Durante a montagem de uma resposta inflamatória, um estímulo reconhecido como um fator de perigo desencadeia a supressão de melatonina noturna pela pineal e a indução da produção em monócitos. A poluição atmosférica é um dos maiores fatores de risco à saúde da população urbana. Neste estudo in vivo, a exposição aguda aos poluentes do ar gera um estresse oxidativo pulmonar, deflagra uma resposta inflamatória a partir da ativação da via de sinalização do NF-κB, do aumento das moléculas de adesão PECAM e ICAM e da sintase de óxido nítrico induzida (iNOS), bem como de citocinas inflamatórias. A medida que o tempo de exposição à poluição progride, a concentração plasmática noturna da melatonina se reduz em 39 %, enquanto que a pulmonar aumenta 55%. Tanto as enzimas AA-NAT e ASMT envolvidas na biossíntese da melatonina, quanto as enzimas antioxidantes SOD, CAT e GPx tem suas expressões gênicas no pulmão duplicadas, bem como suas atividades aumentadas. Os mRNAs das enzimas antioxidantes SOD e CAT pulmonar foram reduzidos a partir do bloqueio dos receptores MT1 e MT2. Tais resultados fundamentam ações farmacológicas que protejam ou revertam os efeitos lesivos gerados pela poluição atmosférica através do eixo imune-pineal tendo a melatonina como um agente terapêutico. / During assembly of an inflammatory response a stimulation recognized as a risk factor triggers the suppression of nocturnal pineal melatonin and by inducing the production in immunocompetent cells. Air pollution is one of the major risk factors to health of the urban population. In this in vivo study, acute exposure to air pollutants generates a pulmonary oxidative stress triggers an inflammatory response from the signaling pathway of activation of NF-κB, the increase in adhesion molecules PECAM and ICAM and nitric oxide synthase induced (iNOS) as well as inflammatory cytokines. As time progresses exposure to pollution, nocturnal plasma melatonin concentration is reduced by 39%, while the lung increases by 55%. Both AA-NAT enzymes and ASMT involved in the biosynthesis of melatonin, as the antioxidant enzymes SOD, CAT and GPx has its gene expression in lung duplicate, as well as its increased activities. The mRNAs of antioxidant enzymes SOD and CAT lung were reduced from blocking the MT1 and MT2 receptors. These results support pharmacological actions to protect or reverse the harmful effects caused by air pollution through the immune-pineal axis taking melatonin as a therapeutic agent.

Este trabalho teve como objetivo a identificação e quantificação das fontes do Material Particulado fino (MP2,5) da Região Metropolitana de Porto Alegre (RMPA), em especial, as fontes veiculares. Foram utilizadas amostras coletadas diariamente durante 24 horas, entre junho/2007 a fevereiro/2009 na Universidade Federal de Ciências da Saúde de Porto Alegre, próxima a vias de intenso tráfego. As amostras foram analisadas para determinação da concentração em massa, composição elementar e iônica do MP2,5. A concentração média do particulado fino durante o experimento foi de 13,4 µg m-3 e do Black Carbon foi de 3,8 µg m-3. Os elementos-traço S, K e Fe destacaram-se com concentrações mais elevadas. Através de Modelagem Receptora (Análise de Fatores AF e Fatoração de Matriz Positiva, Positive Matrix Factorization PMF), identificaram-se as possíveis fontes de MP2,5 da região. A utilização do PMF, modelo multivariado mais avançado, embora não tenha mostrado uma clara separação das fontes, possibilitou uma quantificação mais acurada das fontes identificadas. Por essa metodologia foram identificadas como fontes do MP2,5 as emissões veiculares, a ressuspensão do solo e as indústrias. Para ambos os modelos, a principal fonte identificada está relacionada com as emissões veiculares, respondendo por aproximadamente 50 % da massa do particulado fino. Dos resultados obtidos com o PMF, o solo tem uma pequena participação (2,5 %). A dificuldade na identificação das fontes pode ser atribuída a falta de medida de traçadores específicos dos combustíveis utilizados no setor de transporte e as limitações analíticas do sistema de Fluorescência de Raio-X, que possui baixos limites de detecção para importantes traçadores de fontes móveis e industriais como V, Ni, Cr, Se e Cu. / The aim of this work was to identify and quantify the sources of fine particles in the Metropolitan Region of Porto Alegre, specially the vehicular sources. PM2.5 samples collected daily for 24 hours between june/2007 to february/2009 at the Universidade Federal de Ciências da Saúde de Porto Alegre, near heavy traffic routes. The samples were analyzed for determination of mass concentration, elemental and ionic composition. The average concentration of fine particulate matter during the experiment was 13.4 µg m-3 and Black Carbon was 3.8 µg m-3. The trace elements S, K and Fe stood out with higher concentrations. Through Receptor Modeling (Factor Analysis AF and Positive Matrix Factorization PMF), identified the possible sources of PM2,5 in the region. Using the most advanced multivariate model PMF, although it has not shown a clear separation of sources, enabled a more accurate quantification of the identified sources. For this methodology have been identified as sources of PM2,5 vehicle emissions, ressuspension of soil and industries. For both models, the main source identified is related to vehicle emissions approximately 50 % of the mass of fine particulate was explained by vehicular emission (light- and heavy-duty fleet). In the results obtained with PMF, participation of the dust soil was small (2.5 %). The difficulty in identifying the sources can be attributed to lack of measurement of specific tracers of fuels used in the transport sector and the limitations of the analytical system by X-Ray Fluorescence, which has low detection limits for important tracers of industrial and mobile sources as V, Ni, Cr, Se and Cu.

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Les poussières émises par l'industrie métallurgique concourent à la qualité de l'air des zones urbaines voisines. Ces particules, émises par des procédés à "haute température", sont susceptibles d'évoluer rapidement au sein des panaches. L'objectif de l'étude est de caractériser la phase particulaire sur un site d'émission métallurgique et de déterminer la nature et l'amplitude des transformations physico-chimiques subies par ces particules dans les premières minutes de leur émission. Des prélèvements d'aérosols ont été réalisés au sein des cheminées et dans l'environnement proche d'une usine métallurgique (production d'alliage de ferromanganèse), dont l'atelier d'agglomération est le principal émissaire. Le spectre granulométrique des particules dans l'environnement montre un enrichissement de nanoparticules (10-100nm) après survol des masses d'air au dessus du site industriel. Les rejets caractéristiques de l'usine (émission d'oxydes de fer et de manganèse, mais également d'aluminosilicates) se trouvent la plupart du temps sous forme d'agglomérats de composition chimique hétérogène et de structure morphologique complexe. Ces agglomérats semblent évoluer rapidement par adsorption de composés organiques volatils ou de suies. L'étude de la spéciation du Fe et du Mn au sein de ces particules indique qu'elles sont sujettes à des réactions d'oxydation via des mécanismes de conversion gaz/particules au sein même du procédé industriel, aboutissant notamment à une oxydation du fer inversement proportionnelle à la taille des particules. Par contre, aucune évolution significative du degré d'oxydation du Fe et du Mn n'a été observée dans l'environnement proche de l'émissaire. / Steelworks activities are important sources of fine particles which may affect air quality in urban areas close to plants. Those particles are emitted by "high-temperature" processes and could evolve very quickly in the plumes. The main objective of this study is to evaluate the nature and the amplitude of physico-chemical evolutions of those particles in the few minutes after the emission. Aerosol samplings were performed inside the chimneys and in the close environment of a FeMn alloys manufacturing plant where the sintering unit is the most important source of particles. The number size distributions in the close environment show a higher abundance of nanoparticles (10-100nm) inside the plume, by comparison with air masses upwind from the plant. The chemical analysis indicates that particles characteristic of the plant emissions (iron and manganese oxides but also aluminosilicates) are mostly constituted of agglomerates. These agglomerates combine various compounds inside a same particle in a complex structure. Moreover, they evolve rapidly (in a few minutes) after emission by mixing with organic compounds inside the plume. This evolution results from the adsorption of volatile organic compound or the agglomeration with soot particles. The study of iron and manganese speciation inside particles shows that they are prone to oxidation reactions via gas/particle conversion mechanisms during the industrial process, leading notably to a higher iron oxidation state for the smallest particles. However, no change of iron and manganese oxidation state was observed in the close environment of the plant.

A queima de biomassa em fornos de pizzaria se constitui como importante fonte de poluição do ar. Entre outros tipos de poluentes emitidos, o material particulado finoMP2,5 se destaca como o mais agressivo à saúde humana, além de poder interferir no balanço radiativo global. Objetiva-se, desta forma, através de estudo de caso em três pizzarias na cidade de São Paulo, quantificar e caracterizar o MP2,5 emitido pela queima da biomassa na área interna (indoor) e externa (junto á chaminé). Dentre as três pizzarias, duas fazem uso da lenha de eucalipto e a outra faz uso do briquete, formado a partir da compactação de pedaços de biomassa, serragem, bagaço e outros resíduos madeireiros. As amostras foram coletadas utilizando-se o amostrador Minivol. A análise do material foi realizada por meio de técnicas complementares: gravimetria (para a concentração em massa), refletância (para a concentração de black carbon), fluorescência de raios-X (para a concentração elementar) e utilização do microscópio eletrônico de varredura (MEV) (para identificar a morfologia do material particulado). Além disso, foram feitas inferências na saúde do trabalhador quanto á exposição ao MP2,5, e por fim foi estimada as emissões de MP2,5 e black carbon dado o elevado número de pizzarias existentes na cidade de São Paulo. Os resultados apresentaram concentrações médias elevadas de MP2,5, 6171,14 g/m3 no ambiente externo, e 68,24 g/m3 no ambiente interno para as três pizzarias. A queima do briquete apresentou menores concentrações para MP2,5. Os elementos químicos potássio, cloro e enxofre foram os mais representativos em termos de concentração. Os resultados para o MEV revelaram partículas com morfologia esférica individual, conglomerado de partículas esféricas, partículas achatadas com o formato de fibras, sobreposição de camadas e aglomerados de partículas com aspecto esponjoso. Embora no Brasil não exista padrão de exposição para o MP2,5 em ambiente interno, quando comparado com o padrão de exposição da Alemanha, as concentrações obtidas nas três pizzarias são superiores. Concentrações em massa de elementos prejudiciais à saúde como o cromo e zinco se mostraram demasiadamente elevadas. Os fatores de emissão para o MP2,5 e black carbon provenientes da queima da lenha foram 0,38g/kg e 0,23g/kg, respectivamente; e para o briquete 1,04g/kg e 0,37g/kg respectivamente. As emissões de MP2,5 e black carbon foram de 0,958t/ano e 0,340t/ano para a queima do briquete e 116,736t/ano e 70,656t/ano para a queima da lenha / The burning of biomass in pizza ovens constitutes itself as an important source of air pollution. Compared with other types of pollutants emitted, the fine particulate matter PM2,5 highlights itself as one of the most aggressive to human health, besides the power to interfere with global radiative balance. Therefore, through the study of three São Paulo pizzerias, the quantification and characterization of PM2,5 emitted by the burning of biomass within internal areas and external (where chimney´s were present). Among the three pizzerias, two used eucalyptus timber logs while the remaining other used wooden briquettes; formed by the compression of biomass: chips and shavings and other wood residue. Samples were collected using Minivol. The analysis of the material was completed via complementary techniques: gravimetrically (to establish mass concentration) Reflectance (to establish black carbon concentration) X-ray fluorescence (to establish element concentration) and the use of an electro-microscopic sweep (SEM) (to indentify the morphology of the particulate matter). Beyond this, inferences were made about the health of workers exposed to PM2,5, by way of estimated emissions of PM2,5 due to the elevated number of pizzerias in São Paulo. The results from the three pizzerias revealed elevated average concentrations of PM2,5, 6171,14 g/m3 in external areas and 68,24 g/m3 in internal areas. The burning of briquette revealed lower concentrations of PM2,5. The chemical elements: potassium, chlorine and sulfur were the most represented in terms of concentration. The results of the SEM (electro-microscopic sweep) revealed particles with an individual and spherical morphology, the conglomeration of spherical particles, flattened particles in the formation of fibers, the overlapping of layers and the clustering of particles with sponge-like qualities. Although in Brazil there are no existing parameters for PM2,5 exposure in internal areas, when compared with the established exposure parameters in Germany, the concentrations obtained within the three pizzerias exceeded those parameters. Concentration en masse of elements dangerous to health such as chrome and zinc were shown to be excessive. The rate of emissions of PM2,5 and black carbon due to the burning of logs were 0,38g/kg and 0,23g/kg, respectively; and for briquettes were 1,04g/kg and 0,37g/kg, respectively. The emissions of PM2,5 and black carbon were from 0,958t/year to 0,340t/year in the burning of briquettes and from 116,736t/year to 70,656t/year in the burning of timber logs

A queima de biomassa em fornos de pizzaria se constitui como importante fonte de poluição do ar. Entre outros tipos de poluentes emitidos, o material particulado finoMP2,5 se destaca como o mais agressivo à saúde humana, além de poder interferir no balanço radiativo global. Objetiva-se, desta forma, através de estudo de caso em três pizzarias na cidade de São Paulo, quantificar e caracterizar o MP2,5 emitido pela queima da biomassa na área interna (indoor) e externa (junto á chaminé). Dentre as três pizzarias, duas fazem uso da lenha de eucalipto e a outra faz uso do briquete, formado a partir da compactação de pedaços de biomassa, serragem, bagaço e outros resíduos madeireiros. As amostras foram coletadas utilizando-se o amostrador Minivol. A análise do material foi realizada por meio de técnicas complementares: gravimetria (para a concentração em massa), refletância (para a concentração de black carbon), fluorescência de raios-X (para a concentração elementar) e utilização do microscópio eletrônico de varredura (MEV) (para identificar a morfologia do material particulado). Além disso, foram feitas inferências na saúde do trabalhador quanto á exposição ao MP2,5, e por fim foi estimada as emissões de MP2,5 e black carbon dado o elevado número de pizzarias existentes na cidade de São Paulo. Os resultados apresentaram concentrações médias elevadas de MP2,5, 6171,14 g/m3 no ambiente externo, e 68,24 g/m3 no ambiente interno para as três pizzarias. A queima do briquete apresentou menores concentrações para MP2,5. Os elementos químicos potássio, cloro e enxofre foram os mais representativos em termos de concentração. Os resultados para o MEV revelaram partículas com morfologia esférica individual, conglomerado de partículas esféricas, partículas achatadas com o formato de fibras, sobreposição de camadas e aglomerados de partículas com aspecto esponjoso. Embora no Brasil não exista padrão de exposição para o MP2,5 em ambiente interno, quando comparado com o padrão de exposição da Alemanha, as concentrações obtidas nas três pizzarias são superiores. Concentrações em massa de elementos prejudiciais à saúde como o cromo e zinco se mostraram demasiadamente elevadas. Os fatores de emissão para o MP2,5 e black carbon provenientes da queima da lenha foram 0,38g/kg e 0,23g/kg, respectivamente; e para o briquete 1,04g/kg e 0,37g/kg respectivamente. As emissões de MP2,5 e black carbon foram de 0,958t/ano e 0,340t/ano para a queima do briquete e 116,736t/ano e 70,656t/ano para a queima da lenha / The burning of biomass in pizza ovens constitutes itself as an important source of air pollution. Compared with other types of pollutants emitted, the fine particulate matter PM2,5 highlights itself as one of the most aggressive to human health, besides the power to interfere with global radiative balance. Therefore, through the study of three São Paulo pizzerias, the quantification and characterization of PM2,5 emitted by the burning of biomass within internal areas and external (where chimney´s were present). Among the three pizzerias, two used eucalyptus timber logs while the remaining other used wooden briquettes; formed by the compression of biomass: chips and shavings and other wood residue. Samples were collected using Minivol. The analysis of the material was completed via complementary techniques: gravimetrically (to establish mass concentration) Reflectance (to establish black carbon concentration) X-ray fluorescence (to establish element concentration) and the use of an electro-microscopic sweep (SEM) (to indentify the morphology of the particulate matter). Beyond this, inferences were made about the health of workers exposed to PM2,5, by way of estimated emissions of PM2,5 due to the elevated number of pizzerias in São Paulo. The results from the three pizzerias revealed elevated average concentrations of PM2,5, 6171,14 g/m3 in external areas and 68,24 g/m3 in internal areas. The burning of briquette revealed lower concentrations of PM2,5. The chemical elements: potassium, chlorine and sulfur were the most represented in terms of concentration. The results of the SEM (electro-microscopic sweep) revealed particles with an individual and spherical morphology, the conglomeration of spherical particles, flattened particles in the formation of fibers, the overlapping of layers and the clustering of particles with sponge-like qualities. Although in Brazil there are no existing parameters for PM2,5 exposure in internal areas, when compared with the established exposure parameters in Germany, the concentrations obtained within the three pizzerias exceeded those parameters. Concentration en masse of elements dangerous to health such as chrome and zinc were shown to be excessive. The rate of emissions of PM2,5 and black carbon due to the burning of logs were 0,38g/kg and 0,23g/kg, respectively; and for briquettes were 1,04g/kg and 0,37g/kg, respectively. The emissions of PM2,5 and black carbon were from 0,958t/year to 0,340t/year in the burning of briquettes and from 116,736t/year to 70,656t/year in the burning of timber logs

Les particules atmosphériques sont responsables de 3,2 millions de morts par an, cette mortalité faisant suite à des cardiopathies, bronchopathies ou encore des cancers. De nombreuses études épidémiologiques et mécanistiques associent l’augmentation de la prévalence des cancers pulmonaires avec l’exposition à la pollution atmosphérique et aux particules fines (PM2.5), d’où leur classification très récente comme cancérogène avéré pour l’homme par le Centre International de Recherche contre le Cancer (CIRC groupe 1). Les mécanismes cellulaires et moléculaires impliqués dans la pathogénicité pulmonaire des polluants atmosphériques restent encore très controversés, ceci étant notamment lié à l’utilisation de modèles de culture cellulaire très éloignées des conditions in vivo. De plus, les PM2.5 présente une complexité physico-chimique (taille, nombre, morphologie et composition chimique) et une grande variabilité temporelle. En effet, ces particules sont constituées de nombreux polluants toxiques organiques, notamment des Hydrocarbures Aromatiques Polycycliques (HAP), ou encore des métaux, et ce à des teneurs parfois importantes. La complexité de leur composition rend les données toxicologiques difficilement interprétables, d’autant plus que la majorité des études toxicologiques publiées jusqu’à récemment ont souvent négligé la détermination de leur caractéristiques physico-chimiques.Mon projet de thèse a pour objectif d’évaluer le rôle des PM2.5, prélevées sur un site urbain (Lille), dans la cancérogenèse pulmonaire et ce, par une approche pluridisciplinaire qui permettra d’établir un lien étroit entre la physico-chimie et la toxicologie de ces particules.La première partie de mon projet est consacrée aux prélèvements des PM2.5, à Lille, au cours de deux saisons contrastées, et à l’évaluation de leurs principales caractéristiques physico-chimiques, à savoir leur granulométrie, leur composition chimique (métaux et HAP) ou encore leur bioaccessibilité dans des milieux de culture cellulaire ou des fluides bronchiques.La seconde partie consiste au développement d’un modèle de cellules épithéliales bronchiques humaines, issues de sujets sains et de patients atteints de Broncho-Pneumopathies Chroniques Obstructives (BPCO), différentiées à l’interface air/liquide, puis exposées de manière réitérée à des concentrations relativement faibles des PM2.5 prélevées à Lille. Ce modèle innovant permet de mieux intégrer un certain nombre de facteurs liés à la préexistence d’un état inflammatoire chronique et d’obtenir un état de différenciation cellulaire le plus proche possible des conditions d’exposition in vivo. Sur ce modèle cellulaire, après exposition, le phénotype inflammatoire, l’état de stress oxydatif ainsi que les modifications génétiques et épigénétiques sont étudiés.Les résultats de ce travail contribueront par une approche pluridisciplinaire à mieux comprendre les mécanismes moléculaires liés à la toxicité voire la cancérogénicité des PM2.5, et à expliquer pourquoi les individus atteints de BPCO sont plus sensibles que les sujets sains à l’exposition à long terme à des niveaux usuels de PM2.5. / Atmospheric particles are responsible for 3.2 million deaths per year, this mortality is due to heart diseases, bronchial diseases or cancers. Numerous epidemiological and toxicological studies associate the lung cancer prevalence increase with exposure to air pollution and particularly fine particulate matter (PM2.5). PM2.5 were recently classified as carcinogen to humans by International Agency for Research in Cancer (IARC group 1). Cellular and molecular mechanisms involved in air pollutants pulmonary pathogenicity are still very controversial. This is particularly related to the use of cell culture models far from in vivo conditions. In addition, PM2.5 have a physico-chemical complexity (size, number, morphology and chemical composition) and a high temporal variability. Indeed, these particles contain many toxic organic pollutants, including polycyclic aromatic hydrocarbons (PAH), or metals, and sometimes at significant levels. The complexity of their composition makes the toxicological datas difficult to interpret, especially as the majority of toxicological studies published until recently have often overlooked the determination of their physicochemical characteristics.My thesis project aims at assessing the role of PM2.5, sampled on an urban site (Lille), in lung carcinogenesis through a multidisciplinary approach which will establish a tight connection between chemistry and toxicology of these particles.The first part of my project consisted of the PM2.5 sampling, in Lille, during two contrasting seasons, and the evaluation of their main physical and chemical characteristics, as their size, chemical composition (metals and PAHs ) or their bioavailability in cell culture media or bronchial fluids.The second part consisted of the development of human bronchial epithelial cells from healthy subjects and patients with chronic obstructive pulmonary disease (COPD), differentiated in air / liquid interface conditions, and exposed to repeated low concentrations of PM2.5 collected in Lille. This innovative model better integrates a number of factors related to the pre-existence of a chronic inflammatory state and gets the closest cell differentiation state possible to the in vivo exposure conditions. On this cellular model, after exposure, the inflammatory phenotype, the oxidative state as well as genetic and epigenetic status were studied.Using a multidisciplinary approach, the results of this work will contribute to better understand the molecular mechanisms related to PM2.5 toxicity or carcinogenicity, and to explain why COPD patients are more sensitive than healthy people to PM2.5 long term exposure.