Sarcoidosis is a multisystem inflammatory disorder of unknown aetiology. The immune pathology is characterised by dysregulated T cell (T_H1) activity, macrophage activation and granuloma formation, resulting in systemic inflammation, and organ dysfunction. I hypothesised that, as the systemic precursor to the macrophage, altered monocyte activity in sarcoidosis may contribute to the early immune pathology of the disease. In this thesis, I examined their phenotype, four key monocytic functions: cytokine production, suppression of T cell proliferation, phagocytosis and fusion (as a precursor to granulomagenesis); and their gene expression profile compared to monocytes from healthy controls. My data show that the expanded monocyte compartment comprise a greater proportion of the inflammatory (CD14⁺⁺CD16⁺) and patrolling (CD14⁺CD16⁺⁺) subsets, increased TNFα and IL-12 and decreased IL-10 and IL-4 production in sarcoidosis compared with healthy controls. The IL-10 deficit renders the monocytes less able to regulate T cell proliferation or their own fusion to multinucleate giant cells, potentially contributing to T cell expansion and granuloma formation respectively. Additionally, sarcoidosis monocytes are less able to phagocytose inert material. I also showed that previously reported deficiency in invariant NKT cells and low serum vitamin D levels in sarcoidosis may be linked to reduced IL-10 production by monocytes. Vitamin D treatment in vitro restored most of these deficiencies and provides a potential therapeutic method for manipulating monocyte function and disease genesis in sarcoidosis.

A dissertation submitted to the Faculty of Science, University of the Witwatersrand, Johannesburg, in fulfillment of the requirements for the Master of Science degree. 2 November 2017. / Screening methodologies have identified specific targets that could serve as potential therapeutic markers in cancer drug design, and the Retinoblastoma binding protein 6 (RBBP6) which is predominately expressed in lung and breast cancers is one critical protein identified. This study seeks to understand the 3D structure of RBBP6 domains, with emphasis on cancer. Three of these domains have been studied in this project, i.e. the Domain With No Name (DWNN), RING Finger, and the p53-binding domain. The ubiquitin-like structure of the DWNN has implicated this domain as a ubiquitin-like modifier of other proteins such as p53, whilst the RING Finger domain has intrinsic E3 Ligase activity like MDM2 the prototypical negative regulator of p53. The DWNN and RING Finger domains have resolved solution NMR structures, whilst the p53-binding domain has none. Thus, the first initiative undertaken was to model the RBBP6 p53-binding domain using I-TASSER and eThread-Modeller web-severs. Our results demonstrated that this domain mainly constitutes of alpha-helices and loop structures. Structural quality validations of both I-TASSER and eThread-Modeller models were further assessed using Swiss-Model and ProSA (Protein structure analysis) web-servers. Analyses were focussed on specific statistical parameters (Anolea, DFire, QMEAN, ProCheck and the ProSA Z-score). Results from these analyses show that the first I-TASSER model is the best possible representation of the RBBP6 p53-binding domain depicting minimal deviation from native state. Furthermore, screening and docking studies were performed using Schrödinger-Maestro v10.7: Glide SP and drug-like molecules that would potentially serve as agonist or antagonist of RBBP6 were identified. / MT 2018

A Thesis submitted to the Faculty of Health Sciences (Internal Medicine), University of the Witwatersrand, in fulfillment of the requirements for the degree of Doctor of Philosophy. Johannesburg, 2017 / South Africa has the largest ARV treatment programme in the world, wherein highly active antiretroviral treatment (HAART) has improved the health related quality of life (HRQoL) in HIV/AIDS patients. On the contrary, cancers not previously associated with HIV/AIDS (non-Aids defining cancers; NADCs) have been shown to be increasing, compared to the AIDS defining cancers (ADCs). Lung cancer, as a NADC has been documented in the HIV/AIDS population as a leading malignancy. The poor understanding of the association between ARV drugs and lung cancer places a burden on public health, both globally and in South Africa (SA). Furthermore, the deregulation of the cell-cycle is one of the hallmarks of cancer, including lung cancer. The main aim of this study was to elucidate the effects of HAART components Efavirenz (EFV) and Lopinavir/ritonavir (LPV/r) on cell-cycle related genes in an in vitro lung cancer model. To achieve this, cellular based, molecular and Bio-Informatics approaches were employed. First, the cytotoxic effects of EFV (at 4, 13, 26, 50 μM) and LPV/r (at 10, 32, 50, 80 μM), for 24h, 48h and 72h on normal lung fibroblasts (MRC-5) and lung adenocarcinoma (A549) cells, were evaluated using the Alamar Blue (AB) assay. This was then followed by cell-impedance “xCELLigence” real-time cell analysis (RTCA) assay. This was done to determine the effects of EFV (at 4, 13, 50 μM) and LPV/r (at 10, 32, 80 μM) on cell viability, cell death and proliferation. Cell-cycle analysis using propidium iodide (PI) by Fluorescence-activated cell sorting (FACS) was done to quantify DNA present at each of the cell-cycle stages of the cell-cycle in response to ARV treatment. Subsequently, an apoptosis assay using Annexin V FITC and Propidium iodide (PI) dual staining by FACS was carried out to confirm and quantify the ARVs potential apoptotic effects. Then, 4′,6-diamidino-2-phenylindole (DAPI) staining was used to assess changes in nuclear morphology exerted by the ARVs’ effects. A more in depth interrogation of the cell-cycle was performed using a focussed gene array panel of some 84 human cell-cycle related genes. First, total RNA was isolated from both treated and untreated MRC-5 and A549 cells and reverse transcribed to cDNA for use as template in the PCR array reactions. From the array gene expression results, by convention a ±2 fold up-or-down-regulation was used as the basis of target selection. Following this, a real-time quantitative PCR (RT-qPCR) validation of selected genes of interest was done to quantify and confirm the PCR array results. This was followed by in-silico Bio-informatics analysis to map the molecular pathways regulated by the identified targets. For this purpose, STRING, Database for Annotation, Visualization and Integrated Discovery (DAVID), Reactome and Ingenuity Pathway Analysis (IPA) databases were used. Interestingly, double-edged oncogenic properties of both EFV and LPV/r at different concentrations were identified. The proliferative effects of EFV at 4, 13μM and LPV/r at10 μM, were elucidated, while 26, 50μM of EFV, and 32μM of LPV/r had slight inhibitory effects on cell proliferation. LPV/r at concentrations of 50 and 80μM exerted cytotoxic effects on the cells, as demonstrated by the AB and xCELLigence RTCA assays. Cell-cycle analysis using PI staining, particularly showed cell-cycle arrest at 32μM LPV/r, and a shift to G2/M by 13μM EFV, plasma relevant doses, compared to the untreated cells. An increasing apoptosis percentage was observed with increasing LPV/r concentrations, that is, 80μM LPV/r raised the apoptosis percentage almost two-fold compared to 32μM. This was coupled by necrosis, observed in a time-dependant manner. DAPI staining confirmed loss of nuclear integrity post ARV exposure, suggesting that both EFV and LPV/r impose damage to the genomic DNA. To further assess the observed changes in nuclear morphology, the effects of EFV and LPV/r on the expression of an arrayed panel of human cell-cycle genes in cancer and normal lung cells was determined. Significantly differentially expressed targets were identified and further quantified and confirmed by RT-qPCR. Such targets included ATM, p53, cyclin-dependant kinase inhibitors (CDKIs), such as, p21, aurora kinase B (AURKB), Mitotic Arrest Deficient-Like 2 (MAD2L2) and the apoptosis related gene, caspase 3 (CASP3). Bio-Informatics analyses revealed close and direct protein-protein interactions (PPIs) between these targets, notably, with change in interaction between the gene products involved in DNA repair mechanisms, observed between ARV treated and untreated groups, as illustrated by STRING interactions. DAVID, Reactome and IPA analysis showed changes in expression of genes related to stress and toxicity and DNA damage response genes. In particular, ATM, p53 and its downstream targets such as GADD45A (growth arrest and DNA damage inducible alpha) gene were up-regulated by ARV treatment, while cyclin/CDK activity was down-regulated, resulting in reduced cell proliferation. Thus in summary, both EFV and LPV/r altered the expression levels of cell-cycle related genes, influencing overall cellular health, acting to either inhibit or stimulate cell proliferation. This suggests EFV’s and LPV/r’s proliferative and inhibitory roles in the proliferation of lung cells. Moreover, future directions can include the transfection of lung cells with HIV provirus followed by treatment of the cells with the same ARVs under study. This could be substantiated by including HIV positive patient samples on and off ARV drug treatment with lung cancer, including HIV negative patients with cancer as one of the controls. / MT2018

Les anticorps monoclonaux (Acm) ont révolutionné la prise en charge de nombreuses maladies inflammatoires chroniques. L’administration par voie systémique des Acm ne semble pas optimale pour le traitement des maladies respiratoires. Ce travail a eu pour objectif d’étudier le comportement des anticorps après leur administration par voie pulmonaire. Le cetuximab, un anticorps anti-EGFR, a été étudié dans un modèle murin de tumeur pulmonaire bioluminescente et chez le macaque. Le G6-31, un anticorps anti-VEGF, a été étudié dans un modèle murin transgénique de tumeur pulmonaire spontanée. Les résultats montrent que les anticorps administrés par voie pulmonaire sont efficaces, persistent durablement dans le poumon et passent peu dans le compartiment sanguin. L’administration par voie pulmonaire d’Acm pourrait donc augmenter l’index thérapeutique de ces médicaments. Ces résultats ouvrent la voie pour l’administration par voie pulmonaire d’Acm dans les pathologies respiratoires en général. / Monoclonal antibodies (mAbs) modified profoundly the treatment of many chronic inflammatory diseases. Systemic administration of mAbs does not seem to be optimal for the treatment of respiratory diseases. This work aims at studying the fate of mAbs after pulmonary delivery. The lung delivery of Cetuximab, an anti-EGFR antibody, was assessed in an orthotopic mouse model of lung tumor and in macaques. G6-31, an anti-VEGF antibody, was studied in a transgenic murine model of spontaneous lung tumors. The results showed that mAbs, after pulmonary delivery, were pharmacologically effective, persisted durably into the lung and passed slowly into the bloodstream. Pulmonary delivery of mAbs might increase the therapeutic index of these drugs. Altogether, these results open the way for the pulmonary administration of mAbs in respiratory disorders

As estrongiloidíases são parasitoses intestinais causadas por várias espécies do gênero Strongyloides e apresentam distribuição cosmopolita. O objetivo deste estudo foi investigar a interferência do tratamento diário com dexametasona no ciclo pulmonar durante a infecção por Strongyloides venezuelensis em ratos. Investigamos o efeito do tratamento com glicocorticóides na migração de eosinófilos, mastócitos e macrófagos no parênquima pulmonar. Demonstramos ainda, como os efeitos do tratamento diário com a dexametasona atuam na formação do granulomas. Três principais aspectos foram encontrados: 1) Aumento da inflamação hemorrágica, provocado pela passagem das larvas para o espaço alveolar; 2) Significante redução da migração de eosinófilos e mastócitos no eixo axial pulmonar e, 3) Interferência crucial na migração de eosinófilos para os focos de passagem das larvas e, conseqüente, impedimento da organização do granuloma, sugerindo que a formação da rede de fibras reticulares deve ter um papel crucial no aprisionamento do parasita, favorecendo um melhor desempenho das células inflamatórias na eliminação do mesmo. Este trabalho mostrou que o uso de drogas com ação imuno-modulatória, tais como a dexametasona, pode interferir na morbidade no ciclo pulmonar durante a infecção por S. venezuelensis, contribuindo para revelar os mecanismos envolvidos na sua patogênese. / The aim of this study was investigate the interference of dexamethasone treatment in the pulmonary cycle of Strongyloides venezuelensis infection in rats. The immunomodulatory effects on the inflammatory process generated by the passage of the larvae into pulmonary parenchyma during their migration were analyzed. Three principal effects were found: 1) Increased alveolar hemorrhagic inflammation provoked by the passage of larvae into the alveolar spaces; 2) Significant decrease of eosinophil and mast cell migration to the axial septum of the lungs and 3) Impaired eosinophil migration to the parasite foci and deficient formation of the reticular fiber network, interfering with the granuloma organization. This study demonstrated that the use of drugs with immunomodulatory actions, such as dexamethasone, in addition to interfere with the morbidity from the pulmonary cycle of S. venezuelensis infection, can contribute to reveal the mechanisms involved in its pathogenesis.

O organismo apresenta diversas reações integradas em resposta à injúria, com o objetivo de restaurar a homeostase. Dentre esses mecanismos, destaca-se a resposta inflamatória, já que sem ela a injúria que acometeu o organismo dificilmente seria resolvida. Todo procedimento cirúrgico representa uma injúria para o organismo. As técnicas cirúrgicas minimamente invasivas tendem a gerar respostas deletérias mais brandas aos animais; as cirurgias torácicas envolvem, porém, um trauma adicional caracterizado pelo colapso pulmonar, que se faz necessário mesmo nas técnicas minimamente invasivas. Foram realizados em humanos diversos estudos que avaliam as vantagens desta técnica em relação à toracotomia; na espécie eqüina, a toracoscopia vem sendo aplicada na rotina hospitalar desde a década de 80 e relatos afirmam ser um procedimento cirúrgico seguro. No entanto, não foram descritos dados referentes à resposta inflamatória decorrente deste procedimento. Desta forma, este estudo visou avaliar a resposta inflamatória sistêmica e local decorrente da técnica, na qual a indução e redução do colapso pulmonar foram feitas de maneira controlada. Foram utilizados 12 eqüinos hígidos, de raça e idade variadas, de ambos os sexos. Os animais foram divididos em dois grupos, submetidos à toracoscopia com duração de 30 e 60 minutos (grupos 1 e 2, respectivamente). As pressões intratorácicas foram controladas em todos os procedimentos, permitindo controle da indução e redução do colapso pulmonar, diminuindo assim a ocorrência de pneumotórax residual. Amostras de sangue, líquido pleural e lavado bronco alveolar foram coletadas antes do procedimento (M1), e duas (M6), seis (M7) e 24 horas (M8) após o início do colapso pulmonar. Estas foram usadas para avaliação da resposta inflamatória por meio de mensuração da produção de espécies reativas de oxigênio (ERO) pelas células presentes em cada tipo de amostra, utilizando-se como metodologia a citometria de fluxo, e para a quantificação de citocinas por ELISA (IL-1β) ou por ensaio biológico (TNF-α e IL-6). Para análise dos resultados foi considerada a possível influência dos fatores grupo e momento experimental em cada uma das variáveis estudadas. Os valores de burst oxidativo apresentados pelas células das amostras em questão não sofreram influência dos fatores avaliados. Não foi possível avaliar a variação dos níveis de IL-1β pela metodologia aplicada. Os níveis de TNF-α sofreram influência estatisticamente significativa do fator momento experimental nas amostras de lavado broncoalveolar e líquido pleural, sendo que M6 apresentou maiores níveis desta citocina; não foi observada influência desses fatores nos níveis plasmáticos da mesma. Em relação a IL-6, foi observada influência do fator momento experimental nas amostras de plasma e lavado broncoalveolar, e de ambos os fatores nas amostras de líquido pleural, sendo que os níveis dessa citocina apresentaram um padrão de aumento mais tardio que o apresentado pelo TNF-α. Concluímos que o colapso pulmonar induzido por infusão de gás CO2 em eqüinos hígidos provocou uma reação inflamatória localizada na cavidade torácica, em que não foram observadas diferenças significativas entre os dois grupos experimentais. Assim, a cirurgia torácica videoassistida em eqüinos com até 60 minutos de duração pode ser indicado sem que fatores oriundos da técnica cirúrgica agravem a enfermidade. Uma vez que não foi observada influência dos fatores estudados nos valores de pressão intratorácica, acreditamos que a metodologia aplicada foi adequada para a realização da técnica, provendo adequado controle e redução da ocorrência de pneumotórax residual, que somente foi observado nos casos onde ocorreu pneumotórax bilateral durante o procedimento cirúrgico. / Organisms present several integrative reactions to injury, aiming at the reestablishment of homeostasis. Among these mechanisms is the inflammatory reaction, for without it the initial injury would hardly be solved. Every surgical procedure represents an injury for living organisms. Minimally invasive surgical techniques tend to induce milder negative reactions in animals; nonetheless, thoracic surgery leads to an additional trauma characterized by lung collapse, required even in minimally invasive surgical techniques. Several human studies have assessed the advantages of this technique compared to thoracotomy; in horses, the use of thoracoscopy has increased in routine procedures since the 1980s, and reports point to the safety of its usage. Nevertheless, no data regarding the inflammatory reaction induced by this procedure has been reported. In this matter, our study aimed at the evaluation the local and systemic inflammatory response associated with this technique, in which the induction and reduction of lung collapse were carefully controlled. 12 healthy horses of varied breeds, age, and of both genders were used. Animals were divided in two groups, and submitted to thoracoscopy for 30 or 60 minutes (groups 1 and 2, respectively). Intrathoracic pressure was controlled in every procedure, allowing the induction and reduction of lung collapse, reducing the chance of residual pneumothorax. Samples of blood, pleural fluid, and bronchoalveolar fluid were harvested before the procedure (M1), and two (M6), six (M7) and twenty-four hours (M8) after the onset of lung collapse. These samples were employed for the evaluation of the inflammatory reaction through measurement of reactive oxygen species (ROS) by cells present in each sample, using flow cytometry, and for cytokine quantification by ELISA (IL-1β) or bioassay (TNF-α and IL-6). For the analysis of our results the factors group and experimental timepoint were considered for every variable studied. Values of oxidative burst displayed by cells in each sample did not depend on the factors analyzed. Variation of IL-1β levels could not be detected by the methods employed here. Levels of TNF-α were statistically influenced by the factor experimental timepoint in pleural fluid and bronchoalvolar fluid, and the highest levels of this cytokine were observed in M6; no influence of these factors on its plasmatic levels was observed. Regarding IL-6, we found an influence of the factor timepoint in samples of plasma and bronchoalveolar fluid, and an influence of both factors in samples of pleural fluid, being the highest levels of this cytokine found later than the TNF-α peak. We conclude that the lung collapse induced by CO2 in healthy horses caused an inflammatory reaction restricted to the thoracic cavity, without significant differences between groups 1 and 2. Thus, video-assisted thoracic surgery in horses lasting up to 60 minutes can be recommended leads to no signs of direct negative effects of the technique that could worsen the patient condition. Since we found no influence of either factor studied on values of thoracic pressure, we conclude that the methods employed for the surgery were adequate, supplying sufficient control over the occurrence of residual pneumothorax, observed only in cases of bilateral pneumothorax during the procedure.

O câncer é uma doença que pode ser caracterizada pelo crescimento desordenado de células malignas, que podem se disseminar pelo organismo tornando-se agressivas e até mesmo incontroláveis. O câncer de pulmão é uma doença caracterizada por uma baixa sobrevida, em torno de 15% em cinco anos. O presente trabalho avaliou o perfil epidemiológico de câncer de pulmão na região de Governador Valadares e os fatores de risco associados, determinando a frequência do câncer de pulmão no período de 2010 a 2015. É um estudo observacional, analítico e retrospectivo com característica quantitativa que foi realizado a partir do banco de dados do Núcleo de Especialistas em Oncologia, foram analisados 7035 prontuários de pacientes preenchidos eletronicamente pelas equipes de saúde. A amostra selecionada corresponde a 227 pacientes com diagnóstico de câncer de Pulmão e suas sub localizações anatômicas sendo aplicado em dados estatísticos e encontrando alguns resultados relevantes como: relação entre sexo e Histórico familiar onde 65 pacientes afirmaram que possuíam casos de câncer na família. Outro fator é o consumo de bebida alcoólica e câncer de pulmão onde 27,65% entram em contato com a bebida alcóolica. Foi verificado que 161 pacientes entraram em contato com o tabaco diretamente ao longo da vida desenvolvendo o câncer de pulmão. Outro dado importante que 176 pacientes vieram do Sistema Único de Saúde, tornando-se uma importante via de atendimento aos pacientes com câncer de pulmão. / Cancer is a disease that can be characterized by the disordered growth of malignant cells, which can spread through the body becoming aggressive and even uncontrollable. Lung cancer is a disease characterized by a low survival rate, around 15% in five years. The present study aims to evaluate the epidemiological profile for lung cancer in the region of Governador Valadares and associated risk factors, determining the frequency of lung cancer in the period from 2010 to 2015. It is an observational, analytical and retrospective study with a quantitative trait which was carried out from the database of the Nucleus of Specialists in Oncology. 7035 medical records of patients, filled electronically by health teams were analyzed. The selected sample corresponds to 227 patients diagnosed with Lung cancer and its sub-anatomical locations being applied in statistical data and finding some relevant results such as: relationship between sex and family history where 65 patients stated that they had cases of cancer in the family. Another factor is the consumption of alcoholic beverage and lung cancer where 27.65% come in contact with the alcoholic beverage. It was verified that 161 patients came into contact with tobacco directly throughout their lives developing lung cancer. Another important fact is that 176 patients came from the Unified Health System, becoming an important route of care for patients with lung cancer.

Since the release of the Cyberknife Multileaf Collimator (CK-MLC), it has been a constant concern on the realistic dose differences computed with its early-available Finite Size Pencil Beam algorithm (FSPB) from those computed by using industry well-accepted algorithms such as the Monte Carlo (MC) dose algorithm. In this study dose disparities between FSPB and MC dose calculation algorithms for selected CK-MLC treatment plans were quantified. The dosimetry for planning target volume (PTV) and major organs at risks (OAR) was compared by calculating normalized percentage deviations (Ndev) between the two algorithms. It is found that the FSPB algorithm overestimates D95 of PTV when compared with the MC algorithm by averaging 24.0% in detached lung cases, and 15.0% in non-detached lung cases which is attributed to the absence of heterogeneity correction in the FSPB algorithm. Average dose differences are 0.3% in intracranial and 0.9% in pancreas cases. Ndev for the D95 of PTV range from 8.8% to 14.1% for the CK-MLC lung treatment plans with small field (SF ≤ 2x2cm2). Ndev is ranged from 0.5-7.0% for OARs. / Includes bibliography. / Thesis (M.S.)--Florida Atlantic University, 2018. / FAU Electronic Theses and Dissertations Collection

A avaliação da técnica de cintilografia da perfusão pulmonar foi realizada em 10 cães machos, da raça Rottweiler, radiograficamente normais e soronegativos para dirofilariose, utilizando-se o macroagregado de albumina sérica humana marcado com tecnécio-99m ([99mTc](MAA)) como radiofármaco. Cada animal sedado foi submetido a três diferentes tratamentos, com administração de 50.000, 100.000 e 300.000 partículas de MAA. As imagens obtidas com as doses variadas do radiofármaco, foram comparadas de forma qualitativa e quantitativa, incluindo nesta última a avaliação do índice de perfusão pulmonar e homogeneidade das imagens. Não foram observadas diferenças significativas entre as imagens durante a avaliação visual e cálculo da quantificação relativa da perfusão pulmonar. Porém, o cálculo da uniformidade integral demonstrou diferença significativa na homogeneidade da imagem pulmonar entre as diferentes doses de MAA. Pode-se concluir que existe um aumento na homogeneidade da imagem diretamente relacionado ao número de partículas de magroagregado de albumina injetado, ainda que tal diferença não tenha sido percebida pela análise qualitativa. / The evaluation of pulmonary perfusion scintigraphy technique was accomplished in 10 Rottweiler male dogs, with normal thoracic radiographs and negative for Dirofilaria immitis, using macroaggregated human serum albumin tagged with technetium-99m ([99mTc](MAA)) as radiopharmaceutical. Each sedated animal was subimited to 3 different treatments, with administration of 50.000, 100.000 and 300.000 particles of MAA. The obtained images with diverse radiopharmaceutical doses were qualitative and quantitative compared, including in this the evaluation of radiopharmaceutical distribution and the homogeneity index. There were observed no significative differences between the images during the visual evaluation and calculation of the relative quantification of the lung perfusion. However, the integral uniformity calculation demonstrated significative difference at the homogeneity of the lung image between the different MAA doses. That leads to the conclusion that there is an increase at the images homogeneity directly related to the number of albumin macroaggregated particles injected, though difference has not been realized by the qualitative analysis.

É feita a análise da evolução de provas funcionais ventilatórias de dois grupos de crianças clinicamente sadias, residentes no Município de Cubatão, examinadas inicialmente em dois estudos transversais realizados respectivamente em 1983 (verão) e em 1985 (inverno). O princípio epidemiológico que norteou essa pesquisa foi a realização de um estudo de Coorte Não-Controlada, ou mais apropriadamente, um Estudo Ecológico Longitudinal, onde esses dois grupos de crianças foram anualmente submetidos a exames espirométricos no período de 1987 a 1989, mantida a estrita sazonalidade, ou seja, o Grupo de 1983 foi sempre reexaminado no verão, enquanto que o Grupo de 1985 sempre no inverno. Aproximadamente 1.110 crianças, oriundas de todas as áreas do Município foram submetidas a provas de função pulmonar utilizando-se espirômetro seco, com especial ênfase na análise do comportamento da Capacidade Vital Forçada (CVF), do Volume Expiratório Forçado no Primeiro Segundo (VEF1,0), do \"Peak-Flow\" ou Pico de Fluxo Expiratório (PFE), e do Fluxo Médio Expiratório Forçado (FMF25-75 por cento ), todos considerados como indicadores sensíveis às influências dos níveis de poluição atmosférica registrados em Cubatão. As informações concernentes à poluição do ar foram obtidas através dos relatórios de pesquisas efetuadas pela Companhia de Tecnologia de Saneamento Ambiental do Estado de São Paulo (CETESB) e envolveram a análise das estimativas de emissões das indústrias prioritárias de Cubatão, das concentrações horárias de material particulado (MP), dióxido de enxofre (SO2) e do ozona (O3) registradss nas estações amostradoras de Vila Parisi, Cubatão-Centro e Vila Nova no período de Novembro de 1983 a Dezembro de 1989. Também integrou o contexto de análise, a avaliação das principais metas do Programa de Controle de Poluição do Ar instituído pela CETESB na região a partir de 1984, com o objetivo de se verificar se as reduções pretendidas nos níveis de poluição do ar se fizeram acompanhar de melhorias nas provas funcionais pulmonares das crianças estudadas. Verificou-se que os episódios agudos de poluição do ar, principalmente devidos ao material particulado, mostraram algum decréscimo. No entanto, aqueles devidos a oxidantes fotoquímicos, representados pelos níveis de ozona, tiveram progressivo incremento no período de 1984 a 1988, tanto em relação ao número de episódios, como na persistência e gravidade dos mesmos. Os resultados espirométricos indicaram que em ambos os grupos de crianças a função pulmonar mostrou decrementos significativos, com perdas em tomo de 5 a 8 por cento ao ano, em média, quando comparados com os valores inicialmente registrados por ocasião dos estudos transversais. Apesar das reduções terem sido observadas em todas as variáveis espirométricas, os maiores decrementos verificaram-se principalmente nas medidas de fluxo (PFE e FMF25_75 por cento ), e coincidiram com o ano em que foram assinalados os mais graves episódios de poluição devida a oxidantes fotoquímicos. Os bairros Cota 95, Cota 200, Jardim das Indústrias e Vila Natal, localizados na área de influência do núcleo industrial químicofpetroquímico sobressairam-se como os mais críticos em função dos piores resultados espirométricos apresentados ao longo de todo o estudo. Pôde-se concluir que apesar da função pulmonar das crianças ainda não ter atingido níveis considerados como patológicos, mesmo registrando valores inferiores aos limites da normalidade nas variáveis de fluxo no ano de 1988, verificou-se que de ano para ano a função pulmonar vem decrescendo progressivamente indicando que esta vai sendo afetada pela exposição as poluentes da região e que as medidas de controle da poluição instituídas em Cubatão não tiveram a eficácia esperada. Continuando nessa mesma trajetória evolutiva, isso poderá acarretar sérios e irreparáveis prejuízos à saúde da população. É necessário, portanto, a adoção de urgentes medidas para a melhoria da qualidade do ar em Cubatão nos anos futuros, no intuito de prevenir sérios agravos à Saúde Pública. / The purpose of this study was to investigate the effects of exposure to air pollution on lung function of children. Two groups of clinically healthy children, living at different areas of the city of Cubatão, who had been submitted to lung function tests in a previous cross-sectional study (1983 summertime and 1985 wintertime) were annually reexamined using the same type of test during the period 1987 to 1989. On epidemiological basis this is a longitudinal study, where every individual of the two groups of children was measured at each ocasion, always in the same season of the previous examination. About 1,110 children from all areas of the city were examined once a year using dry spirometer, with special emphasis on FVC, FEV 1,0, PEF and FMF25-75 per cent measurements, since they were considered as those which could be most affected by the local air pollution. Information regarding the conditions of air pollution were obtained from the CETESB\'s written reports. They include the estimate emissions of the main industries of the region; the hourly concentrations of particulate matter, sulfur dioxide and ozone measured in the sampling stations located in Vila Parisi, Cubatão-Centro and Vila Nova during the October/1983 to December/1989 period and also the results of the Source Control Strategy introduced by CETESB since 1984. It was observed that the acute episodes of air pollution due to PM were reduced in number. However, those due to photochemicaf oxidants, mainly represented by ozone leveis, were progressively more frequent during the period from 1984 to 1988; both their number and their severity increased during this period. Spirometric results shows that in both groups of children the lung function was significantly impaired, with losses of 5 to 8 per cent per year, when compared with the initial values of the cross-sectional studies. Despite the fact that all lung function parameters decline, the flow (PFE and FMF2s-7s per cent ) values were those most affected and closely related to the most serious episodes of air pollution due to photochemical oxidants mainly those observed in 1988. Children living in the areas of Cota 95, Cota 200, Jardim das Indústrias and Vila Natal, situated in the nearest area of influence of the chemical and petrochemical industries, presented worst spirometric results than children living in other places of Cubatão. The lung function of the examined children did not attain pathological values, despite the fact of presenting the worst results in flow parameters during the year of 1988. It was observed that their lung function is progressively impaired year by year, a clear indication of the progressive effects of air pollution on their lung function, and if such impairment continues there will carne the time when lung function will probably reach a pathologicallevel. It is concluded that there is an urgent need of improving the quality of air of Cubatão to avoid serious Public Health problems in a quite near future.