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Impairment of innate immune cell function and metabolism underlies immunosuppression in sepsis; however, a promising therapy to orchestrate this impairment is currently lacking. In this study, high levels of NOD-like receptor family CARD domain containing-3 (NLRC3) correlated with the glycolytic defects of monocytes/macrophages from septic patients and mice that developed immunosuppression. Myeloid-specific NLRC3 deletion improved macrophage glycolysis and sepsis-induced immunosuppression. Mechanistically, NLRC3 inhibits nuclear factor (NF)-κB p65 binding to nuclear factor of activated T cells 5 (NFAT5), which further controls the expression of glycolytic genes and proinflammatory cytokines of immunosuppressive macrophages. This is achieved by decreasing NF-κB activation-co-induced by TNF-receptor-associated factor 6 (TRAF6) or mammalian target of rapamycin (mTOR)-and decreasing transcriptional co-activator p300 activity by inducing NLRC3 sequestration of mTOR and p300. Genetic inhibition of NLRC3 disrupted the NLRC3-mTOR-p300 complex and enhanced NF-κB binding to the NFAT5 promoter in concert with p300. Furthermore, intrapulmonary delivery of recombinant adeno-associated virus harboring a macrophage-specific NLRC3 deletion vector significantly improved the defense of septic mice that developed immunosuppression upon secondary intratracheal bacterial challenge. Collectively, these findings indicate that NLRC3 mediates critical aspects of innate immunity that contribute to an immunocompromised state during sepsis and identify potential therapeutic targets.
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Tolerancia Inmunológica , Péptidos y Proteínas de Señalización Intercelular , Macrófagos , FN-kappa B , Sepsis , Factores de Transcripción , Animales , Ratones , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Macrófagos/inmunología , FN-kappa B/metabolismo , Sepsis/inmunología , Sepsis/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Factores de Transcripción/metabolismo , Huésped InmunocomprometidoRESUMEN
Transient Receptor Potential Vanilloid 4 (TRPV4) ion channel is thought to be an essential component of inflammatory response. However, its role and mechanism in regulating acute lung injury (ALI) and macrophages activation are not well characterized. In our study, we observe that blockade of TRPV4 using GSK2193874 or HC-067047 greatly improve the pneumonedema, the lung pathologic changes, the up-regulation of proinflammatory cytokines and the neutrophil infiltration in LPS-induced lung injury. In vitro, knockdown of TRPV4 in macrophages reduces the levels of pro-inflammatory cytokines, ROS production, Ca2+ concentration in cytoplasma and the activation of calcineurin/NFATc3 signaling. Importantly, change of extracellular Ca2+ in culture medium prevents LPS-induced NFATc3 nuclear translocation, up-regulation of proinflammatory cytokines and ROS production in macrophages. Inhibition of calcineurin with cyclosporine A, FK506 down-regulates the levels of NFATc3 nuclear translocation and proinflammatory cytokines expression. Our results demonstrate that TRPV4-dependent Ca2+ influx contributes to LPS-induced macrophage activation by calcineurin-NFATc3 pathway.
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Calcineurina/metabolismo , Inflamación/inducido químicamente , Factores de Transcripción NFATC/metabolismo , Transducción de Señal , Canales Catiónicos TRPV/fisiología , Lesión Pulmonar Aguda , Animales , Calcio/metabolismo , Células Cultivadas , Humanos , Lipopolisacáridos/farmacología , Activación de Macrófagos , Morfolinas/farmacología , Piperidinas/farmacología , Pirroles/farmacología , Quinolinas/farmacología , Canales Catiónicos TRPV/antagonistas & inhibidoresRESUMEN
Sevoflurane is associated with a relatively high incidence of emergence agitation (EA) in children. Prophylactic treatment, including midazolam, dexmedetomidine, ketamine, fentanyl and propofol, has been used to prevent EA. However, the question of which prophylactic treatment should be preferred to decrease the incidence of EA is still unclear. We conducted a network meta-analysis of randomized controlled trials to investigate the comparative efficacy of midazolam, dexmedetomidine, ketamine, fentanyl, and propofol for the prevention of sevoflurane-related EA in children. First, we used the odds ratios and 95% confidence interval as effect size. The results revealed that dexmedetomidine 0.19 (0.14-0.27), midazolam 0.22 (0.07-0.60), ketamine 0.28 (0.16-0.51), propofol 0.23 (0.10-0.53), and fentanyl 0.25 (0.17-0.36) led to a significant reduction of the incidence of EA when compared with placebo. With placebo as the standard of comparison, the degree of incoherence (a measure of how closely the entire network fits together) was small (ω = 8.66728e-08). The logor were dexmedetomidine -1.75 (-2.11 to -1.39), midazolam -1.07 (-1.54 to -0.60), ketamine -1.292 (-1.92 to -0.66), and fentanyl -1.13 (-1.56 to -0.70). When compared with dexmedetomidine, the logor were placebo 1.75 (1.39-2.11), midazolam 0.67 (0.09-1.25), ketamine 0.45 (-0.25-1.15), propofol 0.75 (0.19-1.31), and fentanyl 0.617 (0.13-1.11). When compared with ketamine, the logor were placebo 1.29 (0.66-1.92), midazolam 0.22 (-0.56 to 1.00), dexmedetomidine -0.45 (-1.15-0.25); propofol 0.29 (-0.45-1.03); and fentanyl 0.16 (-0.59-0.92). The study that showed dexmedetomidine, midazolam, ketamine, propofol, and fentanyl could significantly decrease the incidence of EA when compared with placebo. One interesting finding of this network meta-analysis is that dexmedetomidine might be the best choice to prevent EA. However, there is weak evidence that dexmedetomidine is better than ketamine for the prevention of sevoflurane-related EA in children. As a result, more studies are needed to compare dexmedetomidine with ketamine.
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Anestésicos por Inhalación/efectos adversos , Delirio del Despertar/inducido químicamente , Delirio del Despertar/prevención & control , Hipnóticos y Sedantes/administración & dosificación , Éteres Metílicos/efectos adversos , Niño , Preescolar , Dexmedetomidina , Fentanilo/administración & dosificación , Humanos , Hipnóticos y Sedantes/uso terapéutico , Lactante , Ketamina/administración & dosificación , Midazolam/administración & dosificación , Metaanálisis en Red , Oportunidad Relativa , Propofol/administración & dosificación , Ensayos Clínicos Controlados Aleatorios como Asunto , SevofluranoRESUMEN
To compare the efficacy and safety of dexmedetomidine with other alternative sedative agents used for performing awake intubation. We conducted a meta-analysis of randomized controlled trials (RCTs) that compared the effects of dexmedetomidine with other alternative sedative agents used during awake intubation. The biomedical databases PubMed, Science Direct, and the Cochrane Library were searched for relevant RCTs with no restriction on the language of publication. The efficacy (level of sedation, success rate for intubation at the first attempt, intubation time, intubation conditions, and patient satisfaction) and safety (incidence of hypertension, hypotension, tachycardia, bradycardia, hypoxia, postsurgical memory, hoarseness, and sore throat) were assessed. Thirteen RCTs with a combined subject population of 591 patients came within the purview of this meta-analysis. Use of dexmedetomidine was associated with a higher Ramsay sedation scale score [mean difference (MD): 1.02, 95% confidence interval (CI), 0.77-1.28, P < 0.00001], vocal cord movement score (MD = 0.72, 95% CI, 0.20-1.24, P = 0.007), coughing scores (MD = 0.66, 95% CI, 0.10-1.22, P = 0.02), limb movement scores (MD = 0.69, 95% CI, 0.47-0.91, P < 0.00001); increased risk of bradycardia [relative risk (RR): 3.03, 95% CI, 1.38-6.68, P = 0.006] and hypotension (RR: 2.87, 95% CI, 1.44-5.75, P = 0.003); and lower risk of hypoxia (RR: 0.32, 95% CI, 0.15-0.70; P = 0.004) and postsurgical memory (RR: 0.50, 95% CI, 0.35-0.72, P = 0.0002). As indicated by our results, dexmedetomidine appears to be an effective and well-tolerated agent for performing awake intubation. Its use was associated with better intubation conditions, preservation of airway patency, and reduced recall of intubation, as compared with the traditional sedative agents. The risk of bradycardia and hypotension was significantly higher with dexmedetomidine as compared with that with other sedatives. However, these were easily managed with atropine and vasoactive agents.
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Dexmedetomidina/administración & dosificación , Hipnóticos y Sedantes/administración & dosificación , Intubación Intratraqueal/métodos , Bradicardia/inducido químicamente , Bradicardia/epidemiología , Dexmedetomidina/efectos adversos , Humanos , Hipnóticos y Sedantes/efectos adversos , Hipotensión/inducido químicamente , Hipotensión/epidemiología , Ensayos Clínicos Controlados Aleatorios como Asunto , VigiliaRESUMEN
Cytokine release syndrome (CRS) can be induced by immune checkpoint inhibitors (ICIs). Although the incidence of CRS is low, it is often underreported. Here, we report two severe CRS cases and summarize and review 51 patients with ICI-induced CRS to explore the possible contributing factors to the disease prognosis and provide assistance for therapy. Our analysis found that the population with ICI-induced CRS consists mainly of male patients with an average age of 61.74 years. The primary malignant tumor type was lung cancer, and the clinical stage of most patients was stage IV. Notably, patients who experience a longer time to CRS onset, higher IL-6 levels, and lower platelet counts may be more likely to develop severe CRS. Cardiovascular, respiratory, neurological, and coagulation toxicities are more common in higher-grade CRS and may serve as markers for patient experiencing ICU admission, oxygen supplementation, hypotension, high-dose vasopressors usage, and intubation.
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STUDY OBJECTIVE: Fospropofol disodium is a propofol prodrug that is water-soluble and has a reduced risk of bacterial contamination and hypertriglyceridemia compared with propofol. Prior to implementing a large randomized trial, we investigated the feasibility, initial efficacy, and safety of fospropofol disodium compared with propofol in long-term mild-to-moderate sedation in intensive care units (ICUs). DESIGN: Single-centered, prospective, unblind, randomized, parallel-group clinical trial. SETTING: The general ICU of university-affiliated teaching hospital. PATIENTS: Adult patients (n = 60) expected to have mechanical ventilation for >24 h were enrolled and randomly assigned to the fospropofol or propofol group. INTERVENTIONS: The fospropofol group received continuous fospropofol disodium infusions and the propofol group received continuous propofol infusions. The sedation goal was a score of -3 to 0 on the Richmond Agitation and Sedation Scale (RASS). MEASUREMENTS: The primary outcome was the percentage of time spent in the target sedation range without rescue sedation. Safety outcomes were based on adverse events. Blood samples were collected to measure formate concentration in plasma. MAIN RESULTS: The median dose was 4.33 (IQR, 3.08-4.94) mg/kg/h in the fospropofol group and 1.96 (IQR, 1.44-2.94) mg/kg/h in the propofol group. The median percentage of time spent in the target RASS range without rescue sedation was identical in both groups, with 83.33% (IQR, 74.43%-100.00%) in the fospropofol group and 83.33% (IQR, 77.45%-100.00%) in the propofol group (p = 0.887). At least one adverse event was identifed in 23 (76.7%) fospropofol patients and 27 (90.0%) propofol patients. The most common adverse events were tachycardia and hypotension. No paresthesia, catheter-related bloodstream infection or propofol infusion syndrome in both groups was reported. Three patients in the fospropofol group had mild hypertriglyceridemia, and nine patients in propofol group had hypertriglyceridemia (mild in eight patients and moderate in one patient) (10% versus 30%, p = 0.104). The formate concentration in plasma was very low, and no significant difference was identified at any time point between the two groups. CONCLUSIONS: Fospropofol disodium appears to be a feasible, effective and safe sedative for patients receiving invasive mechanical ventilation with long-term sedation.
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Hipnóticos y Sedantes , Propofol , Propofol/análogos & derivados , Respiración Artificial , Humanos , Propofol/administración & dosificación , Propofol/efectos adversos , Masculino , Femenino , Persona de Mediana Edad , Proyectos Piloto , Respiración Artificial/efectos adversos , Estudios Prospectivos , Hipnóticos y Sedantes/administración & dosificación , Hipnóticos y Sedantes/efectos adversos , Anciano , Unidades de Cuidados Intensivos , Estudios de Factibilidad , Adulto , Sedación Consciente/métodos , Sedación Consciente/efectos adversos , Infusiones Intravenosas , Profármacos/administración & dosificación , Profármacos/efectos adversosRESUMEN
Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. In sepsis, a complicated immune response is initiated, which varies over time with sustained excessive inflammation and immunosuppression. Identifying a promising way to orchestrate sepsis-induced immunosuppression is a challenge. Myeloid-derived suppressor cells (MDSCs) comprise pathologically activated neutrophils and monocytes with potent immunosuppressive activity. They play an important part in inhibiting innate and adaptive immune responses, and have emerged as part of the immune response in sepsis. MDSCs numbers are persistently high in sepsis patients, and associated with nosocomial infections and other adverse clinical outcomes. However, their characteristics and functional mechanisms during sepsis have not been addressed fully. Our review sheds light on the features and suppressive mechanism of MDSCs. We also review the potential applications of MDSCs as biomarkers and targets for clinical treatment of sepsis.
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Células Supresoras de Origen Mieloide , Sepsis , Humanos , Terapia de Inmunosupresión , Tolerancia Inmunológica , MonocitosRESUMEN
INTRODUCTION: Pulmonary fibrosis is a major cause of the poor prognosis of acute respiratory distress syndrome (ARDS). While mechanical ventilation (MV) is an indispensable life-saving intervention for ARDS, it may cause the remodeling process in lung epithelial cells to become disorganized and exacerbate ARDS-associated pulmonary fibrosis. Piezo1 is a mechanosensitive ion channel that is known to play a role in regulating diverse physiological processes, but whether Piezo1 is necessary for MV-exacerbated ARDS-associated pulmonary fibrosis remains unknown. OBJECTIVES: This study aimed to explore the role of Piezo1 in MV-exacerbated ARDS-associated pulmonary fibrosis. METHODS: Human lung epithelial cells were stimulated with hydrochloric acid (HCl) followed by mechanical stretch for 48 h. A two-hitmodel of MV afteracidaspiration-inducedlunginjuryin mice was used. Mice were sacrificed after 14 days of MV. Pharmacological inhibition and knockout of Piezo1 were used to delineate the role of Piezo1 in MV-exacerbated ARDS-associated pulmonary fibrosis. In some experiments, ATP or the ATP-hydrolyzing enzyme apyrase was administered. RESULTS: The stimulation of human lung epithelial cells to HCl resulted in phenotypes of epithelial-mesenchymal transition (EMT), which were enhanced by mechanical stretching. MV exacerbated pulmonary fibrosis in mice exposed to HCl. Pharmacologicalinhibitionorknockout of Piezo1 attenuated the MV-exacerbated EMT process and lung fibrosis in vivo and in vitro. Mechanistically, the observed effects were mediated by Piezo1-dependent Ca2+ influx and ATP release in lung epithelial cells. CONCLUSIONS: Our findings identify a key role for Piezo1 in MV-exacerbated ARDS-associated pulmonary fibrosis that is mediated by increased ATP release in lung epithelial cells. Inhibiting Piezo1 may constitute a novelstrategyfor the treatment of MV-exacerbated ARDS-associated pulmonary fibrosis.
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Fibrosis Pulmonar , Síndrome de Dificultad Respiratoria , Ratones , Humanos , Animales , Respiración Artificial/efectos adversos , Síndrome de Dificultad Respiratoria/complicaciones , Canales Iónicos , Adenosina TrifosfatoRESUMEN
Sepsis is a life-threatening organ dysfunction resulting from dysregulated host responses to infection. Macrophages play significant roles in host against pathogens and the immunopathogenesis of sepsis, such as phagocytosis of pathogens, secretion of cytokines, and phenotype reprogramming. However, the rapid progression of sepsis impairs macrophage function, and conventional antimicrobial and supportive treatment are not sufficient to restore dysregulated macrophages roles. Nanoparticles own unique physicochemical properties, surface functions, localized surface plasmon resonance phenomenon, passive targeting in vivo, good biocompatibility and biodegradability, are accessible for biomedical applications. Once into the body, NPs are recognized by host immune system. Macrophages are phagocytes in innate immunity dedicated to the recognition of foreign substances, including nanoparticles, with which an immune response subsequently occurs. Various design strategies, such as surface functionalization, have been implemented to manipulate the recognition of nanoparticles by monocytes/macrophages, and engulfed by them to regulate their function in sepsis, compensating for the shortcomings of sepsis traditional methods. The review summarizes the mechanism of nanomaterials targeting macrophages and recent advances in nanomedicine targeting macrophages in sepsis, which provides good insight for exploring macrophage-based nano-management in sepsis.
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Nanopartículas , Sepsis , Humanos , Macrófagos , Inmunidad Innata , Fagocitosis , Nanopartículas/uso terapéutico , Nanopartículas/químicaRESUMEN
Intensive care unit (ICU)-acquired infection is a common cause of poor prognosis of sepsis in the ICU. However, sepsis-associated ICU-acquired infections have not been fully characterized. The study aims to assess the risk factors and develop a model that predicts the risk of ICU-acquired infections in patients with sepsis. Methods: We retrieved data from the Medical Information Mart for Intensive Care (MIMIC) IV database. Patients were randomly divided into training and validation cohorts at a 7:3 ratio. A multivariable logistic regression model was used to identify independent risk factors that could predict ICU-acquired infection. We also assessed its discrimination and calibration abilities and compared them with classical score systems. Results: Of 16,808 included septic patients, 2,871 (17.1%) developed ICU-acquired infection. These patients with ICU-acquired infection had a 17.7% ICU mortality and 31.8% in-hospital mortality and showed a continued rise in mortality from 28 to 100 days after ICU admission. The classical Systemic Inflammatory Response Syndrome Score (SIRS), Sequential Organ Failure Assessment (SOFA), Oxford Acute Severity of Illness Score (OASIS), Simplified Acute Physiology Score II (SAPS II), Logistic Organ Dysfunction Score (LODS), Charlson Comorbidity Index (CCI), and Acute Physiology Score III (APS III) scores were associated with ICU-acquired infection, and cerebrovascular insufficiency, Gram-negative bacteria, surgical ICU, tracheostomy, central venous catheter, urinary catheter, mechanical ventilation, red blood cell (RBC) transfusion, LODS score and anticoagulant therapy were independent predictors of developing ICU-acquired infection in septic patients. The nomogram on the basis of these independent predictors showed good calibration and discrimination in both the derivation (AUROC = 0.737; 95% CI, 0.725-0.749) and validation (AUROC = 0.751; 95% CI, 0.734-0.769) populations and was superior to that of SIRS, SOFA, OASIS, SAPS II, LODS, CCI, and APS III models. Conclusions: ICU-acquired infections increase the likelihood of septic mortality. The individualized prognostic model on the basis of the nomogram could accurately predict ICU-acquired infection and optimize management or tailored therapy.
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Puntuaciones en la Disfunción de Órganos , Sepsis , Humanos , Unidades de Cuidados Intensivos , Estudios Retrospectivos , Factores de Riesgo , Sepsis/epidemiologíaRESUMEN
OBJECTIVES: Mechanical stretch-induced alveolar epithelial cell (AEC) apoptosis participates in the onset of ventilator-induced lung injury (VILI). In this study, we explored whether death-associated protein kinase 1 (DAPK1) mediated cyclic stretch (CS)-induced AEC apoptosis and VILI though P53 pathway. MATERIALS AND METHODS: AEC apoptosis was induced by CS using the FX-5000T Flexercell Tension Plus system. C57BL/6 mouse received high tidal volume ventilation to build VILI model. DAPK1 inhibitor, P53 inhibitor, or DAPK1 plasmid was used to regulate the expression of DAPK1 and P53, respectively. Flow cytometery was performed to assay cell apoptosis and the changes of mitochondrial membrane potential (MMP); immunoblotting was adopted to analyze related protein expression. The binding of related proteins was detected by coimmunoprecipitation; AEC apoptosis in vivo was determined by immunohistochemistry assay. RESULTS: CS promoted AEC apoptosis, increased DAPK1 and P53 expression, and induced the binding of DAPK1 and P53; inhibition of DAPK1 or P53 reduced CS-induced AEC apoptosis, suppressed the expression of Bax, increased Bcl-2 level, and stabilized MMP; AEC apoptosis and the level of P53 were both increased after overexpressing of DAPK1. Moreover, DAPK1 plasmid transfection also promoted the expression of Bax and the change of MMP, but decreased the level of Bcl-2. Inhibition of DAPK1 or P53 in vivo alleviated high tidal volume ventilation-induced AEC apoptosis and lung injury. CONCLUSIONS: DAPK1 contributes to AEC apoptosis and the onset of VILI though P53 and its intrinsic pro-apoptotic pathway. Inhibition of DAPK1 or P53 alleviates high tidal volume ventilation-induced lung injury and AEC apoptosis.
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Células Epiteliales Alveolares/patología , Proteínas Quinasas Asociadas a Muerte Celular/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Lesión Pulmonar Inducida por Ventilación Mecánica , Animales , Apoptosis , Células Cultivadas , Ratones Endogámicos C57BL , Transducción de SeñalRESUMEN
COVID-19 is an acute, complex disorder that was caused by a new ß-coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Based on current reports, it was surprising that the characteristics of many patients with COVID-19, who fulfil the Berlin criteria for acute respiratory distress syndrome (ARDS), are not always like those of patients with typical ARDS and can change over time. While the mechanisms of COVID-19-related respiratory dysfunction in COVID-19 have not yet been fully elucidated, pulmonary microvascular thrombosis is speculated to be involved. Considering that thrombosis is highly related to other inflammatory lung diseases, immunothrombosis, a two-way process that links coagulation and inflammation, seems to be involved in the pathophysiology of COVID-19, including respiratory dysfunction. Thus, the current manuscript will describe the proinflammatory milieu in COVID-19, summarize current evidence of thrombosis in COVID-19, and discuss possible interactions between these two.
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COVID-19/inmunología , COVID-19/patología , Inflamación/virología , Síndrome de Dificultad Respiratoria/virología , Trombosis/virología , Humanos , Inflamación/inmunología , Inflamación/patología , Síndrome de Dificultad Respiratoria/inmunología , Síndrome de Dificultad Respiratoria/patología , SARS-CoV-2 , Trombosis/inmunología , Trombosis/patologíaRESUMEN
Mechanotransduction couples mechanical stimulation with ion flux, which is critical for normal biological processes involved in neuronal cell development, pain sensation, and red blood cell volume regulation. Although they are key mechanotransducers, mechanosensitive ion channels in mammals have remained difficult to identify. In 2010, Coste and colleagues revealed a novel family of mechanically activated cation channels in eukaryotes, consisting of Piezo1 and Piezo2 channels. These have been proposed as the long-sought-after mechanosensitive cation channels in mammals. Piezo1 and Piezo2 exhibit a unique propeller-shaped architecture and have been implicated in mechanotransduction in various critical processes, including touch sensation, balance, and cardiovascular regulation. Furthermore, several mutations in Piezo channels have been shown to cause multiple hereditary human disorders, such as autosomal recessive congenital lymphatic dysplasia. Notably, mutations that cause dehydrated hereditary xerocytosis alter the rate of Piezo channel inactivation, indicating the critical role of their kinetics in normal physiology. Given the importance of Piezo channels in understanding the mechanotransduction process, this review focuses on their structural details, kinetic properties and potential function as mechanosensors. We also briefly review the hereditary diseases caused by mutations in Piezo genes, which is key for understanding the function of these proteins.
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Sepsis is a clinical syndrome that resulting from a dysregulated inflammatory response to infection that leads to organ dysfunction. The dysregulated inflammatory response transitions from a hyper-inflammatory phase to a hypo-inflammatory or immunosuppressive phase. Currently, no phase-specific molecular-based therapies are available for monitoring the complex immune response and treating sepsis due to individual variations in the timing and overlap of the dysregulated immune response in most patients. Glucocorticoid-induced leucine zipper (GILZ), is broadly present in multiple tissues and circumvent glucocorticoid resistance (GCR) or unwanted side effects. Recently, the characteristics of GILZ downregulation during acute hyperinflammation and GILZ upregulation during the immunosuppressive phase in various inflammatory diseases have been well documented, and the protective effects of GILZ have gained attention in the field of sepsis. However, whether GILZ could be a promising candidate biomarker for monitoring and treating septic patients remains unknown. Here, we discuss the effect of GILZ in sepsis and sepsis-induced immunosuppression.
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Sepsis/sangre , Factores de Transcripción/sangre , Animales , Antiinflamatorios/uso terapéutico , Biomarcadores/sangre , Glucocorticoides/uso terapéutico , Humanos , Inmunosupresores/uso terapéutico , Valor Predictivo de las Pruebas , Pronóstico , Sepsis/diagnóstico , Sepsis/tratamiento farmacológico , Sepsis/inmunología , Transducción de SeñalRESUMEN
The activation of NLRP3 inflammasome and NF-κB pathway, associating with oxidativestress, have been implicated in the development of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). NecroX-5 has been reported to exhibit theeffectsofanti-oxidation and anti-stress in various diseases. However, the role of NecroX-5 in ALI has not been explicitly demonstrated. The aim of this study was to explore the therapeutic effects and potential mechanism action of NecroX-5 on ALI. Here, we found that NecroX-5 pretreatment dramatically diminished the levels of IL-1ß, IL-18 and ROS in in RAW264.7 cells challenged with LPS and ATP. Furthermore, NecroX-5 suppressed the activation of NLRP3 inflammasome and NF-κB signalpathway. In addition, NecroX-5 also inhibited the thioredoxin-interacting protein (TXNIP) expression. In vivo, NecroX-5 reduced the LPS-induced lung histopathological injury, the number of TUNEL-positive cells, lung wet/dry (W/D) ratio, levels of total protein and inflammatory cytokines in the bronchoalveolar lavage fluid (BALF) in mice. Additionally, LPS-induced upregulation of myeloperoxidase (MPO), ROS production and malondialdehyde (MDA) were inhibited by NecroX-5 administration. Thus, our results demonstrate that NecroX-5 protects against LPS-induced ALI by inhibiting TXNIP/NLRP3 and NF-κB.
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Antiinflamatorios/uso terapéutico , Proteínas Portadoras/metabolismo , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Pulmón/metabolismo , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , Sulfonas/uso terapéutico , Tiorredoxinas/metabolismo , Animales , Proteínas Portadoras/genética , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Humanos , Lipopolisacáridos/inmunología , Pulmón/patología , Masculino , Ratones , FN-kappa B/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Peroxidasa/metabolismo , Células RAW 264.7 , Síndrome de Dificultad Respiratoria/inmunología , Transducción de Señal , Tiorredoxinas/genéticaRESUMEN
Ventilatorinduced lung injury (VILI) is a lifethreatening condition caused by the inappropriate use of mechanical ventilation (MV). However, the precise molecular mechanism inducing the development of VILI remains to be elucidated. In the present study, it was revealed that the calcineurin/NFATc4 signaling pathway mediates the expression of adhesion molecules and proinflammatory cytokines essential for the development of VILI. The present results revealed that a high tidal volume ventilation (HV) caused lung inflammation and edema in the alveolar walls and the infiltration of inflammatory cells. The calcineurin activity and protein expression in the lungs were increased in animals with VILI, and NFATc4 translocated into the nucleus following calcineurin activation. Furthermore, the translocation of NFATc4 and lung injury were prevented by a calcineurin inhibitor (CsA). Thus, the present results highlighted the critical role of the calcineurin/NFATc4 signaling pathway in VILI and suggest that this pathway coincides with the release of ICAM1, VCAM1, TNFα and IL1ß.
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Calcineurina/metabolismo , Factores de Transcripción NFATC/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Lesión Pulmonar Inducida por Ventilación Mecánica/metabolismo , Animales , Calcineurina/genética , Inhibidores de la Calcineurina/farmacología , Núcleo Celular/metabolismo , Edema/complicaciones , Edema/metabolismo , Inflamación/complicaciones , Inflamación/metabolismo , Molécula 1 de Adhesión Intercelular/genética , Molécula 1 de Adhesión Intercelular/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Masculino , Factores de Transcripción NFATC/antagonistas & inhibidores , Factores de Transcripción NFATC/genética , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Proteínas del Tejido Nervioso/genética , Peroxidasa/metabolismo , Ratas , Ratas Wistar , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo , Molécula 1 de Adhesión Celular Vascular/genética , Molécula 1 de Adhesión Celular Vascular/metabolismo , Lesión Pulmonar Inducida por Ventilación Mecánica/enzimología , Lesión Pulmonar Inducida por Ventilación Mecánica/genética , Lesión Pulmonar Inducida por Ventilación Mecánica/patologíaRESUMEN
OBJECTIVES: Carotid endarterectomy (CEA) is efficient in preventing stroke for patients with significant carotid stenosis, but results in mild cognitive dysfunction. Dexmedetomidine is neuroprotective in stroke models. We hypothesized that dexmedetomidine may improve cognition after CEA. METHODS: Forty-nine patients scheduled for elective CEA were randomly assigned to intravenous dexmedetomidine treatment group (n = 25) and control group C (normal saline, n = 24). Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MOCA), as well as lactate, TNF-α, IL-6, and BDNF levels in blood, were assessed before, during, and after surgery. RESULTS: MMSE and MOCA scores showed subtle decline in both groups at 24 hours postoperatively; this decline remained at 48 hours postoperatively in group C. Both scores were higher in group D than in group C at 48 and 72 hours postoperatively. TNF-α and IL-6 were lower from 5 minutes post-clamping through 24 hours postoperatively in group D; lactate was lower at 5 minutes post-clamping in group D. BDNF was higher from 5 minutes post-clamping through 1 hour postoperatively in both groups, and remained high in group D at 24 hours postoperatively. CONCLUSIONS: Dexmedetomidine improved recovery of cognition after CEA, potentially due to reduced inflammation and enhanced BDNF expression.
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Isquemia Encefálica/prevención & control , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Estenosis Carotídea/cirugía , Trastornos del Conocimiento/tratamiento farmacológico , Dexmedetomidina/uso terapéutico , Endarterectomía Carotidea/efectos adversos , Inflamación/prevención & control , Agonistas de Receptores Adrenérgicos alfa 2/uso terapéutico , Anciano , Anciano de 80 o más Años , Isquemia Encefálica/etiología , Isquemia Encefálica/patología , Estenosis Carotídea/patología , Estudios de Casos y Controles , Trastornos del Conocimiento/etiología , Trastornos del Conocimiento/patología , Femenino , Estudios de Seguimiento , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Inflamación/etiología , Inflamación/patología , Masculino , PronósticoRESUMEN
Progressive lung injury and pulmonary inflammation can be induced by an intraperitoneal injection of lipopolysaccharide (LPS). Interleukin-1ß (IL-1ß) is a key pro-inflammatory cytokine that can further exaggerate inflammation, which is cleaved and activated by the NALP3 inflammasome. Although the nuclear receptor Rev-erbα attenuates the level of LPS-induced pulmonary inflammation, the mechanism remains unclear. In this study, we investigated the influence of LPS-induced production of IL-1ß and Rev-erbα on the development of lung inflammation. Herein, we demonstrate that Rev-erbα reduces IL-1ß production and lung injury following an intraperitoneal injection of LPS, which is dependent on the NF-κB/NALP3 pathway. Thus, Rev-erbα is able to decrease the extent of acute lung injury by regulating IL-1ß production. This mechanism may represent a potential novel therapeutic approach for lung injury.
Asunto(s)
Lesión Pulmonar Aguda/inmunología , FN-kappa B/inmunología , Proteína con Dominio Pirina 3 de la Familia NLR/inmunología , Miembro 1 del Grupo D de la Subfamilia 1 de Receptores Nucleares/inmunología , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/patología , Animales , Glicina/análogos & derivados , Glicina/farmacología , Interleucina-1beta/inmunología , Isoquinolinas/farmacología , Lipopolisacáridos , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Pulmón/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Miembro 1 del Grupo D de la Subfamilia 1 de Receptores Nucleares/agonistas , Miembro 1 del Grupo D de la Subfamilia 1 de Receptores Nucleares/antagonistas & inhibidores , Células RAW 264.7 , Transducción de Señal , Tiofenos/farmacologíaRESUMEN
The aim of the present study was to investigate the effects of preconditioning of physiological cyclic stretch (CS) on the overexpression of early pro-inflammatory cytokines [including tumor necrosis factor (TNF)-α, interleukin (IL)-1ß and IL-8] during the inflammatory response induced by pathologically mechanical stretch in lung epithelial cells, and to determine its molecular mechanism of action. Cells were subjected to 5% CS for various durations (0, 15, 30, 60 and 120 min) prior to 6 h treatment with pathological 20% CS. In a separate experiment, cells were preconditioned with physiological 5% CS or incubated with a nuclear factor (NF)-κB inhibitor, pyrroldine dithiocarbamate (PDTC). The expression levels of inflammatory mediators were measured using reverse transcription-quantitative polymerase chain reaction. NF-κB was quantified using western blot analysis. Preconditioning with physiological 5% CS for 30, 60 and 120 min was demonstrated to significantly attenuate the release of pathologically mechanical stretch-induced early pro-inflammatory cytokines (TNF-α, IL-1ß and IL-8) in alveolar epithelial cells (P<0.05) and significantly reduce the expression of NF-κB (P<0.05). Peak suppression was observed in cells preconditioned for 60 min. In the second set of experiments, it was demonstrated that mechanical stretch-induced release of TNF-α, IL-1ß and IL-8 was significantly inhibited by both PDTC pretreatment and 5% CS pretreatment alone (all P<0.05). Furthermore, significant inhibition was also observed when both 5% CS pretreatment and PDTC pretreatment was used on mechanical stretch-induced cells (P<0.05), which was markedly greater than the inhibition induced by either pretreatment alone. The present findings suggest that preconditioning with physiological 5% CS is able to inhibit the inflammatory response induced by pathologically mechanical stretch in alveolar epithelial cells. These anti-inflammatory effects are induced, at least in part, by suppressing the NF-κB signaling pathway.
RESUMEN
Ultrasound-guided interscalene brachial plexus blockade (IBPB) has a relatively high success rate in shoulder surgery; however, whether multiple injections are superior to a single injection (SI) is currently unknown. In the present study, ultrasound-guided SI and triple-injection (TI) IBPBs were compared in a prospective randomized trial. A total of 111 patients undergoing arthroscopic shoulder surgery and presenting with an American Society of Anesthesiologists physical status grading of I-II were randomly allocated to receive IBPB with 15 ml of 1% ropivacaine as a SI or TI. Performance time, procedure-related pain scores, success rate and prevalence of complications were recorded. The distribution of sensory and motor block onset in the radial, median, ulnar and axillary nerves were assessed every 5 min until 30 min post-local anesthetic injection. The duration of sensory and motor blocks were also assessed. A significantly longer performance time was recorded in the TI group (P<0.001). No significant difference was observed in success rate (91% in TI vs. 88% in SI) 30 min post-injection, and the prevalence of complications and procedure-related pain were similar between the two groups. Sensory and motor blocks of the ulnar nerve in the TI group were significantly faster and more successful compared with the SI group at all time points (P<0.041). It was also observed that sensory and motor blocks in the TI group were prolonged compared with the SI group (P<0.041). In conclusion, the TI method exhibited a faster time of onset and resulted in a more successful blockade of the ulnar nerve. TI method may be a more effective approach for IBPB in a clinical setting.