indirect indications of the involvement of NLRs in disease pathogenesis. In this study we investigated the presence of mRNA and protein of various NLRs, AIM2, caspase-1, adaptor protein ASC and IL-1? in human atherosclerotic plaques. We observed that atheroma samples from asymptomatic patients had higher mRNA relative expression of NLRP1, NLRP2, NLRP3, NLRC2, NLRC3, NLRC4, NLRC5, NAIP and ASC. Risk factors have no influence in mRNA expression for any of them. Immunohistochemistry technique revealed the presence of NLRP1, NLRP3, AIM-2, NLRC2, NLRC3, NLRC5 and caspase-1, especially among macrophages, giant cells and foam cells. The presence of cholesterol crystals in monocytes and macrophages cultures stimulated with LPS, had an additive effect on IL-1? production. On the other hand, pharmacological inhibitors inhibited this cytokine production by THP-1 cells stimulated with cholesterol crystals. The ability of IL-1?to induce inflammatory mediators production by smooth muscle cells and endothelial cells was also evaluated. Cathepsin S, MMP3, CXCL10, CXCL16 and CX3CL1 were produced only by smooth muscle cells after stimulation, but CCL2, CXCL8 and CCL5 were produced by both smooth muscle cells and endothelial cells. In conclusion, our study revealed the presence of various NLRs mRNA and protein in human atherosclerotic plaques. Furthermore, we demonstrated the role of cholesterol crystals in the activation of IL-1? producers monocytes and macrophages, probably due to NLRP3 expressed in large amounts on the lesions analyzed. Finally, stimulation of smooth muscle cells and endothelial cells highlighted the importance of IL-1? as an inflammatory and destabilizing agent in lesions, confirming its potential as a therapeutic target that could restrain the prevailing inflammation in atherosclerosis / Mestrado / Ciencias Biomedicas / Mestra em Ciências Médicas

Exaggerated postprandial lipaemia has been implicated in the development of atherosclerosis. Thus, by reducing postprandial TAG concentrations, exercise may play a role in delaying atherogenic progression. This thesis sought to explore the qualitative nature of, and the mechanisms behind, the moderate exercise-induced attenuation to postprandial lipaemia. Before the experimental studies commenced, a reproducibility study was undertaken. This showed that in a group of eight middle-aged men, the postprandial plasma TAG response differed by only 1.9 ± 5.1 % (mean ± standard error) on a testretest basis, indicating that the oral fat tolerance test had enough precision to detect the effect of exercise on TAG metabolism. Previous work suggested that the exercise-induced reduction to lipaemia was linked to the energy expended by exercise. As the attenuation may have been mediated by energy deficit, rather than exercise per se, a study comparing the effect of a 90-minute moderate exercise session with an equivalent dietary-induced energy deficit on postprandial lipid metabolism was undertaken, in a group of eleven postmenopausal women. This showed that the reduction in postprandial lipaemia elicited by exercise was far greater than that elicited by intake-restriction (20 % vs. 7 %). The second experimental study aimed to establish the effect of a 90-minute moderate exercise session on postprandial chylomicron- and very-Iow-density lipoprotein (VLDL)-TAG concentrations, and its effect on exogenous (through use of a l3e-Iabelled lipid) and endogenous fat oxidation, in a group oftwelve middle-aged men. Exercise reduced postprandial lipaemia by 23 %, and over three-quarters of this reduction was due to lower VLDL-TAG concentrations. Increases in endogenous fat oxidation accounted for over half of the increase in postprandial fat oxidation. In the third experimental study, the effect of a 90-minutes moderate exercise session on Intralipid clearance, and postprandial lipaemia, was determined in a group of eight middle-aged men. Exercise attenuated postprandial lipaemia by 18 %, but did not increase Intralipid clearance. Taken together, these data imply that moderate exercise predominantly reduced postprandial TAG concentrations by reducing hepatic VLDL secretion, rather than increasing TAG clearance, and this effect is not mediated by whole-body energy deficit. In addition, this work has shown that moderate exercise is effective at attenuating postprandial lipaemia in middle-aged men and postmenopausal women.