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Edwardsiella ictaluri causes enteric septicemia of catfish (ESC), a devastating disease in the channel catfish industry. Our research group has developed several E. ictaluri live attenuated vaccine (LAV) candidates (EiΔevpB, EiΔevpBΔfur, EiΔevpBΔhfq, EiΔevpBΔfurΔhfq), which were able to stimulate an immune response in vaccinated channel catfish and reduce ESC. However, innate, and adaptive immune responses in the lymphoid tissues of channel catfish to these LAVs are not known well. The overall goal of the project is to determine the role of adaptive and innate immune responses in catfish after vaccination with LAVs. Analysis of innate and adaptive immune-related gene expressions showed that the LAVs induced expression of adaptive immune-related genes in lymphoid tissues with less inflammation compared to wild type control. Also, the LAVs induced the expression of IgM in the sera of catfish.

By 2030 major depression is predicted to be the leading cause of disease burden in the world; as such, it is critical to understand factors that contribute to the development of depression. The social signal transduction theory of depression hypothesizes that adversity and social threat upregulate pro-inflammatory biomarkers leading to depression. The current study examined whether pro-inflammatory biomarkers (interleukin-6, interleukin-8, c-reactive protein, and tumor necrosis factor alpha) mediate the association between various types of childhood maltreatment (physical abuse, sexual abuse, emotional abuse, physical neglect, emotional neglect) and adult depression symptoms in a sample of 740 adults (372 female; Mage= 51.6 years, SD = 13.6) who provided retrospective report of childhood maltreatment as part of the Midlife in the United States (MIDUS) Refresher Biomarker study. Additionally, it explored whether these relations differ for males versus females. A series of linear regression analyses were run in SPSS; separate models were run for each form of childhood maltreatment and for interleukin-6, interleukin-8, c-reactive protein, and tumor necrosis factor-alpha. The results showed that childhood maltreatment is a robust predictor of adulthood depression; however, this association did not differ between biological sexes. In addition, only interleukin-6 was shown to partially mediate the association between childhood maltreatment and adulthood depression. These findings highlight the need to explore the use of interleukin-6 to screen for depression in youth. / M.S. / By 2030 major depression is predicted to be the leading cause of disease burden in the world; as such, it is critical to understand factors that contribute to the development of depression. It has been hypothesized that adversity and social threat activate pro-inflammatory biomarkers, which are proteins that can detect inflammation in the body, leading to depression. The current study examined whether several pro-inflammatory biomarkers explain the association between several types of childhood maltreatment (physical abuse, sexual abuse, emotional abuse, physical neglect, emotional neglect) and adult depression symptoms in a sample of 740 adults (372 female; Mage= 51.6 years, SD = 13.6) who provided report of past experiences of childhood maltreatment. Additionally, it explored whether these relations differ for males versus females. The results showed that childhood maltreatment is a robust predictor of adulthood depression for males and females. Of the inflammatory biomarkers examined, only interleukin-6 was shown to partially explain the association between childhood maltreatment and adulthood depression symptoms. These findings highlight the need to explore the use of interleukin-6 to screen for depression in youth.

Yes / Recent clinical trials of the hypoglycaemic sodium-glucose co-transporter-2 (SGLT2) inhibitors, which inhibit renal glucose reabsorption, have reported beneficial cardiovascular outcomes. Whether SGLT2 inhibitors directly affect cardiovascular tissues, however, remains unclear. We have previously reported that the SGLT2 inhibitor canagliflozin activates AMP-activated protein kinase (AMPK) in immortalised cell lines and murine hepatocytes. As AMPK has anti-inflammatory actions in vascular cells, we examined whether SGLT2 inhibitors attenuated inflammatory signalling in cultured human endothelial cells. Incubation with clinically-relevant concentrations of canagliflozin, but not empagliflozin or dapagliflozin activated AMPK and inhibited IL-1β-stimulated adhesion of pro-monocytic U937 cells and secretion of IL-6 and monocyte chemoattractant protein-1 (MCP-1). Inhibition of MCP-1 secretion was attenuated by expression of dominant-negative AMPK and was mimicked by the direct AMPK activator, A769662. Stimulation of cells with either canagliflozin or A769662 had no effect on IL-1β-stimulated cell surface levels of adhesion molecules or nuclear factor-κB signalling. Despite these identical effects of canagliflozin and A769662, IL-1β-stimulated IL-6/MCP-1 mRNA was inhibited by canagliflozin, but not A769662, whereas IL-1β-stimulated c-jun N-terminal kinase phosphorylation was inhibited by A769662, but not canagliflozin. These data indicate that clinically-relevant canagliflozin concentrations directly inhibit endothelial pro-inflammatory chemokine/cytokine secretion by AMPK-dependent and -independent mechanisms without affecting early IL-1β signalling. / Project Grant (PG/13/82/30483 to IPS and TMP) and PhD studentships (FS/16/55/32731 and FS/14/61/31284 to DB and AS) from the British Heart Foundation and an equipment grant (BDA11/0004309 to IPS and TMP) from Diabetes UK. OJK was supported by a Scholarship from the Iraqi Ministry of Higher Education and Scientific Research. TAA was supported by a Libyan Ministry of Education PhD Studentship.

Résumé : Dans les maladies respiratoires chroniques, les propriétés biochimiques et mécaniques des muscles lisses des voies respiratoires (MLVR) ont été analysées, mais les modes d’action des médiateurs lipidiques endogènes dérivés des oméga-3 (époxy- ou polyhydroxy- éicosanoïdes) restent à clarifier. Mon travail de recherche a pour but de caractériser le rôle potentiel de monoacyglycéride de l’acide éicosapentaénoϊque (MAG-EPA) et de monoacylglycéride de l’acide docosahexaénoϊque (MAG-DHA) ainsi que leurs métabolites (acide 17,18-époxyéicosatétraénoϊque : 17,18-EpETE, résolvine D1 : RvD1), sur le statut inflammatoire et l’activité contractile des voies respiratoires mises en culture organoϊde avec des cytokines pro-inflammatoires. Sur des trachées de cobayes (TC) natives précontractées au U-46619 (agoniste du récepteur thromboxane prostanoϊde), le 17,18-EpETE relaxe les tissus de manière plus importante que son précurseur, le MAG-EPA. Dans les TC mises en culture pendant 3 jours, les niveaux de TNF-α ont augmenté dans les fractions microsomales par rapport aux trachées natives. Sur ces tissues cultivés et traités avec 0.3 µM 17,18-EpETE, une réduction de la sensibilité au Ca2+ a été démontrée. De plus, une diminution de niveaux de détection des P-p65-NFκB, c-fos et c-Jun a été quantifiée en présence de 17,18-EpETE et des inhibiteurs de PKC ou Rho kinase lorsque les TC sont préalablement traités par 10 ng/ml TNF-α. Les cytokines pro-inflammatoires (IL-13 et TNF-α, etc…) jouent un rôle majeur dans la physiopathologie de l’asthme. Le projet de bronchioles humaines évalue l’effet de la RvD1 et de ses précurseurs (MAG-DHA, MAG-DPA et 17(S)-HpDoHE) sur le statut inflammatoire et la bronchoréactivité, in vitro. Dans les bronchioles stimulées par l’IL-13 pendant 48 h, le MAG-DHA ainsi que ces métabolites diminuent l’activation de la voie TNF-α/NFκB et la sensibilité au Ca2+ des tissus prétraités avec l’IL-13 vers des niveaux proches des conditions contrôles. Dans les bronchioles prétraitées par le TNF-α, l’inflammation et l’hypersensibilité au Ca2+ sont abolies par 1 µM MAG-DPA. De plus, l’aspirine combinée au MAG-oméga-3 potentialise les effets inhibiteurs de ce dernier sur l’inflammation et l’hyperréactivité bronchique induite par les cytokines, tout en régulant à la hausse les niveaux de détection du GPR-32 (le récepteur de RvD1). En conclusion, les dérivés des oméga-3 à longue chaîne pourraient résoudre l’inflammation et contrer les causes de l’hyperréactivité bronchique (HRB). / Abstract : In chronic respiratory diseases, the biochemical and mechanical properties of airway smooth muscle were analyzed, but the mode of action of omega-3 derivatives (epoxy or polyhydroxy-eicosanoids) remains to be clarified. My research work aims to characterize the potential role of eicosapentaenoic acid monoacyglyceride (MAG-EPA) and docosahexaenoic acid monoacylglyceride (MAGDHA) and their bioactive metabolites (17,18-epoxyeicosatetraenoic acid: 17 18-EpETE, resolvin D1: RvD1) on the inflammatory status and the contractile activity of organcultured airway explants with pro-inflammatory cytokines. On 30 nM U-46619 (Thromboxane prostanoid receptor agonist) pre-contracted fresh guinea pig trachea, 17,18 EpETE displays a greater ability than its precursor, MAG-EPA to relax airways. In 72-h-cultured tracheal rings, TNF-α levels increase in the microsomal fractions when compared to native trachea. In cultured and pre-treated tracheal rings with 0.3 µM 17,18-EpETE, the Ca2+ hypersensitivity is alleviated in comparaison to 3 day cultured tracheal rings. In addition, the detection levels of P-NFκB, c-fos and c-Jun were abolished in the presence of 17,18-EpETE and PKC or Rho kinase inhibitors in short term-TNF-α- incubated tracheal rings. Pro-inflammatory cytokines (IL-13, TNF-α, etc…) play a major role in asthma pathophysiology. The human bronchi project evaluates the effect of RvD1 and its precursors (MAG-DHA, MAG-DPA and 17 (S)-HpDoHE) on the inflammatory status and bronchial reactivity, in vitro. In IL-13 stimulated human bronchi for 48 h, the MAG-DHA and its metabolites decrease the activation of TNF-α / NFκB pathway and blunt the Ca2+ hypersensitivity triggered by IL-13. In TNF-α-pretreated human bronchi, airway inflammation and Ca2+ hypersensitivity are reversed by 1 µM MAG-DPA. Hence, aspirin combined with MAG-omega-3 potentiate the inhibitory effects of MAG-DHA on inflammation and bronchial hyperrresponsiveness triggered by pro-inflammatory cytokines, while upregulating the GPR-32 detection levels (RvD1 receptor). In conclusion, omega-3 derivatives could counteract the causes of airway hyperrresponsiveness (AHR).

Une des difficultés majeures dans le traitement des cancers est l’acquisition de résistance par les cellules tumorales vis-à-vis de la mort induite par les différentes chimiothérapies. Au sein du laboratoire, nous nous intéressons aux propriétés anti-tumorales d’un donneur de monoxyde d’azote (NO), le Glycéryl TriNitrate (GTN), fréquemment utilisé dans le traitement de l’angine de poitrine. Au cours de ce travail, nous avons étudié les mécanismes moléculaires par lesquels le GTN sensibilise les cellules tumorales de plusieurs types de cancer (colique, mammaire, prostatique) à la mort impliquant des voies de signalisation régulées par des cytokines telles que le TNFα, l’IL-6 ou encore le GDF-15.Une meilleure compréhension des mécanismes sous-jacents à l’action anti-tumorale du GTN permettrait de potentialiser son utilisation comme nouvelle thérapie anti-cancéreuse.Modèle colique : le GTN, en présence de la cytokine pro-inflammatoire TNFα, sensibilise les cellules cancéreuses coliques et mammaires à l’apoptose. Du point de vue mécanistique, le GTN induit la S-nitrosylation de cIAP1, inhibant ainsi son activité ubiquitine E3 ligase. Ce qui abroge la voie de signalisation classique NF-кB de survie cellulaire activée par la voie TNFα/TNFR1 en faveur d’une voie de signalisation pro-apoptotique.Modèle mammaire : le GTN intervient au niveau de la migration cellulaire en altérant la voie de signalisation Jak2/STAT3 activée par la cytokine pro-inflammatoire IL-6, dans un modèle de cancer du sein triple négatif. En présence de dérivés du platine (carboplatine) générant de l’IL-6, le GTN freine la migration des cellules en induisant la S-nitrosylation, et probablement l’inactivation, de la kinase Jak-2, indispensable pour l’activation de la voie.Modèle prostatique : le GTN sensibilise à la mort les cellules cancéreuses prostatiques résistantes au docétaxel en modulant le taux de deux marqueurs de résistance à cette chimiothérapie : la clusterine (CLU) et le growth differentiation factor 15 (GDF-15). Au niveau moléculaire, le GTN diminue le taux de l'isoforme cytoprotectrice soluble de la CLU (sCLU) et augmente le taux de l'isoforme cytotoxique nucléaire (nCLU) dans les cellules prostatiques résistantes au docétaxel. Plus particulièrement, en présence de GTN, nous avons établi un lien entre le GDF-15 et la modulation du taux des isoformes de la CLU. / One of the main difficulties in the treatment of cancers is the acquisition of resistance by the tumor cells vis-à-vis the death induced by the different chemotherapies. In the laboratory, we are interested in the anti-tumor properties of a nitric oxide (NO) donor, Glyceryl TriNitrate (GTN), frequently used in the treatment of angina pectoris. In this work, we investigated the molecular mechanisms by which GTN sensitizes tumor cells of several types of cancer (colonic, mammary, prostate) to death involving signaling pathways regulated by cytokines such as TNFα, IL-6 or GDF-15.A better understanding of the mechanisms underlying the GTN's anti-tumor action would make it possible to use it as a new anti-cancer therapy.Colon model: GTN, in the presence of the pro-inflammatory cytokine TNFα, sensitizes colon and mammary cancer cells to apoptosis. From a mechanistic point of view, GTN induces S-nitrosylation of cIAP1, thus inhibiting its ubiquitin E3 ligase activity. This abrogates the classical NF-κB signaling pathway of TNFα / TNFR1 activated cell survival in favor of a pro-apoptotic signaling pathway.Mammary model: GTN intervenes at the level of cell migration by altering the Jak2 / STAT3 signaling pathway activated by the pro-inflammatory cytokine IL-6, in a model of triple negative breast cancer. In the presence of platinum (carboplatin) derivatives generating IL-6, GTN inhibits cell migration by inducing S-nitrosylation, and probably inactivation, of Jak-2 kinase, essential for the activation of the way.Prostate model: GTN sensitizes prostatic prostate cancer cells to death by modulating the level of two markers of resistance to this chemotherapy: clusterin (CLU) and growth differentiation factor 15 (GDF-15). At the molecular level, GTN decreases the level of the soluble cytoprotective isoform of CLU (sCLU) and increases the level of nuclear cytotoxic isoform (nCLU) in prostatic cells resistant to docetaxel. More particularly, in the presence of GTN, we have established a link between GDF-15 and the modulation of the isoform rate of the CLU.

Made available in DSpace on 2016-08-10T10:38:42Z (GMT). No. of bitstreams: 1 CELINA KASSUMI KUNIEDA SUZUKI.pdf: 2013145 bytes, checksum: c807ebe49c872194bb7af7cd6bb5d17f (MD5) Previous issue date: 2012-06-29 / The increased prevalence of childhood obesity in recent years suggests the existence of a genetic predisposition or susceptibility to conditioning factors for obesity which act on the environmental factors related to lifestyle involving diet and physical activity. Food education programs and physical activities have been developed in order to reverse this situation. The chewing is considered one of the early stages of the digestive process and therefore primordial important because performing correctly promotes natural hunger satiety as well as a healthy digestion. The aim of this study is to investigate the polymorphism of the TNF-α and DRD2 genes and the influence of masticatory profile in childhood obesity to enable the preparation of proposals for more effective interventions to control weight gain. For this purpose the study has been divided into two articles. ARTICLE 1: This study evaluated the profile of the obese child chewing through survey and evaluation of clinical history miofunctional from the protocols of MgBr and AMIOFE-A (attached) in 11 normal children representing the control population (Group I) and 16 obese children (Group B) participating in the CAIS Group of Obesity in Goiânia Municipal and School of Clinical Speech Therapy PUC Goiás aged between 6 and 13 years for both sexes. According to the findings obtained in the research, it is concluded that obese group (OB) presents an incision chewing food made with the central and lateral incisors with the majority labial sealing with or without excessive movement, unilateral pattern, with higher presence of altered behaviors in chewing and shorter chewing time. ARTICLE 2: This study evaluated the genetic polymorphism of TNF-α gene (G308A) and DRD2 (Taq1α - C32806T) in 27 patients with childhood obesity (16) and controls (11) using the method ARMS-PCR and PCR-RFLP, respectively, in peripheral blood samples. The results suggest that the genetic polymorphism of Taq1α (C32806T) in the DRD2 gene was associated with the increase of obesity in the childhood. Still genetic variants of the SNP G308A TNF-α gene is not possible to confirm it s influence on children s weight gain. Understanding how genetic variations affect the tendency to become or remain obese is an important step to comprehend the mechanisms that lead to obesity. / O aumento da prevalência da obesidade infantil nestes últimos anos sugere a existência de predisposição ou suscetibilidade genética como fatores condicionantes para a obesidade, sobre a qual atuam fatores ambientais relacionados ao estilo de vida, que envolvem hábitos alimentares e atividade física. Programas de educação alimentar e de atividades físicas foram desenvolvidos visando reverter este quadro. A mastigação é considerada uma das fases iniciais do processo digestório e de primordial importância, pois quando realizada de forma correta, promove a saciedade natural da fome, bem como uma digestão saudável. O objetivo deste estudo foi investigar o polimorfismo dos genes TNF-α e DRD2 e a influência da mastigação na obesidade infantil para possibilitar a elaboração de propostas de intervenções mais eficazes para o controle do ganho de peso Para esta finalidade, o estudo foi dividido em dois artigos. ARTIGO 1: Este estudo avaliou o perfil mastigatório da criança obesa, por meio de levantamento de histórico clínico e avaliação miofuncional orofacial a partir dos protocolos do MGBR e AMIOFE-A (anexos), em 11 crianças eutróficas representando a população controle (Grupo EU) e 16 crianças obesas (Grupo OB) participantes de Grupo de Obesidade dos CAIS Municipais da cidade de Goiânia e da Clínica- Escola de Fonoaudiologia da PUC Goiás, com idade entre 6 e 13 anos de ambos os sexos. Conforme os achados obtidos na pesquisa, conclui-se que o grupo obeso (OB) apresenta uma mastigação com incisão do alimento feito com os incisivos centrais e laterais, sendo a maioria com vedamento labial sem ou com movimentação excessiva, padrão unilateral, com maior presença de comportamentos alterados na mastigação e tempo de mastigação reduzido. ARTIGO 2: Este estudo avaliou o polimorfismo genético dos genes TNF-α (G308A) e DRD2 (Taq1α - C32806T) em 27 pacientes com obesidade infantil (16) e de controle (11), utilizando o método de ARMS-PCR e PCR-RFLP, respectivamente, em amostras do sangue periférico. Os resultados sugerem que o polimorfismo genético em Taq1α (C32806T) no gene DRD2 apresentou associação com o incremento na obesidade infantil. Por outro lado, as variantes genéticas do SNP G308A do gene TNF-α não permitiram confirmar sua participação no ganho de peso em crianças. Entender como variações genéticas afetam a obesidade consiste em um passo importante na compreensão dos mecanismos desencadeadores da obesidade.

A dor neuropática pode ser causada por lesões e/ou disfunções no sistema somatossensorial. Nestes tipos de dores, alterações plásticas ao longo de todo o sistema sensorial nociceptivo estão associadas à cronificação do processo doloroso. A plasticidade observada pode ser resultante da indução e/ou repressão de genes, os quais geralmente são modulados por fatores de transcrição. Um dos principais fatores de transcrição até então conhecido é a proteína ativadora-1 (AP-1), que pode ser estruturalmente formado principalmente por proteínas das famílias Jun e Fos. Entretanto, na dor neuropática, a participação e o papel do AP-1 não estão bem elucidados. Dessa forma, a hipótese deste trabalho é que a ativação do AP-1 contribua para a indução e/ou manutenção da dor neuropática, através da ativação de células gliais e de proteinocinases ativadas por mitógenos (MAPK) e por indução da produção e liberação de mediadores pró-inflamatórios, bem como de metaloproteinases da matriz extracelular (MMP) na medula espinal. Esses fatores contribuem para sensibilização central causada pela SNI, facilitando a transmissão dolorosa. Assim, a inibição do AP-1 seria uma potencial estratégia terapêutica no tratamento da dor neuropática. Foi utilizado o modelo experimental de dor neuropática de lesão limitada do nervo isquiático (SNI, Spared Nerve Injury) em camundongos, os quais receberam injeção intratecal (i.t.) do inibidor de AP-1, SR11302, ou seu veículo (DMSO, tween® 20 e salina). O tratamento com o inibidor de AP-1 reduziu a hipernocicepção mecânica causada pela SNI, e o perfil de redução sugeriu que esse fator de transcrição esteja relacionado com a manutenção da dor neuropática. No sétimo dia após a SNI, observou-se na medula espinal dos camundongos, ativação da microglia, dos astrócitos e das MAPK, além de aumento na expressão de TNF-, interleucina (IL)-6, IL-1, IL-17A, quimiocina derivada de queratinócito (KC), proteína quimiotáxica de monócitos (MCP-1), óxido nítrico (NO), NO sintase induzível e das MMP-2 e -9. Todos esses eventos estão associados à sensibilização central, portanto, contribuem para a facilitação da transmissão nociceptiva. O tratamento com o inibidor de AP-1 SR11302 impediu, pelo menos parcialmente, a ativação das células gliais e das MAPK e bloqueou o aumento na expressão de todos esses mediadores pró-inflamatórios e das MMPs na medula espinal. Assim, o fator de transcrição AP-1 e, consequentemente, suas vias a jusante (downstream) são potenciais alvos farmacológicos no tratamento da dor neuropática. / Neuropathic pain results from nerve damage or dysfunction, which is associated to the painful process of chronification. This process may include participation of the inducible genes, which may be modulated by transcription factors, including the activator protein-1 (AP-1), which can structurally be formed by proteins from Jun and Fos families. However, the participation and the role of AP-1 neuropathic pain remain unclear. Our hypothesis is that the activation of AP-1 would contribute for the induction and/or maintenance of neuropathic pain, by inducing the glial cells activation and mitogen-activated protein kinases, and by inducing the production/release of pro-inflammatory mediators and extracellular matrix metalloproteinase (MMP) in mices spinal cord. All these factors are contributing to SNI-evoked central sensitization, facilitating pain transmission. Thus, inhibition of AP-1 would be a potential drug target in the treatment of neuropathic pain. The animals received inhalatory anesthesia (2% isoflurane) and were submitted to an experimental model of neuropathic pain Spared Nerve Injury (SNI). The animals were treated intrathecally (i.t.) with AP-1 inhibitor SR11302 or vehicle (DMSO, tween®20 and saline). Treatment with AP-1 inhibitor reduced the SNI-induced mechanical hypernociception, suggesting that this transcription factor is related to the maintenance of neuropathic pain. On the seventh day after SNI, there was in the spinal cord of mice microglia, astrocytes and MAPK activation, increased of expression of TNF-, interleukin (IL)-6, IL-1, IL-17A, keratinocyte-derived chemokine (KC), monocyte chemoattractant protein-1 (MCP-1), nitric oxide (NO) and inducible NO synthase, and increased the expression of MMP-2 and -9. All of these effects are related with central sensitization, thus facilitating nociceptive transmission. However, treatment with SR11302 prevented, at least partially, activation of MAPK and glial cells, as well as prevented the increase in expression of all these pro-inflammatory mediators and MMPs in the spinal cord. Thus, inhibition of AP-1 and hence its way downstream is a potential pharmacological target in the treatment of neuropathic pain.

INTRODUÇÃO: A urticária crônica igmaidiopática (UCI) é uma doença desencadeada pela desgranulação de basófilos e mastócitos com consequente liberação de histamina, sendo que o perfil imunológico nesta doença não é bem estabelecido. As estatinas, inibidores da 3-hidroxi-3-metilglutaril coenzima A redutase, apresentam efeitos antiinflamatórios e imunomodulatórios. O efeito desta droga tem sido estudado em muitas doenças inflamatórias crônicas, incluindo doenças autoimunes, mas não existem evidências na UCI. OBJETIVOS: O objetivo deste estudo foi analisar o efeito das estatinas na resposta imune e sua a influência na expressão de genes regulatórios e relacionados com a resposta inflamatória. MÉTODOS: A resposta limfoproliferativa a mitógenos e antígeno-específica de 22 pacientes com UCI e 41 controles na presença de estatinas (0,25-25 µM) foi analisada pela incorporação de timidina após 3 ou 6 dias de cultura. A progressão do ciclo celular e apoptose foi realizada pela incorporação de bromodeoxiuridina (Brdu) ao DNA após estímulo por PHA ou PWM e analisada por citometria de fluxo. A secreção de citocinas foi quantificada por ELISA e a expressão de mRNA de fatores regulatórios e pró-inflamatórios quantificados por real-time PCR. RESULTADOS: Os resultados evidenciaram que as estatinas em elevadas concentrações são capazes de inibir a capacidade mitogênica das células T e B seja dos indivíduos saudáveis ou de pacientes com UCI. A inibição da proliferação celular mediada pelas estatinas foi decorrente ao bloqueio na etapa inicial do ciclo celular (Fase G0/1), o que impediu o prosseguimento para outras fases do ciclo (S e G2/M). A diminuição da resposta proliferativa em resposta a um mitógeno como a PHA resultou na inibição da ativação celular pela estatina e a significante redução na produção de citocinas como IFN-?, IL-10, IL-17A e IL-5. Em contraste, o efeito modulatório das estatinas ao estímulo com LPS inibiu a produção de TNF-? e MIP-1? pelas células dos controles, mas não influenciou na produção de citocinas pró-inflamatórias pelas CMN dos pacientes com UCI. Somente a incubação prévia das células com as drogas, em alta concentração (25µM), foi possível verificar a modulação negativa na produção de IL-6 e MIP1-? para ambos os grupos, mas não para o TNF-? para os pacientes. A sinvastatina foi capaz exercer efeito modulatório mais pronunciado que a lovastatina na produção de citocinas induzidas por LPS. Os resultados evidenciaram que os pacientes com UCI possuem uma diminuição da expressão da enzima IDO e aumento de SOCS3 nas CMN. A sinvastina não altera esse perfil e previne a expressão de fatores inflamatórios como RORC?t e NALP3 inflamassomas. CONCLUSÕES: Em conjunto, os resultados sugerem um desequilíbrio dos mecanismos regulatórios que poderiam contribuir com a cronicidade e o perfil inflamatório na UCI. As estatinas apresentam maior efeito antiinflamatório que pró-inflamatório, sugerindo ter potencial clínico para o tratamento de doenças crônicas como a UCI. / INTRODUCTION: Chronic Idiopathic Urticaria (CIU) is a disease triggered by degranulation of basophils and mast cells with consequent histamine release and the CIU immunological profile is not well established. Statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, also display a broad immunomodulatory property. Statins have been studied in several chronic inflammatory diseases, including autoimmune disorders, but there are no evidences in CIU disease. OBJECTIVES: The aim of this study was to verify the effect of statins the immune response, and the expression of genes related to regulatory and inflammatory response focusing in CIU patients and healthy controls (HC). METHODS: Lymphoproliferative response to mitogens or recall antigens of 22 patients with CIU and 41 HC with statins (0,25-25µM) was analyzed by timidine incorporation after 3 or 6 days of cell cultures. Cell cycle progression and apoptosis were assessed by bromodeoxyiridine (BrDU) incorporation to DNA upon PHA or PWM stimulus by flow cytometry. Cytokines secretion was measured by ELISA and mRNA of regulatory and proinflammatory genes were analyzed by quantitative real-time PCR. RESULTS: The results showed that high concentrations of statins can inhibit the mitogenic capacity of T and B cells of HC or CIU patients. The inhibition of cell proliferation mediated by statins was due to blockage in the initial phase of the cell cycle (G0/1), which prevented progress to cycle phases (S and G2/M). The decreased proliferative response in response to PHA mediated by statin resulted in a significant inhibition of IFN-?, IL-10, IL-17A and IL-5 secretion levels. Statin effect in response to LPS showed inhibition of TNF-? and MIP-1? secretion by cells from HC, but did not influence the production by PBMC of CIU. It was necessary the pre-incubation of cells with drugs at high concentration (25µM) to verify the negative modulation of IL-6 and MIP1-? secretion in both groups, except for TNF-? in CIU. Simvastatin was able to exert more pronounced modulatory effect than lovastatin in cytokine production induced by LPS. Furthermore, CIU patients have a decreased expression of the enzyme IDO and increased of SOCS3 in PBMC, which were not modified by simvastatin, whereas prevented the upregulation of proinflammatory factor as RORC?t and NALP3 inflammasomes. CONCLUSIONS: Altogether, the results evidenced an imbalance of regulatory mechanisms that could contribute to chronic evolution and inflammatory profile in CIU. Statins exhibited more anti-inflammatory effects than proinflammatory, suggesting a potential clinical role for treatment in chronic diseases as CIU.

O canabidiol (CBD), o principal canabinóide não psicotrópico extraído da marijuana (Cannabis sativa), é reconhecido por sua potente propriedade imunosupressora e anti-inflamatória. A injúria pulmonar aguda (ALI) é uma doença inflamatória para qual ainda não foi desenvolvida terapias específicas e a única alternativa de tratamento é meramente de suporte em UTI. Desta forma, foi proposta uma investigação sobre os efeitos anti-inflamatórios do CBD em um modelo murino de ALI, induzida pela instilação intra-nasal de LPS (lipopolissacarídeo), dentro de uma perspectiva imune-neuro-endocrinológica. Para a análise do potencial anti-inflamatório do CBD, avaliou-se a contagem total e diferencial de células do lavado broncoalveolar (LBA) (análise da migração de leucócitos para os pulmões), a atividade de mieloperoxidase (MPO) no tecido pulmonar (análise indireta da atividade de neutrófilos), a produção de citocinas e quimicionas no sobrenadante do LBA (análise do perfil inflamatório pulmonar), a concentração de proteínas (albumina) no sobrenadante do LBA (análise indireta da permeabilidade vascular pulmonar) e a expressão de moléculas de adesão (ICAM-1 e VLA-4) em leucócitos do LBA. Analisou-se, ainda, o mecanismo farmacológico dos efeitos anti-inflamatórios do CBD no modelo de ALI, utilizando-se de um antagonista altamente seletivo para o receptor de adenosina A2A (ZM241385). Por fim, avaliou-se os efeitos neuroendócrinos do CBD na vigência da inflamação pulmonar; analisou-se a atividade geral dos animais no campo aberto (análise do comportamento doentio) e os níveis séricos de corticosterona (análise da ativação do eixo Hipotálamo-Hipófise-Adrenal (HPA)). Mostrou-se que tanto o tratamento prolifático (antes da indução da inflamação) como o tratamento terapêutico (depois da indução da inflamação), com uma dose única de CBD (20 ou 80 mg/kg) apresenta um efeito anti-inflamatório prolongado em camundongos submetidos ao modelo de ALI (principalmente 1 e 2 dias após a indução da inflamação). Mostrou-se que o CBD diminuiu a migração de leucócitos para os pulmões (neutrófilos, macrófagos e linfócitos), diminuiu a produção de citocinas (TNF e IL-6) e quimicinas (MCP-1 e MIP-2) no LBA, diminuiu a atividade MPO no tecido pulmonar, diminuiu a concentração de albumina no LBA e diminuiu a expressão de moléculas de adesão (ICAM-1) em neutrófilos do LBA. Mostrou-se, ainda, que o receptor de adenosina A2A está envolvido nos efeitos anti-inflamatórios do CBD na ALI, uma vez que o tratamento com o ZM241385 aboliu todos os efeitos anti-inflamatórios descritos previamente. Por fim, mostrou-se que o CBD apresentou poucos efeitos comportamentais no campo aberto e que não ativou o eixo HPA. Desta forma, mostrou-se pela primeira vez que o tratamento profilático e, também, o tratamento terapêutico com CBD (20 ou 80 mg/kg) tem um efeito anti-inflamatório prolongado em um modelo murino de ALI, muito provavelmente em decorrência de um aumento da sinalização via receptor de adenosina A2A. Por esta razão, acredita-se que o CBD possa ser considerado, no futuro, uma ferramenta terapêutica útil no tratamento de doenças inflamatórias pulmonares. / Cannabidiol (CBD), the major non-psychotropic plant (Cannabis sativa)-derived cannabinoid, is recognized for its immunossupressant and anti-inflammatory properties. Acute lung injury (ALI) is an inflammatory condition for which treatment is mainly supportive (ICU patients), because effective therapies have not been developed. Therefore, it was proposed an investigation in order to address the anti-inflammatory effects of CBD in a murine model of LPS-induced ALI, within an immune-neuro-endocrine perspective. To analyze the potential anti-inflammatory effect of CBD, it was evaluated total and differencial cell count of leukocytes present in the bronchoalveolar lavage (BAL) (migration of leukocytes into the lungs), myeloperoxidase activity in the lung tissue (indirect analysis of neutrophil activity), production of cytokines and chemokines in the BAL (analysis of the pulmonar inflammatory profile), protein (albumin) concentration in the BAL (indirect analysis of pulmonar vascular permeability), and expression of adhesion molecules (ICAM-1 and VLA-4) in leukocytes of the BAL. It was also analyzed the pharmacologic mechanism of the anti-inflammatory effects of CBD in the model of ALI, by using a highly selective antagonist of the adenosine A2A receptor (ZM241385). Finally, it was analyzed the neuro-endocrine effects of CBD in the context of lung inflammation; it was analyzed the general activity of the mice in the open field (analysis of sickness behavior) and the seric levels of corticosterone (activation of HPA (Hypothalamus-Hypophysis-Adrenal) axis). It was shown that both prophylactic (before the induction of inflammation) and therapeutic (after the induction of inflammation) protocols of treatment, with a sigle dose of CBD (20 or 80 mg/kg), has a long-term anti-inflammatory effect in mice submitted to the model of ALI (specially, after 1 and 2 days of the induction of inflammation). It was shown that CBD decreased leukocyte (neutrophil, macrophage, and lymphocytes) migration into the lungs, decreased cytokines (TNF and IL-6) and chemokines (MCP-1 and MIP-2) in the BAL, decreased MPO activity in the lung tissue, decreased albumin concentration in the BAL, and decreased adhesion molecule expression (ICAM-1) in neutrophils of the BAL. It was also shown that adenosine A2A receptor is involved in the anti-inflammatory effects of CBD on LPS-induced ALI, because ZM241385 abrogated all of the anti-inflammatory effects of cannabidiol previously described. Finally, it was shown that CBD has discreet behavioral effects in the open field and was not able to activate the HPA axis. Thus, it was shown for the first time that both prophylactic and also therapeutic treatment with CBD (20 or 80 mg/kg) has a long-term anti-inflammatory effect in a murine model of ALI, most likely associated with an increase in the signaling through the adenosine A2A receptor. Hence, it is possible that in the future CBD may prove useful as a therapeutical tool in the treatment of pulmonar inflammatory conditions.