H ιδιοπαθής θρομβοπενική πορφύρα είναι ένα αυτοάνοσο νόσημα που χαρακτηρίζεται από χαμηλό αριθμό αιμοπεταλίων και αιμορραγίες. Επιπλέον αυτή η ασθένεια κατηγοριοποιείται σε οξεία (όταν διαρκεί λιγότερο από έξι μήνες) και χρόνια μορφή. Η λεπτίνη είναι μια ορμόνη/κυτταροκίνη που παράγεται από τα αδιποκύτταρα και ρυθμίζει την όρεξη και τον μεταβολισμό. Ως κυτταροκίνη η λεπτίνη προάγει την Th1 απόκριση και παίζει πολύ σημαντικό ρόλο στα αυτοάνοσα νοσήματα όπως έχει παρατηρηθεί σε πολλά μοντέλα ζώων. Στην εργασία αυτή μελετήσαμε τον ρόλο της λεπτίνης στην παιδική ιδιοπαθή θρομβοπενική πορφύρα (ΙΘΠ). Από τα πειράματά μας διαπιστώσαμε ότι τα επίπεδα της λεπτίνης συσχετίζονται αρνητικά με τον αριθμό των αιμοπεταλίων των ασθενών. Επιπλέον αποδείξαμε ότι στην ασθένεια που μελετήσαμε η λεπτίνη έχει αντί-φλεγμονώδη ρόλο αφού επάγει την έκφραση της IL-10 από το μονοκύτταρα Το μόριο της εκλυτικής ορμόνης της κορτικοτροπίνης (CRH) εκφράζεται κυρίως στον υποθάλαμο και ενεργοποιεί μέσω του άξονα υποθάλαμος-υπόφυση-επινεφρίδια τα γλυκοκορτικοειδή τα οποία έχουν ανοσοκατασταλτική δράση. Η CRH που εντοπίζεται στην περιφέρεια έχει αντιθέτως προ-φλεγμονώδη δράση. Εμείς μετρήσαμε τα επίπεδα της CRH στο πλάσμα υγιώς και ασθενών δοτών και παρατηρήσαμε ότι στους υγιείς δότες η CRH έχει την ικανότητα να ρυθμίζει αρνητικά την έκφραση της λεπτίνης. Ο έλεγχος όμως αυτός χάνεται στους ασθενείς με αποτέλεσμα τα επίπεδα τα λεπτίνης αυξάνονται στον ορό τους / Ιdiopathic thrombocytopenic purpura is an autoimmune disease characterized by a low platelet count and bleeding. Moreover this disorder is classified as acute (of six month or less duration) or chronic. Leptin is an adipocyte-derived hormone/cytokine that regulates food intake and basal metabolism. As a cytokine leptin promotes T helper 1 (TH1)-cell differentiation and can modulate the onset and progression of autoimmune responses in several animal models of disease. Here, we review the role of leptin in childhood idiopathic thrombopenic purpura (ITP). We found that leptin levels negatively correlated with platelet numbersand also that it plays an active anti-inflammatory role by promoting IL-10 secretion by monocytes. Corticotropin-Releasing Hormone (CRH) CRH, the hypothalamic component of the hypothalamic-pituitary,adrenal axis, attenuates inflammation through stimulation of glucocorticoid release, whereas peripherally expressed CRH acts as a proinflammatory mediator. We measured CRH levels in the plasma of children suffering from ITP and in the plasma of the paediatric controls, and we found that in controls CRH down-regulates leptin’s expression but not in patients.

Η σύνθεση της λεπτίνης γίνεται κατά κύριο λόγο από τα αδιποκύτταρα και η δράση της είναι να περιορίζει την πρόσληψη της τροφής και να προάγει τον καταβολισμό του λίπους. Έχει δειχτεί, επίσης, ότι η λεπτίνη προάγει την ενεργοποίηση των μονοκυττάρων και των Τ λεμφοκυττάρων in vitro, και σε πειραματικά μοντέλα (ποντίκια) αυτοάνοσων νοσημάτων συμμετέχει στην επαγωγή της ανοσολογικής απάντησης, πιθανότατα μέσω της κλωνικής έκπτυξης και της διατήρησης παθολογικών Τh1 λεμφοκυττάρων. Για τη διερεύνηση των δράσεων της λεπτίνης στην Αυτοάνοση Ιδιοπαθή Θρομβοπενική Πορφύρα της παιδικής ηλικίας, μετρήσαμε τα επίπεδα της λεπτίνης στο πλάσμα 18 παιδιών με οξεία ΙΘΠ πριν, μετά τη θεραπεία και κατά τη διάρκεια της ύφεσης της νόσου, και τα συγκρίναμε με τα επίπεδα στο πλάσμα 18 υγιών μαρτύρων, ερευνώντας παράλληλα το κατά πόσον τα επίπεδα αυτά σχετίζονται με τη δραστηριότητα της νόσου. Παρατηρήσαμε ότι τα επίπεδα της λεπτίνης του πλάσματος σε ασθενείς με ενεργό νόσο είναι κατά 6 φορές πιο αυξημένα (μέση τιμή 64ng/ml) σε σχέση με την ομάδα ελέγχου (μέση τιμή 11ng/ml). Η χορήγηση ενδοφλέβιας ανοσοσφαιρίνης G προκάλεσε ελάχιστη πτώση των τιμών της λεπτίνης στο πλάσμα (μέση τιμή 57ng/ml) ενώ η θεραπεία με κορτικοστεροειδή προκάλεσε πτώση των τιμών της λεπτίνης σε επίπεδα μικρότερα από την ομάδα ελέγχου (μέση τιμή 6ng/ml). Κατά την ύφεση της νόσου τα επίπεδα της λεπτίνης ήταν ίδια με την ομάδα ελέγχου (μέση τιμή 8ng/ml). Τα επίπεδα της λεπτίνης παρουσίασαν αρνητική συσχέτιση με τον αριθμό των αιμοπεταλίων, τις τιμές του TGF-β και τα επίπεδα γονιδιακής έκφρασης της IL-4. Αντίθετα, τα επίπεδα της λεπτίνης ακολουθούσαν τα μοτίβα της έκφρασης της IL-2, IFN-γ και IL-10. Ανασυνδυασμένη λεπτίνη προστέθηκε σε καλλιέργειες μονοπύρηνων κυττάρων του περιφερικού αίματος, όπου και φάνηκε ότι επάγει την έκφραση IL-10. Σύμφωνα με πειράματα που διενεργήθηκαν με απομονωμένους πληθυσμούς μονοκυττάρων, η IL-10 φαίνεται ότι προέρχεται από τα μονοκύτταρα. Υποστηρίζουμε ότι στην Αυτοάνοση Ιδιοπαθή Θρομβοπενική Πορφύρα της παιδικής ηλικίας, η λεπτίνη,εκτός των άλλων, παρουσιάζει αντιφλεγμονώδη δράση προάγοντας την έκκριση IL-10 από τα μονοκύτταρα. / Leptin is synthesized by adipocytes to limit the intake of food and promote the breakdown of fat. Leptin was also shown to promote monocyte and T-cell activation in vitro, and contribute to the induction and propagation of inflammation in murine models for autoimmune diseases, probably through the expansion and maintenance of pathogenic Th1-cell populations. To assess the role of leptin in the human autoimmune disease childhood Idiopathic Thrombocytopenic Purpura (ITP), we measured leptin levels in the plasma of 18 children suffering from acute ITP before, after therapy and in remission, and 18 healthy age- and Body Mass Index-matched controls, and investigated if and how these correlate with disease activity. We observed a 6-fold increase in plasma leptin (mean 64ng/ml) in the patients with active disease compared to the controls (mean 11ng/ml). Intravenous Immunoglobulin G treatment resulted in a slight decrease in plasma leptin (mean 57ng/ml) while steroid treatment brought down leptin to below control levels (6ng/ml). In remission, leptin levels were within control range (mean 8ng/ml). Leptin levels negatively correlated with platelet numbers, plasma TGF-β and IL-4 gene expression levels. In contrast, leptin levels followed the patterns of IL-2, IFN-γ and IL-10 expression. Recombinant leptin added alone to the patients’ peripheral blood mononuclear cell cultures, induced IL-10 only. Experiments with purified cells identified the monocytes as the exclusive source of leptin-induced IL-10. We propose that in the human autoimmune setting of childhood ITP, leptin plays an active anti-inflammatory role by promoting IL-10 secretion by monocytes.

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Made available in DSpace on 2015-07-22T20:50:53Z (GMT). No. of bitstreams: 0 Previous issue date: 2009-04-29. Added 1 bitstream(s) on 2015-08-11T03:26:20Z : No. of bitstreams: 1 Publico-165a.pdf: 463473 bytes, checksum: cae240c8ee591f50351d96ca3258bfba (MD5). Added 1 bitstream(s) on 2015-08-11T03:26:20Z : No. of bitstreams: 2 Publico-165a.pdf: 463473 bytes, checksum: cae240c8ee591f50351d96ca3258bfba (MD5) Publico-165b.pdf: 155628 bytes, checksum: 1115706461101400dcec7e30309c015b (MD5). Added 1 bitstream(s) on 2015-08-11T03:26:20Z : No. of bitstreams: 3 Publico-165a.pdf: 463473 bytes, checksum: cae240c8ee591f50351d96ca3258bfba (MD5) Publico-165b.pdf: 155628 bytes, checksum: 1115706461101400dcec7e30309c015b (MD5) Publico-165c.pdf: 1838976 bytes, checksum: 98bc6262f927468869ae5e34cde1918a (MD5). 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Added 1 bitstream(s) on 2015-08-11T03:26:20Z : No. of bitstreams: 5 Publico-165a.pdf: 463473 bytes, checksum: cae240c8ee591f50351d96ca3258bfba (MD5) Publico-165b.pdf: 155628 bytes, checksum: 1115706461101400dcec7e30309c015b (MD5) Publico-165c.pdf: 1838976 bytes, checksum: 98bc6262f927468869ae5e34cde1918a (MD5) Publico-165d.pdf: 1269518 bytes, checksum: f1bbb32c8edea554dfa6517033d47653 (MD5) Publico-165e.pdf: 1520227 bytes, checksum: 275186328f675001df3bba84180ce117 (MD5) / Contexto: A síndrome das pernas inquietas (SPI) é uma desordem caracterizada por uma angustiante necessidade de movê-las e, às vezes, mover também outras partes do corpo, geralmente acompanhada de desconforto ou dor. O tratamento desta síndrome com agonistas dopaminérgicos tem sido reconhecido como terapêutica de primeira linha, porque parece eficaz com base em princípios fisiopatológicos; vários grupos farmacológicos compreendem seu tratamento. Objetivos: Avaliar se intervenções farmacológicas são eficazes e seguras para o tratamento da SPI. Método: Revisão Sistemática Cochrane de estudos randomizados ou quasirandomizados sobre agentes farmacológicos utilizados no tratamento da SPI. Foram avaliados os seguintes desfechos para cada fármaco: alívio dos sintomas medido pela escala de gravidade para a síndrome das pernas inquietas (IRLSSG Rating Scale), eventos adversos, parâmetros polissonográficos, melhora subjetiva, qualidade de vida, impressão clínica global, impressão global do paciente, escala de sonolência de Epworth MSLT: Múltiplos Testes de Latência do Sono; PLMI: índice dos Movimentos Periódicos dos Membros. A autora desta tese avaliou os estudos recuperados nas buscas, utilizando critérios que envolviam os métodos randômicos, de cegamento e sigilo de alocação. As divergências foram resolvidas em reunião de consenso. Resultados: As buscas manual e eletrônica encontraram 1.026 estudos. Foram incluídos 94 ensaios clínicos que atendiam aos critérios de inclusão (estudos randomizados ou quasi-randomizados). A análise dos dados considerados em conjunto permitiu concluir que as intervenções farmacológicas foram efetivas para os agonistas dopaminérgicos. Dentre as drogas de segunda linha, apenas a clonidina mostrou-se efetiva. A qualidade dos estudos foi adequada para os ensaios clínicos envolvendo os agonistas dopaminérgicos, parcialmente adequada para levodopa e anticonvulsivantes e pouco adequada para os demais fármacos estudados. Conclusões: Há evidências de que os agonistas dopaminérgicos são eficazes e seguros para o tratamento da SPI a curto prazo, mas não há evidência científica de que os demais fármacos são efetivos nesta doença. / Background: The restless legs syndrome (RLS) is a disorder characterized by a distressing need to move the legs and sometimes other parts of the body. Usually accompanied by a marked sense of discomfort or pain in the leg or other body part affected. The treatment of restless legs syndrome with dopamine agonists has been recognized as the main first-line treatment because it seems to be effective based on pathophysiologic principles. Although, several pharmacological drugs are envolved in the treatment of RLS. Objectives: To assess whether pharmacological interventions are effective and safe for the treatment of RLS. Methods: Systematic Cochrane Review of randomized studies or quasi-randomized on pharmacological agents used to treat RLS. The following outcomes were assessed for each drug: relief of symptoms measured by the restless legs syndrome ranting scale (IRLSSG Rating Scale), adverse events, polysomnographic parameters, subjective improvement, quality of life and clinical global impression, overall impression of the patient , the scale of Epiworth MSLT: Multiple Sleep Latency Test; PLM periodic limb movments and others. The authors evaluated the studies retrieved in searches using criteria involving the method of randomization, blinding and the method of allocation concelment. Disagreements were resolved by consensus. Results: The electronic and manual search found 1,026 studies. Were included 94 studies that met the clinical criteria for inclusion (randomized studies or quasi-randomized). The analysis of data, taken together, indicated that the pharmacological interventions were effective for dopamine agonists. Among the second-line drugs, only clonidine was shown to be effective. The quality of studies was suitable for clinical trials involving the dopamine agonists, partially adequated to levodopa and anticonvulsants, and unsuited for the other drugs studied. Conclusions: There is evidence that dopamine agonists are effective and safe for the treatment of RLS in the short term, there is no scientific evidence that all drugs are effective in this disease. / TEDE / BV UNIFESP: Teses e dissertações

This consecutive nonrandomized comparative interventional study was designed to examine the association between pars plana vitrectomy (PPV) with or without internal limiting membrane (ILM) peeling in the treatment of idiopathic macular holes (IMH). The ILM is the innermost layer of the retina. The macula is located within the retina, and is responsible for central vision. Although IMH manifests in a relatively small region within the retina, patients notice significant drops in visual acuity up to the 20/400 - 20/800 level (legally blind in the affected eye). In the literature, the anatomic success rate of macular hole surgery has been reported between 48% - 94%. To best treat idiopathic macular holes, it is imperative that physicians have access to the most up-to-date information regarding the treatment outcomes. This study included 55 eyes of 52 patients who received surgery at the Beth Israel Deaconess Medical Center for idiopathic macular holes between December 1999 and January 2015. Patients were non-randomly assigned to PPV with or without ILM peeling. Early patients did not receive ILM peeling, while more recent patients did. The primary endpoint measured was macular hole (MH) status as established by ocular coherence tomography (OCT) within 6 to 12 months of the vii procedure. 36 out of 39 (92.3%) eyes in the ILM peeling group had closed MH. In the comparison group without ILM peeling, 11 out of 16 (68.8%) eyes had closed MH. In comparison to the conventional PPV without ILM peeling, these findings suggest that PPV with ILM peeling is associated with a significantly higher anatomic success rate (OR, 5.45; [95% CI, 1.12 to 26.55]; P = 0.023). / 2018-06-16T00:00:00Z

Idiopathic Epiretinal membrane is a proliferation of contractile cells on the surface of the retina that typically occurs after posterior vitreous detachment. Though many questions have been raised on the causes of this condition, a greater debate has been on the treatment of this pathology. The literature suggest the potential benefit in peeling ILM, due to its inherent proliferative characteristics, along with the ERM, during the surgery, however sufficient data has yet to been found. Due to the lack of consensus in treatment of iERM, this study set forth to provide some insight on the surgical outcomes of patients that undergo combined peeling as well attempting to contribute to a potential surgical protocol in treating iERM. This was a retrospective case series study looking at 140 eyes from 126 iERM patients that underwent ERM surgical treatment at Beth Israel Deaconess Medical Center between 1998 and 2015. Pre- and post- operative visual acuities, lens status (phakic, aphakic, pseudophakic), type (kenalog with or without ICG) and duration (0.5min, 1 min, 1.5 min) of the stains used in the procedure, and any prior or successive surgeries were recorded and analyzed. Overall, ERM surgeries demonstrated a significant (p<0.0001) improvement in visual acuity. Furthermore, the combined peel patients demonstrated a significantly (p<0.0467) greater mean change in logMAR score when compared to ERM-only peel procedures. In addition, the combined peel group showed a smaller rate of recurrence. Lastly, simultaneous cataract surgery and the use of ILM stains did not have an impact on the outcome of ERM surgery. The study found that combined (ERM and ILM) peeling along with simultaneous cataract surgery, if a cataract was present, along with the utilization of ILM stains is cost-effective, safe, and effective approach in treating iERM and decreasing its recurrence.

Objetivos: Avaliar associações da velocidade de crescimento com marcadores inflamatórios e dose cumulativa de glicorticóide em uma coorte de pacientes com Artrite Idiopática Juvenil acompanhados por 1 ano. Material e Métodos: Foram avaliados 79 pacientes com AIJ segundo critérios da ILAR. A atividade clínica da doença foi classificada por médicos reumatologistas pediátricos. Os dados antropométricos foram mensurados e classificados de acordo com as normas da Organização Mundial da Saúde. Foram utilizadas curvas de velocidade de crescimento segundo Tanner; considerou-se baixa velocidade de crescimento valores de escore Z ≤ -2. Concentrações séricas de IL-6 foram mensuradas por ELISA no período basal, e valores acima de 1 pg/ml foram considerados elevados. Resultados: Baixa velocidade de crescimento teve uma prevalência de 25,3% e esteve associada com atividade da doença no período do seguimento (p=0,085), valores elevados de IL-6 (interleucina-6) (p=0,003), velocidade de sedimentação globular (VSG) (p=0,022) e proteína C reativa (PCR) (p=0,001) e maior dosagem cumulativa de glicocorticóide (0=0,044). Na regressão linear múltipla tendo como variável dependente a velocidade de crescimento, observou-se que somente os níveis elevados de IL-6 foram independente e negativamente associados com a velocidade de crescimento (p=0,025). Conclusão: Baixa velocidade de crescimento é altamente prevalente em crianças com AIJ. Níveis elevados de IL-6 têm um importante impacto negativo no crescimento desses pacientes, enquanto a exposição ao glicocorticóide total parece ser um fator secundário. / Objective: To evaluate associations of growth velocity with inflammatory markers and cumulative dose of glucocorticoid in a cohort of patients with Juvenile Idiopathic Arthritis (JIA) followed during 1 year. Methods: Seventy-nine patients were evaluated by criteria according to the ILAR. The disease activity was evaluated by a pediatric rheumatologist. The anthropometic data were measured and classified according to the World Health Organization standards. Growth velocity curves were used according to Tanner, values below the Z-score ≤ -2 were considered low growth velocity. Serum concentrations of IL-6 were measured by ELISA in the baseline period, and values over 1pg/ml were considered as elevated. Results: The prevalence of low growth velocity was 25.3%, and it was associated with: active disease on follow-up visit (p=0,085), elevated interleukin-6 (IL-6) (p=0,003), erythrocyte sedimentation rate (ESR) (p=0,022) and C-reactive protein (CRP) (p=0,001) and higher cumulative glucocorticoid doses (0=0,044). In the multiple linear regression with growth velocity as the dependent variable, only elevated IL-6 levels were independently and negatively associated with growth velocity (p=0,025). Conclusion: Low growth velocity is highly prevalent in children with JIA. Elevated IL-6 levels seem to have an important negative impact on growth in these children, while total glucocorticoid exposure appears to be a secondary factor.

A Artrite idiopática juvenil (AIJ) é a artropatia crônica mais prevalente na infância e adolescência. A prevalência da síndrome metabólica, assim como da obesidade, vem apresentando um rápido aumento, atingindo todas as faixas etárias, incluindo a infância. A síndrome metabólica é caracterizada por um conjunto de riscos para doença cardiovascular e diabetes melito tipo 2, incluindo adiposidade abdominal, resistência à insulina, dislipidemias e hipertensão arterial sistêmica. Além destes componentes, a inflamação tem sido reconhecida cada vez mais como um fator importante na síndrome metabólica e obesidade, e pacientes com doenças caracterizadas por processos inflamatórios crônicos, como a AIJ, poderiam representar grupos de risco especiais. Os glicocorticoides são utilizados rotineiramente no controle da inflamação da artrite idiopática juvenil, em doses elevadas e com uso prolongado. O uso crônico do glicocorticoide pode induzir resistência à insulina, hipertensão arterial sistêmica e obesidade, aumentando o risco de desenvolver síndrome metabólica. O presente trabalho tem como objetivo avaliar a prevalência de obesidade e síndrome metabólica em pacientes com AIJ. Em pacientes acompanhados no Serviço de Reumatologia do Hospital de Clínicas de Porto Alegre (HCPA) e Hospital da Criança Santo Antônio (complexo Santa Casa) foram observados uma prevalência de 19,7% de síndrome metabólica e 22,7% de obesidade, sem diferença entre os subtipos da doença. A obesidade foi associada com tempo de duração da doença, obesidade abdominal, pressão arterial elevada, resistência à insulina e presença de síndrome metabólica. O IMC, circunferência da cintura, triglicerídeos, baixos níveis de HDL-c, pressão arterial sistólica e diastólica, níveis séricos de insulina e resistência a insulina (HOMA-ir) mostraram associação com a SM (p<0,05). Não houve associação entre a presença de SM e dose cumulativa de glicocorticoide, atividade da doença e tempo de duração da doença. Os resultados mostram uma alta frequência de obesidade e síndrome metabólica em pacientes com AIJ, sugerindo um aumento do risco de futuras complicações cardiovasculares. e parecem ser independentes do uso de glicocorticoide. Ações de intervenção são necessárias entre os pacientes com AIJ para reduzir o excesso de peso, evitar as complicações metabólicas e fatores de risco cardiovasculares na vida adulta. / Juvenile idiopathic arthritis is the most prevalent chronic arthropathy in childhood and adolescence. The prevalence of metabolic syndrome, as well as obesity, is increasing fast, in all age groups, including the childhood. Metabolic syndrome is defined as a cluster of risk factors for cardiovascular and type 2 diabetes, including abdominal obesity, insulin resistance, dyslipidaemia and hypertension. Besides these components, inflammation has been increasingly considered as a significant component in metabolic syndrome and obesity, and patients with diseases characterized by the presence of chronic inflammation, such as JIA, could represent special groups of risk. Glucocorticoids are used routinely in the management of the inflammation of JIA, in high doses and long-term. Long-term use of the glucocorticoids can cause insulin resistance, hypertension and obesity, increasing the risk for the metabolic syndrome. The aim of the present study was to evaluate prevalence of the obesity and metabolic syndrome in patients with juvenile idiopathic arthritis (JIA). In patients followed in the Hospital de Clínicas de Porto Alegre (HCPA) and Hospital da Criança Santo Antônio (Santa Casa Complex) service of reumatology were observed a prevalence of 19.7% of metabolic syndrome and 22.7% of obese, without difference between the subtypes of the disease. Obesity was associated with disease duration, abdominal obesity, arterial hypertension, insulin resistance and presence of metabolic syndrome. BMI, waist circunference, triglycerides, low HDL-c level, systolic and diastolic BP, fasting insulin serum levels and insulin resistance (HOMA-ir) showed significant association with MetS (p<0,05). There was no correlation between the presence of metabolic syndrome and cumulative glucocorticoid dose, disease activity and duration of disease. The results showed that there were high frequencies of obesity and metabolic syndrome in JIA patients and use appears to be indeoendent of the use glucocorticoid. Intervation actions are needed among JIA patients, to decrease excess weight, metabolic complications and cardiovascular risk factors in adulthood.

Les microARN sont des petits ARN non codants d’une vingtaine de nucléotides qui ont pour fonction de réguler l’expression des gènes en se fixant sur l’extrémité 3’UTR d’ARNm cibles, permettant ainsi leur dégradation ou l’arrêt de leur traduction en protéines. A ce jour, de nombreuses études ont montré l’implication des microARN dans divers processus physiologiques ou pathologiques ; leur rôle dans la réponse de l’organisme aux substances toxiques environnementales commence à être évoqué.La FPI appartient au groupe des pneumopthies interstitielles diffuses idiopathique dont elle est la forme la plus fréquente. Elle se caractérise par la présence de foyers de prolifération de fibroblastes/myofibroblastes responsables d’une production excessive de matrice extracellulaire, une destruction progressive et irréversible de l’architecture pulmonaire entrainant la perte de la fonction respiratoire. L’agression répétée de l’épithélium respiratoire par des composés chimiques environnementaux (ou xénobiotiques) est fortement suspectée dans le déclenchement de la FPI.Le premier objectif de mes travaux de recherche a été d’identifier des microARN susceptibles d’intervenir dans la pathogenèse de la fibrose pulmonaire idiopathique (FPI) et de préciser la (les) fonction(s) de ces microARN d’intérêt. Pour atteindre cet objectif, nous avons étudié deux microARN, le miR-199a-5p et le miR-214-3p qui présentaient la particularité d’être significativement surexprimés dans les poumons de souris souffrant de fibrose pulmonaire. L’analyse systématique des profils d’expression des gènes de fibroblastes surexprimant le miR-199a-5p et le miR-214-3p nous a permis d’identifier un grand nombre de gènes qui étaient significativement modulés par ces deux microARN. Nous avons pu établir l’implication respective du miR-199a-5p et du miR-214-3p dans la régulation de la voie profibrotique TGFβ et dans l’apoptose des fibroblastes pulmonaires médiée par le Fas-ligand. L’ensemble de nos résultats nous permet de suggérer l’utilisation de molécules ciblées contre ces 2 microARN dans le traitement de la FPI.Le second objectif de mes travaux de recherche a été d’identifier le modèle cellulaire in vitro le plus proche du tissu pulmonaire afin d’étudier l’impact des composés toxiques environnementaux sur la pathogenèse des maladies respiratoires et, en particulier, de la FPI. Pour cela, nous avons comparé les profils d’expression génique de l’ensemble des protéines impliquées dans le métabolisme et l’éliminations des xénobiotiques, de 10 lignées cellulaires et de 4 cultures primaires de cellules épithéliales bronchiques humaines, à ceux précédemment observés par notre équipe dans les tissus broncho-pulmonaires humains. L’exposition du modèle cellulaire le plus pertinent à des polluants atmosphériques permettra d’identifier les microARN associés à la toxicité pulmonaire de ces composés chimiques et de vérifier si ces microARN régulent des voies de signalisations communes à celles impliquées dans la pathogenèse de la FPI. / MicroRNAs are small non-coding RNAs with about 20 nucleotides that regulate gene expression by binding to the 3' UTR end of target mRNAs, thus allowing their degradation or stopping their translation into proteins. To date, many studies have shown the involvement of microRNAs in various physiological or pathological processes; their role in the body's response to environmental toxic substances is beginning to be mentioned. It is characterized by the presence of fibroblast/myofibroblast proliferation foci responsible for excessive extracellular matrix production, progressive and irreversible destruction of lung architecture leading to loss of respiratory function. The repeated aggression of the respiratory epithelium by environmental (or xenobiotic) chemicals is strongly suspected in the initiation of IVF. The first objective of my research was to identify microRNAs that may be involved in the pathogenesis of idiopathic pulmonary fibrosis (IVF) and to specify the function(s) of these microRNAs of interest. To achieve this objective, we studied two microRNAs, miR-199a-5p and miR-214-3p, which had the particularity of being significantly overexpressed in the lungs of mice with pulmonary fibrosis. Systematic analysis of the expression profiles of fibroblast genes overexpressing miR-199a-5p and miR-214-3p allowed us to identify a large number of genes that were significantly modulated by these two microRNAs. We were able to establish the respective involvement of miR-199a-5p and miR-214-3p in the regulation of the profibrotic pathway TGFβ and in Fas-ligand mediated apoptosis of pulmonary fibroblasts. The second objective of my research was to identify the in vitro cellular model closest to lung tissue in order to study the impact of environmental toxic compounds on the pathogenesis of respiratory diseases and, in particular, of IVF. To do this, we compared the gene expression profiles of all proteins involved in the metabolism and elimination of xenobiotics, 10 cell lines and 4 primary cultures of human bronchial epithelial cells, with those previously observed by our team in human bronchopulmonary tissues. Exposure of the most relevant cellular model to air pollutants will identify the microRNAs associated with the pulmonary toxicity of these chemical compounds and verify whether these microRNAs regulate signaling pathways common to those involved in the pathogenesis of IVF.

Made available in DSpace on 2015-07-22T20:49:38Z (GMT). No. of bitstreams: 0 Previous issue date: 2011-04-27 / Objetivo: Determinar as concentrações séricas de 25-hidroxicolecalciferol (25(OH)D), cálcio sérico total, fósforo sérico, fosfatase alcalina e paratormônio (PTH) em pacientes com artrite idiopática juvenil (AIJ) poliarticular e associá-las com a atividade e duração da doença, com a densidade mineral óssea e com o uso de medicamentos. Método: Por meio de um estudo transversal e controlado, foram avaliados 30 pacientes com AIJ poliarticular, pareados por sexo e idade com 30 controles saudáveis. Realizou-se avaliação clínica, antropométrica e laboratorial nos pacientes e controles e densitometria óssea nos pacientes. Resultados: Dos 30 pacientes incluídos no estudo, 23 (76,7%) eram meninas, 16 (53,3%) não caucasóides e com média de idade de 14 anos (4 a 20 anos). O tempo médio de doença foi 5 anos. Concentrações médias de cálcio sérico total e fosfatase alcalina foram significantemente mais baixas nos pacientes com AIJ comparativamente aos controles (p< 0,0001 e p= 0,001, respectivamente). Em relação a 25(OH)D, PTH e fósforo sérico não se observaram diferenças entre os grupos AIJ e controle. Quanto às concentrações séricas de 25(OH)D, 8 pacientes (26,7%) e 5 controles (16,7%) apresentaram valores compatíveis com deficiência (inferiores a 20 ng/ml) e 14 pacientes (46,7%) e 18 controles (60%) apresentaram valores compatíveis com insuficiência (entre 20–32 ng/ml). Estes valores não se associaram com a atividade de doença, com o uso de medicamentos ou densidade mineral óssea. Conclusão: Observamos elevada frequência de insuficiência e deficiência de 25(OH)D nas amostras estudadas. O comprometimento do metabolismo ósseo enfatiza a importância do acompanhamento evolutivo dos pacientes com AIJ. / Objective: To determine serum concentrations of 25-hydroxycholecalciferol (25(OH)D) and biochemical markers of bone turnover in patients with polyarticular juvenile idiopathic arthritis (JIA) and to associate them with disease activity and duration, with bone mineral density and with use of medications. Methods: In a cross-sectional and controlled study, 30 patients with polyarticular JIA were assessed, compared with 30 age and sex-matched healthy subjects. We evaluated clinical, anthropometric, laboratory parameters and dual-energy x-ray absorptiometry (DEXA). Results: Out of 30 patients included in the study, 23 (76.7%) were girls, 16 (53.3%) no caucasian and the mean age was 14 years old (4 to 20 years). The mean time of disease was 5 years. The mean serum calcium and phosphatase alkaline were significantly lower in patients with JIA compared to controls (p<0.0001 and p=0.001, respectively). There was no difference between the serum concentrations of 25(OH)D, PTH and phosphorus between patients and controls. Based on serum 25(OH)D concentrations, 8 patients (26.7%) and 5 controls (16.7%) were vitamin D deficient (< 20 ng/ml) and 14 patients (46.7%) and 18 controls (60%) were vitamin D insufficient (between 20 and 32 ng/ml). These values were not associated with disease activity, use of medications or bone mineral density. Conclusions: A high frequency of 25(OH)D insufficiency and defficiency was observed in the study population. The involvement of biochemical bone markers emphasizes the importance of the bone metabolism follow-up in patients with JIA. / TEDE / BV UNIFESP: Teses e dissertações