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1.
Med Hypotheses ; 146: 110473, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33385879

RESUMO

Severe forms of the Coronavirus disease 2019 (COVID-19) are characterized by an enhanced inflammatory syndrome called "cytokine storm" that produces an aberrant release of high amounts of cytokines, chemokines, and other proinflammatory mediators. The pathogenetic role of the "cytokine storm" has been confirmed by the efficacy of immunosuppressive drugs such as corticosteroids along with antiviral drugs in the treatment of the severe forms of this disease. Phenylmethimazole (C10) is a derivative of methimazole with anti-inflammatory properties. Studies performed both in vitro and in vivo have shown that C10 is able to block the production of multiple cytokines, chemokines, and other proinflammatory molecules involved in the pathogenesis of inflammation. Particularly, C10 is effective in reducing the increased secretion of cytokines in animal models of endotoxic shock. We hypothesize that these effects are not limited to the endotoxic shock, but can also be applied to any disease characterized by the presence of a "cytokine storm". Therefore, C10 may be a potential drug to be used alternatively or in association with the corticosteroids or other immunosuppressive agents in the severe forms of COVID-19 as well as other viral diseases that induce a "cytokine storm". Preclinical and clinical studies have to be performed to confirm this hypothesis.


Assuntos
/tratamento farmacológico , Síndrome da Liberação de Citocina/tratamento farmacológico , Metimazol/análogos & derivados , Tionas/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Antivirais/farmacologia , Síndrome da Liberação de Citocina/imunologia , Citocinas/antagonistas & inibidores , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Humanos , Metimazol/farmacologia , Camundongos , Pandemias , Choque Séptico/tratamento farmacológico , Choque Séptico/imunologia , Pesquisa Médica Translacional
2.
Eur Rev Med Pharmacol Sci ; 24(24): 13062-13064, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33378059

RESUMO

Cytokine storm in COVID-19 is linked to disease severity and mortality. 40% of patients with severe COVID-19 require mechanical ventilation. Analgesia and sedation are used for treatment of pain, facilitation of mechanical ventilation, or management of acute agitation. Herein, we present the immunomodulating actions of morphine that may either improve or worsen the clinical course of COVID-19 once cytokine storm develops. A literature search was performed to find articles on potential immunomodulatory effects of morphine. Taken together, the results of in vitro and in vivo models in non-COVID-19 conditions suggest that morphine could have a beneficial effect by mitigating the cytokine storm in the early stages of severe COVID-19. In contrast, it could be potentially harmful in late stages of severe COVID-19, especially in the presence of septic shock.


Assuntos
Analgésicos Opioides/efeitos adversos , Síndrome da Liberação de Citocina/imunologia , Imunomodulação , Morfina/efeitos adversos , Analgésicos Opioides/uso terapêutico , Citocinas/imunologia , Humanos , Morfina/uso terapêutico , Respiração Artificial , Choque Séptico/imunologia
3.
Signal Transduct Target Ther ; 5(1): 128, 2020 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-32712629

RESUMO

The recent novel coronavirus disease (COVID-19) outbreak, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is seeing a rapid increase in infected patients worldwide. The host immune response to SARS-CoV-2 appears to play a critical role in disease pathogenesis and clinical manifestations. SARS-CoV-2 not only activates antiviral immune responses, but can also cause uncontrolled inflammatory responses characterized by marked pro-inflammatory cytokine release in patients with severe COVID-19, leading to lymphopenia, lymphocyte dysfunction, and granulocyte and monocyte abnormalities. These SARS-CoV-2-induced immune abnormalities may lead to infections by microorganisms, septic shock, and severe multiple organ dysfunction. Therefore, mechanisms underlying immune abnormalities in patients with COVID-19 must be elucidated to guide clinical management of the disease. Moreover, rational management of the immune responses to SARS-CoV-2, which includes enhancing anti-viral immunity while inhibiting systemic inflammation, may be key to successful treatment. In this review, we discuss the immunopathology of COVID-19, its potential mechanisms, and clinical implications to aid the development of new therapeutic strategies against COVID-19.


Assuntos
Betacoronavirus , Infecções por Coronavirus , Surtos de Doenças , Imunidade Inata , Imunoterapia , Pandemias , Pneumonia Viral , Choque Séptico , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/terapia , Citocinas/imunologia , Humanos , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , Pneumonia Viral/terapia , Choque Séptico/epidemiologia , Choque Séptico/imunologia , Choque Séptico/terapia
4.
Am J Respir Crit Care Med ; 202(6): 830-842, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32520577

RESUMO

Rationale: Sepsis is characterized by a dysregulated immune response to infection. Norepinephrine, the cornerstone vasopressor used in septic shock, may contribute to immune dysregulation and impact host defense.Objectives: To investigate effects of norepinephrine and the alternative vasopressor vasopressin on the immune response and host defense.Methods: Leukocytes from six to nine donors were stimulated in the presence or absence of norepinephrine and vasopressin. A total of 190 C57BL/6J mice received a continuous infusion of norepinephrine or vasopressin via microosmotic pumps and were challenged with LPS or underwent cecal ligation and puncture. Thirty healthy volunteers were randomized to a 5-hour infusion of norepinephrine, vasopressin, or saline and intravenously challenged with LPS. The relationship between the norepinephrine infusion rate and the use of ß-blockers and plasma cytokines was assessed in 195 patients with septic shock.Measurements and Main Results: Norepinephrine attenuated the production of proinflammatory mediators and reactive oxygen species and augmented antiinflammatory IL-10 production both in vitro and in LPS-challenged mice. Norepinephrine infusion during cecal ligation and puncture resulted in increased bacterial dissemination to the spleen, liver, and blood. In LPS-challenged volunteers, norepinephrine enhanced plasma IL-10 concentrations and attenuated the release of the proinflammatory cytokine IFN-γ-induced protein 10. Vasopressin exerted no immunomodulatory effects across these experimental setups. In patients, higher norepinephrine infusion rates were correlated with a more antiinflammatory cytokine balance, whereas ß-blocker use was associated with a more proinflammatory cytokine balance.Conclusions: Norepinephrine dysregulates the immune response in mice and humans and compromises host defense. Therefore, it may significantly contribute to sepsis-induced immunoparalysis, whereas vasopressin does not have untoward immunologic effects.


Assuntos
Imunidade Ativa/efeitos dos fármacos , Norepinefrina/efeitos adversos , Norepinefrina/imunologia , Choque Séptico/tratamento farmacológico , Choque Séptico/imunologia , Vasoconstritores/efeitos adversos , Vasoconstritores/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Anti-Inflamatórios/efeitos adversos , Anti-Inflamatórios/imunologia , Anti-Inflamatórios/uso terapêutico , Humanos , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Modelos Animais , Países Baixos , Norepinefrina/uso terapêutico , Kit de Reagentes para Diagnóstico , Vasoconstritores/uso terapêutico
6.
Nat Commun ; 11(1): 2607, 2020 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-32451375

RESUMO

Quantification of pathogen and host biomarkers is essential for the diagnosis, monitoring, and treatment of infectious diseases. Here, we demonstrate sensitive and rapid quantification of bacterial load and cytokines from human biological samples to generate actionable hypotheses. Our digital assay measures IL-6 and TNF-α proteins, gram-negative (GN) and gram-positive (GP) bacterial DNA, and the antibiotic-resistance gene blaTEM with femtomolar sensitivity. We use our method to characterize bronchoalveolar lavage fluid from patients with asthma, and find elevated GN bacteria and IL-6 levels compared to healthy subjects. We then analyze plasma from patients with septic shock and find that increasing levels of IL-6 and blaTEM are associated with mortality, while decreasing IL-6 levels are associated with recovery. Surprisingly, lower GN bacteria levels are associated with higher probability of death. Applying decision-tree analysis to our measurements, we are able to predict mortality and rate of recovery from septic shock with over 90% accuracy.


Assuntos
Citocinas/sangue , DNA Bacteriano/sangue , Choque Séptico/imunologia , Choque Séptico/microbiologia , Asma/imunologia , Asma/microbiologia , Carga Bacteriana , Biomarcadores/análise , Biomarcadores/sangue , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/imunologia , Líquido da Lavagem Broncoalveolar/microbiologia , Estudos de Casos e Controles , Citocinas/análise , DNA Bacteriano/genética , Árvores de Decisões , Genes Bacterianos , Bactérias Gram-Negativas/genética , Bactérias Gram-Negativas/isolamento & purificação , Bactérias Gram-Positivas/genética , Bactérias Gram-Positivas/isolamento & purificação , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Interleucina-6/análise , Interleucina-6/sangue , Reação em Cadeia da Polimerase Multiplex/métodos , Reação em Cadeia da Polimerase Multiplex/estatística & dados numéricos , Prognóstico , Sensibilidade e Especificidade , Choque Séptico/mortalidade , Fator de Necrose Tumoral alfa/análise , Fator de Necrose Tumoral alfa/sangue , Resistência beta-Lactâmica/genética
7.
Arch Med Res ; 51(4): 347-348, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32340759

RESUMO

The novel coronavirus (SARS-CoV-2) infection which has been known as Coronavirus diseases 2019 COVID-19 has become an endemic emergent situation by the World Health Organization. So far, no successful specific treatment has been found for this disease. As has been reported, most of non-survivor patients with COVID-19 (70%) had septic shock which was significantly higher than survived ones. Although the exact pathophysiology of septic shock in these patients is still unclear, it seems to be possible that part of it would be due to the administration of empiric antibiotics with inflammatory properties especially in the absence of bacterial infection. Herein, we have reviewed possible molecular pathways of septic shock in the patients who have received antibiotics with inflammatory properties which mainly is release of interleukin 1ß (IL-1ß), IL-6, and tumor necrosis factor α (TNF- α) through different routes. Altogether, we highly recommend clinicians to look after those antibiotics with anti-inflammatory activity for both empiric antibiotic therapy and reducing the inflammation to prevent septic shock in patients with diagnosed COVID-19.


Assuntos
Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/imunologia , Inflamação/virologia , Pneumonia Viral/imunologia , Choque Séptico/virologia , Estudos de Coortes , Infecções por Coronavirus/patologia , Humanos , Inflamação/imunologia , Inflamação/patologia , Pandemias , Pneumonia Viral/patologia , Estudos Retrospectivos , Choque Séptico/imunologia , Choque Séptico/patologia
8.
Crit Care ; 24(1): 96, 2020 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-32188504

RESUMO

BACKGROUND: Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. Numerous studies have explored the complex and dynamic transcriptome modulations observed in sepsis patients, but a large fraction of the transcriptome remains unexplored. This fraction could provide information to better understand sepsis pathophysiology. Multiple levels of interaction between human endogenous retroviruses (HERV) and the immune response have led us to hypothesize that sepsis is associated with HERV transcription and that HERVs may contribute to a signature among septic patients allowing stratification and personalized management. METHODS: We used a high-density microarray and RT-qPCR to evaluate the HERV and Mammalian Apparent Long Terminal Repeat retrotransposons (MaLR) transcriptome in a pilot study that included 20 selected septic shock patients, stratified on mHLA-DR expression, with samples collected on day 1 and day 3 after inclusion. We validated the results in an unselected, independent cohort that included 100 septic shock patients on day 3 after inclusion. We compared septic shock patients, according to their immune status, to describe the transcriptional HERV/MaLR and conventional gene expression. For differential expression analyses, moderated t tests were performed and Wilcoxon signed-rank tests were used to analyze RT-qPCR results. RESULTS: We showed that 6.9% of the HERV/MaLR repertoire was transcribed in the whole blood, and septic shock was associated with an early modulation of a few thousand of these loci, in comparison to healthy volunteers. We provided evidence that a subset of HERV/MaLR and conventional genes were differentially expressed in septic shock patients, according to their immune status, using monocyte HLA-DR (mHLA-DR) expression as a proxy. A group of 193 differentially expressed HERV/MaLR probesets, tested in an independent septic shock cohort, identified two groups of patients with different immune status and severity features. CONCLUSION: We demonstrated that a large, unexplored part of our genome, which codes for HERV/MaLR, may be linked to the host immune response. The identified set of HERV/MaLR probesets should be evaluated on a large scale to assess the relevance of these loci in the stratification of septic shock patients. This may help to address the heterogeneity of these patients.


Assuntos
Retrovirus Endógenos/genética , Choque Séptico , Transcriptoma/genética , Idoso , Feminino , Antígenos HLA-DR , Humanos , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Projetos Piloto , Retroelementos , Choque Séptico/sangue , Choque Séptico/genética , Choque Séptico/imunologia , Sequências Repetidas Terminais
9.
Crit Care ; 24(1): 110, 2020 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-32192532

RESUMO

BACKGROUND: Decreased monocytic (m)HLA-DR expression is the most studied biomarker of sepsis-induced immunosuppression. To date, little is known about the relationship between sepsis characteristics, such as the site of infection, causative pathogen, or severity of disease, and mHLA-DR expression kinetics. METHODS: We evaluated mHLA-DR expression kinetics in 241 septic shock patients with different primary sites of infection and pathogens. Furthermore, we used unsupervised clustering analysis to identify mHLA-DR trajectories and evaluated their association with outcome parameters. RESULTS: No differences in mHLA-DR expression kinetics were found between groups of patients with different sites of infection (abdominal vs. respiratory, p = 0.13; abdominal vs. urinary tract, p = 0.53) and between pathogen categories (Gram-positive vs. Gram-negative, p = 0.54; Gram-positive vs. negative cultures, p = 0.84). The mHLA-DR expression kinetics differed between survivors and non-survivors (p < 0.001), with an increase over time in survivors only. Furthermore, we identified three mHLA-DR trajectories ('early improvers', 'delayed or non-improvers' and 'decliners'). The probability for adverse outcome (secondary infection or death) was higher in the delayed or non-improvers and decliners vs. the early improvers (delayed or non-improvers log-rank p = 0.03, adjusted hazard ratio 2.0 [95% CI 1.0-4.0], p = 0.057 and decliners log-rank p = 0.01, adjusted hazard ratio 2.8 [95% CI 1.1-7.1], p = 0.03). CONCLUSION: Sites of primary infection or causative pathogens are not associated with mHLA-DR expression kinetics in septic shock patients. However, patients showing delayed or no improvement in or a declining mHLA-DR expression have a higher risk for adverse outcome compared with patients exhibiting a swift increase in mHLA-DR expression. Our study signifies that changes in mHLA-DR expression over time, and not absolute values or static measurements, are of clinical importance in septic shock patients.


Assuntos
Antígenos HLA-DR/metabolismo , Choque Séptico/imunologia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Infecção Hospitalar , Feminino , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Prognóstico , Fatores de Risco , Choque Séptico/mortalidade
10.
Adv Exp Med Biol ; 1251: 71-80, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31919709

RESUMO

High cut-off (HCO) continuous veno-venous hemodialysis (CVVHD) is one of the renal replacement therapies which nonselectively removes inflammatory mediators. This study seeks to examine the association between the inflammatory background and the need for catecholamine treatment in hemodynamically instable patients having septic shock and acute kidney injury during HCO-CVVHD. There were 38 patients (F/M; 16/22, mean age 63 ± 16 years) included in the study. The initial content of the cytokines IL-4, IL-12, IL-17, and TNFα, C-reactive protein, and the score of the Sequential Organ Failure Assessment (SOFA) were assessed. The receiver operating characteristic (ROC) plot showed that a combination consisting of IL-17 × SOFA ≤22.3 was a reliable predictive factor of the need for catecholamine treatment during HCO-CVVHD, with 82% sensitivity and 90% specificity, with the area under curve (AUC) of 0.843; p < 0.001. On the other side, SOFA ≤14.0 predicted catecholamine treatment or its discontinuation when started, with both specificity and sensitivity 83% (AUC = 0.899; p < 0.001). In conclusion, the immune system activation, assessed from the initial level of IL-17, and the clinical SOFA evaluation are of practical help in predicting the need for catecholamine treatment or the probability of a reduction thereof in patients on veno-venous hemodialysis due to septic shock.


Assuntos
Lesão Renal Aguda/complicações , Lesão Renal Aguda/terapia , Terapia de Substituição Renal Contínua , Inflamação/sangue , Inflamação/complicações , Choque Séptico/complicações , Choque Séptico/terapia , Lesão Renal Aguda/sangue , Lesão Renal Aguda/imunologia , Idoso , Biomarcadores/sangue , Feminino , Humanos , Inflamação/imunologia , Masculino , Pessoa de Meia-Idade , Curva ROC , Choque Séptico/sangue , Choque Séptico/imunologia
11.
Infect Immun ; 88(4)2020 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-31988176

RESUMO

Streptococcus suis is an emerging zoonotic agent that causes streptococcal toxic shock-like syndrome (STSLS) and meningitis in humans, with high mortality and morbidity. The pathogenesis of both STSLS and central nervous system (CNS) infections caused by S. suis is not well understood. TRIM32, a member of the tripartite motif (TRIM) protein family, has been reported to regulate host inflammatory responses. In this study, we showed that TRIM32 deficiency significantly reduced the level of bacteremia and the production of proinflammatory cytokines following severe S. suis infection, protecting infected mice from STSLS. The influence of TRIM32 gene deletion on a range of processes known to be involved in S. suis meningitis was also examined. Both levels of bacterial loads and indications of brain hemorrhage were reduced in infected Trim32- / - mice compared with infected wild-type (WT) controls. We also found that TRIM32 deficiency increased the permeability of the blood-brain barrier (BBB) and the recruitment of inflammatory monocytes during the early course of S. suis infection, potentially limiting the development of S. suis meningitis. Our results suggest that TRIM32 sensitizes S. suis-induced infection via innate immune response regulation.


Assuntos
Interações Hospedeiro-Patógeno , Meningites Bacterianas/fisiopatologia , Choque Séptico/fisiopatologia , Streptococcus suis/crescimento & desenvolvimento , Ubiquitina-Proteína Ligases/metabolismo , Animais , Modelos Animais de Doenças , Suscetibilidade a Doenças , Imunidade Inata , Meningites Bacterianas/imunologia , Camundongos , Camundongos Knockout , Choque Séptico/imunologia , Ubiquitina-Proteína Ligases/deficiência
12.
Am J Case Rep ; 21: e919974, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31937749

RESUMO

BACKGROUND Intussusception in adults (AI) accounts for 1% of all cases of bowel obstruction. While pediatric intussusception is well known and almost always idiopathic, an underlying cause is usually found in adults. Indication for surgical treatment and intussusception reduction before resection remain controversial in AI. Here, we present an uncommon case of an immunocompromised patient who had multiple intussusceptions. CASE REPORT A 59-year-old woman, who had received a kidney-pancreas transplant for type 1 diabetes with end-stage renal failure, was admitted to our Intensive Care Unit for septic shock of suspected pulmonary origin. A thoraco-abdominal CT scan demonstrated signs of bilateral pneumonia and multiple abdominal intussusceptions, for which she underwent surgery. Four intestinal intussusceptions were found. Manual desinvagination was performed without bowel resection. After surgery, the patient presented a new bowel obstruction, requiring a second surgery, showing recurrence of 1 intussusception. Segmental resection was indicated, but not performed because of the septic shock, requiring high-dose noradrenalin. The patient progressed toward multi-organ failure, leading to her death a few days later. An autopsy revealed that multiple adenomas were responsible for the intussusceptions. CONCLUSIONS This case confirms that AI is rarely a spontaneous disease and that the therapeutic strategy should be planned accordingly. There is currently no systematic approach for AI, and guidelines are needed to improve its management.


Assuntos
Adenoma/complicações , Hospedeiro Imunocomprometido , Intussuscepção/etiologia , Intussuscepção/cirurgia , Fatores Etários , Autopsia , Evolução Fatal , Feminino , Humanos , Imunossupressores/uso terapêutico , Pessoa de Meia-Idade , Insuficiência de Múltiplos Órgãos , Pneumonia/imunologia , Choque Séptico/imunologia
13.
Eur J Pharm Sci ; 141: 105062, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31525434

RESUMO

INTRODUCTION: Shock has been established as a disorder of the microcirculation. Despite various treatments, the mortality rate of infectious shocks remains 30-50%. The study was designed to explore the effects of scopolamine on the survival time, microcirculation and inflammatory cytokine secretion in rats with septic shock. METHODS: SD rats were randomly divided into seven groups: a sham group, a control group, a saline group and four scopolamine group. The rat septic shock model was induced by cecal ligation, perforation and drainage, while the operation in the sham group involved opening and closing the abdominal cavity. The survival time was recorded to determine a suitable dose for the subsequent experiments. The microcirculation of the terminal ileum was observed. The concentrations of IL-10, IL-6 and TNF-α in the plasma and lungs were detected by ELISA, and the wet-dry ratio of the lung was calculated. RESULTS: Compared to the control and saline group, the septic shock rats treated in the scopolamine group had a longer survival time, a lower reduction in arteriolar blood flow, and a decreased change in the average diameter of arterioles and venules. The rat wet-dry lung ratio was less in the sham, control and scopolamine groups compared to the saline group. The plasma and lung cytokine concentrations of the rats belonging to the scopolamine group were less than those of the control and saline groups; however, all of the cytokine concentrations were higher than those of the sham group. CONCLUSIONS: Scopolamine reduced the plasma and lung concentrations of specific cytokines, improved the function of the microcirculation and prolonged the survival time of rats with septic shock.


Assuntos
Escopolamina/farmacologia , Choque Séptico , Animais , Íleo/irrigação sanguínea , Interleucina-1beta/sangue , Interleucina-1beta/imunologia , Interleucina-6/sangue , Interleucina-6/imunologia , Pulmão/imunologia , Masculino , Microcirculação/efeitos dos fármacos , Ratos Sprague-Dawley , Choque Séptico/sangue , Choque Séptico/imunologia , Choque Séptico/fisiopatologia , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/imunologia
14.
Cell Immunol ; 347: 104020, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31767118

RESUMO

High-mobility group box 1 (HMGB1) concentration in serum or plasma has been proposed as an important biological marker in various inflammation-related pathologies. We previously showed that low titer autoantibodies against HMGB1 could emerge during the course of sepsis. Importantly their presence was positively related with patients' survival. In this study, we focused on plasma samples from 2 patients who survived sepsis and exhibited high titer antibodies to HMGB1. These antibodies were proved to be specific for HMGB1 since they did not bind to HMGB2 or to human serum albumin. Following IgG purification, it has shown that both patients secreted HMGB1-hydrolyzing autoantibodies in vitro. These findings suggested that proteolytic antibodies directed against HMGB1 can be produced in patients surviving septic shock.


Assuntos
Autoanticorpos/imunologia , Proteína HMGB1/imunologia , Choque Séptico/imunologia , Autoanticorpos/sangue , Proteína HMGB2/imunologia , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Proteólise , Albumina Sérica Humana/imunologia , Choque Séptico/mortalidade , Choque Séptico/patologia
15.
Inflammation ; 43(1): 231-240, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31802382

RESUMO

Ellipticine, a natural product from Ochrosia elliptica, has been broadly investigated for its anticancer effects. Although inflammation has been clearly identified as a key factor in the onset and progression of cancer, the relationship between ellipticine and inflammation remains unknown. Hence, the aims of the present study were to assess the effects of ellipticine on the inflammatory responses to lipopolysaccharide (LPS)-induced macrophages and to potentially identify the underlying mechanisms involved. Viability testing showed that ellipticine was not significantly toxic to Raw264.7 cells and actually conveyed protective effects to LPS-stimulated Raw264.7 cells and human peripheral blood monocytes by decreasing the secretion of inflammatory factors (TNF-α and IL-6). The results of western blot analysis and electrophoretic mobility shift assays showed that ellipticine markedly suppressed LPS-induced activation of the JNK/AP-1 (c-Fos and c-Jun) signaling pathway, but not ERK/p38/NF-κB pathway (p65 and p50) activation. Furthermore, ellipticine reduced the inflammatory response and mortality in a mouse model of LPS-induced endotoxic shock. Collectively, these data indicate that ellipticine may be a potential therapeutic agent for the treatment of inflammation-associated diseases.


Assuntos
Anti-Inflamatórios/farmacologia , Elipticinas/farmacologia , Inflamação/prevenção & controle , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Choque Séptico/prevenção & controle , Fator de Transcrição AP-1/metabolismo , Adulto , Animais , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Inflamação/induzido quimicamente , Inflamação/enzimologia , Inflamação/imunologia , Interleucina-6/metabolismo , Lipopolissacarídeos , Macrófagos/enzimologia , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células RAW 264.7 , Choque Séptico/induzido quimicamente , Choque Séptico/enzimologia , Choque Séptico/imunologia , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo
16.
Sci Rep ; 9(1): 18751, 2019 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-31822776

RESUMO

Septic shock is a systemic inflammation associated with cell metabolism disorders and cardiovascular dysfunction. Increases in O-GlcNAcylation have shown beneficial cardiovascular effects in acute pathologies. We used two different rat models to evaluate the beneficial effects of O-GlcNAc stimulation at the early phase of septic shock. Rats received lipopolysaccharide (LPS) to induce endotoxemic shock or saline (control) and fluid resuscitation (R) with or without O-GlcNAc stimulation (NButGT-10 mg/kg) 1 hour after shock induction. For the second model, rats received cecal ligature and puncture (CLP) surgery and fluid therapy with or without NButGT. Cardiovascular function was evaluated and heart and blood samples were collected and analysed. NButGT treatment efficiently increased total O-GlcNAc without modification of HBP enzyme expression.Treatment improved circulating parameters and cardiovascular function in both models, and restored SERCA2a expression levels. NButGT treatment also reduced animal mortality. In this study, we demonstrate that in septic shock O-GlcNAc stimulation improves global animal and cardiovascular function outcomes associated with a restoration of SERCA2a levels. This pre-clinical study opens avenues for a potential therapy of early-stage septic shock.


Assuntos
Acetilglucosamina/metabolismo , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Choque Séptico/terapia , beta-N-Acetil-Hexosaminidases/antagonistas & inibidores , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Modelos Animais de Doenças , Hidratação , Humanos , Lipopolissacarídeos/imunologia , Masculino , Ratos , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/sangue , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Choque Séptico/sangue , Choque Séptico/imunologia , Choque Séptico/metabolismo , beta-N-Acetil-Hexosaminidases/metabolismo
17.
BMJ Case Rep ; 12(12)2019 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-31826901

RESUMO

Surgical-site mucormycosis infections in solid-organ transplant recipients are rare conditions, with only 15 previously reported cases. We describe a case of a 49-year-old man who received a liver transplant due to alcoholic cirrhosis. On postoperative day 14, necrosis was noticed at the surgical site. After mucormycosis was diagnosed, monotherapy with amphotericin was started along with surgical debridements. Due to continued clinical deterioration, triple antifungal therapy was started with amphotericin, micafungin and posaconazole. Treatment with a granulocyte-macrophage colony-stimulating factor was also started. Despite therapy, the patient expired on postoperative day 31. We review the risk factors for mucormycosis infection in solid-organ transplant recipients as well as evidence for current treatment options. We also review the 15 previously reported cases of surgical-site mucormycosis infections in solid-organ transplant recipients, including time to infection, infecting organisms, mortality and treatments.


Assuntos
Antifúngicos/uso terapêutico , Desbridamento/métodos , Transplante de Fígado/efeitos adversos , Mucormicose/microbiologia , Choque Séptico/microbiologia , Infecção da Ferida Cirúrgica/microbiologia , Anfotericina B/uso terapêutico , Evolução Fatal , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Mucormicose/imunologia , Mucormicose/terapia , Choque Séptico/imunologia , Choque Séptico/fisiopatologia , Infecção da Ferida Cirúrgica/imunologia , Infecção da Ferida Cirúrgica/terapia , Transplantados , Triazóis/uso terapêutico
18.
Proc Natl Acad Sci U S A ; 116(51): 25923-25931, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31772015

RESUMO

Streptococcal toxic shock syndrome (STSS) is a rapidly progressing, life-threatening, systemic reaction to invasive infection caused by group A streptococci (GAS). GAS superantigens are key mediators of STSS through their potent activation of T cells leading to a cytokine storm and consequently vascular leakage, shock, and multiorgan failure. Mucosal-associated invariant T (MAIT) cells recognize MR1-presented antigens derived from microbial riboflavin biosynthesis and mount protective innate-like immune responses against the microbes producing such metabolites. GAS lack de novo riboflavin synthesis, and the role of MAIT cells in STSS has therefore so far been overlooked. Here we have conducted a comprehensive analysis of human MAIT cell responses to GAS, aiming to understand the contribution of MAIT cells to the pathogenesis of STSS. We show that MAIT cells are strongly activated and represent the major T cell source of IFNγ and TNF in the early stages of response to GAS. MAIT cell activation is biphasic with a rapid TCR Vß2-specific, TNF-dominated response to superantigens and a later IL-12- and IL-18-dependent, IFNγ-dominated response to both bacterial cells and secreted factors. Depletion of MAIT cells from PBMC resulted in decreased total production of IFNγ, IL-1ß, IL-2, and TNFß. Peripheral blood MAIT cells in patients with STSS expressed elevated levels of the activation markers CD69, CD25, CD38, and HLA-DR during the acute compared with the convalescent phase. Our data demonstrate that MAIT cells are major contributors to the early cytokine response to GAS, and are therefore likely to contribute to the pathological cytokine storm underlying STSS.


Assuntos
Citocinas/metabolismo , Células T Invariáveis Associadas à Mucosa/imunologia , Choque Séptico/imunologia , Infecções Estreptocócicas/imunologia , Streptococcus pyogenes/imunologia , Adulto , Idoso , Citocinas/sangue , Antígenos HLA-DR/metabolismo , Humanos , Interferon gama/metabolismo , Interleucina-12/metabolismo , Interleucina-18/metabolismo , Interleucina-1alfa/metabolismo , Interleucina-2/metabolismo , Linfotoxina-alfa/metabolismo , Pessoa de Meia-Idade , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Riboflavina/biossíntese , Streptococcus pyogenes/patogenicidade , Superantígenos/metabolismo
19.
Front Immunol ; 10: 2629, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31781117

RESUMO

Background: Interleukin-6 (IL-6) is a pleiotropic cytokine with a multitude of pro-inflammatory effects. Serum C-reactive protein (CRP) is an acute phase protein induced mainly by IL-6 in response to inflammatory conditions, particularly infection. The biological functions of CRP include opsonisation, induction of phagocytosis, complement activation, or chemotaxis enhancement. Factors interfering with IL-6-mediated recruitment of innate immune responses, such as the presence of anti-IL6 antibodies, may therefore compromise the host resistance to microbial pathogens. This has major implications for the use of IL-6-targeting biologics, such as tocilizumab or sarilumab in rheumatologic, immune dysregulation diseases, and cancer. Case presentation: 20-month-old Czech female developed severe septic shock with clinical and laboratory signs of systemic inflammation but no increase of CRP or IL-6. The offending pathogen was most likely Staphylococcus aureus, detected in a throat swab; the response to antibiotic treatment was prompt. A defect in the integrity of IL-6/CRP axis was suspected and verified by the detection of neutralizing IL-6 antibodies in the serum of the child. Conclusion: We report a first case of systemic bacterial infection in a patient with anti-IL6 autoantibodies. Disturbed IL-6 signaling, whether iatrogenic by targeted IL-6 blockade or endogenous due to the presence of autoantibodies against IL-6, represents a risk factor for increased infectious susceptibility. Patients with severe bacterial infection without elevation of CRP should be examined for the presence of anti-IL6 autoantibodies.


Assuntos
Autoanticorpos/sangue , Interleucina-6/imunologia , Choque Séptico/imunologia , Proteína C-Reativa , Feminino , Humanos , Lactente , Choque Séptico/sangue
20.
Front Immunol ; 10: 2179, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31616411

RESUMO

Background: Septic shock, a major cause of death in critical care, is the clinical translation of a cytokine storm in response to infection. It can be complicated by sepsis-induced immunosuppression, exemplified by blood lymphopenia, an excess of circulating Treg lymphocytes, and decreased HLA-DR expression on circulating monocytes. Such immunosuppression is associated with secondary infections, and higher mortality. The effect of these biological modifications on circulating innate lymphoid cells (ILCs) has been little studied. Methods: We prospectively enrolled patients with septic shock (Sepsis-3 definition) in the intensive care unit (ICU) of Timone CHU Hospital. ICU controls (trauma, cardiac arrest, neurological dysfunction) were recruited at the same time (NCT03297203). We performed immunophenotyping of adaptive lymphocytes (CD3+ T cells, CD19+ B cells, CD4+CD25+FoxP3+ Treg lymphocytes), ILCs (CD3-CD56+ NK cells and helper ILCs - ILC1, ILC2, and ILC3), and monocytes by flow cytometry on fresh blood samples collected between 24 and 72 h after admission. Results: We investigated adaptive and innate circulating lymphoid cells in the peripheral blood of 18 patients in septic shock, 15 ICU controls, and 30 healthy subjects. As expected, the peripheral blood lymphocytes of all ICU patients showed lymphopenia, which was not specific to sepsis, whereas those of the healthy volunteers did not. Circulating CD3+ T cells and CD3-CD56+ NK cells were mainly concerned. There was a tendency toward fewer Treg lymphocytes and lower HLA-DR expression on monocytes in ICU patients with sepsis. Although the ILC1 count was higher in septic patients than healthy subjects, ILC2, and ILC3 counts were lower in both ICU groups. However, ILC3s within the total ILCs were overrepresented in patients with septic shock. The depression of immune responses has been correlated with the occurrence of secondary infections. We did not find any differences in ILC distribution according to this criterion. Conclusion: All ICU patients exhibit lymphopenia, regardless of the nature (septic or sterile) of the initial medical condition. Specific distribution of circulating ILCs, with an excess of ILC1, and a lack of ILC3, may characterize septic shock during the first 3 days of the disease.


Assuntos
Linfócitos/imunologia , Choque Séptico/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Imunidade Inata , Imunofenotipagem , Linfopenia/imunologia , Masculino , Pessoa de Meia-Idade , Adulto Jovem
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