Introduction: Les instillations nasales de solution saline isotonique (INSS) chez les enfants sont recommandées par les pédiatres et des oto-rhino-laryngologistes de notre institution dans le but de prévenir les otites moyennes aigues à répétition (OMAr). Cependant, aucune étude dans la littérature ne vient corroborer ou infirmer cette pratique. Objectifs: Déterminer l’efficacité des INSS dans la prévention des OMAr. Méthode: Projet pilote d’un essai clinique randomisé. Les enfants diagnostiqués avec des OMAr étaient éligibles. Les patients recrutés ont été randomisés en 2 groupes. Seul le groupe traitement procède aux INSS. L’issue primaire est l’incidence d’OMAr pendant une période de 3 mois. Résultats: Vingt-neuf patients satisfaisant les critères d’inclusion et d’exclusion ont consenti à participer. Le taux d’OMAr était inférieur dans le groupe traitement (p=0.03, chi-carré) Conclusion: Les INSS semblent efficaces dans la prévention des OMAr. Une étude multicentrique est indiquée pour vérifier la validité externe et confirmer la sécurité. / Introduction: Normal saline nasal cavity irrigations (NSNI) are commonly recommended by pediatricians and otolaryngologists to prevent recurrent acute otitis media (rAOM). However, no published scientific study corroborates or invalidates this practice. Goal: To determine the efficacy of NSNI to prevent rAOM. Method: Pilot randomized controlled clinical trial. All consecutive patients with a diagnosis of rAOM were eligible. Recruited patients were randomized in 2 groups. Only patients in the treatment group proceeded with NSNI. The primary outcome of the study was the incidence of rAOM observed during a 3 month period. Results: Twenty-nine patients met the inclusion and exclusion criteria and agreed to participate. There was a statistically significant lower incidence of rAOM in the treatment group (p=0.003, Fisher exact). Conclusion: Our results suggest that NSNI could effectively prevent rAOM. A larger scale randomized multicentre study is feasible, and it must be done in order to verify for external validity and to properly assess safety issues.

L’hépatite autoimmune (HAI) est une maladie grave affectant le foie et présentant un haut taux de mortalité lorsque non traitée. Les traitements disponibles sont efficaces, mais de graves effets secondaires leur sont associés. Ces effets secondaires sont généralement le résultat d'une forte immunosuppression et d’autres sont spécifiques à chaque médicament. Aucune immunothérapie spécifique n’est présentement disponible pour le traitement de l’HAI. Récemment, un modèle murin d’HAI a été développé dans notre laboratoire par xénoimmunisation des souris C57BL/6 avec les antigènes humains de l'HAI de type 2. Ce modèle présente la plupart des caractéristiques biochimiques et cliniques retrouvées chez les patients atteints d'HAI de type 2. Dans cette étude, nous avons évaluée l’efficacité de deux types de traitement pour l’HAI de type 2 à l’aide de notre modèle murin. Dans un premier temps, l’anticorps anti-CD3ε a été étudié en prophylaxie et en traitement. Nous avons montré qu’une posologie de 5µg d’anti-CD3 i.v. par jour pendant 5 jours consécutifs induit une rémission chez les souris avec HAI de type 2 établie (traitement). Cette rémission est caractérisée par une normalisation des niveaux d’alanine aminotransférase et une diminution significative de l’inflammation hépatique. Cette rémission semble être associée à une déplétion partielle et transitoire des lymphocytes T CD3+ dans la périphérie et une augmentation des lymphocytes T régulateurs CD4+, CD25+ et Foxp3+ dans le foie. La même posologie lorsqu’elle est appliquée en prophylaxie n’a pas réussi à prévenir l’apparition de l’HAI de type 2. La deuxième voie de traitement consiste en l’administration par voie intranasale d’un forte dose de formiminotransférase cyclodésaminase murin (mFTCD), un autoantigène reconnu dans l’HAI de type 2. Une administration en prophylaxie par voie intranasale de 100µg de mFTCD par jour durant 3 jours consécutifs arrive à prévenir l’HAI de type 2 en diminuant l’inflammation hépatique au bout de deux semaines post-traitement. / Autoimmune hepatitis (AIH) is a severe liver disease with high mortality rates if left untreated. Current treatments, while effective, are associated with deleterious side-effects. These side effects are specific to each drug and the result of broad immunosuppression. Recently, a murine model of type 2 AIH has been created in our laboratory in wild-type naïve mice. In this model, DNA immunization with type 2 AIH human autoantigens breaks immune tolerance and induces an autoimmune response against the liver. Lately, new therapeutic strategies based on depletion of specific immune cell populations have been proposed for the treatment of several diseases, including autoimmune diseases. Currently, no immunotherapies using biological agents are available for the treatment of autoimmune liver diseases. Therefore, the goal of this project is to study the efficacy of new immunotherapeutic agents for the treatment of type 2 AIH in an experimental model. We evaluated the effectiveness of two approaches for treating type 2 AIH. First, we tested the anti-CD3ε antibody in prophylaxis and in treatment of type 2 AIH. We showed that a dosage of 5µg i.v. of anti-CD3ε antibody per day for 5 consecutive days induced remission in mice with established type 2 AIH. This remission was defined as a normalization of serum alanine aminostransferase levels and a significant decrease of liver inflammation in treated mice. This remission seems to be associated with a transitory depletion of CD3+ T lymphocytes in peripheral blood mononuclear cells and increased CD4+CD25+Foxp3+ regulatory T lymphocytes in the liver. But when this dosage was applied in prophylaxis, it could not prevent the induction of type 2 AIH. The second approach was to induce tolerance by nasal administration of murin formiminotransferase cyclodeaminase (mFTCD), an autoantigen of type 2 AIH. We showed that nasal administration of 100µg of mFTCD for 3 consecutive days prevented development of type 2 AIH in prophylaxis by reducing liver inflammation.

Este estudo tem como objetivo verificar a eficácia do Modelo de Ontogenia (MAJOR, 1987), por meio da análise do processo de aquisição do português como segunda língua (L2) por falantes de espanhol no nível fonético-fonológico. Para tanto, reportamo-nos a pressupostos teóricos que antecedem o dito modelo: a Análise Contrastiva (LADO, 1957), o Modelo de Interlíngua (SELINKER, 1972) e a Hipótese da Marcação Diferencial (ECKMAN, 1987). O Modelo de Ontogenia descreve o processo da aquisição de L2 no nível fonético-fonológico dividindo-o em duas fases: interferência, quando o aprendiz passa a sofrer grande influência de sua L1, e desenvolvimento, quando o aprendiz pode passar por um processo semelhante ao da criança em fase de aquisição da L1. Nosso objeto de estudo foi o processo de aquisição das vogais médio-abertas e das vogais nasais do português, realizando uma análise comparativa entre o sistema fonético-fonológico do português e do espanhol, com enfoque no sistema vocálico. Nessa análise, incluímos o percurso histórico da origem das vogais e a questão da nasalidade em ambas as línguas. Embora este estudo seja centrado na observação da interferência da L1 na aquisição de L2, consideramos também, a interferência de fatores extralinguísticos (KRASHEN, 1982). Para elaboração do corpus foram realizadas duas gravações, com intervalo entre 8 a 18 meses, com quatro pós-graduandos da Universidade de São Paulo, denominados Informantes. A metodologia consistiu na aplicação de entrevista espontânea e leitura de palavras, frases e trecho de texto literário. Acreditamos que nosso trabalho possa contribuir para o desenvolvimento da área de Português para Falantes de Outras Línguas (PFOL) por agregar informações sobre as dificuldades dos aprendizes falantes de espanhol na aquisição do sistema vocálico. / This study aims to examine the efficiency of The Ontogeny Model (Major, 1987) through analysis of the phonetic and phonological aspects of the acquisition of Portuguese as a second language (L2) by native speakers of Spanish. To do this, we relied on the following theoretical assumptions which preceded the model: Contrastive Analysis (Lado, 1957), Interlanguage Model (Selinker, 1972) and Differential Markedness Hypothesis (Eckman, 1987). The Ontogeny Model describes the process of L2 acquisition in the phonetic and phonological levels by dividing it in two stages: interference, when the learner has great influence of his/her first language (L1), and development, when the learner may pass through a process similar to the child acquiring L1. Our object of study is the acquisition process of Portuguese open-mid vowels and nasal vowels, establishing a comparative analysis between the phonetic and phonological systems of Portuguese and English, with focus on the vowel system. In this analysis, we include the historical progression of the vowel origins and the issue of nasality in both languages. Despite this study being centered in the observation of L1 interference in L2 acquisition, we also considered the influence of extra-linguistic factors (Krashen, 1982). To compose the corpus, two recordings were done, with an interval between 8 to 18 months, with four informers, postgraduate students at Universidade de São Paulo. The methodology consisted of spontaneous speech interview and the reading of words, sentences and a literary excerpt. We believe that our work can contribute to the development of the area of Portuguese to Speakers of Other Languages (PSOL) as it assembles information about the difficulties that speakers of Spanish have in the acquisition of the vowel system

Para identificar, quantificar e correlacionar os eosinófilos, mastócitos, miofibroblastos e células TGF-beta positivas nos pólipos nasais de pacientes com e sem asma foi realizado a imunoistoquímica. A quantidade de eosinófilos, miofibroblastos e células TGF-beta positivas esteve aumentada no pólipo nasal de indivíduos asmáticos. O número de mastócitos não mostrou diferença entre os grupos. O miofibroblasto foi o denominador comum na correlação entre eosinófilos, mastócitos, células TGF-beta positivas e presença de asma / Introduction: Nasal polyposis is a chronic inflammatory disease of the nasal mucosa or paranasal sinuses characterized by the formation of benign polyps. The pathogenesis is not known, although nasal polyps are associated with several systemic diseases, with asthma being the most frequent. The aim of the present study was to identify, quantify, compare and correlate eosinophils, mast cells, myofibroblasts and TGF-ß-positive cells in nasal polyps of patients with and without asthma. Material and Methods: Seventy-eight subjects with nasal polyps undergoing endoscopic sinus surgery were selected. Control specimens were obtained from eight subjects with a normal sinus mucosa. One group consisted of polyps from 56 patients with asthma and the other of polyps from 22 patients without asthma. Immunohistochemistry was performed using monoclonal antibodies against eosinophil cationic protein to stain eosinophils, against tryptase to stain mast cells, against alpha-smooth muscle actin to stain myofibroblasts, and against TGF-ß to stain TGF-ß-positive cells. Results: The number of eosinophils, myofibroblasts and TGF-ß-positive cells was significantly higher in the asthma group than in the nonasthma group, whereas no significant difference in the number of mast cells was observed between the two groups. The number of eosinophils, mast cells, myofibroblasts and TGF-ß-positive cells was significantly higher in nasal polyps than in the control group. Myofibroblasts showed a significant correlation with eosinophils, mast cells, TGF-ß-positive cells, and asthma. Conclusion: Eosinophils, mast cells, myofibroblasts and TGF-ß-positive cells were identified in all nasal polyps, although the number of eosinophils, myofibroblasts and TGF-ß-positive cells was higher in the asthma group. The number of mast cells was similar regardless of the presence or absence of asthma. Myofibroblasts were a common denominator in the correlation between eosinophils, mast cells, TGF-ß-positive cells, and asthma

Para identificar, quantificar e correlacionar os eosinófilos, mastócitos, miofibroblastos e células TGF-beta positivas nos pólipos nasais de pacientes com e sem asma foi realizado a imunoistoquímica. A quantidade de eosinófilos, miofibroblastos e células TGF-beta positivas esteve aumentada no pólipo nasal de indivíduos asmáticos. O número de mastócitos não mostrou diferença entre os grupos. O miofibroblasto foi o denominador comum na correlação entre eosinófilos, mastócitos, células TGF-beta positivas e presença de asma / Introduction: Nasal polyposis is a chronic inflammatory disease of the nasal mucosa or paranasal sinuses characterized by the formation of benign polyps. The pathogenesis is not known, although nasal polyps are associated with several systemic diseases, with asthma being the most frequent. The aim of the present study was to identify, quantify, compare and correlate eosinophils, mast cells, myofibroblasts and TGF-ß-positive cells in nasal polyps of patients with and without asthma. Material and Methods: Seventy-eight subjects with nasal polyps undergoing endoscopic sinus surgery were selected. Control specimens were obtained from eight subjects with a normal sinus mucosa. One group consisted of polyps from 56 patients with asthma and the other of polyps from 22 patients without asthma. Immunohistochemistry was performed using monoclonal antibodies against eosinophil cationic protein to stain eosinophils, against tryptase to stain mast cells, against alpha-smooth muscle actin to stain myofibroblasts, and against TGF-ß to stain TGF-ß-positive cells. Results: The number of eosinophils, myofibroblasts and TGF-ß-positive cells was significantly higher in the asthma group than in the nonasthma group, whereas no significant difference in the number of mast cells was observed between the two groups. The number of eosinophils, mast cells, myofibroblasts and TGF-ß-positive cells was significantly higher in nasal polyps than in the control group. Myofibroblasts showed a significant correlation with eosinophils, mast cells, TGF-ß-positive cells, and asthma. Conclusion: Eosinophils, mast cells, myofibroblasts and TGF-ß-positive cells were identified in all nasal polyps, although the number of eosinophils, myofibroblasts and TGF-ß-positive cells was higher in the asthma group. The number of mast cells was similar regardless of the presence or absence of asthma. Myofibroblasts were a common denominator in the correlation between eosinophils, mast cells, TGF-ß-positive cells, and asthma

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No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Tese_UsoTecnicaBiologia.pdf: 2281724 bytes, checksum: a45c8462c51f7b087c62763c6118d17b (MD5) Previous issue date: 2016-06-28 / CNPq - Conselho Nacional de Desenvolvimento Científico e Tecnológico / O propósito deste estudo foi aplicar a técnica da biologia molecular em amostra de secreção nasal de contatos intradomiciliares de portadores de hanseníase, em combinação com a avalição dermatoneurológica, na melhoria do diagnóstico precoce da hanseníase. O estudo foi realizado em unidades municipais de saúde de Belém-PA, no período de fevereiro de 2013 a abril de 2015. A amostra foi constituída de 154 contatos intradomiciliares e 58 casos índices de hanseníase, totalizando 212 sujeitos. A coleta de dados se deu por meio de ficha epidemiológica, avaliação dermatoneurológica e exame da cicatriz de BCG. Foi coletada uma amostra de secreção nasal de cada sujeito para a PCR. Nos casos índices, a PCR positiva prevaleceu na faixa etária de 40-59 anos (35,0%); na forma MB (80,0%); casos com 7 a 9 lesões de pele (35,0%) e com ausência de nervos espessados (40,0%). Todos os casos índices positivos para a PCR evidenciaram sinais e sintomas de hanseníase (34,5%) e a maioria não possuía cicatriz de BCG (65,0 %). Entre os contatos, a PCR positiva incidiu no sexo feminino (63,9 %); na faixa etária de 20 a 39 anos (44,4 %); renda familiar de um salário mínimo (47,2 %); ocupação de estudante (33,3 %) e no ensino médio completo (36,1 %). A maior evidência de positividade da PCR nos casos índices e contatos foi na forma multibacilar, respectivamente (37,2 % e 25,6 %). Comprova-se uma concordância altamente significante entre os sinais e sintomas clínicos com a PCR na secreção nasal dos contatos multibacilares, indicando que se estes vierem a adoecer há maior probabilidade de reproduzirem a mesma forma operacional dos casos índices. O maior percentual de PCR positiva foi nos contatos com ausência de cicatriz de BCG (25,8 %). A associação entre os sinais e sintomas e a PCR indica que os contatos com PCR positivo têm 07 vezes mais chance de apresentar sinais e sintomas de hanseníase. Ao estimar o risco potencial para o desenvolvimento da hanseníase nos contatos identificou-se 22 (14,3%) em risco intermediário e 06 (3,9 0%) no alto risco. Cento e quarenta e quatro (144) contatos referiram convívio diário com o caso índice (93,5 %) e destes 36 (25,0 %) foram positivos para a PCR. Verifica-se que com a evolução do tratamento dos casos índices há redução da positividade da PCR, em ambas as formas operacionais. Na correlação entre a PCR e o grau de incapacidade dos casos índices, o grau 1 foi mais prevalente (55,0 %). A detecção do DNA do M. leprae na secreção nasal de contatos intradomiciliares, por PCR, em associação com a avaliação dermatoneurológica eleva a efetividade do diagnóstico precoce na hanseníase, contribuindo com o controle da doença na comunidade. / The purpose of this study was to apply the technique of molecular biology in nasal secretion sample from household contacts of leprosy patients, in combination with dermatological and neurological assessments, improving the early diagnosis of leprosy. The study was conducted in health municipal units of Belém-PA, from February 2013 to April 2015. The sample consisted of 154 household contacts and 58 index cases of leprosy, totaling 212 subjects. Data collection was through epidemiological record, dermatologic and neurological evaluations and BCG scar examination. A nasal secretion sample from each subject for the PCR was collected. In index cases, positive PCR was in the age group of 40-59 years (35.0%), in multibacillary (MB) form (80,0%); cases with 7 to 9 skin lesions (35.0%) and with no enlarged nerves (40.0%). All positive index PCR cases show signs and symptoms of leprosy (34.5%) and most do not have BCG scar (65.0%). Among the contacts, positive PCR prevailed in females (63.9%); in the age group 20-39 years (44.4%); family income of a minimum wage (47.2%); student occupation (33.3%) and completed high school (36.1%). The strongest evidence of positive PCR in index cases and contacts was in multibacillary, respectively (37.2% and 25.6%). Proves to be a highly significant correlation between clinical signs and symptoms with PCR in nasal secretion of multibacillary contacts, indicating that if they get sick are more likely to reproduce the same operating way of index cases. The highest percentage of positive PCR was in contact with the absence of BCG scar (25.8%). The association between the signs, symptoms and PCR indicates that contacts with positive PCR have 07 times more likely to show signs and symptoms of leprosy. In estimating the potential risk for the development of leprosy in contacts, we identified 22 (14.3%) at intermediate risk and 06 (3.9% 0) at high risk. One hundred and forty-four (144) contacts said that they have daily contact with the index case (93.5%) and of these 36 (25.0%) were positive for PCR. The treatment of index cases led to a reduction of PCR positivity in both modes of operation. The correlation between PCR and the degree of disability of the index cases, grade 1 was more prevalent (55.0%). M. leprae DNA detection in the nasal secretion of household contacts for PCR, in association with dermatological and neurological assessments, raises the effectiveness of early diagnosis of leprosy, contributing to the control of the disease in the community.

<p>The blood-brain barrier restricts the access of many compounds, including therapeutic agents, to the brain. Several human studies indicate that nasal administration of hydrophilic compounds, such as peptides, can bypass the blood-brain barrier. The aims of this thesis were to develop and refine models for this direct nose-to-brain transfer.</p><p>In a mouse model, [³H]-dopamine was given as a unilateral nasal dose. The resulting radioactivity in the ipsilateral olfactory bulb was significantly higher than that in the contralateral bulb and peaked at 4 h. Tape section autoradiography showed that the radioactivity was concentrated in the olfactory nerve layer and the glomerular layer of the olfactory bulb. The olfactory transfer of dopamine was also studied <i>in vitro</i>. At a lower donor concentration, the mucosal-to-serosal dopamine permeability was higher than the serosal-to-mucosal permeability, but at a higher concentration, the permeability coefficients were similar. Together, these results suggest that the olfactory transfer of dopamine has an active component.</p><p>Olfactory transfer of fluorescein-labeled dextran through the epithelium and deeper tissues was studied in a rat model, which enabled visualization of the transfer using fluorescence microscopy. Although the epithelial transfer appeared to be mainly intracellular, transfer in the following deeper tissues was extracellular. Without altering the route of uptake, a gellan gum formulation enhanced the uptake of fluorescein dextran. The enhancing effect was considered likely to be the result of an increased residence time in the nasal cavity.</p><p>In conclusion, dopamine and fluorescein-labeled dextran were identified as suitable model compounds for the study of olfactory drug transfer mechanisms and the influence of drug formulation. Two new <i>in vitro</i> models of olfactory transfer were compared. Also, a rat model, which enabled the visualization of the entire nose-to-brain transfer, was developed.</p>

The blood-brain barrier restricts the access of many compounds, including therapeutic agents, to the brain. Several human studies indicate that nasal administration of hydrophilic compounds, such as peptides, can bypass the blood-brain barrier. The aims of this thesis were to develop and refine models for this direct nose-to-brain transfer. In a mouse model, [3H]-dopamine was given as a unilateral nasal dose. The resulting radioactivity in the ipsilateral olfactory bulb was significantly higher than that in the contralateral bulb and peaked at 4 h. Tape section autoradiography showed that the radioactivity was concentrated in the olfactory nerve layer and the glomerular layer of the olfactory bulb. The olfactory transfer of dopamine was also studied in vitro. At a lower donor concentration, the mucosal-to-serosal dopamine permeability was higher than the serosal-to-mucosal permeability, but at a higher concentration, the permeability coefficients were similar. Together, these results suggest that the olfactory transfer of dopamine has an active component. Olfactory transfer of fluorescein-labeled dextran through the epithelium and deeper tissues was studied in a rat model, which enabled visualization of the transfer using fluorescence microscopy. Although the epithelial transfer appeared to be mainly intracellular, transfer in the following deeper tissues was extracellular. Without altering the route of uptake, a gellan gum formulation enhanced the uptake of fluorescein dextran. The enhancing effect was considered likely to be the result of an increased residence time in the nasal cavity. In conclusion, dopamine and fluorescein-labeled dextran were identified as suitable model compounds for the study of olfactory drug transfer mechanisms and the influence of drug formulation. Two new in vitro models of olfactory transfer were compared. Also, a rat model, which enabled the visualization of the entire nose-to-brain transfer, was developed.

No description available.

Ο ρινικός πολύποδας (ΡΠ) είναι μια χρόνια φλεγμονώδης νόσος του ρινικού βλεννογόνου, η οποία χαρακτηρίζεται από διήθηση φλεγμονωδών κυττάρων, όπως ηωσινόφιλα, λεμφοκύτταρα και πλασμοκύτταρα, τροποποιήσεις στη διαφοροποίηση του επιθηλίου και ανάπλαση ιστού, που περιλαμβάνει υπερπλασία της βασικής μεμβράνης, συσσώρευση εξωκυττάριου υλικού και οίδημα. Ο παράγοντας αναστολής της μετανάστευσης μακροφάγων (MIF) είναι μία μοναδική κυτταροκίνη με σημαντικό ρόλο στο σηπτικό σόκ και στις χρόνιες φλεγμονώδεις και αυτοάνοσες ασθένειες.Παράγεται από ενεργοποιημένα Τ-κύτταρα, μακροφάγα αλλά και από ποικιλία άλλων κυττάρων. Εκτός των άλλων, έχει βρεθεί ότι επάγει την έκφραση της IL-6 από διάφορα κύτταρα και ανταγωνίζεται την κατασταλτική επίδραση των γλυκοκορτικοειδών στην έκφρασή της. Απαντάται σε αυξημένα επίπεδα στο ρινικό πολύποδα. Ο αυξητικός παράγοντας μετασχηματισμού-β1 (TGF-β1) θεωρείται ένας αντιφλεγμονώδης παράγοντες, ο οποίος ανταγωνίζεται τη δράση της IL-1β και του TNF-α, στην έκφραση της ΜΜΡ-1 και ΜΜΡ-3. Διεγείρει επίσης την έκφραση του ΤΙΜΡ-1, του κολλαγόνου τύπου Ι και της IL-6 και λόγω των δράσεών του αυτών εμπλέκεται ισχυρά στις διαδικασίες ίνωσης. Απαντάται σε σημαντικά επίπεδα στο ρινικό πολύποδα. Η IL-6 είναι μία Th2 πολυλειτουργική κυτταροκίνη η οποία εμπλέκεται σε ποικίλες φλεγμονώδεις καταστάσεις. Διεγείρει την ανάπτυξη των ινοβλαστών, αυξάνει τη σύνθεση και εναπόθεση του κολλαγόνου και μειώνει την αποικοδόμησή του. Απαντάται σε αυξημένα επίπεδα στο ρινικό πολύποδα και θεωρείται σημαντικός παθαγενετικός παράγοντας μέσω της επαγωγής του σχηματισμού των πλασμοκυττάρων και της σύνθεσης συστατικών του στρώματος, και της προαγωγής της σύνθεσης και εναπόθεσης κολλαγόνου και της ανάπλασης ιστού. Σκοπός της παρούσης εργασίας είναι η μελέτη της συμβολής του MIF και του TGF-β1 στη παραγωγή της IL-6 από ινοβλάστες ρινικού πολύποδα, των σηματοδοτικών μονοπατιών που εμπλέκονται, και η διερεύνηση της πιθανής συνεργειακής δράσης τους στην έκφραση της κυτταροκίνης. Τόσο ο TGF-β1 (0,01-1 ng/ml) όσο και ο MIF (1-100 ng/ml) προκάλεσαν διέγερση της έκφραση της IL-6 σε ινοβλάστες ρινικού πολύποδα κατά δοσοεξαρτώμενο τρόπο, η οποία κατεστάλλει σημαντικά από αναστολέις των ΜΑΡ κινασών και της ΡΙ-3 κινάσης. Ο TGF-β1 (1 ng/ml) προκάλεσε επίσης χρονοεξαρτώμενη αύξηση στα επίπεδα της IL-6 γιά χρόνο επώασης μέχρι 2 ώρες, τα οποιά έμεινα σταθερά στη συνέχεια μέχρι τις 72 ώρες επώασης, επαγωγή της παραγωγής ενδοκυτταρικών ενεργών ειδών οξυγόνου (ROS) με μέγιστο σε δύο χρόνους επώασης 20 και 180 λεπτά, και ενεργοποίηση των ERK κινασών από 15-60 λεπτά επώασης, με μέγιστη ενεργοποίηση στα 30 λεπτά, και στη συνέχεια πτώση στα επίπεδα του μάρτυρα. Ενώ ο MIF σε συγκέντρωση 1-100 ng/ml προκάλεσε μικρή μείωση στην έκφραση της φωσφατάσης-1 των ΜΑΡΚ (ΜΚΡ-1), ο TGF-β1 αντίθετα, σε συγκέντρωση 1 ng/ml προκάλεσε αύξηση στην έκφραση της ΜΚΡ-1 σε δύο χρόνους επώασης 0,5 και 24 ώρες. Μετά από επώαση των ινοβλαστών ρινικού πολύποδα παρουσία TGF-β1 (1 ng/ml) και MIF (100 ng/ml) μαζί, δεν παρατηρήθηκε συνεργειακή επίδραση στην έκφραση της IL-6. Ενώ τόσο ο TGF-β1 όσο και ο MIF προκάλεσαν διέγερση στην έκφραση της IL-6 από ινοβλάστες πνεύμονα, δεν παρατηρήθηκε και πάλι συνεργειακή επίδρασή τους στην έκφραση της κυτταροκίνης αυτής. Συμπερασματικά, φαίνεται ότι ο MIF, ενώ ανταγωνίζεται την κατασταλτική επίδραση των γλυκοκορτικοειδών στην έκφραση της IL-6 μέσω της ρύθμισης των επιπέδων της ΜΚΡ-1, δεν έχει την ίδια επίδραση στην έκφραση της IL-6 από τον TGF-β1, μέσω ρύθμισης της έκφρασης της φωσφατάσης αυτής. Από την άλλη μεριά η επαγωγή της έκφρασης της ΜΚΡ-1 από τον TGF-β1 φαίνεται να μην επηρεάζει την παραγωγή της IL-6 για μικρούς χρόνους επώασης, μέχρι 2 ώρες, πιθανόν λόγω της ανασταλτικής επίδρασης των ROS, που επάγονται από τον TGF-β1, στη δράση της ΜΚΡ-1, ενώ την επηρεάζει για μεγάλους χρόνους επώασης , εξ ού και τα σταθερά επίπεδα της IL-6 μέχρι και 72 ώρες επώασης. / Nasal polyp (NP) is a chronic inflammatory condition of nasal mucosa, characterized by infiltration of inflammatory cells such as eosinophils, lymphocytes and plasma cells, alterations in epithelial differentiation and tissue reconstruction, involving hyperplasia of basal membrane, accumulation of extracellular material and edema. Macrophage migration inhibitory factor (MIF) is a unique cytokine, the role of which in chronic inflammatory and autoimmune diseases and septic shock pathogenesis is very important. MIF is produced by activated T-lymphocytes, macrophages and a plethora of other cells. MIF appears to antagonize the suppressive effect of glucocorticoids as well as induce the expression of IL-6 in multiple cells. High levels of MIF are detected in nasal polyps. Transforming growth factor- β1 (TGF-β1) is an anti-inflammatory factor antagonizing the positive effect of IL-1β and TNF-α on the expression of MMP-1 and MMP-3, TGF-β1 also stimulates the expression of TIMP-1, collagen type I and IL-6; because of these effects, TGF-β1 is involved in the process of fibrosis. TGF-β1 levels in nasal polyps are significantly elevated. IL-6 is a cytokine participating in Th2 response and consequently is involved in a subset of inflammatory reactions. IL-6 stimulates the growth of fibroblasts, increases the production and deposition of collagen and it decreases its degradation. IL-6 is found in nasal polyps at elevated levels and it is thought to be an important pathogenic factor acting mainly in tissue reconstruction, stimulation of plasma cell differentiation, production of stromal material, promotion of collagen synthesis and deposition. The purpose of this paper is to study the effect of MIF and TGF-β1 in IL-6 production by fibroblasts isolated from nasal polyps, dissect the signaling pathways involved, and investigate their synergistic effect on the production of IL-6. Both TGF-β1 (0, 01-1 ng/ml) and MIF (1-100 ng/ml) induced IL-6 expression in nasal polyp fibroblasts in a dose-dependent manner. This effect was significantly suppressed by inhibitors of MAP and PI-3 kinase pathways. TGF-β1 (1 ng/ml) also induced IL-6 expression within 2 hours of administration. Elevated IL-6 levels remained unchanged for 72h further. TGF-β1 also promoted the production of intracellular reactive oxygen species (ROS), which peaked in 20 and 180 minutes and the activation of ERK kinase, peaked in 30 minutes. While MIF, at a concentration of 1-100 ng/ml, caused a slight decrease in the expression of phospatase-1 of MAPK (MKP-1), TGF-β1, at a concentration of 1 ng/ml, increased the expression of MKP-1. No synergistic effect on IL-6 expression was detected after incubating nasal polyp and lung fibroblasts together with TGF-β1 (1 ng/ml) and MIF (100 ng/ml). In conclusion, while MIF antagonizes the suppressive effect of glucocorticoids on the expression of IL-6 by regulating the levels of MKP-1, it fails to antagonize the TGF-β1 inducing effect on IL-6 via MKP-1. The induction of MKP-1expression by TGF-β1 is not affecting the production of IL-6 after short incubation periods; this effect can be explained by the inhibitory effect of TGF-β1 induced ROS on MKP-1. After prolong incubation with TGF-β1 (up to 72 hours), IL-6 levels remain elevated.