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1.
Nutrients ; 11(8)2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31412673

RESUMO

(1) Background: Nutrition is a major lifestyle factor that can prevent the risk of cognitive impairment and dementia. Diet-induced metabolic endotoxemia has been proposed as a major root cause of inflammation and these pathways emerge as detrimental factors of healthy ageing. The aim of this paper was to update research focusing on the relationship between a fat-rich diet and endotoxemia, and to discuss the potential role of endotoxemia in cognitive performances. (2) Methods: We conducted a non-systematic literature review based on the PubMed database related to fat-rich meals, metabolic endotoxemia and cognitive disorders including dementia in humans. A total of 40 articles out of 942 in the first screening met the inclusion criteria. (3) Results: Evidence suggested that a fat-rich diet, depending on its quality, quantity and concomitant healthy food components, could influence metabolic endotoxemia. Since only heterogeneous cross-sectional studies are available, it remains unclear to what extent endotoxemia could be associated or not with cognitive disorders and dementia. (4) Conclusions: A fat-rich diet has the capability to provide significant increases in circulating endotoxins, which highlights nutritional strategies as a promising area for future research on inflammatory-associated diseases. The role of endotoxemia in cognitive disorders and dementia remains unclear and deserves further investigation.


Assuntos
Bactérias/metabolismo , Envelhecimento Cognitivo/psicologia , Disfunção Cognitiva/etiologia , Gorduras na Dieta/efeitos adversos , Endotoxemia/etiologia , Microbioma Gastrointestinal , Adulto , Fatores Etários , Idoso , Cognição , Disfunção Cognitiva/sangue , Disfunção Cognitiva/microbiologia , Disfunção Cognitiva/psicologia , Endotoxemia/sangue , Endotoxemia/microbiologia , Endotoxemia/psicologia , Feminino , Interações Hospedeiro-Patógeno , Humanos , Masculino , Pessoa de Meia-Idade , Valor Nutritivo , Prognóstico , Medição de Risco , Fatores de Risco , Adulto Jovem
2.
Medicine (Baltimore) ; 98(28): e16452, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31305476

RESUMO

Endotoxemia often occurs in patients with gram-positive infections. The possible mechanism is thought to be bacterial translocation after enterocyte hypoperfusion injury. However, the association between endotoxemia and enterocyte injury among patients with gram-positive septic shock has never been assessed. The aim of this study was to evaluate the association between endotoxemia and enterocyte injury in gram-positive septic shock patients and to evaluate the association among endotoxemia, subsequent clinical course, and other related factors.This was a posthoc analysis of a prospective observational study that evaluated the capability of intestinal fatty acid-binding protein (I-FABP), an indicator of enterocyte injury, to predict mortality. Among 57 patients in septic shock, those whose causative microorganisms were gram positive were included. The correlation between endotoxin activity (EA), which indicates endotoxemia, and I-FABP levels upon admission to the intensive care unit (ICU), the clinical course, and other related factors were evaluated.A total of 21 patients were examined. One-third of the patients presented with high EA levels at the time of ICU admission. However, there was no significant correlation between EA and I-FABP levels (Spearman ρ = 0.002, P = .993). Additionally, high EA levels were not associated with abdominal complications after ICU admission or mortality. Similarly, high EA levels were not associated with severity scores, inotropic scores, or lactate levels upon ICU admission, which were previously reported to be factors related to high EA levels.In this posthoc analysis, no correlation was observed between endotoxemia and enterocyte injury among patients in gram-positive septic shock. Additionally, high EA levels were not associated with the clinical course and reported factors related to endotoxemia. Although our results need to be validated in a large prospective cohort study, hypoperfusion enterocyte injury might not be a cause of endotoxemia in these patients. Thus, if there is no correlation between EA and I-FABP levels, other mechanisms that induce high EA levels among patients with gram-positive septic shock should be elucidated.


Assuntos
Endotoxemia/sangue , Proteínas de Ligação a Ácido Graxo/sangue , Infecções por Bactérias Gram-Positivas/sangue , Infecções por Bactérias Gram-Positivas/mortalidade , Choque Séptico/sangue , Choque Séptico/mortalidade , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Cuidados Críticos , Progressão da Doença , Endotoxemia/mortalidade , Endotoxemia/terapia , Enterócitos/metabolismo , Feminino , Infecções por Bactérias Gram-Positivas/terapia , Humanos , Masculino , Prognóstico , Estudos Prospectivos , Choque Séptico/terapia
3.
Transfus Apher Sci ; 58(4): 508-511, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31253560

RESUMO

BACKGROUND: In the critically ill, extracellular vesicles (EV) from red blood cells (RBC) have been related to adverse effects of blood transfusion. Stored RBC units contain high concentrations of RBC- EVs, thereby increasing the concentration of EVs in the circulation after transfusion. The mechanisms underlying the clearance of donor RBC-EVs after transfusion are unknown. This study investigates whether membrane markers that are associated with clearance of RBCs are also implicated in clearance of RBC-EVs in human endotoxemic recipients of a transfusion. METHODS: Six volunteers were injected with Escherichia coli lipopolysaccharide, and after two hours transfused with an autologous RBC unit donated 35 days earlier. Samples were collected from the RBC unit and the volunteers before and after transfusion. RBC-EVs were labeled with (anti) glycophorin A, combined with (anti) CD44, CD47, CD55, CD59, CD147, or lactadherin to detect phosphatidylserine (PS) and analyzed on a A50 Micro flow cytometer. RESULTS: In the RBC unit, RBC-EVs solely exposed PS (7.8%). Before transfusion, circulating RBC-EVs mainly exposed PS (22%) and CD59 (9.1%), the expression of the other membrane markers was much lower. After transfusion, the concentration of RBC- EVs increased 2.4-fold in two hours. Thereafter, the EV concentration decreased towards baseline levels. The fraction of EVs positive for all tested membrane markers decreased after transfusion. CONCLUSION: Besides a minor fraction of PS-exposing EVs, RBC-EVs produced during storage do not expose detectable levels of RBC membrane markers that are associated with clearance, which is in contrast to the EVs produced by the circulating RBCs.


Assuntos
Endotoxemia , Transfusão de Eritrócitos , Escherichia coli/química , Vesículas Extracelulares/metabolismo , Lipopolissacarídeos/toxicidade , Modelos Biológicos , Adolescente , Adulto , Endotoxemia/sangue , Endotoxemia/induzido quimicamente , Endotoxemia/terapia , Humanos , Lipopolissacarídeos/química , Masculino
4.
Br J Anaesth ; 123(2): 177-185, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31084985

RESUMO

BACKGROUND: Remote ischaemic preconditioning (RIPC) consists of repeated cycles of limb ischaemia and reperfusion, which may reduce perioperative myocardial ischaemic damage and kidney injury. We hypothesised that RIPC may be beneficial by attenuating the systemic inflammatory response. We investigated whether RIPC affects the response in humans to bacterial endotoxin (lipopolysaccharide [LPS]) by measuring plasma cytokines and renal cell-cycle arrest mediators, which reflect renal tubular stress. METHODS: Healthy male volunteers were randomised to receive either daily RIPC for 6 consecutive days (RIPCmultiple, n=10) plus RIPC during the 40 min preceding i.v. LPS (2 ng kg-1), RIPC only during the 40 min before LPS (RIPCsingle, n=10), or no RIPC preceding LPS (control, n=10). As a surrogate marker of renal tubular stress, the product of urinary concentrations of two cell-cycle arrest markers was calculated (tissue inhibitor of metalloproteinases-2 [TIMP2]*insulin-like growth factor binding protein-7 [IGFBP7]). Data are presented as median (inter-quartile range). RESULTS: In both RIPC groups, RIPC alone increased [TIMP2]*[IGFBP7]. LPS administration resulted in fever, flu-like symptoms, and haemodynamic alterations. Plasma cytokine concentrations increased profoundly during endotoxaemia (control group: tumor necrosis factor alpha [TNF-α] from 14 [9-16] pg ml-1 at baseline to 480 [284-709] pg ml-1 at 1.5 h after LPS; interleukin-6 [IL-6] from 4 [4-4] pg ml-1 at baseline to 659 [505-1018] pg ml-1 at 2 h after LPS). LPS administration also increased urinary [TIMP2[*[IGFBP7]. RIPC had no effect on LPS-induced cytokine release or [TIMP2]*[IGFBP7]. CONCLUSIONS: RIPC neither modulated systemic cytokine release nor attenuated inflammation-induced tubular stress after LPS. However, RIPC alone induced renal markers of cell-cycle arrest. CLINICAL TRIAL REGISTRATION: NCT02602977.


Assuntos
Endotoxemia/sangue , Endotoxemia/urina , Precondicionamento Isquêmico/métodos , Túbulos Renais/fisiopatologia , Síndrome de Resposta Inflamatória Sistêmica/sangue , Síndrome de Resposta Inflamatória Sistêmica/urina , Adolescente , Adulto , Biomarcadores/sangue , Biomarcadores/urina , Endotoxemia/complicações , Humanos , Masculino , Países Baixos , Estresse Fisiológico/fisiologia , Síndrome de Resposta Inflamatória Sistêmica/etiologia , Síndrome de Resposta Inflamatória Sistêmica/prevenção & controle , Adulto Jovem
5.
Int J Mol Sci ; 20(6)2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30897706

RESUMO

Although dexamethasone (DEX) is a widely used immunoregulatory agent, knowledge about its pharmacological properties in farm animals, especially pigs, is insufficient. Previous studies suggest that compared to other species, pigs are less sensitive to the immunosuppression conferred by DEX and more sensitive to the threat of bacterial endotoxins. However, there is a paucity of studies examining DEX immunomodulation in endotoxemia in this species. In this study, a porcine endotoxemia model was established by lipopolysaccharide (LPS) and the effect of DEX-pretreatment on the magnitude and kinetics of neuroendocrine, metabolic, hematologic, inflammatory, and behavioural responses were examined. DEX decreased cortisol, adrenocorticotropic hormone (ACTH), red blood cell, hemoglobin, hematocrit, and lymphocyte whereas glucose concentration was increased under both normal and endotoxemic conditions. By contrast, DEX decreased triglyceride, lactate, and IL-6 concentrations and increased platelet count only under an endotoxemic condition. DEX also reduced the frequency of sickness behaviour following LPS challenge. PCA showed that glucose and triglyceride metabolism together with red blood cell count mainly contributed to the separation of clusters during DEX treatment. Our study demonstrates that DEX protects pigs from inflammation and morbidity in endotoxemia, in spite of their less sensitivity to DEX. Moreover, its considerable role in the regulation of the metabolic and hematologic responses in endotoxemic pigs is revealed for the first time.


Assuntos
Dexametasona/uso terapêutico , Endotoxemia/tratamento farmacológico , Hormônio Adrenocorticotrópico/sangue , Animais , Citocinas/sangue , Endotoxemia/sangue , Feminino , Glucose/metabolismo , Hidrocortisona/sangue , Inflamação/sangue , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Lipopolissacarídeos/sangue , Masculino , Suínos , Triglicerídeos/sangue
6.
Thromb Res ; 176: 39-45, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30776686

RESUMO

INTRODUCTION: Fluid resuscitation is a cornerstone of severe sepsis management, however there are many uncertainties surrounding the type and volume of fluid that is administered. The entire spectrum of coagulopathies can be seen in sepsis, from asymptomatic aberrations to fulminant disseminated intravascular coagulation (DIC). The aim of this study was to determine if fluid resuscitation with saline contributes to the haemostatic derangements in an ovine model of endotoxemic shock. MATERIALS AND METHODS: Twenty-one adult female sheep were randomly divided into no endotoxemia (n = 5) or endotoxemia groups (n = 16) with an escalating dose of lipopolysaccharide (LPS) up to 4 µg/kg/h administered to achieve a mean arterial pressure below 60 mmHg. Endotoxemia sheep received either no bolus fluid resuscitation (n = 8) or a 0.9% saline bolus (40 mL/kg over 60 min) (n = 8). No endotoxemia, saline only animals (n = 5) underwent fluid resuscitation with a 0.9% bolus of saline as detailed above. Hemodynamic support with vasopressors was initiated if needed, to maintain a mean arterial pressure (MAP) of 60-65 mm Hg in all the groups. RESULTS: Rotational thromboelastometry (ROTEM®) and conventional coagulation biomarker tests demonstrated sepsis induced derangements to secondary haemostasis. This effect was exacerbated by saline fluid resuscitation, with low pH (p = 0.036), delayed clot initiation and formation together with deficiencies in naturally occurring anti-coagulants antithrombin (p = 0.027) and Protein C (p = 0.001). CONCLUSIONS: Endotoxemia impairs secondary haemostasis and induces changes in the intrinsic, extrinsic and anti-coagulant pathways. These changes to haemostasis are exacerbated following resuscitation with 0.9% saline, a commonly used crystalloid in clinical settings.


Assuntos
Endotoxemia/terapia , Hemostasia , Solução Salina/uso terapêutico , Animais , Pressão Sanguínea/efeitos dos fármacos , Modelos Animais de Doenças , Endotoxemia/sangue , Endotoxemia/fisiopatologia , Feminino , Hidratação , Hemostasia/efeitos dos fármacos , Ressuscitação , Ovinos
7.
PLoS One ; 14(2): e0211981, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30789941

RESUMO

Endotoxin, a component of the outer membrane of Gram-negative bacteria, has been extensively studied as a stimulator of the innate immune response. However, the temporal aspects and exposure-response relationship of endotoxin and resulting cytokine induction and tolerance development is less well defined. The aim of this work was to establish an in silico model that simultaneously captures and connects the in vivo time-courses of endotoxin, tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and associated tolerance development. Data from six studies of porcine endotoxemia in anesthetized piglets (n = 116) were combined and used in the analysis, with purified endotoxin (Escherichia coli O111:B4) being infused intravenously for 1-30 h in rates of 0.063-16.0 µg/kg/h across studies. All data were modelled simultaneously by means of importance sampling in the non-linear mixed effects modelling software NONMEM. The infused endotoxin followed one-compartment disposition and non-linear elimination, and stimulated the production of TNF-α to describe the rapid increase in plasma concentration. Tolerance development, observed as declining TNF-α concentration with continued infusion of endotoxin, was also driven by endotoxin as a concentration-dependent increase in the potency parameter related to TNF-α production (EC50). Production of IL-6 was stimulated by both endotoxin and TNF-α, and four consecutive transit compartments described delayed increase in plasma IL-6. A model which simultaneously account for the time-courses of endotoxin and two immune response markers, the cytokines TNF-α and IL-6, as well as the development of endotoxin tolerance, was successfully established. This model-based approach is unique in its description of the time-courses and their interrelation and may be applied within research on immune response to bacterial endotoxin, or in pre-clinical pharmaceutical research when dealing with study design or translational aspects.


Assuntos
Endotoxemia/imunologia , Endotoxinas/administração & dosagem , Escherichia coli/metabolismo , Interleucina-6/sangue , Fator de Necrose Tumoral alfa/sangue , Animais , Simulação por Computador , Modelos Animais de Doenças , Endotoxemia/sangue , Endotoxinas/imunologia , Imunidade Inata , Infusões Intravenosas , Dinâmica não Linear , Análise Espaço-Temporal , Suínos
8.
Transplantation ; 103(1): 191-201, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30130326

RESUMO

BACKGROUND: The concepts that obesity is merely a consequence of overeating, and that metabolic health then reflects obesity, may be insufficient and potentially flawed. The role of fructose intake and metabolic endotoxemia has gained attention recently, but data in kidney transplantation are lacking. This study evaluated the risk factors for metabolic syndrome (MS), its components, and other associated markers in kidney transplant recipients (KTRs), focusing particularly on fructose intake and systemic endotoxemia. METHODS: This cross-sectional observational study enrolled 128 KTRs longer than 1 year posttransplantation. Clinical, biochemical, anthropometric, and questionnaire assessments were undertaken. RESULTS: Obesity (body mass index, ≥30 kg/m) and MS (International Diabetes Federation Definition) were found in 36.7% and 50% of KTRs, respectively. Both increased fructose intake (P = 0.01) and endotoxin level (P = 0.02) were independently associated with MS; and higher fructose intake was independently associated with obesity (P < 0.001). Specifically, increased fructose intake was associated with the central obesity (P = 0.01) and hyperglycemia (P < 0.001) criteria of MS, whereas higher endotoxin level was associated with the hypertriglyceridemia (P = 0.003) and low HDL cholesterol concentration (P = 0.002) criteria of MS. Neither saturated fat nor total caloric intakes were independently associated with obesity and MS; and neither obesity nor central obesity were independently associated with the dyslipidemia and hyperglycemia criteria of MS. Principal component analysis demonstrated relationships between higher levels of endotoxin, soluble endothelial selectin, triglycerides, and insulin resistance (r > 0.6), as well as relationships between increased fructose intake, inflammation, and blood glucose (r > 0.6). CONCLUSIONS: Dietary modifications through decreasing fructose intake and addressing systemic endotoxemia are plausible targets for improving metabolic health of KTRs.


Assuntos
Açúcares da Dieta/efeitos adversos , Endotoxemia/epidemiologia , Frutose/efeitos adversos , Transplante de Rim , Síndrome Metabólica/epidemiologia , Obesidade/epidemiologia , Adulto , Biomarcadores/sangue , Glicemia/metabolismo , Índice de Massa Corporal , Estudos Transversais , Endotoxemia/sangue , Endotoxemia/diagnóstico , Endotoxinas/sangue , Inglaterra/epidemiologia , Feminino , Humanos , Transplante de Rim/efeitos adversos , Lipídeos/sangue , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/diagnóstico , Pessoa de Meia-Idade , Obesidade/sangue , Obesidade/diagnóstico , Prevalência , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
9.
J Clin Endocrinol Metab ; 104(4): 1187-1199, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30252067

RESUMO

CONTEXT: Hypoglycemia is emerging as a risk for cardiovascular events in diabetes. We hypothesized that hypoglycemia activates the innate immune system, which is known to increase cardiovascular risk. OBJECTIVE: To determine whether hypoglycemia modifies subsequent innate immune system responses. DESIGN AND SETTING: Single-blinded, prospective study of three independent parallel groups. PARTICIPANTS AND INTERVENTIONS: Twenty-four healthy participants underwent either a hyperinsulinemic-hypoglycemic (2.5 mmol/L), euglycemic (6.0 mmol/L), or sham-saline clamp (n = 8 for each group). After 48 hours, all participants received low-dose (0.3 ng/kg) intravenous endotoxin. MAIN OUTCOME MEASURES: We studied in-vivo monocyte mobilization and monocyte-platelet interactions. RESULTS: Hypoglycemia increased total leukocytes (9.98 ± 1.14 × 109/L vs euglycemia 4.38 ± 0.53 × 109/L, P < 0.001; vs sham-saline 4.76 ± 0.36 × 109/L, P < 0.001) (mean ± SEM), mobilized proinflammatory intermediate monocytes (42.20 ± 7.52/µL vs euglycemia 20.66 ± 3.43/µL, P < 0.01; vs sham-saline 26.20 ± 3.86/µL, P < 0.05), and nonclassic monocytes (36.16 ± 4.66/µL vs euglycemia 12.72 ± 2.42/µL, P < 0.001; vs sham-saline 19.05 ± 3.81/µL, P < 0.001). Following hypoglycemia vs euglycemia, platelet aggregation to agonist (area under the curve) increased (73.87 ± 7.30 vs 52.50 ± 4.04, P < 0.05) and formation of monocyte-platelet aggregates increased (96.05 ± 14.51/µL vs 49.32 ± 6.41/µL, P < 0.05). Within monocyte subsets, hypoglycemia increased aggregation of intermediate monocytes (10.51 ± 1.42/µL vs euglycemia 4.19 ± 1.08/µL, P < 0.05; vs sham-saline 3.81± 1.42/µL, P < 0.05) and nonclassic monocytes (9.53 ± 1.08/µL vs euglycemia 2.86 ± 0.72/µL, P < 0.01; vs sham-saline 3.08 ± 1.01/µL, P < 0.05), with platelets compared with controls. Hypoglycemia led to greater leukocyte mobilization in response to subsequent low-dose endotoxin challenge (10.96 ± 0.97 vs euglycemia 8.21 ± 0.85 × 109/L, P < 0.05). CONCLUSIONS: Hypoglycemia mobilizes monocytes, increases platelet reactivity, promotes interaction between platelets and proinflammatory monocytes, and potentiates the subsequent immune response to endotoxin. These changes may contribute to increased cardiovascular risk observed in people with diabetes.


Assuntos
Endotoxemia/imunologia , Técnica Clamp de Glucose , Hipoglicemia/imunologia , Imunidade Inata , Lipopolissacarídeos/imunologia , Adulto , Relação Dose-Resposta Imunológica , Endotoxemia/sangue , Endotoxemia/induzido quimicamente , Escherichia coli , Feminino , Glucose/administração & dosagem , Voluntários Saudáveis , Experimentação Humana , Humanos , Hiperglicemia/sangue , Hiperglicemia/induzido quimicamente , Hiperglicemia/imunologia , Hipoglicemia/sangue , Hipoglicemia/induzido quimicamente , Injeções Intravenosas , Insulina/administração & dosagem , Lipopolissacarídeos/administração & dosagem , Masculino , Monócitos/imunologia , Agregação Plaquetária/imunologia , Estudos Prospectivos , Adulto Jovem
10.
Immunology ; 156(3): 277-281, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30472736

RESUMO

Recent studies have suggested that neutrophils can exert anti-inflammatory effects. To determine the role of neutrophils in the acute response to lipopolysaccharide (LPS), a component of the Gram-negative bacterial cell wall, we challenged neutrophil-depleted and control mice with LPS and analyzed the plasma concentrations of biomarkers indicative of the cytokine and chemokine network, activation of coagulation and the vascular endothelium, and cellular injury. We here show that neutrophils serve an anti-inflammatory role upon LPS administration, as reflected by sustained elevations of multiple cytokines and chemokines, and enhanced release of nucleosomes in mice depleted of neutrophils, compared with control mice.


Assuntos
Endotoxemia/imunologia , Interações entre Hospedeiro e Microrganismos/imunologia , Neutrófilos/imunologia , Animais , Biomarcadores/sangue , Parede Celular/imunologia , Quimiocinas/imunologia , Citocinas/imunologia , Endotélio Vascular/imunologia , Endotoxemia/sangue , Feminino , Bactérias Gram-Negativas/imunologia , Lipopolissacarídeos/imunologia , Camundongos , Camundongos Endogâmicos C57BL
11.
PLoS One ; 13(12): e0208279, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30571701

RESUMO

Multiple organ dysfunction caused by hyperinflammation remains the major cause of mortality during sepsis. Excessive M1-macrophage activation leads to systemic inflammatory responses. Gene related to anergy in lymphocytes (Grail) is regarded as an important regulator of T cells that functions by diminishing cytokine production. However, its role in regulating macrophage activation and organ injury during sepsis remains unclear. Our aim was to examine the effects of Grail on macrophage reactivity and organ injury in endotoxemic animals. Wild-type and Grail knockout mice were injected with vehicle or Escherichia coli lipopolysaccharide and observed for 24 h. Changes in blood pressure, heart rate, blood glucose, and biochemical variables were then examined. Moreover, levels of neutrophil infiltration, MMP-9, and caspase 3 were analyzed in the lungs of animals. The expression of pro-inflammatory cytokines in J774A, RAW264.7, and primary peritoneal macrophages stimulated with LPS were also assessed in the presence or absence of Grail. Results indicated that loss of Grail expression enhances the induction of pro-inflammatory cytokines in J774A, RAW264.7, and primary peritoneal macrophages treated with LPS. Furthermore, LPS-induced macrophage hyperactivation was alleviated by ectopic Grail overexpression. In vivo studies showed that Grail deficiency exacerbates organ damage in endotoxemic animals. Levels of neutrophil infiltration, MMP-9, and caspase 3 were significantly increased in the lungs of Grail-deficient endotoxemic mice. Thus, these results suggest that Grail contributes to the attenuation of hyperinflammation caused by activated macrophages and prevents organ damage in endotoxemic mice. We suggest that Grail signaling could be a therapeutic target for endotoxemia.


Assuntos
Inflamação/enzimologia , Inflamação/prevenção & controle , Macrófagos Peritoneais/enzimologia , Especificidade de Órgãos , Ubiquitina-Proteína Ligases/metabolismo , Animais , Peso Corporal , Caspase 3/metabolismo , Creatinina/sangue , Citocinas/metabolismo , Endotoxemia/sangue , Endotoxemia/metabolismo , Endotoxemia/patologia , Deleção de Genes , Hemodinâmica , Inflamação/patologia , Mediadores da Inflamação/metabolismo , L-Lactato Desidrogenase/sangue , Lipopolissacarídeos , Pulmão/enzimologia , Pulmão/patologia , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Infiltração de Neutrófilos , Células RAW 264.7
12.
Sci Rep ; 8(1): 14969, 2018 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-30297806

RESUMO

Sepsis is one of the most common clinical syndromes that causes death and disability. Although many studies have developed drugs for sepsis treatment, none have decreased the mortality rate. The aim of this study was to identify a novel treatment option for sepsis using the library of integrated network-based cellular signatures (LINCS) L1000 perturbation dataset based on an in vitro and in vivo sepsis model. Sepsis-related microarray studies of early-stage inflammatory processes in patients and innate immune cells were collected from the Gene Expression Omnibus (GEO) data repository and used for candidate drug selection based on the LINCS L1000 perturbation dataset. The anti-inflammatory effects of the selected candidate drugs were analyzed using activated macrophage cell lines. CGP-60474, an inhibitor of cyclin-dependent kinase, was the most potent drug. It alleviated tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in activated macrophages by downregulating the NF-κB activity, and it reduced the mortality rate in LPS induced endotoxemia mice. This study shows that CGP-60474 could be a potential therapeutic candidate to attenuate the endotoxemic process. Additionally, the virtual screening strategy using the LINCS L1000 perturbation dataset could be a cost and time effective tool in the early stages of drug development.


Assuntos
Reposicionamento de Medicamentos/métodos , Pirimidinas/uso terapêutico , Sepse/tratamento farmacológico , Animais , Bases de Dados Factuais , Endotoxemia/sangue , Endotoxemia/tratamento farmacológico , Endotoxemia/imunologia , Humanos , Interleucina-6/sangue , Interleucina-6/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/imunologia , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/imunologia , Sepse/sangue , Sepse/imunologia
13.
Med Princ Pract ; 27(6): 570-578, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30184534

RESUMO

OBJECTIVE: To measure plasma glutamine (GLN) levels in systemic and portal circulation after combined enteral and parenteral administration in early endotoxemic swine. We hypothesized that this combination will be more efficient than intravenous administration alone in restoring plasma levels during the course of endotoxemia. MATERIALS AND METHODS: Endotoxemia was induced with Escherichia coli O111:B4 lipopolysaccharide (LPS) (250 µg/kg body weight) in 16 anes-thetized, fasted swine and maintained by constant infusion (2 µg/kg/h) over 180 min. Another 16 swine served as controls. After infusion with LPS or placebo, GLN was administered intravenously, enterally or in combination (0.5 g/kg i.v. plus 0.5 g/kg enterally) over 30 min. At 0, 15, 30, 45, 60, 120 and 180 min, blood was drawn from the systemic and portal circulation for colorimetric assessment of GLN. RESULTS: In healthy, placebo-alone swine, GLN levels remained stable throughout the study. Intravenous and combined infusion increased systemic levels (p = 0.001), but after enteral administration alone, a smaller effect was observed (p = 0.026). Portal levels were increased after combined, enteral and intravenous administration (p = 0.001). In endotoxemia, systemic and portal levels decreased significantly. Intravenous and, to a greater extent, combined administration increased systemic levels (p = 0.001), while enteral administration only had a small effect (p = 0.001). In the portal vein, intravenous and combined treatment increased plasma levels (p = 0.001), whereas enteral supplementation alone had again a small, yet significant effect (p = 0.001). CONCLUSIONS: The findings indicate that combined GLN supplementation is superior to intravenous treatment alone, in terms of enhanced availability in systemic and portal circulations. Thus, combined treatment at the onset of endotoxemia is a beneficial practice, ensuring adequate GLN to compensate for the resulting intracellular shortage.


Assuntos
Vias de Administração de Medicamentos , Endotoxemia/tratamento farmacológico , Infecções por Escherichia coli/tratamento farmacológico , Glutamina/administração & dosagem , Doenças dos Suínos/tratamento farmacológico , Doenças dos Suínos/microbiologia , Administração Intravenosa , Animais , Suplementos Nutricionais , Modelos Animais de Doenças , Endotoxemia/sangue , Escherichia coli , Infecções por Escherichia coli/sangue , Feminino , Glutamina/análise , Grécia , Sistema Porta/efeitos dos fármacos , Suínos , Doenças dos Suínos/sangue
14.
EBioMedicine ; 33: 144-156, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29983349

RESUMO

Hypoxia and inflammation are closely intertwined phenomena. Critically ill patients often suffer from systemic inflammatory conditions and concurrently experience short-lived hypoxia. We evaluated the effects of short-term hypoxia on systemic inflammation, and show that it potently attenuates pro-inflammatory cytokine responses during murine endotoxemia. These effects are independent of hypoxia-inducible factors (HIFs), but involve augmented adenosine levels, in turn resulting in an adenosine 2B receptor-mediated post-transcriptional increase of interleukin (IL)-10 production. We translated our findings to humans using the experimental endotoxemia model, where short-term hypoxia resulted in enhanced plasma concentrations of adenosine, augmentation of endotoxin-induced circulating IL-10 levels, and concurrent attenuation of the pro-inflammatory cytokine response. Again, HIFs were shown not to be involved. Taken together, we demonstrate that short-term hypoxia dampens the systemic pro-inflammatory cytokine response through enhanced purinergic signaling in mice and men. These effects may contribute to outcome and provide leads for immunomodulatory treatment strategies for critically ill patients.


Assuntos
Adenosina/metabolismo , Endotoxemia/imunologia , Hipóxia/imunologia , Interleucina-10/sangue , Adenosina/sangue , Animais , Modelos Animais de Doenças , Endotoxemia/sangue , Endotoxemia/genética , Humanos , Hipóxia/sangue , Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Interleucina-10/genética , Interleucina-10/metabolismo , Camundongos , Receptores Purinérgicos P1/metabolismo , Regulação para Cima
15.
Arch Biochem Biophys ; 654: 70-76, 2018 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-30009781

RESUMO

In this study, we examined the effects of uridine on plasma cytokine levels, heat shock protein (HSP) 72 expression, and nuclear factor (NF)-κB signaling in spleen lymphocytes after exposure of male BALB/c mice to Escherichia coli lipopolysaccharide (LPS). Mice were treated with uridine (30 mg/kg body weight, intraperitoneal injection [i.p.]) or saline solution of LPS (2.5 mg/kg, i. p.). Endotoxin increased plasma levels of tumor necrosis factor-α, interferon-γ, interleukin (IL)-1, IL-2, and IL-6 by 2.1-, 1.9-, 1.7-, 1.6-, and 2.3-fold, respectively. Prior treatment with uridine prevented LPS-induced increases in all studied cytokines. In splenic lymphocytes, LPS treatment increased the expression of HSP 72 by 2.4-fold, whereas preliminary treatment with uridine completely prevented this effect. LPS also activated NF-κB signaling in splenic lymphocytes, and uridine decreased NF-κB pathway activity. Inhibitory analysis showed that the mechanism of uridine action was associated with the formation of the UDP-metabolic activator of the mitochondrial ATP-dependent potassium channel (mitoKATP) and the UTP-activator of glycogen synthesis in the tissues. A specific inhibitor of mitoKATP, 5-hydroxydecanoate (5 mg/kg), and an inhibitor of glycogen synthesis, galactosamine (110 mg/kg), prevented the effects of uridine. Thus, uridine itself or uridine phosphates, which increased after uridine treatment, appeared to inhibit pro-inflammatory responses induced by LPS application. Overall, these findings demonstrated that the mechanisms mediating the effects of uridine were regulated by activation of glycogen synthesis and opening of the mitoKATP, which in turn increased the energy potential of the cell and reduced oxidative stress.


Assuntos
Anti-Inflamatórios/uso terapêutico , Endotoxemia/tratamento farmacológico , Canais de Potássio/fisiologia , Uridina/uso terapêutico , Animais , Citocinas/sangue , Endotoxemia/sangue , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Transdução de Sinais
16.
Am J Respir Crit Care Med ; 198(8): 1043-1054, 2018 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-29882682

RESUMO

RATIONALE: Fluid resuscitation is widely considered a life-saving intervention in septic shock; however, recent evidence has brought both its safety and efficacy in sepsis into question. OBJECTIVES: In this study, we sought to compare fluid resuscitation with vasopressors with the use of vasopressors alone in a hyperdynamic model of ovine endotoxemia. METHODS: Endotoxemic shock was induced in 16 sheep, after which they received fluid resuscitation with 40 ml/kg of 0.9% saline or commenced hemodynamic support with protocolized noradrenaline and vasopressin. Microdialysis catheters were inserted into the arterial circulation, heart, brain, kidney, and liver to monitor local metabolism. Blood samples were recovered to measure serum inflammatory cytokines, creatinine, troponin, atrial natriuretic peptide, brain natriuretic peptide, and hyaluronan. All animals were monitored and supported for 12 hours after fluid resuscitation. MEASUREMENTS AND MAIN RESULTS: After resuscitation, animals that received fluid resuscitation required significantly more noradrenaline to maintain the same mean arterial pressure in the subsequent 12 hours (68.9 mg vs. 39.6 mg; P = 0.04). Serum cytokines were similar between groups. Atrial natriuretic peptide increased significantly after fluid resuscitation compared with that observed in animals managed without fluid resuscitation (335 ng/ml [256-382] vs. 233 ng/ml [144-292]; P = 0.04). Cross-sectional time-series analysis showed that the rate of increase of the glycocalyx glycosaminoglycan hyaluronan was greater in the fluid-resuscitated group over the course of the study (P = 0.02). CONCLUSIONS: Fluid resuscitation resulted in a paradoxical increase in vasopressor requirement. Additionally, it did not result in improvements in any of the measured microcirculatory- or organ-specific markers measured. The increase in vasopressor requirement may have been due to endothelial/glycocalyx damage secondary to atrial natriuretic peptide-mediated glycocalyx shedding.


Assuntos
Endotoxemia/terapia , Hidratação/efeitos adversos , Animais , Biomarcadores/sangue , Citocinas/sangue , Modelos Animais de Doenças , Endotoxemia/sangue , Endotoxemia/fisiopatologia , Feminino , Hemodinâmica , Ressuscitação/efeitos adversos , Ressuscitação/métodos , Ovinos , Choque Séptico/etiologia , Choque Séptico/terapia
17.
Thromb Haemost ; 118(7): 1176-1184, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29864779

RESUMO

The protease-activated receptor-1 (PAR-1) is critically involved in the co-activation of coagulation and inflammatory responses. Vorapaxar is a reversible, orally active, low molecular weight, competitive antagonist of PAR-1.We investigated the effects of PAR-1 inhibition by vorapaxar on the inflammatory response, the activation of coagulation, fibrinolysis and endothelium during experimental endotoxemia. In this randomized, double blind, crossover trial, 16 healthy volunteers received a bolus infusion of 2 ng/kg lipopolysaccharide (LPS) ± placebo/vorapaxar with a washout period of 8 weeks. Vorapaxar dosing was guided by thrombin receptor-activating peptide-6-induced whole blood aggregometry. Participants received 10 mg vorapaxar or placebo as an initial dose and, depending on the aggregometry, potentially an additional 10 mg. Goal was > 80% inhibition of aggregation compared with baseline. Vorapaxar significantly reduced the LPS-induced increase in pro-thrombin fragments F1 + 2 by a median of 27% (quartiles: 11-49%), thrombin-anti-thrombin concentrations by 22% (-3 to 46%) and plasmin-anti-plasmin levels by 38% (23-53%). PAR-1 inhibition dampened peak concentrations of tumour necrosis factor -α, interleukin-6 and consequently C-reactive protein by 66% (-11-71%), 50% (15-79%) and 23% (16-38%), respectively. Vorapaxar decreased maximum von Willebrand factor levels by 29% (26-51%) and soluble E-selectin concentrations by 30% (25-38%) after LPS infusion. PAR-1 inhibition did not affect thrombomodulin, soluble P-selectin and platelet factor-4 concentrations.PAR-1 inhibition significantly reduced the activation of coagulation, fibrinolysis, the inflammatory response and endothelial activation during experimental human endotoxemia.


Assuntos
Anti-Inflamatórios/administração & dosagem , Anticoagulantes/administração & dosagem , Coagulação Sanguínea/efeitos dos fármacos , Plaquetas/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Endotoxemia/prevenção & controle , Lactonas/administração & dosagem , Inibidores da Agregação de Plaquetas/administração & dosagem , Piridinas/administração & dosagem , Receptor PAR-1/antagonistas & inibidores , Administração Oral , Adulto , Anti-Inflamatórios/efeitos adversos , Anticoagulantes/efeitos adversos , Áustria , Biomarcadores/sangue , Plaquetas/metabolismo , Estudos Cross-Over , Método Duplo-Cego , Monitoramento de Medicamentos/métodos , Endotélio Vascular/metabolismo , Endotoxemia/sangue , Endotoxemia/induzido quimicamente , Endotoxemia/diagnóstico , Feminino , Fibrinólise/efeitos dos fármacos , Humanos , Inflamação/sangue , Inflamação/induzido quimicamente , Inflamação/diagnóstico , Inflamação/prevenção & controle , Mediadores da Inflamação/sangue , Infusões Intravenosas , Lactonas/efeitos adversos , Lipopolissacarídeos/administração & dosagem , Masculino , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/efeitos adversos , Estudos Prospectivos , Piridinas/efeitos adversos , Receptor PAR-1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo
18.
Br J Clin Pharmacol ; 84(9): 2129-2141, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29856470

RESUMO

AIMS: Adrenomedullin (ADM) is an important regulator of endothelial barrier function and vascular tone, and may represent a novel treatment target in sepsis. The non-neutralizing ADM antibody adrecizumab has shown promising results in preclinical sepsis models. In the present study, we investigated the safety, tolerability and pharmacokinetics (PK)/pharmacodynamics of adrecizumab in a first-in-man study and in a second study during experimental human endotoxaemia. METHODS: Forty-eight healthy male volunteers were enrolled in two randomized, double-blind, placebo-controlled phase I studies. In both studies, subjects received placebo or one of three doses of adrecizumab (n = 6 per group). In the second study, a bolus of 1 ng kg-1 endotoxin was followed by infusion of 1 ng kg-1 h-1 endotoxin for 3 h to induce systemic inflammation, and the study medication infusion started 1 h after endotoxin bolus administration. RESULTS: Adrecizumab showed an excellent safety profile in both studies. PK analyses showed proportional increases in the maximum plasma concentration of adrecizumab with increasing doses, a small volume of distribution, a low clearance rate and a terminal half-life of ~14 days. adrecizumab elicited a pronounced increase in plasma ADM levels, whereas levels of mid-regional pro-adrenomedullin remained unchanged, indicating that de novo synthesis of ADM was not influenced. In the second study, no effects of adrecizumab on cytokine clearance were observed, whereas endotoxin-induced flu-like symptoms resolved more rapidly. CONCLUSIONS: Administration of adrecizumab is safe and well tolerated in humans, both in the absence and presence of systemic inflammation. These findings pave the way for further investigation of adrecizumab in sepsis patients.


Assuntos
Adrenomedulina/antagonistas & inibidores , Anticorpos Monoclonais Humanizados/administração & dosagem , Endotoxemia/tratamento farmacológico , Administração Oral , Adrenomedulina/sangue , Adulto , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacocinética , Relação Dose-Resposta a Droga , Método Duplo-Cego , Endotoxemia/sangue , Endotoxemia/induzido quimicamente , Escherichia coli , Meia-Vida , Voluntários Saudáveis , Experimentação Humana , Humanos , Lipopolissacarídeos/administração & dosagem , Lipopolissacarídeos/toxicidade , Masculino , Taxa de Depuração Metabólica , Resultado do Tratamento , Adulto Jovem
19.
Med Sci Monit ; 24: 2975-2982, 2018 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-29735976

RESUMO

BACKGROUND The aim of this study was to evaluate the protective effects of sodium tanshinone IIA sulfonate (STS) on hemodynamic parameters, cytokine release, and multiple organ damage in an animal model of lipopolysaccharide (LPS)-induced endotoxemia. MATERIAL AND METHODS Twenty-four rabbits were randomly divided into 3 groups: control (n=8), LPS (n=8), and STS pretreatment + LPS (n=8) groups. With arterial invasive monitoring, hemodynamic variables were observed at 30 min before and at 0, 10, 20, 30, 60, 120, 180, 240, and 300 min after LPS injection. Circulatory inflammatory cytokines, including tumor necrosis factor-α (TNF-α) and interleukin-10 (IL-10), and relevant biochemical markers, including arterial partial pressure of oxygen (PaO2), plasma cardiac troponin I (cTnI), alanine aminotransferase (ALT), and creatinine (Cr), were measured at each time point. At the end of the experiment, all rabbits were sacrificed; histopathological examination of the heart, lung, liver, and kidney tissue was performed and organ injury was semi-quantitatively scored for each organ. RESULTS Mean arterial pressure (MAP) and heart rate (HR) significantly decreased within 30 min and again after 120 min following LPS injection. However, STS pretreatment gradually normalized MAP and HR after 120 min following LPS injection. In addition, STS ameliorated LPS-induced decrease of PaO2, LPS-induced increase of TNF-α, cTnI, and ALT, and enhanced LPS-induced increase of IL-10. Moreover, STS reduced heart, lung, and liver histopathologic injury. CONCLUSIONS STS can significantly stabilize LPS-induced hemodynamic deterioration, regulate inflammatory cytokine secretion, and protect heart, lung, and liver in rabbits.


Assuntos
Citocinas/metabolismo , Endotoxemia/sangue , Endotoxemia/tratamento farmacológico , Hemodinâmica , Insuficiência de Múltiplos Órgãos/sangue , Insuficiência de Múltiplos Órgãos/tratamento farmacológico , Fenantrenos/uso terapêutico , Animais , Biomarcadores/metabolismo , Endotoxemia/complicações , Hemodinâmica/efeitos dos fármacos , Mediadores da Inflamação/metabolismo , Interleucina-10/sangue , Lipopolissacarídeos , Masculino , Insuficiência de Múltiplos Órgãos/complicações , Especificidade de Órgãos , Oxigênio/metabolismo , Pressão Parcial , Fenantrenos/farmacologia , Coelhos , Choque Séptico/sangue , Choque Séptico/tratamento farmacológico , Fator de Necrose Tumoral alfa/sangue
20.
Food Funct ; 9(5): 2617-2622, 2018 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-29770393

RESUMO

Gut microbiota dysbiosis alters the intestinal barrier function, increases plasma lipopolysaccharide (LPS) levels, which promotes endotoxemia, and contributes to the onset and development of colorectal cancer (CRC). We report here for the first time the reduction of plasma LPS-binding protein (LBP) levels, a marker of endotoxemia, after pomegranate consumption in newly diagnosed CRC patients.


Assuntos
Proteínas de Transporte/sangue , Neoplasias Colorretais/sangue , Neoplasias Colorretais/dietoterapia , Endotoxemia/sangue , Lythraceae/metabolismo , Glicoproteínas de Membrana/sangue , Proteínas da Fase Aguda , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/metabolismo , Endotoxemia/diagnóstico , Biomarcadores Ambientais , Feminino , Frutas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade
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