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BACKGROUND: Endothelial dysfunction, assessed by flow-mediated dilation (FMD), is related to poor prognosis in patients with COVID-19 pneumonia (CP). In this study, we explored the interplay among FMD, NADPH oxidase type 2 (NOX-2) and lipopolysaccharides (LPS) in hospitalised patients with CP, community acquired pneumonia (CAP) and controls (CT). METHODS: We enrolled 20 consecutive patients with CP, 20 hospitalised patients with CAP and 20 CT matched for sex, age, and main cardiovascular risk factors. In all subjects we performed FMD and collected blood samples to analyse markers of oxidative stress (soluble Nox2-derived peptide (sNOX2-dp), hydrogen peroxide breakdown activity (HBA), nitric oxide (NO), hydrogen peroxide (H2O2)), inflammation (TNF-α and IL-6), LPS and zonulin levels. RESULTS: Compared with controls, CP had significant higher values of LPS, sNOX-2-dp, H2O2,TNF-α, IL-6 and zonulin; conversely FMD, HBA and NO bioavailability were significantly lower in CP. Compared to CAP patients, CP had significantly higher levels of sNOX2-dp, H2O2, TNF-α, IL-6, LPS, zonulin and lower HBA. Simple linear regression analysis showed that FMD inversely correlated with sNOX2-dp, H2O2, TNF-α, IL-6, LPS and zonulin; conversely FMD was directly correlated with NO bioavailability and HBA. Multiple linear regression analysis highlighted LPS as the only predictor of FMD. CONCLUSION: This study shows that patients with COVID-19 have low-grade endotoxemia that could activate NOX-2, generating increased oxidative stress and endothelial dysfunction.
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COVID-19 , Endotoxemia , Neumonía , Enfermedades Vasculares , Humanos , Endotoxemia/diagnóstico , Lipopolisacáridos , Peróxido de Hidrógeno , Interleucina-6 , Factor de Necrosis Tumoral alfa , COVID-19/diagnóstico , Estrés OxidativoAsunto(s)
Endotoxemia , Síndrome Metabólico , Osteoartritis de la Rodilla , Humanos , Endotoxemia/diagnóstico , Endotoxemia/complicaciones , Síndrome Metabólico/diagnóstico , Síndrome Metabólico/complicaciones , Osteoartritis de la Rodilla/diagnóstico , Osteoartritis de la Rodilla/complicaciones , Biomarcadores , PermeabilidadRESUMEN
PURPOSE: Isolated coronary artery ectasia (ICAE) is a rare coronary artery disease (CAD) encountered during coronary angiography. Although many mechanisms have been suggested today that may be associated with ICAE, the underlying pathogenesis has not been fully understood. In this study, we aimed to reveal the possible relationship between intestinal permeability and ICAE. METHODS: Of the 12 850 patients who underwent coronary angiography, 138 consecutive patients with ICAE and 140 age- and sex-matched subjects with normal coronary arteries as the control group and 140 subjects with stenotic CAD were included in the study. RESULTS: Serum zonulin and lipopolysaccharide levels were significantly higher in patients with ICAE than in the control group and CAD group. Additionally, zonulin and lipopolysaccharide levels were significantly higher in the CAD group than in the ICAE group. In the correlation analysis, serum zonulin levels were correlated with the mean diameter and length of the ecstatic segment. In multivariate analysis, zonulin and lipopolysaccharide were identified as independent predictors for ICAE. CONCLUSION: These results suggest that there may be a pathophysiological relationship between increased intestinal permeability and ICAE.
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Aneurisma Coronario , Enfermedad de la Arteria Coronaria , Endotoxemia , Humanos , Dilatación Patológica , Endotoxemia/diagnóstico , Lipopolisacáridos , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/etiología , Angiografía Coronaria/métodos , PermeabilidadRESUMEN
Circulating endotoxin, also called lipopolysaccharide (LPS) and (1â3)-ß-d-Glucan (ß-d-glucan), major constituents of bacterial and fungal cell walls, respectively, are determined as biomarkers for Gram-negative sepsis and invasive fungal diseases [...].
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Endotoxemia/diagnóstico , Endotoxemia/metabolismo , Infecciones Fúngicas Invasoras/diagnóstico , Proteoglicanos/metabolismo , Sepsis/diagnóstico , Pared Celular/química , Hongos/aislamiento & purificación , Bacterias Gramnegativas/aislamiento & purificación , Infecciones por Bacterias Gramnegativas/diagnóstico , Infecciones por Bacterias Gramnegativas/metabolismo , Humanos , Infecciones Fúngicas Invasoras/metabolismo , Sepsis/tratamiento farmacológico , Sepsis/metabolismo , Sepsis/microbiologíaRESUMEN
Chronic kidney disease induces disruption of the intestinal epithelial barrier, leading to gut bacterial translocation. Here, we appreciated bacterial translocation by analyzing circulating lipopolysaccharides (LPS) using two methods, one measuring only active free LPS, and the other quantifying total LPS as well as LPS lipid A carbon chain length. This was done in end-stage renal disease (ESRD) patients and healthy volunteers (HV). We observed both higher LPS concentration in healthy volunteers and significant differences in composition of translocated LPS based on lipid A carbon chain length. Lower LPS activity to mass ratio and higher concentration of high-density lipoproteins were found in HV, suggesting a better plasma capacity to neutralize LPS activity. Higher serum concentrations of soluble CD14 and pro-inflammatory cytokines in ESRD patients confirmed this hypothesis. To further explore whether chronic inflammation in ESRD patients could be more related to LPS composition rather than its quantity, we tested the effect of HV and patient sera on cytokine secretion in monocyte cultures. Sera with predominance of 14-carbon chain lipid A-LPS induced higher secretion of pro-inflammatory cytokines than those with predominance of 18-carbon chain lipid A-LPS. TLR4 or LPS antagonists decreased LPS-induced cytokine production by monocytes, demonstrating an LPS-specific effect. Thereby, septic inflammation observed in ESRD patients may be not related to higher bacterial translocation, but to reduced LPS neutralization capacity and differences in translocated LPS subtypes.
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Traslocación Bacteriana , Susceptibilidad a Enfermedades , Trasplante de Microbiota Fecal , Microbioma Gastrointestinal , Fallo Renal Crónico/etiología , Fallo Renal Crónico/terapia , Adulto , Anciano , Biomarcadores , Estudios de Casos y Controles , Comorbilidad , Citocinas/sangre , Manejo de la Enfermedad , Susceptibilidad a Enfermedades/inmunología , Endotoxemia/diagnóstico , Endotoxemia/etiología , Femenino , Humanos , Mediadores de Inflamación/sangre , Mediadores de Inflamación/metabolismo , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/diagnóstico , Trasplante de Riñón , Lipopolisacáridos/inmunología , Lipopolisacáridos/metabolismo , Masculino , Persona de Mediana Edad , Monocitos/inmunología , Monocitos/metabolismoRESUMEN
INTRODUCTION: Early diagnosis and treatment can reduce the risk of organ failure and mortality in systemic inflammatory conditions. Heart rate variability (HRV) has potential for early identification of the onset of systemic inflammation, as it may detect changes in sympathetic nervous system activity resulting from the developing inflammatory response before clinical signs appear. With the use of new methodologies, we investigated the onset and kinetics of HRV changes as well as several inflammatory parameters and symptoms during experimental human endotoxemia, a model of systemic inflammation in humans in vivo. PATIENTS AND METHODS: Healthy volunteers were intravenously administered LPS (nâ=â15) or placebo (nâ=â15). HRV was determined using a wireless wearable device, and parameters low to high frequency (LF:HF) ratio, root mean square of the successive differences (RMSSD), and standard deviation of normal-to-normal R-R intervals (SDNN)were calculated through 1-min-rolling 6-min windows. Plasma cytokine levels and flu-like symptoms and vital signs were serially assessed. RESULTS: The increase in LF:HF ratio, reflecting sympathetic predominance, was more pronounced in the LPS group compared to the placebo group, with the difference becoming statistically significant 65âmin following LPS administration (1.63 [1.42-1.83] vs. 1.28 [1.11-1.44], Pâ=â0.005). Significant between-group differences in RMSSD and SDNN were observed from 127 to 140âmin post-LPS administration onwards, respectively. Plasma cytokine levels showed significant between-group differences staring 60âmin post-LPS. For symptom score, heart rate, temperature, and diastolic blood pressure, significant differences compared with the placebo group were observed at 90, 118, 120, and 124âmin post-LPS, respectively. CONCLUSION: In a controlled human model of systemic inflammation, elevations in the LF:HF ratio followed very shortly after elevations in plasma cytokine levels and preceded onset of flu-like symptoms and alterations in vital signs. HRV may represent a promising non-invasive tool for early detection of a developing systemic inflammatory response.
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Electrocardiografía Ambulatoria/instrumentación , Endotoxemia/diagnóstico , Endotoxemia/fisiopatología , Frecuencia Cardíaca/fisiología , Sistema Nervioso Simpático/fisiopatología , Dispositivos Electrónicos Vestibles , Citocinas/sangre , Endotoxemia/etiología , Humanos , Lipopolisacáridos , Masculino , Adulto JovenRESUMEN
SOCS3 is the main inhibitor of the JAK/STAT3 pathway. This pathway is activated by interleukin 6 (IL-6), a major mediator of the cytokine storm during shock. To determine its role in the vascular response to shock, we challenged mice lacking SOCS3 in the adult endothelium (SOCS3iEKO) with a nonlethal dose of lipopolysaccharide (LPS). SOCS3iEKO mice died 16-24 hours postinjection after severe kidney failure. Loss of SOCS3 led to an LPS-induced type I IFN-like program and high expression of prothrombotic and proadhesive genes. Consistently, we observed intraluminal leukocyte adhesion and neutrophil extracellular trap-osis (NETosis), as well as retinal venular leukoembolization. Notably, heterozygous mice displayed an intermediate phenotype, suggesting a gene dose effect. In vitro studies were performed to study the role of SOCS3 protein levels in the regulation of the inflammatory response. In human umbilical vein endothelial cells, pulse-chase experiments showed that SOCS3 protein had a half-life less than 20 minutes. Inhibition of SOCS3 ubiquitination and proteasomal degradation led to protein accumulation and a stronger inhibition of IL-6 signaling and barrier function loss. Together, our data demonstrate that the regulation of SOCS3 protein levels is critical to inhibit IL-6-mediated endotheliopathy during shock and provide a promising therapeutic avenue to prevent multiorgan dysfunction through stabilization of endothelial SOCS3.
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Endotelio Vascular/patología , Endotoxemia/inmunología , Proteína 3 Supresora de la Señalización de Citocinas/metabolismo , Animales , Modelos Animales de Enfermedad , Endotoxemia/diagnóstico , Endotoxemia/mortalidad , Endotoxemia/patología , Heterocigoto , Células Endoteliales de la Vena Umbilical Humana , Humanos , Interleucina-6/metabolismo , Lipopolisacáridos/administración & dosificación , Lipopolisacáridos/inmunología , Ratones , Ratones Noqueados , Proteolisis , Índice de Severidad de la Enfermedad , Proteína 3 Supresora de la Señalización de Citocinas/análisis , Proteína 3 Supresora de la Señalización de Citocinas/genética , UbiquitinaciónRESUMEN
INTRODUCTION: Patients with community-acquired pneumonia display enhanced levels of lipopolysaccharides (LPS) compared with controls, suggesting that low-grade endotoxemia may be implicated in vascular disturbances. It is unknown whether this occurs in patients with coronavirus 2019 (COVID-19) and its impact on thrombotic complications. METHODS: We measured serum levels of zonulin, a marker of gut permeability, LPS, and D-dimer in 81 patients with COVID-19 and 81 healthy subjects; the occurrence of thrombotic events in COVID-19 during the intrahospital stay was registered. RESULTS: Serum LPS and zonulin were higher in patients with COVID-19 than in control subjects and, in COVID-19, significantly correlated (R = 0.513; P < 0.001). Among the 81 patients with COVID-19, 11 (14%) experienced thrombotic events in the arterial (n = 5) and venous circulation (n = 6) during a median follow-up of 18 days (interquartile range 11-27 days). A logistic regression analysis showed that LPS (P = 0.024) and D-dimer (P = 0.041) independently predicted thrombotic events. DISCUSSION: The study reports that low-grade endotoxemia is detectable in patients with COVID-19 and is associated with thrombotic events. The coexistence of low-grade endotoxemia with enhanced levels of zonulin may suggest enhanced gut permeability as an underlying mechanism.
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COVID-19 , Endotoxemia , Haptoglobinas/metabolismo , Mucosa Intestinal , Precursores de Proteínas/metabolismo , SARS-CoV-2 , Trombosis , Biomarcadores/sangre , COVID-19/sangre , COVID-19/complicaciones , COVID-19/fisiopatología , Correlación de Datos , Endotoxemia/diagnóstico , Endotoxemia/metabolismo , Endotoxemia/virología , Femenino , Productos de Degradación de Fibrina-Fibrinógeno/análisis , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/virología , Lipopolisacáridos/análisis , Masculino , Persona de Mediana Edad , Permeabilidad , Neumonía Viral/diagnóstico , Neumonía Viral/etiología , SARS-CoV-2/patogenicidad , SARS-CoV-2/fisiología , Trombosis/sangre , Trombosis/diagnóstico , Trombosis/etiologíaRESUMEN
Severe acute respiratory syndrome coronavirus 2 infection has been associated with both endotoxemia and thrombosis of small and large vessels, but the relationship between these 2 phenomena has not been pursued. Oliva et al. in this issue of Clinical and Translational Gastroenterology demonstrate an association between the 2 findings and suggest that increased intestinal permeability is a possible mechanism to explain the endotoxemia. Although the evidence to support this hypothesis is only suggestive, the role of the small intestine in the illness produced by the virus needs to be further explored.
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COVID-19 , Endotoxemia , Intestino Delgado , SARS-CoV-2 , Trombosis , COVID-19/sangre , COVID-19/complicaciones , COVID-19/fisiopatología , Correlación de Datos , Endotoxemia/diagnóstico , Endotoxemia/metabolismo , Endotoxemia/virología , Humanos , Intestino Delgado/metabolismo , Intestino Delgado/virología , Permeabilidad , SARS-CoV-2/patogenicidad , SARS-CoV-2/fisiología , Trombosis/sangre , Trombosis/diagnóstico , Trombosis/etiologíaRESUMEN
In veterinary medicine, inflammation in swine is evaluated principally by clinical signs. This method is often unreliable when assessing large animal populations because of inconsistent interpretations of clinical observations. This study examined whether changes in miRNA expression can predict the severity of the inflammatory response in swine after administration of Escherichia coli lipopolysaccharide (LPS). Whole blood from swine challenged with LPS at 0.125 µg/kg to 2.0 µg/kg body weight was collected at 0, 1, 3, and 8 h post LPS-challenge. Mature miRNAs were extracted from plasma and quantitative real-time-PCR (qRT-PCR) was used to evaluate the 84 most abundant swine miRNAs found in plasma. The miRNA changes in expression were assessed using the comparative CT Method (ΔΔCT method) for normalization with an exogenous control. The results revealed that expression of ssc-let-7e-5p, ssc-mir-22-3p, and ssc-miR-146a-5p were the most significantly changed miRNA over the time course. At 1 h post-LPS, ssc-let-7e-5p decreased as the LPS dosage levels increased from 0.125 to 1.0 µg/kg. Similarly, as the LPS doses increased from 0.125 to 0.5 µg/kg, ssc-miR-22-3p levels significantly decreased at 1 h post-LPS. In the 2.0 µg/kg LPS, ssc-miR-146a-5p levels increased between 0 and 3 h post-LPS; however, expression was downregulated with a 145 % decrease from 3 to 8 h. The three miRNA biomarkers suggest potentially useful surrogate endpoints for the evaluation of inflammatory and endotoxemia responses in swine.
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Inflamación/veterinaria , Lipopolisacáridos/farmacología , MicroARNs/sangre , Enfermedades de los Porcinos/genética , Transcriptoma/efectos de los fármacos , Animales , Biomarcadores/sangre , Endotoxemia/sangre , Endotoxemia/diagnóstico , Endotoxemia/veterinaria , Inflamación/sangre , Inflamación/diagnóstico , Inflamación/genética , Reacción en Cadena en Tiempo Real de la Polimerasa/veterinaria , Porcinos , Enfermedades de los Porcinos/sangreRESUMEN
BACKGROUND: Dysregulation of coagulation occurs commonly in sepsis, ranging from mild coagulopathy with decreased platelets to disseminated intravascular coagulation (DIC). We investigated the effect of induced normothermia on coagulation during lipopolysaccharide (LPS)-induced endotoxaemia in healthy volunteers. METHODS: Twelve volunteers received an infusion of bacterial lipopolysaccharide (Escherichia coli; 2 ng kg-1) and were assigned to either induced normothermia or control. Induced normothermia to maintain core temperature at 37°C consisted of external surface cooling, cold i.v. fluids, and medication to reduce shivering (buspirone, clonidine, and magnesium sulphate). The primary outcome was the DIC score (International Society on Thrombosis and Haemostasis guideline). Prothrombin time (PT), activated partial thromboplastin time (aPTT), D-dimer, plasma von Willebrand factor (vWf), and rotational thromboelastometry (ROTEM) were measured before and 1, 3, 6, and 8 h after LPS infusion. Differences between groups were tested with a mixed effects model. RESULTS: In control subjects, lipopolysaccharide caused a fever, transiently decreased platelet levels and lowered activated partial thromboplastin time, while prolonging prothrombin time and increasing D-Dimer and vWf levels. Normothermia prevented the DIC-score exceeding 4, which occurred in 50% of control subjects. Normothermia also reduced the fall in platelet count by 67x109 L-1([95%CI:27-107]; p=0.002), aPTT (mean difference:3s [95%CI:1-5]; p=0.005) and lowered vWf levels by 89% ([95%CI:6-172]; p=0.03), compared to the fever group. ROTEM measurements were unaffected by lipopolysaccharide. CONCLUSION: In human endotoxaemia, induced normothermia decreases markers of endothelial activation and DIC. Maintaining normothermia may reduce coagulopathy in hyperinflammatory states.
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Coagulación Sanguínea , Coagulación Intravascular Diseminada/prevención & control , Endotoxemia/terapia , Hipotermia Inducida , Adolescente , Adulto , Biomarcadores/sangre , Pruebas de Coagulación Sanguínea , Estudios de Casos y Controles , Coagulación Intravascular Diseminada/sangre , Coagulación Intravascular Diseminada/diagnóstico , Coagulación Intravascular Diseminada/etiología , Endotoxemia/sangre , Endotoxemia/inducido químicamente , Endotoxemia/diagnóstico , Endotoxinas/administración & dosificación , Voluntarios Sanos , Humanos , Hipotermia Inducida/efectos adversos , Infusiones Parenterales , Masculino , Factores de Tiempo , Adulto JovenRESUMEN
BACKGROUND: Paraoxonase-1 (PON-1) is an antioxidant enzyme, whose activity decreases during the acute phase response in many species. Little is known about PON-1 and its role as a negative acute phase protein during septic inflammation in horses, but promising findings about its utility in diagnosing SIRS and predicting the outcome in diseased horses, were recently highlighted. The objective of the study was to investigate the behaviour of PON-1 in horses after experimentally induced endotoxemia. To this aim, PON-1 activity was measured on 66 plasma samples collected from six clinically healthy mares, previously included in another study, before and at multiple time points between 12 and 240 h after intravenous infusion of Escherichia coli O55:B5 lipopolysaccharide (LPS). RESULTS: Compared with baseline values, a progressive transient decrease of PON-1 activity was observed starting from 24 h post-infusion, with lowest values observed between 3 to 7 days post-infusion, followed by a normalisation to pre-infusion levels the tenth day. CONCLUSIONS: The results of this study suggest that measurement and monitoring of PON-1 activity might be useful to evaluate progression and recovery from endotoxemia in horses. Further studies in horses with naturally occurring sepsis are warranted.
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Arildialquilfosfatasa/sangre , Endotoxemia/inducido químicamente , Enfermedades de los Caballos/diagnóstico , Animales , Endotoxemia/sangre , Endotoxemia/diagnóstico , Endotoxemia/enzimología , Escherichia coli , Femenino , Enfermedades de los Caballos/sangre , Enfermedades de los Caballos/enzimología , Caballos , Lipopolisacáridos/administración & dosificaciónRESUMEN
Intracellular adenosine monophosphate (AMP) is indispensable for cellular metabolic processes, and it is interconverted to ADP and/or ATP or activates AMP-activated protein kinase (AMPK). However, the specific biological function of extracellular AMP has not been identified. We evaluated the effect of extracellular AMP using in vivo and in vitro models of endotoxemia. We found that AMP inhibited inflammation and neutrophil activation in lipopolysaccharide (LPS)-induced endotoxemic mice. The effects of extracellular AMP were abolished by an adenosine 1 receptor (A1R) antagonist but were not influenced by inhibiting the conversion of AMP to adenosine (ADO), indicating that AMP inhibited inflammation by directly activating A1R. In addition, in vitro experiments using LPS-stimulated mouse neutrophils showed that AMP inhibited LPS-induced reactive oxygen species (ROS) production, degranulation, and cytokine production, while the effects were reversed by an A1R antagonist. Further research showed that AMP regulated LPS-stimulated neutrophil functions by inhibiting the p38 MAPK pathway. These findings were also confirmed in primary neutrophils derived from healthy human blood. Moreover, we collected serum samples from septic patients. We found that AMP levels were increased compared with those of healthy volunteers and that AMP levels were negatively correlated with disease severity. Together, these data provide evidence that extracellular AMP acts on A1R to suppress endotoxemia-induced inflammation by inhibiting neutrophil overactivation and that the p38 MAPK signaling pathway is involved.
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Endotoxemia/etiología , Endotoxemia/metabolismo , Activación Neutrófila/inmunología , Neutrófilos/inmunología , Neutrófilos/metabolismo , Adenosina Monofosfato/metabolismo , Animales , Apoptosis , Adhesión Celular/inmunología , Modelos Animales de Enfermedad , Endotoxemia/diagnóstico , Espacio Extracelular/metabolismo , Humanos , Inmunofenotipificación , Lipopolisacáridos/efectos adversos , Masculino , Ratones , Infiltración Neutrófila/inmunología , Fagocitosis , Proteómica/métodos , Especies Reactivas de Oxígeno/metabolismo , Receptores Purinérgicos P1/metabolismo , Índice de Severidad de la Enfermedad , Transducción de Señal/efectos de los fármacos , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
BACKGROUND: Under normal physiological conditions, endotoxin (ET) released during self-renewal of the colibacillus pool is an obligate stimulus for the formation of the immune system and homeostasis of the body. Violation of the barrier function of the intestinal wall and the mechanisms of neutralization of endotoxin lead to systemic endotoxemia of intestinal origin. Its development is facilitated by stress, intoxication, a decrease in nonspecific resistance of the body, as well as damage to the intestinal mucosa and dysbiosis, where the mucous membrane is more vulnerable and permeable to endotoxin. PURPOSE OF THE RESEARCH: The aim of this study is to compare and assess the severity and nature of hepatocyte damage from endotoxin exposure and the degree of manifestation of stress due to oxidation, to determine the characteristics of structural changes in hepatocytes and to assess the oxidation stress during endotoxin intoxication in the experiment with biochemical markers. MATERIALS AND METHODS: The experiments were conducted on 40 non-linear rats, divided into two groups of 20 animals. Group 1 animals received intraperitoneal injections of ET of Escherichia coli drug (Sigma USA K-235) for seven days at a rate of 0.1 mg/kg of the body weight. Animals of the second group served as the control group. Character and stage of liver damage were studied using morphological methods, including electron and light microscopy. In studying oxidizing stress, biochemical methods were used to define the changes, such as conjugated dienes and dienketones, spontaneous oxidizing modification of proteins. RESULTS AND CONCLUSION: 1. The severity and depth of morphological changes in the liver during endotoxin intoxication were correlated with the dynamics of the content of lipid oxidation products (CD and DK, MDA) and proteins. There was a tendency for a more significant increase in the oxidative modification of proteins in serum. This confirms the data on the primary damage of proteins by free radicals. 2. When exposed to intestinal microflora endotoxin, pronounced dyscirculatory changes, fatty and hydropic degeneration of hepatocytes with signs of toxic damage to their nuclei were determined, but at the same time, the increased hyperplastic activity of sinusoidal cells remained associated with the effects of endotoxin. These changes are associated with both the direct toxic effect of endotoxin, and the effects of oxidative stress, in which endotoxin is a potent inducer.
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Endotoxemia/diagnóstico , Hepatopatías/diagnóstico , Hígado/patología , Animales , Modelos Animales de Enfermedad , Endotoxemia/complicaciones , Endotoxemia/fisiopatología , Endotoxinas/toxicidad , Mucosa Intestinal , Hígado/metabolismo , Hepatopatías/etiología , Hepatopatías/fisiopatología , Pruebas de Función Hepática , Ratas , Ratas WistarRESUMEN
The objective of this study was to examine whether serum iron (Fe) concentration is useful as a prognostic biomarker for cows with acute coliform mastitis (ACM). Our study was composed of determining the reproducibility of serum Fe concentration as a prognostic criterion in cows with ACM (Study 1) and clarifying the sequential changes in serum Fe concentration in cattle that received endotoxin (Study 2). Seventy-seven cows with (n = 47) or without (n = 30) ACM were enrolled in Study 1. The proposed diagnostic cut-off value of serum Fe concentration indicating a poor prognosis of ACM based on the analysis of the receiver operating characteristic curves was < 31.5 µg/dL. Ten young cattle aged 176.8 ± 23.7 days were enrolled in Study 2. Five young cattle received endotoxin (LPS group) and the remaining five received physiological saline (control group). Blood collections were carried out before endotoxin challenge (pre), and 0.5, 1, 2, 4, 8, 12, 24, and 48 h after the challenge. As a result, a significant decrease in serum Fe concentration was not observed until 24 h after endotoxin challenge. Because in cows with clinical ACM it is difficult to know the time course after infection, the alteration in serum Fe concentrations alone may be an insufficient prognostic criterion.
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Endotoxemia/veterinaria , Infecciones por Escherichia coli/veterinaria , Hierro/sangre , Infecciones por Klebsiella/veterinaria , Mastitis Bovina/diagnóstico , Enfermedad Aguda , Animales , Biomarcadores/sangre , Bovinos , Endotoxemia/diagnóstico , Endotoxemia/microbiología , Endotoxinas/administración & dosificación , Escherichia coli/fisiología , Infecciones por Escherichia coli/complicaciones , Infecciones por Escherichia coli/diagnóstico , Infecciones por Escherichia coli/microbiología , Femenino , Infecciones por Klebsiella/complicaciones , Infecciones por Klebsiella/diagnóstico , Infecciones por Klebsiella/microbiología , Klebsiella pneumoniae/fisiología , Mastitis Bovina/microbiología , Pronóstico , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND: Constipation is a common functional gastrointestinal disorder and its etiology is multifactorial. Growing evidence suggests that intestinal dysbiosis is associated with the development of constipation. Prebiotics are subjected to bacterial fermentation in the gut to produce short-chain fatty acids (SCFAs), which can help relieve constipation symptoms. The prebiotic UG1601 consists of inulin, lactitol, and aloe vera gel, which are known laxatives, but randomized, controlled clinical trials that examine the effects of this supplement on gut microbiota composition are lacking. AIM: To assess the efficacy of the prebiotic UG1601 in suppressing constipation-related adverse events in subjects with mild constipation. METHODS: Adults with a stool frequency of less than thrice a week were randomized to receive either prebiotics or a placebo supplement for 4 wk. All participants provided their fecal and blood samples at baseline and at the end of intervention. Gastrointestinal symptoms and stool frequency were evaluated. The concentrations of serum endotoxemia markers and fecal SCFAs were determined. The relative abundance of SCFA-producing bacteria and the gut microbial community in the responders and non-responders in the prebiotics supplementation group were evaluated. RESULTS: There were no significant differences in gastrointestinal symptoms between groups, although the prebiotic group showed greater symptom improvement. However, after prebiotic usage, serum cluster of differentiation (CD) 14 and lipopolysaccharide (LPS) concentrations were significantly decreased (CD14, P = 0.012; LPS, P < 0.001). The change in LPS concentration was significantly larger in the prebiotic group than in the placebo group (P < 0.001). Fecal SCFAs concentrations did not differ between groups, while the relative abundance of Roseburia hominis, a major butyrate producer, was significantly increased in the prebiotic group (P = 0.045). The abundances of the phylum Firmicutes and the family Lachnospiraceae (phylum Firmicutes, class Clostridia) (P = 0.009) were decreased in the responders within the prebiotic group. In addition, the proportions of the phylum Firmicutes, the class Clostridia, and the order Clostridiales were inversely correlated with several fecal SCFAs (P < 0.05). CONCLUSION: Alterations in gut microbiota composition, including a decrease in the phylum Firmicutes and an increase in butyrate-producing bacteria, following prebiotic UG1601 supplementation might help alleviate symptom scores and endotoxemia.
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Estreñimiento/dietoterapia , Disbiosis/dietoterapia , Endotoxemia/dietoterapia , Microbioma Gastrointestinal/efectos de los fármacos , Prebióticos/administración & dosificación , Adulto , Clostridiales/efectos de los fármacos , Clostridiales/aislamiento & purificación , Estreñimiento/complicaciones , Estreñimiento/diagnóstico , Método Doble Ciego , Disbiosis/diagnóstico , Disbiosis/microbiología , Endotoxemia/diagnóstico , Endotoxemia/microbiología , Ácidos Grasos Volátiles/análisis , Heces/química , Heces/microbiología , Femenino , Humanos , Inulina/administración & dosificación , Masculino , Persona de Mediana Edad , Placebos/administración & dosificación , Preparaciones de Plantas/administración & dosificación , Índice de Severidad de la Enfermedad , Alcoholes del Azúcar/administración & dosificación , Resultado del Tratamiento , Adulto JovenRESUMEN
Sepsis is defined as life-threatening organ dysfunction caused by the dysregulated host response to infection. Despite serious mortality and morbidity, no sepsis-specific drugs exist. Endotoxemia is often used to model the hyperinflammation associated with early sepsis. This model classically uses lipopolysaccharide (LPS) from Gram-negative pathogens to activate the immune system, leading to hyperinflammation, microcirculatory disturbances and death. Other toxins may also be used to activate the immune system including Gram-positive peptidoglycan (PG) and lipoteichoic acid (LTA). In addition to these standard toxins, other bacterial components can induce inflammation. These molecules activate different signaling pathways and produce different physiological responses which can be taken advantage of for sepsis modeling. Endotoxemia modeling can provide information on pathways to inflammation in sepsis and contribute to preclinical drug development.
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Inflamación/etiología , Inflamación/metabolismo , Sepsis/etiología , Toxinas Biológicas/efectos adversos , Animales , Endotoxemia/diagnóstico , Endotoxemia/etiología , Endotoxemia/metabolismo , Interacciones Huésped-Patógeno/inmunología , Humanos , Inflamación/diagnóstico , Lipopolisacáridos/efectos adversos , Lipopolisacáridos/inmunología , Sepsis/diagnóstico , Sepsis/metabolismo , Transducción de SeñalRESUMEN
Lipopolysaccharide, also known as endotoxin, is a fundamental component of gram-negative bacteria and plays a crucial role in the development of sepsis and septic shock. The early identification of an infectious process that is rapidly evolving to a critical illness might prompt a quicker and more intensive treatment, thereby potentially leading to better patient outcomes. The Endotoxin Activity (EA) assay can be used at the bedside as a reliable biomarker of systemic endotoxemia. The detection of elevated endotoxin activity levels has been repeatedly shown to be associated with an increased disease severity in patients with sepsis and septic shock. The assay is quick and easy to perform. Briefly, after sampling, an aliquot of whole blood is mixed with an anti-endotoxin antibody and with added LPS. Endotoxin activity is measured as the relative oxidative burst of primed neutrophils as detected by chemioluminescence. The assay's output is expressed on a scale from 0 (absent) to 1 (maximal) and categorized as "low" (<0.4 units), "intermediate" (0.4-0.59 units), or "high" (≥0.6 units). The detailed methodology and rationale for the implementation of the EA assay are reported in this manuscript.
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Bioensayo/métodos , Enfermedad Crítica , Endotoxemia/sangre , Endotoxemia/diagnóstico , Endotoxinas/metabolismo , Anciano , Biomarcadores/sangre , Femenino , Humanos , Lipopolisacáridos , Masculino , Choque Séptico/sangreAsunto(s)
Endotoxemia/etiología , Endotoxemia/metabolismo , Hepcidinas/biosíntesis , Hipoxia/metabolismo , Biomarcadores , Susceptibilidad a Enfermedades , Endotoxemia/diagnóstico , Endotoxemia/terapia , Hepcidinas/sangre , Homeostasis , Humanos , Inflamación/metabolismo , Hierro/sangre , Hierro/metabolismo , Unión ProteicaRESUMEN
BACKGROUND & AIMS: The quantification of lipopolysaccharide (LPS) in biological fluids is challenging. We aimed to measure plasma LPS concentration using a new method of direct quantification of 3-hydroxymyristate (3-HM), a lipid component of LPS, and to evaluate correlations between 3-HM and markers of liver function, endothelial activation, portal hypertension and enterocyte damage. METHODS: Plasma from 90 noninfected cirrhotic patients (30 Child-Pugh [CP]-A, 30 CP-B, 30 CP-C) was prospectively collected. The concentration of 3-HM was determined by high-performance liquid chromatography coupled with mass spectrometry. RESULTS: 3-HM levels were higher in CP-C patients (CP-A/CP-B/CP-C: 68/70/103 ng/mL, P = 0.005). Patients with severe acute alcoholic hepatitis (n = 16; 113 vs 74 ng/mL, P = 0.012), diabetic patients (n = 22; 99 vs 70 ng/mL, P = 0.028) and those not receiving beta blockers (n = 44; 98 vs 72 ng/mL, P = 0.034) had higher levels of 3-HM. We observed a trend towards higher baseline levels of 3-HM in patients with hepatic encephalopathy (n = 7; 144 vs 76 ng/mL, P = 0.45) or SIRS (n = 10; 106 vs 75 ng/mL, P = 0.114). In multivariate analysis, high levels of 3-HM were associated with CP (OR = 4.39; 95%CI = 1.79-10.76) or MELD (OR = 8.24; 95%CI = 3.19-21.32) scores. Patients dying from liver insufficiency (n = 6) during a 12-month follow-up had higher baseline levels of 3-HM (106 vs 75 ng/mL, P = 0.089). CONCLUSIONS: In noninfected cirrhotic patients, 3-HM arises more frequently with impairment of liver function, heavy alcohol consumption, diabetic status, nonuse of beta blockers and a trend towards poorer outcome is also observed. The direct mass measurement of LPS using 3-HM appears reliable to detect transient endotoxaemia and promising to manage the follow-up of cirrhotic patients.