RESUMO
Cytosolic sensing of pathogens and damage by myeloid and barrier epithelial cells assembles large complexes called inflammasomes, which activate inflammatory caspases to process cytokines (IL-1ß) and gasdermin D (GSDMD). Cleaved GSDMD forms membrane pores, leading to cytokine release and inflammatory cell death (pyroptosis). Inhibiting GSDMD is an attractive strategy to curb inflammation. Here we identify disulfiram, a drug for treating alcohol addiction, as an inhibitor of pore formation by GSDMD but not other members of the GSDM family. Disulfiram blocks pyroptosis and cytokine release in cells and lipopolysaccharide-induced septic death in mice. At nanomolar concentration, disulfiram covalently modifies human/mouse Cys191/Cys192 in GSDMD to block pore formation. Disulfiram still allows IL-1ß and GSDMD processing, but abrogates pore formation, thereby preventing IL-1ß release and pyroptosis. The role of disulfiram in inhibiting GSDMD provides new therapeutic indications for repurposing this safe drug to counteract inflammation, which contributes to many human diseases.
Assuntos
Dissulfiram/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Proteínas de Ligação a Fosfato/antagonistas & inibidores , Piroptose/efeitos dos fármacos , Sepse/tratamento farmacológico , Animais , Caspase 1/genética , Caspase 1/metabolismo , Inibidores de Caspase/farmacologia , Caspases/metabolismo , Caspases Iniciadoras/genética , Caspases Iniciadoras/metabolismo , Linhagem Celular Tumoral , Dissulfiram/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Reposicionamento de Medicamentos , Feminino , Células HEK293 , Ensaios de Triagem em Larga Escala , Humanos , Interleucina-1beta/imunologia , Interleucina-1beta/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lipopolissacarídeos/administração & dosagem , Lipopolissacarídeos/imunologia , Lipossomos , Camundongos , Mutagênese Sítio-Dirigida , Proteínas de Ligação a Fosfato/genética , Proteínas de Ligação a Fosfato/metabolismo , Piroptose/imunologia , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Sepse/imunologia , Células Sf9 , SpodopteraRESUMO
Several classes of antibiotics have long been known to have beneficial effects that cannot be explained strictly on the basis of their capacity to control the infectious agent. Here, we report that tetracycline antibiotics, which target the mitoribosome, protected against sepsis without affecting the pathogen load. Mechanistically, we found that mitochondrial inhibition of protein synthesis perturbed the electron transport chain (ETC) decreasing tissue damage in the lung and increasing fatty acid oxidation and glucocorticoid sensitivity in the liver. Using a liver-specific partial and acute deletion of Crif1, a critical mitoribosomal component for protein synthesis, we found that mice were protected against sepsis, an observation that was phenocopied by the transient inhibition of complex I of the ETC by phenformin. Together, we demonstrate that mitoribosome-targeting antibiotics are beneficial beyond their antibacterial activity and that mitochondrial protein synthesis inhibition leading to ETC perturbation is a mechanism for the induction of disease tolerance.
Assuntos
Antibacterianos/uso terapêutico , Doxiciclina/uso terapêutico , Fígado/imunologia , Pulmão/imunologia , Mitocôndrias/metabolismo , Sepse/tratamento farmacológico , Tetraciclina/uso terapêutico , Animais , Proteínas de Ciclo Celular/genética , Modelos Animais de Doenças , Transporte de Elétrons , Células Hep G2 , Humanos , Metabolismo dos Lipídeos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
Heparin, a mammalian polysaccharide, is a widely used anticoagulant medicine to treat thrombotic disorders. It is also known to improve outcomes in sepsis, a leading cause of mortality resulted from infection-induced immune dysfunction. Whereas it is relatively clear how heparin exerts its anticoagulant effect, the immunomodulatory mechanisms enabled by heparin remain enigmatic. Here, we show that heparin prevented caspase-11-dependent immune responses and lethality in sepsis independent of its anticoagulant properties. Heparin or a chemically modified form of heparin without anticoagulant function inhibited the alarmin HMGB1-lipopolysaccharide (LPS) interaction and prevented the macrophage glycocalyx degradation by heparanase. These events blocked the cytosolic delivery of LPS in macrophages and the activation of caspase-11, a cytosolic LPS receptor that mediates lethality in sepsis. Survival was higher in septic patients treated with heparin than those without heparin treatment. The identification of this previously unrecognized heparin function establishes a link between innate immune responses and coagulation.
Assuntos
Anticoagulantes/uso terapêutico , Caspases/metabolismo , Heparina/uso terapêutico , Macrófagos/imunologia , Sepse/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Caspases/genética , Linhagem Celular , Feminino , Glucuronidase/genética , Glucuronidase/metabolismo , Glicocálix/metabolismo , Proteína HMGB1/metabolismo , Humanos , Imunomodulação , Lipopolissacarídeos/metabolismo , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Sepse/mortalidade , Análise de Sobrevida , Adulto JovemRESUMO
Infections caused by Gram-negative pathogens are increasingly prevalent and are typically treated with broad-spectrum antibiotics, resulting in disruption of the gut microbiome and susceptibility to secondary infections1-3. There is a critical need for antibiotics that are selective both for Gram-negative bacteria over Gram-positive bacteria, as well as for pathogenic bacteria over commensal bacteria. Here we report the design and discovery of lolamicin, a Gram-negative-specific antibiotic targeting the lipoprotein transport system. Lolamicin has activity against a panel of more than 130 multidrug-resistant clinical isolates, shows efficacy in multiple mouse models of acute pneumonia and septicaemia infection, and spares the gut microbiome in mice, preventing secondary infection with Clostridioides difficile. The selective killing of pathogenic Gram-negative bacteria by lolamicin is a consequence of low sequence homology for the target in pathogenic bacteria versus commensals; this doubly selective strategy can be a blueprint for the development of other microbiome-sparing antibiotics.
Assuntos
Antibacterianos , Descoberta de Drogas , Microbioma Gastrointestinal , Bactérias Gram-Negativas , Infecções por Bactérias Gram-Negativas , Simbiose , Animais , Feminino , Humanos , Masculino , Camundongos , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Linhagem Celular , Clostridioides difficile/efeitos dos fármacos , Infecções por Clostridium/microbiologia , Infecções por Clostridium/tratamento farmacológico , Modelos Animais de Doenças , Desenho de Fármacos , Farmacorresistência Bacteriana Múltipla , Microbioma Gastrointestinal/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Infecções por Bactérias Gram-Negativas/microbiologia , Lipoproteínas/metabolismo , Camundongos Endogâmicos C57BL , Transporte Proteico/efeitos dos fármacos , Sepse/microbiologia , Sepse/tratamento farmacológico , Especificidade por Substrato , Simbiose/efeitos dos fármacosRESUMO
The acute phase of sepsis is characterized by a strong inflammatory reaction. At later stages in some patients, immunoparalysis may be encountered, which is associated with a poor outcome. By transcriptional and metabolic profiling of human patients with sepsis, we found that a shift from oxidative phosphorylation to aerobic glycolysis was an important component of initial activation of host defense. Blocking metabolic pathways with metformin diminished cytokine production and increased mortality in systemic fungal infection in mice. In contrast, in leukocytes rendered tolerant by exposure to lipopolysaccharide or after isolation from patients with sepsis and immunoparalysis, a generalized metabolic defect at the level of both glycolysis and oxidative metabolism was apparent, which was restored after recovery of the patients. Finally, the immunometabolic defects in humans were partially restored by therapy with recombinant interferon-γ, which suggested that metabolic processes might represent a therapeutic target in sepsis.
Assuntos
Citocinas/imunologia , Endotoxemia/imunologia , Metabolismo Energético/imunologia , Tolerância Imunológica/imunologia , Imunidade Inata/imunologia , Macrófagos/imunologia , Monócitos/imunologia , Sepse/imunologia , Trifosfato de Adenosina/metabolismo , Adulto , Animais , Antifúngicos/uso terapêutico , Aspergilose/tratamento farmacológico , Aspergilose/imunologia , Aspergilose/metabolismo , Candidíase Invasiva/tratamento farmacológico , Candidíase Invasiva/imunologia , Candidíase Invasiva/metabolismo , Endotoxemia/metabolismo , Infecções por Escherichia coli/imunologia , Infecções por Escherichia coli/metabolismo , Feminino , Glicólise , Humanos , Immunoblotting , Interferon gama/uso terapêutico , Ácido Láctico/metabolismo , Leucócitos/imunologia , Leucócitos/metabolismo , Lipopolissacarídeos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Monócitos/metabolismo , NAD/metabolismo , Fosforilação Oxidativa , Consumo de Oxigênio , Estudos Prospectivos , Sepse/tratamento farmacológico , Sepse/metabolismo , Transcriptoma , Adulto JovemRESUMO
Hemolysis drives susceptibility to bacterial infections and predicts poor outcome from sepsis. These detrimental effects are commonly considered to be a consequence of heme-iron serving as a nutrient for bacteria. We employed a Gram-negative sepsis model and found that elevated heme levels impaired the control of bacterial proliferation independently of heme-iron acquisition by pathogens. Heme strongly inhibited phagocytosis and the migration of human and mouse phagocytes by disrupting actin cytoskeletal dynamics via activation of the GTP-binding Rho family protein Cdc42 by the guanine nucleotide exchange factor DOCK8. A chemical screening approach revealed that quinine effectively prevented heme effects on the cytoskeleton, restored phagocytosis and improved survival in sepsis. These mechanistic insights provide potential therapeutic targets for patients with sepsis or hemolytic disorders.
Assuntos
Infecções por Bactérias Gram-Negativas/imunologia , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Heme/metabolismo , Hemólise/imunologia , Macrófagos/imunologia , Fagocitose , Sepse/imunologia , Animais , Antibacterianos/uso terapêutico , Citoesqueleto/metabolismo , Feminino , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Fatores de Troca do Nucleotídeo Guanina/genética , Heme Oxigenase-1/genética , Hemólise/efeitos dos fármacos , Humanos , Evasão da Resposta Imune , Macrófagos/efeitos dos fármacos , Macrófagos/microbiologia , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fagocitose/efeitos dos fármacos , Quinina/uso terapêutico , Células RAW 264.7 , Sepse/tratamento farmacológico , Proteína cdc42 de Ligação ao GTP/metabolismoRESUMO
Protection against endothelial damage is recognized as a frontline approach to preventing the progression of cytokine release syndrome (CRS). Accumulating evidence has demonstrated that interleukin-6 (IL-6) promotes vascular endothelial damage during CRS, although the molecular mechanisms remain to be fully elucidated. Targeting IL-6 receptor signaling delays CRS progression; however, current options are limited by persistent inhibition of the immune system. Here, we show that endothelial IL-6 trans-signaling promoted vascular damage and inflammatory responses via hypoxia-inducible factor-1α (HIF1α)-induced glycolysis. Using pharmacological inhibitors targeting HIF1α activity or mice with the genetic ablation of gp130 in the endothelium, we found that inhibition of IL-6R (IL-6 receptor)-HIF1α signaling in endothelial cells protected against vascular injury caused by septic damage and provided survival benefit in a mouse model of sepsis. In addition, we developed a short half-life anti-IL-6R antibody (silent anti-IL-6R antibody) and found that it was highly effective at augmenting survival for sepsis and severe burn by strengthening the endothelial glycocalyx and reducing cytokine storm, and vascular leakage. Together, our data advance the role of endothelial IL-6 trans-signaling in the progression of CRS and indicate a potential therapeutic approach for burns and sepsis.
Assuntos
Receptor gp130 de Citocina , Subunidade alfa do Fator 1 Induzível por Hipóxia , Interleucina-6 , Receptores de Interleucina-6 , Sepse , Animais , Camundongos , Receptor gp130 de Citocina/genética , Síndrome da Liberação de Citocina , Células Endoteliais , Receptores de Interleucina-6/genética , Sepse/tratamento farmacológico , Subunidade alfa do Fator 1 Induzível por Hipóxia/genéticaRESUMO
The presence of bacteria in the bloodstream is associated with severe clinical outcomes. In mice, intravenous inoculation of Escherichia coli can lead to the formation of macroscopic abscesses in the liver. Abscesses are regions of severe necrosis and consist of millions of bacteria surrounded by inflammatory immune cells. Liver abscess susceptibility varies widely across strains of mice, but the host factors governing this variation are unknown. Here, we profiled hepatic transcriptomes in mice with varying susceptibility to liver abscess formation. We found that transcripts from endogenous retroviruses (ERVs) are robustly induced in the liver by E. coli infection and ERV expression positively correlates with the frequency of abscess formation. Hypothesizing that ERV-encoded reverse transcriptase may generate cytoplasmic DNA and heighten inflammatory responses, we tested whether nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) influence abscess formation. Strikingly, a single NRTI dose administered immediately following E. coli inoculation prevented abscess formation, leading to a concomitant 100,000-fold reduction in bacterial burden. We provide evidence that NRTIs inhibit abscess formation by preventing the tissue necrosis that facilitates bacterial replication. Together, our findings suggest that endogenous reverse transcriptases drive inflammatory responses during bacterial bloodstream infection to drive abscess formation. The high efficacy of NRTIs in preventing abscess formation suggests that the consequences of reverse transcription on inflammation should be further examined, particularly in infectious diseases where inflammation drives negative clinical outcomes, such as sepsis.
Assuntos
Infecções Bacterianas , Retrovirus Endógenos , Infecções por Escherichia coli , Abscesso Hepático , Sepse , Animais , Camundongos , Inibidores da Transcriptase Reversa/farmacologia , Escherichia coli/genética , Infecções por Escherichia coli/genética , Abscesso Hepático/tratamento farmacológico , Abscesso Hepático/genética , Infecções Bacterianas/tratamento farmacológico , Nucleotídeos , Sepse/tratamento farmacológico , Necrose/genéticaRESUMO
Sepsis is a lethal syndrome manifested by an unregulated, overwhelming inflammation from the host in response to infection. Here, we exploit the use of a synthetic heparan sulfate octadecasaccharide (18-mer) to protect against sepsis. The 18-mer not only inhibits the pro-inflammatory activity of extracellular histone H3 and high mobility group box 1 (HMGB1), but also elicits the anti-inflammatory effect from apolipoprotein A-I (ApoA-I). We demonstrate that the 18-mer protects against sepsis-related injury and improves survival in cecal ligation and puncture mice and reduces inflammation in an endotoxemia mouse model. The 18-mer neutralizes the cytotoxic histone-3 (H3) through direct interaction with the protein. Furthermore, the 18-mer enlists the actions of ApoA-I to dissociate the complex of HMGB1 and lipopolysaccharide, a toxic complex contributing to cell death and tissue damage in sepsis. Our study provides strong evidence that the 18-mer mitigates inflammatory damage in sepsis by targeting numerous mediators, setting it apart from other potential therapies with a single target.
Assuntos
Endotoxemia , Proteína HMGB1 , Sepse , Camundongos , Animais , Proteína HMGB1/metabolismo , Apolipoproteína A-I , Sepse/tratamento farmacológico , Sepse/metabolismo , Lipopolissacarídeos , Heparitina Sulfato , Modelos Animais de DoençasRESUMO
Acute respiratory distress syndrome (ARDS) is a deadly clinical presentation in sepsis, COVID, and other lung disorders where vascular fluid leakage is a severe problem. Recent findings by Shadab et al. in the JBC show that a well-known player in immune function, Syk, also regulates vascular leakage in response to sepsis. An existing FDA-approved inhibitor of Syk, fostamatinib, prevents the vascular leakage and improves survival in a mouse sepsis model, providing promise for ARDS treatment in the clinic.
Assuntos
Aminopiridinas , Morfolinas , Inibidores de Proteínas Quinases , Pirimidinas , Síndrome do Desconforto Respiratório , Quinase Syk , Humanos , Aminopiridinas/uso terapêutico , Morfolinas/uso terapêutico , Pirimidinas/uso terapêutico , Quinase Syk/antagonistas & inibidores , Quinase Syk/metabolismo , Síndrome do Desconforto Respiratório/tratamento farmacológico , Animais , Camundongos , Inibidores de Proteínas Quinases/uso terapêutico , Sepse/tratamento farmacológicoRESUMO
BACKGROUND: Studies that have evaluated the use of intravenous vitamin C in adults with sepsis who were receiving vasopressor therapy in the intensive care unit (ICU) have shown mixed results with respect to the risk of death and organ dysfunction. METHODS: In this randomized, placebo-controlled trial, we assigned adults who had been in the ICU for no longer than 24 hours, who had proven or suspected infection as the main diagnosis, and who were receiving a vasopressor to receive an infusion of either vitamin C (at a dose of 50 mg per kilogram of body weight) or matched placebo administered every 6 hours for up to 96 hours. The primary outcome was a composite of death or persistent organ dysfunction (defined by the use of vasopressors, invasive mechanical ventilation, or new renal-replacement therapy) on day 28. RESULTS: A total of 872 patients underwent randomization (435 to the vitamin C group and 437 to the control group). The primary outcome occurred in 191 of 429 patients (44.5%) in the vitamin C group and in 167 of 434 patients (38.5%) in the control group (risk ratio, 1.21; 95% confidence interval [CI], 1.04 to 1.40; P = 0.01). At 28 days, death had occurred in 152 of 429 patients (35.4%) in the vitamin C group and in 137 of 434 patients (31.6%) in the placebo group (risk ratio, 1.17; 95% CI, 0.98 to 1.40) and persistent organ dysfunction in 39 of 429 patients (9.1%) and 30 of 434 patients (6.9%), respectively (risk ratio, 1.30; 95% CI, 0.83 to 2.05). Findings were similar in the two groups regarding organ-dysfunction scores, biomarkers, 6-month survival, health-related quality of life, stage 3 acute kidney injury, and hypoglycemic episodes. In the vitamin C group, one patient had a severe hypoglycemic episode and another had a serious anaphylaxis event. CONCLUSIONS: In adults with sepsis receiving vasopressor therapy in the ICU, those who received intravenous vitamin C had a higher risk of death or persistent organ dysfunction at 28 days than those who received placebo. (Funded by the Lotte and John Hecht Memorial Foundation; LOVIT ClinicalTrials.gov number, NCT03680274.).
Assuntos
Ácido Ascórbico , Sepse , Adulto , Ácido Ascórbico/efeitos adversos , Humanos , Hipoglicemiantes/uso terapêutico , Unidades de Terapia Intensiva , Insuficiência de Múltiplos Órgãos , Qualidade de Vida , Sepse/tratamento farmacológico , Vasoconstritores/efeitos adversos , Vitaminas/efeitos adversosRESUMO
Early in sepsis, a hyperinflammatory response is dominant, but later, an immunosuppressive phase dominates, and the host is susceptible to opportunistic infections. Anti-inflammatory agents may accelerate the host into immunosuppression, and few agents can reverse immunosuppression without causing inflammation. Specialized pro-resolving mediators (SPMs) such as resolvin D2 (RvD2) have been reported to resolve inflammation without being immunosuppressive, but little work has been conducted to examine their effects on immunosuppression. To assess the effects of RvD2 on immunosuppression, we established a model of macrophage exhaustion using two lipopolysaccharide (LPS) treatments or hits. THP-1 monocyte-derived macrophages were first treated with RvD2 or vehicle for 1 h. One LPS hit increased NF-κB activity 11-fold and TNF-α release 60-fold compared to unstimulated macrophages. RvD2 decreased LPS-induced NF-κB activity and TNF-α production but increased bacterial clearance. Two LPS hits reduced macrophage bacterial clearance and decreased macrophage NF-κB activity (45%) and TNF-α release (75%) compared to one LPS hit, demonstrating exhaustion. RvD2 increased NF-κB activity, TNF-α release, and bacterial clearance following two LPS hits compared to controls. TLR2 inhibition abolished RvD2-mediated changes. In a mouse sepsis model, splenic macrophage response to exogenous LPS was reduced compared to controls and was restored by in vivo administration of RvD2, supporting the in vitro results. If RvD2 was added to monocytes before differentiation into macrophages, however, RvD2 reduced LPS responses and increased bacterial clearance following both one and two LPS hits. The results show that RvD2 attenuated macrophage suppression in vitro and in vivo and that this effect was macrophage-specific.
Assuntos
Ácidos Docosa-Hexaenoicos , Lipopolissacarídeos , Sepse , Camundongos , Animais , Lipopolissacarídeos/toxicidade , NF-kappa B/farmacologia , Fator de Necrose Tumoral alfa/farmacologia , Macrófagos , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Sepse/induzido quimicamente , Sepse/tratamento farmacológicoRESUMO
Sepsis, septic shock, and their sequelae are the leading causes of death in intensive care units, with limited therapeutic options. Disease resistance and tolerance are two evolutionarily conserved yet distinct defense strategies that protect the host against microbial infection. Here, we report that taurolidine administered at 6 h before septic challenge led to strong protection against polymicrobial sepsis by promoting both host resistance and disease tolerance characterized by accelerated bacterial clearance, ameliorated organ damage, and diminished vascular and gut permeability. Notably, taurolidine administered at 6 h after septic challenge also rescued mice from sepsis-associated lethality by enhancing disease tolerance to tissue and organ injury. Importantly, this in vivo protection afforded by taurolidine depends on an intact autophagy pathway, as taurolidine protected wild-type mice but was unable to rescue autophagy-deficient mice from microbial sepsis. In vitro, taurolidine induced light chain 3-associated phagocytosis in innate phagocytes and autophagy in vascular endothelium and gut epithelium, resulting in augmented bactericidal activity and enhanced cellular tolerance to endotoxin-induced damage in these cells. These results illustrate that taurolidine-induced autophagy augments both host resistance and disease tolerance to bacterial infection, thereby conferring protection against microbial sepsis.
Assuntos
Sepse , Tiadiazinas , Animais , Autofagia , Camundongos , Fagocitose , Sepse/tratamento farmacológico , Sepse/metabolismo , Taurina/análogos & derivados , Tiadiazinas/farmacologiaRESUMO
Fatty acid composition in the Western diet has shifted from saturated to polyunsaturated fatty acids (PUFAs), and specifically to linoleic acid (LA, 18:2), which has gradually increased in the diet over the past 50 y to become the most abundant dietary fatty acid in human adipose tissue. PUFA-derived oxylipins regulate a variety of biological functions. The cytochrome P450 (CYP450)formed epoxy fatty acid metabolites of LA (EpOMEs) are hydrolyzed by the soluble epoxide hydrolase enzyme (sEH) to dihydroxyoctadecenoic acids (DiHOMEs). DiHOMEs are considered cardioprotective at low concentrations but at higher levels have been implicated as vascular permeability and cytotoxic agents and are associated with acute respiratory distress syndrome in severe COVID-19 patients. High EpOME levels have also correlated with sepsis-related fatalities; however, those studies failed to monitor DiHOME levels. Considering the overlap of burn pathophysiology with these pathologies, the role of DiHOMEs in the immune response to burn injury was investigated. 12,13-DiHOME was found to facilitate the maturation and activation of stimulated neutrophils, while impeding monocyte and macrophage functionality and cytokine generation. In addition, DiHOME serum concentrations were significantly elevated in burn-injured mice and these increases were ablated by administration of 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), a sEH inhibitor. TPPU also reduced necrosis of innate and adaptive immune cells in burned mice, in a dose-dependent manner. The findings suggest DiHOMEs are a key driver of immune cell dysfunction in severe burn injury through hyperinflammatory neutrophilic and impaired monocytic actions, and inhibition of sEH might be a promising therapeutic strategy to mitigate deleterious outcomes in burn patients.
Assuntos
Queimaduras , Sepse , Animais , Epóxido Hidrolases/metabolismo , Humanos , Imunidade Inata , Inflamação/tratamento farmacológico , Ácido Linoleico/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Compostos de Fenilureia/farmacologia , Piperidinas/farmacologia , Sepse/tratamento farmacológicoRESUMO
SOURCE CITATION: Chaudhuri D, Nei AM, Rochwerg B, et al. 2024 focused update: guidelines on use of corticosteroids in sepsis, acute respiratory distress syndrome, and community-acquired pneumonia. Crit Care Med. 2024;52:e219-e233. 38240492.
Assuntos
Corticosteroides , Infecções Comunitárias Adquiridas , Síndrome do Desconforto Respiratório , Sepse , Humanos , Síndrome do Desconforto Respiratório/tratamento farmacológico , Sepse/tratamento farmacológico , Corticosteroides/uso terapêutico , Infecções Comunitárias Adquiridas/tratamento farmacológico , Pneumonia/tratamento farmacológico , AdultoRESUMO
Severe sepsis induces a sustained immune dysfunction associated with poor clinical behavior. In particular, lymphopenia along with increased lymphocyte apoptosis and decreased lymphocyte proliferation, enhanced circulating regulatory T cells (Treg), and the emergence of myeloid-derived suppressor cells (MDSCs) have all been associated with persistent organ dysfunction, secondary infections, and late mortality. The mechanisms involved in MDSC-mediated T cell dysfunction during sepsis share some features with those described in malignancies such as arginine deprivation. We hypothesized that increasing arginine availability would restore T cell function and decrease sepsis-induced immunosuppression. Using a mouse model of sepsis based on cecal ligation and puncture and secondary pneumonia triggered by methicillin-resistant Staphylococcus aureus inoculation, we demonstrated that citrulline administration was more efficient than arginine in increasing arginine plasma levels and restoring T cell mitochondrial function and proliferation while reducing sepsis-induced Treg and MDSC expansion. Because there is no specific therapeutic strategy to restore immune function after sepsis, we believe that our study provides evidence for developing citrulline-based clinical studies in sepsis.
Assuntos
Citrulina/farmacologia , Mitocôndrias/metabolismo , Sepse/tratamento farmacológico , Animais , Arginina/deficiência , Arginina/metabolismo , Disponibilidade Biológica , Citrulina/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Tolerância Imunológica/imunologia , Terapia de Imunossupressão/métodos , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Células Supressoras Mieloides/imunologia , Sepse/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T Reguladores/imunologiaRESUMO
Infectious events, such as sepsis and invasive fungal disease (IFD), pose significant risks in patients with acute myeloid leukemia (AML). Previous studies, including our own, have suggested a potential role of single nucleotide polymorphisms (SNPs) within the innate immune system in influencing individual infection susceptibility. However, many of these associations lack validation in independent cohorts. This study sought to validate the impact of 11 candidate SNPs across 6 genes (TLR2, TLR4, Dectin-1, DC-SIGN, PTX3, L-Ficolin) in an independent cohort of patients. Two cohorts with newly diagnosed AML patients receiving intensive induction chemotherapy were analyzed: a stratification cohort comprising 186 patients and a validation cohort consisting of 138 patients. Multiple SNPs in each cohort were found to be associated to infectious complications, notably the DC-SIGN SNP rs4804800 demonstrated a significant association with sepsis in both cohorts. SNPs within the PTX3 and Dectin-1 genes were linked to IFD development in one cohort each. This study represents the first validation study of candidate genes associated with infectious events in AML patients after intensive induction chemotherapy. Identifying genetic predispositions to infections could significantly impact the management of antimicrobial prophylaxis and treatment in AML patients.
Assuntos
Imunidade Inata , Lectinas Tipo C , Leucemia Mieloide Aguda , Polimorfismo de Nucleotídeo Único , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Feminino , Pessoa de Meia-Idade , Masculino , Adulto , Lectinas Tipo C/genética , Idoso , Imunidade Inata/genética , Sepse/genética , Sepse/tratamento farmacológico , Quimioterapia de Indução , Receptores de Superfície Celular/genética , Moléculas de Adesão Celular/genética , Receptor 2 Toll-Like/genética , Componente Amiloide P Sérico/genética , Adolescente , Receptor 4 Toll-Like/genética , Infecções Fúngicas Invasivas/genética , Infecções Fúngicas Invasivas/tratamento farmacológico , Estudos de Coortes , Predisposição Genética para Doença , Proteína C-ReativaRESUMO
In recent years, inflammatory disorders have emerged as a significant concern for human health. Through ongoing research on anti-inflammatory agents, alpinetin has shown promising anti-inflammatory properties, including involvement in epigenetic modification pathways. As a crucial regulator of epigenetic modifications, Mecp2 may play a role in modulating the epigenetic effects of alpinetin, potentially impacting its anti-inflammatory properties. To test this hypothesis, two key components, p65 (a member of NF-KB family) and p300 (a type of co-activator), were screened by the expression profiling microarray, which exhibited a strong correlation with the intensity of LPS stimulation in mouse macrophages. Meanwhile, alpinetin demonstrates the anti-inflammatory properties through its ability to disrupt the synthesis of p65 and its interaction with promoters of inflammatory genes, yet it did not exhibit similar effects on p300. Additionally, Mecp2 can inhibit the binding of p300 by attaching to the methylated inflammatory gene promoter induced by alpinetin, leading to obstacles in promoter acetylation and subsequently impacting the binding of p65, ultimately enhancing the anti-inflammatory capabilities of alpinetin. Similarly, in a sepsis mouse model, it was observed that homozygotes overexpressing Mecp2 showed a greater reduction in organ damage and improved survival rates compared to heterozygotes when administered by alpinetin. However, blocking the expression of DNA methyltransferase 3A (DNMT3A) resulted in the loss of Mecp2's anti-inflammatory assistance. In conclusion, Mecp2 may augment the anti-inflammatory effects of alpinetin through epigenetic 'crosstalk', highlighting the potential efficacy of a combined therapeutic strategy involving Mecp2 and alpinetin for anti-inflammatory intervention.
Assuntos
Anti-Inflamatórios , Epigênese Genética , Flavanonas , Proteína 2 de Ligação a Metil-CpG , Regiões Promotoras Genéticas , Proteína 2 de Ligação a Metil-CpG/metabolismo , Proteína 2 de Ligação a Metil-CpG/genética , Animais , Flavanonas/farmacologia , Epigênese Genética/efeitos dos fármacos , Camundongos , Anti-Inflamatórios/farmacologia , Células RAW 264.7 , Metilação de DNA/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Fator de Transcrição RelA/metabolismo , Sepse/tratamento farmacológico , Sepse/genética , Sepse/metabolismo , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Inflamação/tratamento farmacológico , Inflamação/patologia , Inflamação/genética , Inflamação/metabolismo , DNA Metiltransferase 3A/metabolismo , Masculino , Proteína p300 Associada a E1A/metabolismo , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , DNA (Citosina-5-)-Metiltransferases/metabolismo , DNA (Citosina-5-)-Metiltransferases/genéticaRESUMO
BACKGROUND: Persistent Staphylococcus aureus bacteremia is associated with metastatic infection and adverse outcomes, whereas gram-negative bacteremia is normally transient and shorter course therapy is increasingly advocated for affected patients. Whether the prolonged detection of pathogen DNA in blood by culture-independent systems could have prognostic value and guide management decisions is unknown. METHODS: We performed a multicenter, prospective, observational study on 102 patients with bloodstream infection (BSI) to compare time to bloodstream clearance according to T2 magnetic resonance and blood cultures over a 4-day follow-up. We also explored the association between duration of detectable pathogens according to T2 magnetic resonance (magnetic resonance-DNAemia [MR-DNAemia]) and clinical outcomes. RESULTS: Time to bloodstream clearance according to T2 magnetic resonance was significantly longer than blood culture clearance (HR, .54; 95% CI, .39-.75) and did not differ according to the causative pathogen (P = .5). Each additional day of MR-DNAemia increased the odds of persistent infection (defined as metastatic infection or delayed source control) both in the overall population (OR, 1.98; 95% CI, 1.45-2.70) and in S. aureus (OR, 1.92; 95% CI, 1.12-3.29) and gram-negative bacteremia (OR, 2.21; 95% CI, 1.35-3.60). MR-DNAemia duration was also associated with no improvement in Sequential Organ Failure Assessment score at day 7 from infection onset (OR, 1.76; 95% CI, 1.21-2.56). CONCLUSIONS: T2 magnetic resonance may help diagnose BSI in patients on antimicrobials with negative blood cultures as well as to identify patients with metastatic infection, source control failure, or adverse short-term outcome. Future studies may inform its usefulness within the setting of antimicrobial stewardship programs.
Assuntos
Bacteriemia , Sepse , Humanos , Prognóstico , Staphylococcus aureus , Estudos Prospectivos , Sepse/tratamento farmacológico , Bacteriemia/tratamento farmacológico , Espectroscopia de Ressonância Magnética , Antibacterianos/uso terapêuticoRESUMO
BACKGROUND: Several studies have suggested that short-course antibiotic therapy was effective in Pseudomonas aeruginosa (PA) bloodstream infections (BSI) in immunocompetent patients. But similar studies in patients with hematological malignancies were rare. METHODS: This cohort study included onco-hematology patients at 2 hematology centers in China. Inverse probability of treatment weighting was used to balance the confounding factors. Multivariate regression model was used to evaluate the effect of short-course antibiotic therapy on clinical outcomes. RESULTS: In total, 434 patients met eligibility criteria (short-course, 7-11 days, n = 229; prolonged, 12-21 days, n = 205). In the weighted cohort, the univariate and multivariate analysis indicated that short course antibiotic therapy had similar outcomes to the prolonged course. The recurrent PA infection at any site or mortality within 30 days of completing therapy occurred in 8 (3.9%) patients in the short-course group and in 10 (4.9%) in the prolonged-course group (P = .979). The recurrent infection within 90 days occurred in 20 (9.8%) patients in the short-course group and in 13 (6.3%) patients in the prolonged-course group (P = .139), and the recurrent fever within 7 days occurred in 17 (8.3%) patients in the short-course group and in 15 (7.4%) in the prolonged-course group (P = .957). On average, patients who received short-course antibiotic therapy spent 3.3 fewer days in the hospital (P < .001). CONCLUSIONS: In the study, short-course therapy was non-inferior to prolonged-course therapy in terms of clinical outcomes. However, due to its biases and limitations, further prospective randomized controlled trials are needed to generalize our findings.