Sepse é uma síndrome, na qual, o paciente apresenta lesões de órgãos com risco a vida, em decorrência de uma inflamação exagerada desencadeada por uma infecção. Estima-se uma ocorrência anual de 31,5 milhões de casos de sepse e 19,4 milhões de casos de choque séptico no mundo, causando potencialmente 5,3 milhões de mortes. Esses índices alarmantes fizeram com que em 2017, a Organização Mundial da Saúde (OMS) adotasse uma resolução com o objetivo de aperfeiçoar a prevenção, diagnóstico e tratamento dessa condição clínica que vem sendo negligenciada. A iniciação da sepse, ocorre quando há um descontrole da infecção, acarretando excessiva ativação de células do sistema imune inato. Isso resulta em uma inflamação sistêmica danosa que é responsável pela maioria das alterações fisiopatológicas da sepse. Nesse contexto do sistema imune inato, o papel de neutrófilos já é bem compreendido da patogênese da sepse. Contudo, a função dos monócitos inflamatórios ainda não é bem estabelecida. Ao mesmo tempo que essas células podem participar do controle de infecções, elas também podem contribuir com a inflamação sistêmica e a lesão de órgãos. Deste modo, a compreensão do papel dessas células se faz importante para determinação de novos alvos terapêuticos para essa condição clínica. Nossos resultados demonstraram, em modelo experimental de sepse, que o aumento da emigração de monócitos inflamatórios da medula óssea está relacionado com maior taxa de mortalidade dos animais e exacerbação da inflamação sistêmica. A migração dessas células para órgãos, como rim e pulmão, está relacionado com inflamação e aumento de lesões, nesses locais. Deste modo, conclui-se que monócitos inflamatórios possuem um papel deletério na patogênese da sepse / Sepsis is a syndrome in which the patient has life-threatening organ damage due to an exaggerated inflammation triggered by an infection. The annual occurrence is 31.5 million cases of sepsis and 19.4 million cases of septic shock in the world, which potentially cause 5.3 million deaths. In concern of these alarming reports in 2017, the World Health Organization (WHO) adopted a resolution aimed at improving the prevention, diagnosis and treatment of this neglected clinical condition. The initiation of sepsis occurs when the infection was not controlled, causing excessive activation of the innate immune cells. This excessive activation causes a systemic inflammation that is responsible for most pathophysiological phenomena in sepsis. In this context of the innate immune system, the role of neutrophils is already well understood in the pathogenesis of sepsis. However, the role of inflammatory monocytes is not yet well established. These cells can participate in the control of infections, or can also contribute to systemic inflammation and organs damage. Thus, the understanding of the roles of these cells become important for the development of new therapeutic targets for this clinical condition. Our results demonstrated that the systemic increase of the inflammatory monocytes frequency is related to higher mortality rate, exacerbation of systemic inflammation, increased migration to organs (lung and kidney), and in these sites, are related to inflammation and lesions. Thus, we concluded that these cells have a deleterious role in the pathogenesis of sepsis

No description available.

Sepsis é uma disfunção de órgãos causada por uma resposta desregulada do hospedeiro em decorrência de uma infecção e que eventualmente leva a morte. A identificação de moléculas que minimizem este processo pode fornecer alvos terapêuticos para prevenir a falência de órgãos durante a sepse. O supressor de sinalização de citocinas 1 (SOCS1) é conhecido por regular negativamente a sinalização de receptores de citocinas e de receptores do tipo Toll (TLRs). No entanto, os alvos celulares e mecanismos moleculares envolvidos nas ações de SOCS1 durante a sepse são desconhecidos. Para determinar o papel de SOCS1 durante a sepse polimicrobiana, camundongos C57BL/6 foram tratados com um peptídeo inibidor do domínio KIR (kinase inhibitor region) do SOCS1 (iKIR) e submetidos à CLP (ligação e perfusão do ceco). O tratamento com iKIR aumentou a mortalidade, a carga bacteriana e a produção de citocinas inflamatórias induzida pela CLP. Além disso, observou-se que animais deficientes de SOCS1 nas células mielóides (SOCS1?myel) também tiveram aumento na carga bacteriana e na produção de citocinas proinflamatórias, quando comparados com camundongos SOCS1fl. O aumento na susceptibilidade a sepse foi acompanhado pelo aumento da via glicolítica nas células peritoneias e no pulmão desses animais. Assim, foi observado aumento da produção de ácido láctico e da expressão de enzimas glicolíticas como hexoquinase-1 (Hk1), lactato desidrogenase A (Ldha) e o transportador de glicose 1 (Glut-1) em camundongos sépticos tratados com iKIR ou SOCS1?myel. A expressão desses genes da via glicolítica foi dependente da via de ativação STAT3/HIF-1?. O tratamento com 2-deoxiglicose (inibidor da via glicolítica) diminuiu a susceptibilidade à sepse em camundongos tratados com iKIR. Estes resultados indicam um papel até agora desconhecido de SOCS1, como um regulador de reprogramação metabólica que reduz a resposta inflamatória exacerbada e o dano de órgãos durante a sepse. / Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Identification of pleiotropic molecular brakes might provide therapeutic targets to prevent organ failure during sepsis. Suppressor of cytokine signaling 1 (SOCS1) is known to negatively regulate signaling by cytokine and Tolllike receptors (TLRs). However, the cellular targets and molecular mechanisms involved in SOCS1 actions during sepsis are unknown. To address this in a cecal ligation puncture (CLP) model of sepsis, we treated C57BL/6 mice with an antagonist peptide (iKIR) that blocks the kinase inhibitory region (KIR) domain of SOCS1 and prevents its actions. iKIR treatment increased mortality, bacterial burden and inflammatory cytokine production induced after CLP. We also found that myeloid cell-specific SOCS1 deletion (SOCS1?myel) rendered mice more susceptible to sepsis, shown by higher bacterial loads and inflammatory cytokines than SOCS1fl littermate control mice. O aumento na susceptibilidade a sepse foi acompanhado pelo aumento da via glicolítica nas células peritoneias e pulmão desses animais. These effects were accompanied by increase of glycolysis function in peritoneal cells and lung of SOCS1?myel. Thus, it was observed increased expression of the glycolytic enzymes, hexoquinase-1 (Hk1), lactate dehydrogenase A (Ldha), and glucose transporter 1 (Glut-1) in iKIR-treated or SOCS1?myel septic mice. These events were dependent on the activation of STAT3/HIF-1? pathway. Blocking glycolysis with 2-deoxyglucose ameliorated the increased susceptibility to sepsis in iKIR-treated CLP mice. Together, we unveiled a heretofore unknown role of SOCS1 as a regulator of metabolic reprograming that reduces overwhelming inflammatory response and organ damage during sepsis.

Sepsis é uma disfunção de órgãos causada por uma resposta desregulada do hospedeiro em decorrência de uma infecção e que eventualmente leva a morte. A identificação de moléculas que minimizem este processo pode fornecer alvos terapêuticos para prevenir a falência de órgãos durante a sepse. O supressor de sinalização de citocinas 1 (SOCS1) é conhecido por regular negativamente a sinalização de receptores de citocinas e de receptores do tipo Toll (TLRs). No entanto, os alvos celulares e mecanismos moleculares envolvidos nas ações de SOCS1 durante a sepse são desconhecidos. Para determinar o papel de SOCS1 durante a sepse polimicrobiana, camundongos C57BL/6 foram tratados com um peptídeo inibidor do domínio KIR (kinase inhibitor region) do SOCS1 (iKIR) e submetidos à CLP (ligação e perfusão do ceco). O tratamento com iKIR aumentou a mortalidade, a carga bacteriana e a produção de citocinas inflamatórias induzida pela CLP. Além disso, observou-se que animais deficientes de SOCS1 nas células mielóides (SOCS1?myel) também tiveram aumento na carga bacteriana e na produção de citocinas proinflamatórias, quando comparados com camundongos SOCS1fl. O aumento na susceptibilidade a sepse foi acompanhado pelo aumento da via glicolítica nas células peritoneias e no pulmão desses animais. Assim, foi observado aumento da produção de ácido láctico e da expressão de enzimas glicolíticas como hexoquinase-1 (Hk1), lactato desidrogenase A (Ldha) e o transportador de glicose 1 (Glut-1) em camundongos sépticos tratados com iKIR ou SOCS1?myel. A expressão desses genes da via glicolítica foi dependente da via de ativação STAT3/HIF-1?. O tratamento com 2-deoxiglicose (inibidor da via glicolítica) diminuiu a susceptibilidade à sepse em camundongos tratados com iKIR. Estes resultados indicam um papel até agora desconhecido de SOCS1, como um regulador de reprogramação metabólica que reduz a resposta inflamatória exacerbada e o dano de órgãos durante a sepse. / Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Identification of pleiotropic molecular brakes might provide therapeutic targets to prevent organ failure during sepsis. Suppressor of cytokine signaling 1 (SOCS1) is known to negatively regulate signaling by cytokine and Tolllike receptors (TLRs). However, the cellular targets and molecular mechanisms involved in SOCS1 actions during sepsis are unknown. To address this in a cecal ligation puncture (CLP) model of sepsis, we treated C57BL/6 mice with an antagonist peptide (iKIR) that blocks the kinase inhibitory region (KIR) domain of SOCS1 and prevents its actions. iKIR treatment increased mortality, bacterial burden and inflammatory cytokine production induced after CLP. We also found that myeloid cell-specific SOCS1 deletion (SOCS1?myel) rendered mice more susceptible to sepsis, shown by higher bacterial loads and inflammatory cytokines than SOCS1fl littermate control mice. O aumento na susceptibilidade a sepse foi acompanhado pelo aumento da via glicolítica nas células peritoneias e pulmão desses animais. These effects were accompanied by increase of glycolysis function in peritoneal cells and lung of SOCS1?myel. Thus, it was observed increased expression of the glycolytic enzymes, hexoquinase-1 (Hk1), lactate dehydrogenase A (Ldha), and glucose transporter 1 (Glut-1) in iKIR-treated or SOCS1?myel septic mice. These events were dependent on the activation of STAT3/HIF-1? pathway. Blocking glycolysis with 2-deoxyglucose ameliorated the increased susceptibility to sepsis in iKIR-treated CLP mice. Together, we unveiled a heretofore unknown role of SOCS1 as a regulator of metabolic reprograming that reduces overwhelming inflammatory response and organ damage during sepsis.

Les asthmes en relation avec le travail (ART) incluent l’asthme professionnel (AP), dû à des causes et conditions attribuables à un environnement professionnel particulier, et l’asthme aggravé par le travail (AAT), qui est une forme pré-existante ou coïncidente d’asthme, aggravée par l’environnement professionnel. Le diagnostic des ART constitue un véritable enjeu. Le premier chapitre est une revue de la littérature, mettant en évidence les points discutés et notamment la place éventuelle des marqueurs de l’inflammation. Le deuxième chapitre présente une analyse de données épidémiologiques chez 417 apprentis coiffeurs et boulangers, des filières à risques d’AP. Des modèles mixtes montrent une association entre le degré de sensibilisation à douze allergènes communs et l’hyperréactivité bronchique (HBR) ainsi que les niveaux de FeNO expiré. Ce dernier est plus élevé de 83% (p<0,01) chez les sujets fortement sensibilisés et de 30% chez les sujets faiblement sensibilisés (p<0,01) comparé au groupe des sujets non sensibilisés. Le troisième chapitre relate l’élaboration d’un protocole de recherche (ARPEIGE) visant à acquérir des connaissances cliniques, épidémiologiques et économiques sur les ART, et aux développement et choix des outils et algorithmes décisionnels. L’analyse des questionnaires de repérage montre qu’en visite de routine en médecine du travail, une part non négligeable de salariés déclare des symptômes respiratoires évoquant un asthme actif, dont certains pourraient être en lien avec le travail. Ce protocole met en évidence la difficulté d’effectuer un dépistage des ART par le faible taux de retours des questionnaires approfondis. Malgré l’importance du diagnostic des ART, les stratégies diagnostiques restent discutées. Si les données chez les apprentis ont montré une association entre certains marqueurs de l’inflammation bronchique (FeNO) et des marqueurs d’atopie (tests cutanés), leur place dans le diagnostic clinique de l’asthme reste discutée. Au-delà des stratégies visant au diagnostic individuel, se pose également la question des stratégies diagnostiques utilisables en population professionnelle. Dans l’étude ARPEIGE, un questionnaire de repérage des symptômes fournit des données relatives à la prévalence des symptômes évocateurs d’asthme. Cependant, peu de sujets repérés acceptent de poursuivre les investigations, d’où l’importance de réfléchir à des stratégies qui permettraient un dépistage des ART au-delà de l’étape de repérage. / Work-related asthma (WRA) includes work aggravation of preexisting asthma (WEA) and new-onset asthma induced by occupational exposure (OA). Making an accurate diagnosis of WRA is important, the condition having significant health consequences and substantial socio-economic impacts. The first part is based on a literature review including data on prevalence, risk factors and diagnosis procedures of WRA. The issues in diagnosing WRA are also discussed, as well as the use of airway inflammation markers (FeNO levels and sputum eosinophils). The second part shows an analysis of epidemiological data in 417 apprentices in baking, pastry-cooking and hairdressing, which are populations at risk of OA. Mixed-effect models were applied and showed that the degree of sensitization was related to bronchial hyperresponsiveness (BHR) and FeNO levels. Compared to non-sensitized subjects, FeNO levels were 83% higher (p>0,01) in highly sensitized subjects and 30% higher (p<0,01) in weakly sensitized subjects. The third part describes the protocol of a field study aiming to collect new data on clinical, epidemiological and economical aspects of WRA. It focuses especially on the design of tools and decision algorithms, such as a screening questionnaire, and more advanced questionnaires on control, quality of life, expositions and socio-economic consequences, and a peak-flow journal. Screening results show that a substantial number of workers declare asthma-like respiratory symptoms, some of which being possibly related to work. Despite the importance of WRA diagnosis, diagnostic procedures are still being discussed. Although the apprentice study showed an association between airway inflammation markers (FeNO levels) and atopy markers (prick-tests), their use in the diagnostic procedure is still under discussion. Diagnostic procedures that could be used in populations at work are also subject to think about, in particular in epidemiological study, with the difficulty of differentiating OA from WEA. Thus, in the ARPEIGE study, a screening questionnaire was useful to collect data on asthma-like respiratory symptoms. Nevertheless, few screened workers agreed to go further and fill in the peak flow journal. Similarly, in the literature asthma and COPD screening campaigns using spirometry seemed difficult to implement. There is a lack of strategies that would enable a more accurate screening of WRA.

Introdução: O estudo dos fatores clínicos associados ao prognóstico da rinossinusite crônica (rsc), seja associada à polipose nasossinusal (RSCcPN) ou não (RSCsPN), ainda é pouco abordado a longo prazo. Objetivo: Avaliar pacientes submetidos à ESS (cirurgia endoscópica nasal, do inglês endoscopic sinus surgery) para o tratamento de RSC no Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo, entre 1996 e 2006, e correlacionar a recidiva em longo prazo com parâmetros como a extensão da doença, atopia, tabagismo, asma, eosinofilia e doença respiratória exacerbada pela aspirina (DREA). Métodos: Duzentos e um pacientes foram seguidos por um período médio de 12 anos. Os dados clínicos foram levantados, assim como exames de endoscopia nasal, Tomografia Computadorizada (TC), exames séricos, prick test e prova de função pulmonar. O tempo de seguimento pós-operatório foi analisado, sendo considerado fator de mau prognóstico a indicação de novo procedimento cirúrgico. Foi realizada comparação entre os fatores pela curva de Kaplan-Meyer, e pós-teste de Log-rank. Resultados e Discussão: Pacientes com RSCcPN tiveram chance de nova cirurgia três vezes maior do que aqueles sem pólipos nasais, no período seguido. Entre os pacientes com RSCsPN, apenas a asma foi um fator de pior prognóstico significativo, levando à chance de cirurgia 5,5 vezes maior do que os não-asmáticos. Já entre os pacientes com RSCcPN, aqueles com recidiva apresentaram maior extensão da doença à TC antes da primeira cirurgia. Foram ainda considerados fatores significativamente de pior prognóstico nos pacientes com RSCcPN: asma (odds ratio [OR] de 3,2); atopia a fungos (OR de 1,9); eosinofilia periférica (considerada como >500/µL, levando a OR de 1,9); e intolerância ao Ácido Acetil Salicílico (AAS) (DREA, apresentando OR de 2,5). Conclusões: Concluiu-se que a presença de pólipos per se é fator de pior prognóstico, aumentando em três vezes a chance de recorrência cirúrgica. Entre os pacientes com RSCsPN, apenas a asma influenciou o prognóstico. Já naqueles com RSCcPN, a asma, eosinofilia periférica, atopia a fungos e DREA aumentaram significativamente a probabilidade de nova intervenção cirúrgica. / Introduction: The analysis of prognostic factors associated with the recurrence of chronic rhinosinusitis (CRS), either with nasal polyps (CRSwNP) or without (CRSsNP), is still poorly discussed in the literature. Objective: To evaluate the patients that underwent endoscopic sinus surgery (ESS) due to CRS in Clinics Hospital of Ribeirão Preto Medical School, University of São Paulo, between 1996 and 2006, and to correlate the long-term recurrence to clinical factors, such as extensiveness of the disease, atopy, smoking habits, eosinophilia, and Aspirinexacerbated respiratory disease (AERD). Methods: We collected data of 201 patients, who were followed during an average period of 12 years. Clinical data collected were: extensiveness of the disease at endoscopy and at CT scans, prick test, blood exams, and pulmonary function. The follow-up period after surgery was assessed, and the indication of a new surgical procedure was considered as a poor prognostic factor. Comparison between factors was performed by Kaplan-Meyer curve, with Log-rank post-test. Results and discussion: CRSwNP patients were 3 times more likely to need a revisional surgery than CRSsNP during the follow-up period. Only asthma was a significant prognostic factor in patients with CRSsNP, leading to 5.5 times higher chance of recurrence than non-asthmatic patients. Among patients with CRSwNP, patients with recurrence presented, prior to surgery, higher CT scan extension of the disease. Other factors that influenced the prognosis on CRSwNP were: asthma (odds ratio [OR]: 3.2); atopy for fungi (OR: 1.9); peripheral eosinophilia (considered as >500/?L, leading to an OR: 1.9); and ASA intolerance (AERD; OR: 2.5). Conclusions: The presence of polyps were related to poor prognosis per se, leading to a higher chance of surgical recurrence. Among patients with CRSsNP, only asthma influenced the prognosis. Among the patients with CRSwNP, asthma, peripheral eosinophilia, fungi atopy, and AERD significantly increased the likelihood of further surgical intervention.

Introduction: L’asthme relié au travail (ART) est induit ou aggravé par le milieu du travail. L’asthme professionnel (AP) et l’asthme exacerbé au travail (AET) sont difficiles à distinguer en pratique clinique puisque dans les deux conditions les travailleurs se plaignent d’une détérioration de leur asthme au travail. De plus, les médecins sont souvent confrontés à des patients ayant des symptômes respiratoires reliés au travail (SRT) sans être asthmatiques. Ces patients sont souvent exclus des études qui visent à mieux caractériser l’ART. Objectifs : 1. Comparer la variabilité quotidienne des débits expiratoires de pointe (DEP) durant les périodes au et hors travail chez des sujets atteints d’AP et d’AET. 2. Évaluer la prévalence des patients ayant des SRT parmi les sujets référés pour possibilité d’ART, et comparer leurs caractéristiques et leur environnement professionnel avec ceux ayant l’ART. Résultats : L’exposition professionnelle induit une variabilité accrue des DEP chez les sujets avec AP et AET mais celle-ci est plus prononcée dans l’AP. Les sujets ayant des SRT sans être asthmatiques représentent une grande proportion des sujets référés pour possibilité d’ART. Conclusions : L’ART devrait être considéré chez tous les individus qui présentent un asthme de novo, ou une aggravation de leur asthme. La similitude des symptômes entre les sujets ayant des SRT et l’ART rend nécessaire d’effectuer une évaluation extensive. Cette évaluation devrait se faire selon une approche par étapes dans laquelle des tests objectifs améliorent la certitude du diagnostic et aident à différencier entre l’AP et l’AET. / Background: Work related asthma (WRA) refers to asthma that is induced or exacerbated by the workplace. Occupational asthma (OA) and work-exacerbated asthma (WEA) are difficult to distinguish in clinical practice since in both conditions workers complain of deterioration of their asthma while at work. In addition, physicians are often faced with subjects with work related respiratory symptoms (WRS) without being asthmatics. These subjects are often excluded from studies whose aim is to better characterize WRA. Objectives: 1. To compare the diurnal variability of peak expiratory flow (PEF) during periods at and away from work between subjects with OA and WEA. 2. To assess the prevalence of subjects with work related respiratory symptoms but without asthma among subjects referred for possible WRA, and to compare their characteristics and work environment to subjects with WRA. Results: Work exposures induce a significant PEF variability in both OA and WEA. However, the magnitude of variability is higher in OA than in WEA during work exposures. Subjects with WRS without asthma represent a large proportion of the subjects referred for possible WRA. Conclusions: WRA should be considered in all individuals who present with new-onset or worsening asthma. The similarity of the symptoms between subjects with WRA and WRS emphasizes the need to perform an extensive investigation. This investigation should be based on a stepwise approach in which multiple objective testing improves the certainty of diagnosis and help to differentiate between OA and WEA.

Introduction: L’asthme relié au travail (ART) est induit ou aggravé par le milieu du travail. L’asthme professionnel (AP) et l’asthme exacerbé au travail (AET) sont difficiles à distinguer en pratique clinique puisque dans les deux conditions les travailleurs se plaignent d’une détérioration de leur asthme au travail. De plus, les médecins sont souvent confrontés à des patients ayant des symptômes respiratoires reliés au travail (SRT) sans être asthmatiques. Ces patients sont souvent exclus des études qui visent à mieux caractériser l’ART. Objectifs : 1. Comparer la variabilité quotidienne des débits expiratoires de pointe (DEP) durant les périodes au et hors travail chez des sujets atteints d’AP et d’AET. 2. Évaluer la prévalence des patients ayant des SRT parmi les sujets référés pour possibilité d’ART, et comparer leurs caractéristiques et leur environnement professionnel avec ceux ayant l’ART. Résultats : L’exposition professionnelle induit une variabilité accrue des DEP chez les sujets avec AP et AET mais celle-ci est plus prononcée dans l’AP. Les sujets ayant des SRT sans être asthmatiques représentent une grande proportion des sujets référés pour possibilité d’ART. Conclusions : L’ART devrait être considéré chez tous les individus qui présentent un asthme de novo, ou une aggravation de leur asthme. La similitude des symptômes entre les sujets ayant des SRT et l’ART rend nécessaire d’effectuer une évaluation extensive. Cette évaluation devrait se faire selon une approche par étapes dans laquelle des tests objectifs améliorent la certitude du diagnostic et aident à différencier entre l’AP et l’AET. / Background: Work related asthma (WRA) refers to asthma that is induced or exacerbated by the workplace. Occupational asthma (OA) and work-exacerbated asthma (WEA) are difficult to distinguish in clinical practice since in both conditions workers complain of deterioration of their asthma while at work. In addition, physicians are often faced with subjects with work related respiratory symptoms (WRS) without being asthmatics. These subjects are often excluded from studies whose aim is to better characterize WRA. Objectives: 1. To compare the diurnal variability of peak expiratory flow (PEF) during periods at and away from work between subjects with OA and WEA. 2. To assess the prevalence of subjects with work related respiratory symptoms but without asthma among subjects referred for possible WRA, and to compare their characteristics and work environment to subjects with WRA. Results: Work exposures induce a significant PEF variability in both OA and WEA. However, the magnitude of variability is higher in OA than in WEA during work exposures. Subjects with WRS without asthma represent a large proportion of the subjects referred for possible WRA. Conclusions: WRA should be considered in all individuals who present with new-onset or worsening asthma. The similarity of the symptoms between subjects with WRA and WRS emphasizes the need to perform an extensive investigation. This investigation should be based on a stepwise approach in which multiple objective testing improves the certainty of diagnosis and help to differentiate between OA and WEA.