La schizophrénie est une maladie mentale grave qui présente une comorbidité fréquente avec la toxicomanie et avec divers troubles immunitaires. Une méta-analyse réalisée récemment dans notre laboratoire a montré une augmentation d’IL-6 (une cytokine pro-inflammatoire), du récepteur soluble d’IL-2 (un marqueur d’activation du système immunitaire), et d’IL-1RA (une cytokine anti-inflammatoire) dans la schizophrénie, suggérant l’existence d’un syndrome inflammatoire dans cette maladie. La toxicomanie aussi est associée au dérèglement du réseau des cytokines inflammatoires, mais les effets dépendent du type de drogues et ils sont parfois diamétralement opposés. On dispose encore de peu d’informations sur le statut immunitaire et inflammatoire des patients qui ont un double diagnostic de schizophrénie et de toxicomanie. Le but de ce travail était d’explorer l’existence d’un état inflammatoire systémique chez les patients schizophrènes et toxicomanes, et l’influence du traitement avec un médicament antipsychotique atypique, la quétiapine. Les objectifs spécifiques étaient : 1) Mesurer les concentrations plasmatiques des cytokines inflammatoires chez les schizophrènes et toxicomanes avant, pendant et après traitement avec la quétiapine ; et 2) Faire des études de corrélations entre les taux de cytokines, les symptômes cliniques, et la consommation de drogues. Les résultats montrent que comparativement aux contrôles normaux, les patients avec un double diagnostic présentent une augmentation d’IL-6, d’IL-1RA, du sIL-2R et d’IL-8 avant traitement à la quétiapine. Les augmentations des concentrations plasmatiques d’IL-1RA sont particulièrement importantes chez les patients avec double diagnostic, si on les compare à celles publiées chez les schizophrènes sans toxicomanie. Le traitement à la quétiapine n’influence pas les concentrations plasmatiques de ces cytokines, sauf sIL-2R qui augmente davantage au cours du traitement. Des corrélations positives de puissance modérée sont retrouvées entre IL-6 et dépression, IL-6 et alcool, IL-1RA et cognition, IL-8 et dépression, IL-8 et alcool, sIL-2R et cannabis. Notre étude révèle que la réponse inflammatoire est activée chez les schizophrènes et toxicomanes. De plus, la toxicomanie semble jouer un rôle facilitant ou potentialisateur dans les augmentations des taux circulants d’IL-1RA. Les études en cours sur différentes populations de schizophrènes avec ou sans toxicomanie, et chez des toxicomanes non schizophrènes permettront de préciser le rôle des différentes drogues d’abus dans le syndrome inflammatoire chez les schizophrènes, ainsi que les implications de ce syndrome sur le plan clinique et thérapeutique. / Schizophrenia is a psychosis which presents a frequent comorbidity with substance use disorders (SUD) and with various immune alterations. Using meta-analysis, we have demonstrated previously establishment of an inflammatory syndrome in schizophrenia patients, illustrated by elevated circulating levels of IL-6 (a pro-inflammatory cytokine), sIL-2R (marker of immune activation) and IL-1RA (an anti-inflammatory cytokine). SUD is also associated with dysregulation of inflammatory cytokines, but the effects may depend on the type of substance of abuse. The goal of this project was: 1) To measure plasma concentrations of inflammatory cytokines in schizophrenia patients with comorbid SUD, before, during and after treatment with an atypical antipsychotic, quetiapine; and 2) To perform correlation studies between plasma concentrations of inflammatory cytokines and clinical symptoms, including positive and negative symptoms, cognition, depression and substance use. Relative to normal controls, patients with a dual diagnosis showed increased plasma concentrations of IL-6, IL-1RA, sIL-2R, and IL-8 at baseline, IL-1RA increases being the most important. Quetiapine treatment did not influence plasma cytokine concentrations, except sIL-2R which increased further. Moderate positive correlations were found between IL-6 and depression, IL-6 and alcohol, IL-1RA and cognition, IL-8 and depression, IL-8 and alcohol and between sIL-2R and cannabis. This study demonstrates that the immune and inflammatory response is activated in schizophrenia patients with comorbid SUD. Furthermore, SUD may play a facilitating or potentiating role in the increases in peripheral levels of IL-1RA. Ongoing studies in different patient populations with schizophrenia with or without SUD, and patients with SUD alone will help elucidate the role of different substances of abuse in the inflammatory syndrome in schizophrenia, as well as the clinical and therapeutic relevance of this syndrome.

Increasing evidence implicates the presence of bacteria in intrauterine tissues as an important risk factor for spontaneous preterm labor. Epigenetic alterations of innate immunity genes may increase the mother’s sensitivity to subclinical levels of bacteria. This study examined the presence of TET2, TLR-2, and TLR-9 in intrauterine tissue, and evaluated whether epigenetic alterations of these genes, as well as IL-8, changed their expression in human decidual tissue and a macrophage cell culture. Immunohistochemicalstaining was used to detect the presence of these proteins in intrauterine tissue. Gene expression changes were evaluated in stimulated monocytes and macrophages. Fluorescence immunohistochemistry was used to track translocation of TET2 in stimulated monocytes and macrophages. Secreted IL-8 concentration was detected with ELISA. Decidual expression of TET2, TLR-2, and TLR-9 increased in the order TNL < TL < sPTL < iPTL. This study found that TET2, TLR-2, TLR-9, and IL-8 are regulated by epigenetic mechanisms. This study was the first to report activation of TET2 involves its translocation from the cytosol to the nucleus in macrophages.

La schizophrénie est une maladie mentale grave qui présente une comorbidité fréquente avec la toxicomanie et avec divers troubles immunitaires. Une méta-analyse réalisée récemment dans notre laboratoire a montré une augmentation d’IL-6 (une cytokine pro-inflammatoire), du récepteur soluble d’IL-2 (un marqueur d’activation du système immunitaire), et d’IL-1RA (une cytokine anti-inflammatoire) dans la schizophrénie, suggérant l’existence d’un syndrome inflammatoire dans cette maladie. La toxicomanie aussi est associée au dérèglement du réseau des cytokines inflammatoires, mais les effets dépendent du type de drogues et ils sont parfois diamétralement opposés. On dispose encore de peu d’informations sur le statut immunitaire et inflammatoire des patients qui ont un double diagnostic de schizophrénie et de toxicomanie. Le but de ce travail était d’explorer l’existence d’un état inflammatoire systémique chez les patients schizophrènes et toxicomanes, et l’influence du traitement avec un médicament antipsychotique atypique, la quétiapine. Les objectifs spécifiques étaient : 1) Mesurer les concentrations plasmatiques des cytokines inflammatoires chez les schizophrènes et toxicomanes avant, pendant et après traitement avec la quétiapine ; et 2) Faire des études de corrélations entre les taux de cytokines, les symptômes cliniques, et la consommation de drogues. Les résultats montrent que comparativement aux contrôles normaux, les patients avec un double diagnostic présentent une augmentation d’IL-6, d’IL-1RA, du sIL-2R et d’IL-8 avant traitement à la quétiapine. Les augmentations des concentrations plasmatiques d’IL-1RA sont particulièrement importantes chez les patients avec double diagnostic, si on les compare à celles publiées chez les schizophrènes sans toxicomanie. Le traitement à la quétiapine n’influence pas les concentrations plasmatiques de ces cytokines, sauf sIL-2R qui augmente davantage au cours du traitement. Des corrélations positives de puissance modérée sont retrouvées entre IL-6 et dépression, IL-6 et alcool, IL-1RA et cognition, IL-8 et dépression, IL-8 et alcool, sIL-2R et cannabis. Notre étude révèle que la réponse inflammatoire est activée chez les schizophrènes et toxicomanes. De plus, la toxicomanie semble jouer un rôle facilitant ou potentialisateur dans les augmentations des taux circulants d’IL-1RA. Les études en cours sur différentes populations de schizophrènes avec ou sans toxicomanie, et chez des toxicomanes non schizophrènes permettront de préciser le rôle des différentes drogues d’abus dans le syndrome inflammatoire chez les schizophrènes, ainsi que les implications de ce syndrome sur le plan clinique et thérapeutique. / Schizophrenia is a psychosis which presents a frequent comorbidity with substance use disorders (SUD) and with various immune alterations. Using meta-analysis, we have demonstrated previously establishment of an inflammatory syndrome in schizophrenia patients, illustrated by elevated circulating levels of IL-6 (a pro-inflammatory cytokine), sIL-2R (marker of immune activation) and IL-1RA (an anti-inflammatory cytokine). SUD is also associated with dysregulation of inflammatory cytokines, but the effects may depend on the type of substance of abuse. The goal of this project was: 1) To measure plasma concentrations of inflammatory cytokines in schizophrenia patients with comorbid SUD, before, during and after treatment with an atypical antipsychotic, quetiapine; and 2) To perform correlation studies between plasma concentrations of inflammatory cytokines and clinical symptoms, including positive and negative symptoms, cognition, depression and substance use. Relative to normal controls, patients with a dual diagnosis showed increased plasma concentrations of IL-6, IL-1RA, sIL-2R, and IL-8 at baseline, IL-1RA increases being the most important. Quetiapine treatment did not influence plasma cytokine concentrations, except sIL-2R which increased further. Moderate positive correlations were found between IL-6 and depression, IL-6 and alcohol, IL-1RA and cognition, IL-8 and depression, IL-8 and alcohol and between sIL-2R and cannabis. This study demonstrates that the immune and inflammatory response is activated in schizophrenia patients with comorbid SUD. Furthermore, SUD may play a facilitating or potentiating role in the increases in peripheral levels of IL-1RA. Ongoing studies in different patient populations with schizophrenia with or without SUD, and patients with SUD alone will help elucidate the role of different substances of abuse in the inflammatory syndrome in schizophrenia, as well as the clinical and therapeutic relevance of this syndrome.

No description available.

Orientador: Prof. Dr. Sergio Daishi Sasaki / Tese (doutorado) - Universidade Federal do ABC, Programa de Pós-Graduação em Biossistemas, São Bernardo do Campo, 2018. / A doença pulmonar obstrutiva crônica é uma doença caracterizada por progressiva limitação do fluxo aéreo e suas principais manifestações são a bronquite crônica e o enfisema pulmonar. O quadro é geralmente irreversível e engloba uma série de processos que incluem a resposta inflamatória anormal dos pulmões com participação ativa de macrófagos, neutrófilos e linfócitos, a falha na reparação de células anormais, a apoptose precoce e a destruição da matriz extracelular ocasionada pelo desequilíbrio entre proteases e antiproteases, sendo esse desequilíbrio apontado como um dos principais mecanismos que levam à instalação da doença. O tabagismo é a principal causa atribuída ao seu aparecimento, seguida por fatores genéticos e ambientais. Algumas enzimas estão relacionadas ao processo de patogênese da DPOC como a elastase de neutrófilos humana e as metaloproteinases 9 e 12. Em trabalhos anteriores o uso do inibidor de serinoproteases rBmTI-A, inibidor do tipo Kunitz-BPTI, resultou na prevenção do enfisema pulmonar por meio do controle da resposta inflamatória comumente observada, além de redução da atividade proteolítica presente no lavado broncoalveolar. Nesse trabalho, o objetivo inicial foi dar prosseguimento à pesquisa com rBmTI-A, com a caracterização da expressão gênica diferencial no modelo de enfisema animal utilizando camundongos, indução realizada com a administração de elastase pancreática porcina (PPE); para isso foi utilizado o ensaio de micro arranjo de DNA (Microarray). Os ensaios de Microarray resultaram na identificação de genes que respondem ao tratamento nos animais induzidos ao enfisema e que receberam o tratamento com rBmTI-A, dentre estes genes estão: genes do sistema imune e inflamação, genes da contração muscular, genes da tradução em mitocôndria e genes de outras funções celulares. Na segunda parte do trabalho, o inibidor de serinoproteases rBmTI-6-D1, inibidor Kunitz-BPTI, foi aplicado no modelo de enfisema pulmonar em camundongos, resultados obtidos previamente já haviam mostrado que rBmTI-6 também apresenta a capacidade de prevenir o desenvolvimento do enfisema induzido por PPE, neste trabalho mostramos que o tratamento utilizando rBmTI-6-D1 evita a perda do recolhimento elástico dos pulmões dos animais induzidos ao enfisema, bem como também evita a degradação alveolar, e o aumento do número de macrófagos e linfócitos nos lavados broncoalveolares dos animais que receberam tratamento em comparação com os que não receberam. Também foi demonstrado que rBmTI-6 evita o aumento de atividade proteolítica (calicreínas e elastase de neutrófilos) no lavado broncoalveolar de animais tratados com o inibidor e induzidos ao enfisema em comparação aos controles. Na terceira parte do trabalho, foram realizados ensaios em cultura de células A549 para investigar o potencial anti-inflamatório dos inibidores rBmTI-A, rBmTI-6-D1 e rBmTI-6-D2/3, a aplicação dos inibidores nestas células mostrou um aparente papel antiinflamatório por meio da diminuição da secreção das citocinas IL-6 e IL-8, no tratamento utilizando rBmTI-6-D1 e rBmTI-6-D2/3. Concluímos que os inibidores rBmTI-A e rBmTI-6 apresentam atividade que previne o desenvolvimento do enfisema induzido por PPE, devido às atividades antiproteases destes inibidores e por interferirem na resposta inflamatória. / Chronic obstructive pulmonary disease is characterized by progressive airflow limitation and its main manifestations are chronic bronchitis and pulmonary emphysema. It is generally irreversible and encompasses a series of processes that include the abnormal inflammatory response of the lungs with active involvement of macrophages, neutrophils and lymphocytes, failure to repair abnormal cells, early apoptosis, and destruction of the extracellular matrix caused by the imbalance between proteases and antiproteases, and this imbalance is one of the main mechanisms that lead to the establishment of the disease. Smoking is the main cause attributed to its onset, followed by genetic and environmental factors. Some enzymes are related to the pathogenesis of COPD such as human neutrophil elastase and metalloproteinases 9 and 12. In previous studies, the use of the serine proteinase inhibitor, rBmTI-A, a Kunitz- BPTI inhibitor type, resulted in the prevention of pulmonary emphysema by controlling of the inflammatory response commonly observed, as well as reducing the proteolytic activity present in bronchoalveolar lavage. In this work, the initial objective was to continue the research with rBmTI-A, with the characterization of differential gene expression in the emphysema model using mice, induced to emphysema by porcine pancreatic elastase (PPE) instillation; to reach this aim a microarray assay was performed. The microarray results in the identification of some genes which are affected by the treatment using rBmTI-A in animals that received PPE instillation previously. Among these genes were identified immune and inflammatory related genes, muscular contraction related genes, translation in mitochondria related genes and genes of other cellular functions. In the second part of this work, the serine proteinase inhibitor rBmTI-6-D1, other Kunitz-BPTI inhibitor type, was applied in the emphysema model using mice; previous results had shown that rBmTI-6 also presented the ability to avoid the emphysema development in the PPE instillation model. The present work we showed that the rBmTI-6-D1 treatment was sufficient to avoid the loss of elastic recoil, an effective decrease in alveolar enlargement and in the number of macrophages and lymphocytes in bronchoalveolar lavage fluid. Proteolytic analysis showed a significant increase in elastase activity in induced emphysema group that is controlled by rBmTI-6-D1. Kallikrein activity was decreased in the induced emphysema and inhibitor treated group when compared to induced emphysema group without treatment. In the third part of this work, assays using A549 cells were performed to investigate the anti-inflammatory potential of rBmTI-A, rBmTI- 6-D1 and rBmTI-6-D2/3 inhibitors. These inhibitors presented an apparent antiinflammatory role, due the reduced levels of IL-6 and IL-8 that were secreted by A549 cell when treated with rBmTI-6-D1 and rBmTI-6-D2/3. We concluded that rBmTI-A and rBmTI-6 inhibitors prevent the emphysema development induced by PPE, due the anti-proteinases activities of these inhibitors and by its interference in inflammatory response.

No description available.

No description available.