TY - JOUR. T1 - Ghrelin protects mice against endotoxemia-induced acute kidney injury. AU - Wang, Wei. AU - Bansal, Shweta. AU - Falk, Sandor. AU - Ljubanovic, Danica. AU - Schrier, Robert. PY - 2009/10/1. Y1 - 2009/10/1. N2 - Acute kidney injury (AKI) in septic patients drastically increases the mortality to 50-80%. Sepsis is characterized by hemodynamic perturbations as well as overwhelming induction of proinflammatory cytokines. Since ghrelin has been shown to have anti-inflammatory properties, we hypothesized that ghrelin may afford renal protection during endotoxemia-induced AKI. Studies were conducted in a normotensive endotoxemia-induced AKI model in mice by intraperitoneal injection of 3.5 mg/kg LPS. Serum ghrelin levels were increased during endotoxemia accompanied by increased ghrelin receptor (GHSR-1a) protein expression in the kidney. Ghrelin administration (1.0 mg/kg sc 6 h and 30 min before and 14 h after LPS) significantly decreased serum cytokine levels (TNF-α, IL-1β, and IL-6) ...
Acute lung injury is a leading cause of death in bacterial sepsis due to the wholesale destruction of the lung endothelial barrier, which results in protein-rich lung edema, influx of proinflammatory leukocytes, and intractable hypoxemia. Pyroptosis is a form of programmed lytic cell death that is triggered by inflammatory caspases, but little is known about its role in EC death and acute lung injury. Here, we show that systemic exposure to the bacterial endotoxin lipopolysaccharide (LPS) causes severe endothelial pyroptosis that is mediated by the inflammatory caspases, human caspases 4/5 in human ECs, or the murine homolog caspase-11 in mice in vivo. In caspase-11-deficient mice, BM transplantation with WT hematopoietic cells did not abrogate endotoxemia-induced acute lung injury, indicating a central role for nonhematopoietic caspase-11 in endotoxemia. Additionally, conditional deletion of caspase-11 in ECs reduced endotoxemia-induced lung edema, neutrophil accumulation, and death. These ...
Acute lung injury is a leading cause of death in bacterial sepsis due to the wholesale destruction of the lung endothelial barrier, which results in protein-rich lung edema, influx of proinflammatory leukocytes, and intractable hypoxemia. Pyroptosis is a form of programmed lytic cell death that is triggered by inflammatory caspases, but little is known about its role in EC death and acute lung injury. Here, we show that systemic exposure to the bacterial endotoxin lipopolysaccharide (LPS) causes severe endothelial pyroptosis that is mediated by the inflammatory caspases, human caspases 4/5 in human ECs, or the murine homolog caspase-11 in mice in vivo. In caspase-11-deficient mice, BM transplantation with WT hematopoietic cells did not abrogate endotoxemia-induced acute lung injury, indicating a central role for nonhematopoietic caspase-11 in endotoxemia. Additionally, conditional deletion of caspase-11 in ECs reduced endotoxemia-induced lung edema, neutrophil accumulation, and death. These ...
Acute lung injury is a leading cause of death in bacterial sepsis due to the wholesale destruction of the lung endothelial barrier, which results in protein-rich lung edema, influx of proinflammatory leukocytes, and intractable hypoxemia. Pyroptosis is a form of programmed lytic cell death that is triggered by inflammatory caspases, but little is known about its role in EC death and acute lung injury. Here, we show that systemic exposure to the bacterial endotoxin lipopolysaccharide (LPS) causes severe endothelial pyroptosis that is mediated by the inflammatory caspases, human caspases 4/5 in human ECs, or the murine homolog caspase-11 in mice in vivo. In caspase-11-deficient mice, BM transplantation with WT hematopoietic cells did not abrogate endotoxemia-induced acute lung injury, indicating a central role for nonhematopoietic caspase-11 in endotoxemia. Additionally, conditional deletion of caspase-11 in ECs reduced endotoxemia-induced lung edema, neutrophil accumulation, and death. These ...
Abstract Diabetes and obesity are characterized by a low grade inflammation whose molecular origin is unknown. We previously determined first, that metabolic endotoxemia controls the inflammatory tone, body weight gain, and diabetes, second, that high-fat feeding modulates gut microbiota and the plasma concentration of lipopolysaccharide (LPS) i.e. metabolic endotoxemia. Hence, it remained to demonstrate whether changes in gut microbiota control the occurrence of metabolic diseases.. Objective: first, to demonstrate that changes in gut microbiota, by the mean of antibiotic treatment, could be responsible for the control of metabolic endotoxemia, the low grade inflammation, obesity, and type 2 diabetes, and second to provide some mechanisms responsible for such effect.. Results: We found that changes of gut microbiota induced by an antibiotic treatment reduced metabolic endotoxemia and the ceacal content of LPS in both high-fat fed and ob/ob mice. This effect was correlated with reduced glucose ...
Diet induced metabolic endotoxemia is emerging as an important contributory factor to the development of a wide range of chronic disease including cardio metab...
Adrenomedullin (ADM) is a natural occurring 52 amino acid peptide which is mainly expressed in endothelial and smooth muscle cells. ADM plasma levels are increased in patients with sepsis and related with severity of disease. ADM is a key regulator of vasotonus and of endothelial integrity in sepsis. Adrecizumab is an antibody against the N-terminus of ADM which only partially inhibits the bioactivity of ADM. Several septic animal studies have shown that administration of Adrecizumab leads to stabilization of hemodynamics in mice and pigs, improved renal function, reduced catecholamine demand, improved fluid balance and improved survival. The administration of Adrecizumab to rodents, non-human primates and recently humans, has been tolerated very well.. The experimental human endotoxemia model, in which healthy male volunteers receive a low dose of lipopolysaccharide (LPS) derived from Escherichia coli, is widely used to study the effects of systemic inflammation in humans in vivo and is ...
TY - JOUR. T1 - Impact of endotoxin on UCP homolog mRNA abundance, thermoregulation, and mitochondrial proton leak kinetics. AU - Yu, Xing Xian. AU - Barger, Jamie L.. AU - Boyer, Bert. AU - Brand, Martin D.. AU - Pan, Guohua. AU - Adams, Sean H.. PY - 2000/9/14. Y1 - 2000/9/14. N2 - Linking tissue uncoupling protein (UCP) homolog abundance with functional metabolic outcomes and with expression of putative genetic regulators promises to better clarify UCP homolog physiological function. A murine endotoxemia model characterized by marked alterations in thermoregulation was employed to examine the association between heat production, UCP homolog expression, and mitochondrial proton leak (uncoupling). After intraperitoneal lipopolysaccharide (LPS, ≃6 mg/kg) injection, colonic temperature (T(c)) in adult female C57BL6/J mice dropped to a nadir of ≃30°C by 8 h, preceded by a four- to fivefold drop in liver UCP2 and UCP5/brain mitochondrial carrier protein 1 mRNA levels, with no change in their ...
New York City, NY: December 17, 2019 - Published via (Wired Release) - New Strategic Research Report on Endotoxemia Market contains detailed information on factors that will accelerate the growth of the market during the forecast period from 2020-2029 The report provides a complete summary of the key market competitors who majorly hold the market shares in terms of trade, and revenue through their products, supply, and after deal processes. Moreover, the drivers, constraints, and opportunities for the market are also listed in the report. Acute Growth of Endotoxemia Market presents Size, Industry Analysis Report, Regional Outlook, competitive landscape and a corresponding detailed analysis of the major vendor/key players. The company profiles presented in the report include LG Life Sciences, GlaxoSmithKline, Exponential Biotherapies, BASF SE, Dupont Danisco, CoMentis, Radboud University, Vienna University of Vienna.. As per the analysis, huge information present in the endotoxemia market report ...
The main finding of this study was that prolonged endotoxemia impaired the efficiency of hepatic mitochondrial complex I and complex II respiration, whereas mitochondrial respiration in the skeletal muscle remained unchanged. The altered mitochondrial function occurred despite well-maintained total and microcirculatory hepatic blood flow. In spite of the reduced hepatic mitochondrial RCR, the hepatic oxygen consumption and extraction remained unchanged. The reduced glutamate-dependent RCR in the liver mitochondria was mainly due to an increase in the mitochondrial resting respiration rate, suggesting partial uncoupling of oxygen consumption from ATP production. These results are supported by the well-maintained hepatic oxygen consumption and by the reduction in the ADP:O ratios. The alterations in the succinate-dependent respiration were due to reduced function of the complex II, as suggested by reduced state 3 respiration. The partial uncoupling in the glutamate-dependent and ...
Mitochondria, that provide most of the ATP needed for cell work, and that play numerous specific functions in biosyntheses and degradations, as well as contributing to Ca2+; signaling, also play a key role in the pathway to cell death. Impairment of mitochondrial functions caused by mutations of mt-genome, and by acute processes, are responsible for numerous diseases.. The involvement of impaired mitochondria in the pathogenesis of sepsis is discussed. By means of the skinned fiber technique and high resolution respirometry, we have detected significantly reduced rates of mitochondrial respiration in heart and skeletal muscle of endotoxaemic rabbits. Mitochondria from heart were more affected than those from skeletal muscle. Decreased respiration rates were accompanied by reduced activities of complex I+III of the respiratory chain. Endotoxin-caused impairment was also detectable at the level of the Langendorff perfused heart, where the coronary vascular resistance was significantly ...
TY - JOUR. T1 - Endogenous Interleukin 18 Suppresses Hyperglycemia and Hyperinsulinemia during the Acute Phase of Endotoxemia in Mice. AU - Yamashita, Hayato. AU - Aoyama-Ishikawa, Michiko. AU - Takahara, Miki. AU - Yamauchi, Chisato. AU - Inoue, Taketo. AU - Miyoshi, Makoto. AU - Maeshige, Noriaki. AU - Usami, Makoto. AU - Nakao, Atsunori. AU - Kotani, Joji. PY - 2015/2/1. Y1 - 2015/2/1. N2 - Background: Hyperglycemia associated with insulin resistance is common among critically ill patients. Interleukin (IL)-18 has been linked with hyperglycemia and insulin resistance in chronic disease, but the relation between IL-18 and insulin resistance during critical illness was unexplored. This study investigated whether IL-18 modulates hyperglycemia and insulin resistance during acute inflammation. Methods: We injected lipopolysaccharide (LPS) 40 mg/kg into wild-type (WT) and IL-18 knockout (KO) mice to induce endotoxemia and examined insulin resistance and insulin-dependent signaling pathways during ...
Although it is known that during endotoxemic shock the use of β-adrenergic agonists can improve organs blood flow independently of cardiac output increase, there is no study in the literature concerning the remodelling of the vascular β-adrenoceptors (β-AR), β1, β2 and β3. Male Sprague-Dawley rats received either 5 mg/kg of lipopolisaccharide (LPS) or the same volume of the vehicle (C) intravenously. Three hours later, the thoracic aorta rings were harvested to perform functional and mRNA expression studies. To take into account the failure of the vascular constriction in sepsis, aortic rings were preconstricted with an appropriate concentration of phenylephrine (α1-adrenergic agonist) in order to obtain 80% of the maximal contraction in both groups. Concentration-relaxation curves were then constructed with several β-AR agonists: isoproterenol (ISO), a non selective agonist; dobutamine (DOBU), salbutamol (SALBU) and SR 58611A (SR) respectively β1-, β2- and β3-AR agonists. The ...
International Journal of Inflammation is a peer-reviewed, Open Access journal that publishes original research and review articles on the molecular basis, cell biology and pharmacology of inflammation, including acute/chronic inflammation, mediators of inflammation, as well as cellular processes and molecular mechanisms involved in the production of inflammatory responses. The journal especially welcomes the submission of articles on anti-inflammatory drug development, trials and therapies.
OBJECTIVE: Overfeeding with a high-fat and/or high-carbohydrate (CHO) diet is known to increase plasma concentrations of endotoxin (lipopolysaccharide [LPS]) that may lead to metabolic disturbances like insulin resistance. The impact of CHO quality (i.e., the glycemic index [GI]) independent of fat intake on metabolic endotoxemia remains unclear. In the present study, the effects of changes in energy balance and GI on plasma endotoxin were studied. METHODS: Fifteen healthy young men overconsumed diets containing 65% CHO and 20% fat for 1 week (OF; +50% of energy requirement) followed by 3 weeks of caloric restriction (CR; -50% of energy requirement) and were then randomized to 2 weeks hypercaloric refeeding (RF, +50% of energy requirement) with either a low- or high-GI (40 vs 74) diet. RESULTS: During OF, subjects gained 1.9 ± 0.7 kg body weight (+0.6 ± 0.8% fat mass) followed by a weight loss of 6.1 ± 0.8 kg (-2.0 ± 0.6% fat mass) and weight regain of 4.0 ± 0.6 kg (0.9 ± 0.8% fat mass). ...
Objective The primary aim of this work was to study the relationships between cardiac patients spirometric values after coronary artery bypass graft (CABG) surgery and each of the following three variables: patients perceived benefits from and perceived self-efficacy and performance accuracy in the use of an incentive spirometer. The secondary aim was to study the relationships between the three variables. Method Incentive spirometers were introduced to patients who had undergone elective CABG. The patients were advised to use the incentive spirometers for breathing exercises 10 times per hour during waking hours after the surgery, according to the American Association for Respiratory Care clinical practice guidelines. The spirometric values were measured preoperatively and on the first postoperative day. Two numeric scales were used to record the patients perceived benefits from the incentive spirometer in enhancing the recovery of spirometric values following CABG and the patients ...
One pig died earlier (not included). Data are presented as the median (range). P , 0.05, Friedman test. Muscle mitochondrial respiration was similar at baseline and the end of experiment; state 3 (317 (222-594) vs 409 (295-468)), state 4 (29 (22-58) vs 40 (31-49)), respiratory control ratio (11 (7-15) vs 10 (9-11)) (not significant). Hepatic mitochondrial state 4 was higher (27 (16-31) vs 19 (13-22)) and respiratory control ratio lower (3 (3-4) vs 5 (4-6)) in the hemorrhage/endotoxemia group, compared with controls. ...
Sigma-Aldrich offers abstracts and full-text articles by [Aiwen Feng, Guangrong Zhou, Xiaoming Yuan, Xinli Huang, Zhengyuan Zhang, Ti Zhang].
Obesity and its related disorders have been associated with the presence in the blood of gut bacteria-derived lipopolysaccharides (LPS). However, the factors underlying this low-grade elevation in plasma LPS, so-called metabolic endotoxemia, are not fully elucidated. We aimed to investigate the effects of Western diet (WD) feeding on intestinal and hepatic LPS handling mechanisms in a rat model of diet-induced obesity (DIO). Rats were fed either a standard chow diet (C) or a Western Diet (WD, 45% fat) for 6 wk. They were either fed ad libitum or pair-fed to match the caloric intake of C rats for the first week, then fed ad libitum for the remaining 5 wk. Six-week WD feeding led to a mild obese phenotype with increased adiposity and elevated serum LPS-binding protein (LBP) levels relative to C rats, irrespective of initial energy intake. Serum LPS was not different between dietary groups but exhibited strong variability. Disrupted ileal mucus secretion and decreased ileal Reg3-γ and -β gene expression
This mRNA microarray analysis of human adipose tissue during experimental endotoxemia is the first attempt to identify novel adipocytokines using an in vivo evoked adipose inflammatory model. Our strategy identified genes encoding established adipokines implicated in obesity-related insulin resistance as well as emerging adipose tissue-secreted factors (1) and multiple secreted proteins with unknown adipose functions. These experimental human studies are internally consistent, provide independent validation, and define the likely cellular origin. Such candidates may represent new biomarkers and therapeutic targets for the treatment of obesity-related complications.. Microarray analysis of gene expression is established for discovery of disease-related genes (43). Indeed, mRNA profiling of adipose has identified novel genes involved in obesity and type 2 diabetes (44). Several reports identified genes involved in inflammation, insulin signaling, and lipid metabolism as differentially expressed in ...
Metabolic syndrome (MetS) is a cluster of conditions that conjoined represents a 1.5-2.5 fold increased risk of developing cardiovascular disease (CVD). Recent studies have reported that gut dysbiosis and leakage of bacterial components, may contribute to the metabolic disturbances and systemic inflammation observed in subjects with MetS. Chronic exposure to lipopolysaccharide (LPS) has been shown to induce features of MetS in experimental studies. LPS interacts with the innate immune system, facilitated through LPS-binding protein (LBP) and the co-receptor CD14, both regarded as markers of gut leakage. We investigated whether circulating levels of LBP and sCD14 are associated with the presence of MetS and its components, and further any association with systemic inflammation. We examined 482 men, aged between 65 and 75 years, all at high CVD risk. MetS criterias according to the US National Cholesterol Education Program Adult Treatment Panel III were met in 182 subjects (38%). Levels of LBP and sCD14
TY - JOUR. T1 - Pulmonary microvascular changes following fluid resuscitation in an ovine model of endotoxemia. AU - Lubbesmeyer, H. J.. AU - Kimura, R.. AU - Maguire, J. P.. AU - Irei, M.. AU - Traber, L. D.. AU - Traber, D. L.. AU - Herndon, David. PY - 1988. Y1 - 1988. N2 - Fluid resuscitation is complicated in hypotensive septic patients by their susceptibility to pulmonary edema. This problem was evaluated in the ovine model of endotoxemia with a chronic lung lymph fistula. Escherichia coli endotoxin (lipopolysaccharide, 1.5 μg/kg) was given intravenously over 30 minutes. Group M (n=9) continued to receive baseline fluids (2 mL/kg/h), while group R (n=6) received 7 mL/kg/h of Ringers lactate. After an initial drop in cardiac index, animals in both groups developed a hyperdynamic state. The fall in mean arterial pressure seen in group M was absent from group R. The higher fluid volume resulted in a rise in left atrial pressure and pulmonary microvascular pressure. The lung lymph flow and ...
Sickness behavior in humans is characterized by low mood and fatigue, which have been suggested to reflect changes in motivation involving reorganization of priorities. However, it is unclear which specific processes underlying motivation are altered. We tested whether bacterial endotoxin E. coli lipopolysaccharide (LPS) affected two dissociable constructs of motivational behavior, ie, effort and reward sensitivity. After familiarization with 5 effort levels, participants made a series of accept/reject decisions on whether the stake offered (1, 4, 8, 12, or 15 apples) was worth the effort (10%, 27.5%, 45%, 62.5%, and 80% of maximal voluntary contraction in a hand-held dynamometer). Effort and reward levels were parametrically modulated to dissociate their influence on choice. Overall, 29 healthy young males were administered LPS (2 ng/kg; n=14) or placebo (0.9% saline; n=15). The effort-stake task, and self-reported depression and fatigue were assessed prior to LPS/placebo injection, 2 and 5 h post
Myocardial circulation during septic shock is often characterized by an inappropriately high coronary flow.14 15 NO plays an important role in the regulation of myocardial flow.9 10 11 12 13 Therefore, we investigated the role of NO in the hyperdynamic changes of coronary flow in hearts of endotoxin-treated rats. The data in the present study indicate that these vascular changes are predominantly due to the vasodilatory action of NO. However, inhibition of the NO pathway can result in focal areas of ischemia in endotoxin-treated hearts, suggesting an imbalance of local oxygen supply to demand.. A rat model of endotoxemia using a sublethal low dose of endotoxin was selected; this model produced a hyperdynamic coronary circulation36 that is also seen in human sepsis.14 15 Comparable to human sepsis, the model resulted in raised temperature,36 reduced blood pressure, and increased levels of plasma lactate37 and nitrate plus nitrite. The 12 hours needed to establish this model provides sufficient ...
Endotoxemia, inflammation, and atrial fibrillation.: There is emerging evidence to support a link between inflammation and atrial fibrillation (AF). Lipopolysac
The hypothesis being advanced in this paper is that there is a new medical paradigm emerging from the biomedical research carried out in this century, mainly due to the explosion of the so called "omics" and associated techniques. The main idea is that there is a common pathway from wellbeing and health to chronic disease ("chronopathy") and even to death, which comprises following steps: 1) unhealthy diet, sedentary life style and permanent exposition to xenobiotics and all kinds of noxious stimuli;→2) intestinal dysbiosis;→3) alteration of the intestinal mucus layer (especially that of the colon);→4) disruption of the endothelial tight junctions;→5) metabolic endotoxemia+bacterial translocation;→6) inflammation;→7) exacerbation of the enteric nervous system (ENS) and consequent maladaptation and malfunctioning of the colon;→8) epigenetic manifestations;→9) "chronopathy" and premature death ...
PURPOSE: To evaluate the clinical pharmacology of exogenous alkaline phosphatase (AP). METHODS: Randomized, double-blind, placebo-controlled sequential protocols of (1) ascending doses and infusion duration (volunteers) and (2) fixed dose and duration (patients) were conducted at clinical pharmacology and intensive care units. A total of 103 subjects (67 male volunteers and 36 patients with severe sepsis) were administered exogenous, 10-min IV infusions (three ascending doses) or 24-72 h continuous (132.5-200 U kg(-1) 24 h(-1)) IV infusion with/without preceding loading dose and experimental endotoxemia for evaluations of pharmacokinetics, pharmacodynamics, safety parameters, antigenicity, inflammatory markers, and outcomes. RESULTS: Linearity and dose-proportionality were shown during 10-min infusions. The relatively short elimination half-life necessitated a loading dose to achieve stable enzyme levels. Pharmacokinetic parameters in volunteers and patients were similar. Innate immunity ...
Con la presentennotità di un protocollo per misurare al capezzale lattività di endotossina dei campioni di sangue intero umano. Il...
Sepsis-associated acute brain inflammation, if unresolved, may cause chronic neuroinflammation and resultant neurodegenerative diseases. However, little is known how the transition from acute to chronic neuroinflammation, which is critical for the following progressive neurodegeneration, occurs in sepsis. The goal of this study was to investigate potential immune factors regulating the transition process using a widely used endotoxemia LPS mouse model. This model shows distinct acute and chronic phases of neuroinflammation and recapitulates many cardinal features of Parkinsons disease, thus, providing a unique opportunity for studying phase transition of neuroinflammation. C57BL/6 J, NLRP3−/−, and IL-1R1−/− mice were employed. Mild and severe endotoxemia were produced by LPS ip injection at 1 or 5 mg/kg. Neuroinflammation in vitro and in vivo was assessed with proinflammatory cytokine expression by qPCR or ELISA and microglial activation by immunohistochemical analysis. Neurodegeneration was
estimated also in 20 malignant patients: 10 of them with breast cancer and the other 10 with bladder cancer. The preoperative level mean was 28.73 and 38.06 pg/ml and the postoperative one was 29.2 and 40.68 pg/ml respectively. TNF level was found high in the malignant patients in the preoperative and postoperative samples in comparison with the control group and the difference was statistically significant [P ...
Endotoxin is a potent mediator of a broad range of patho-physiological effects in humans. It is present in all Gram negative (GN) bacteria. It would be expected that anti-endotoxin therapies, whether antibody based or not, would have an important adjuvant therapeutic role along with antibiotics and other supportive therapies for GN infections. Indeed there is an extensive literature relating to both pre-clinical and clinical studies of anti-endotoxin antibodies. However, the extent of disconnect between the generally successful pre-clinical studies versus the failures of the numerous large clinical trials of antibody based and other anti-endotoxin therapies is under-appreciated and unexplained. Seeking a reconciliation of this disconnect is not an abstract academic question as clinical trials of interventions to reduce levels of endotoxemia levels are ongoing. The aim of this review is to examine new insights into the complex relationship between endotoxemia and sepsis in an attempt to bridge this
Widespread time-dependent changes in tissue cytokine concentrations in brain regions during the acute phase of endotoxemia in mice.: Sepsis-associated encephalo
Cystine/glutamate transporter, system xc-, contributes to the maintenance of intracellular glutathione levels and the redox balance in the extracellular space. The main component of the transporter, xCT, is known to be strongly induced by various stimuli like oxidative stress in mammalian cultured cells. We examined the expression of xCT mRNA in vivo in the experimental endotoxemia. Northern blot analysis and in situ hybridization were used to investigate the expression of xCT mRNA in the tissues of the mice exposed to bacterial lipopolysaccharide (LPS). Northern blot analysis revealed that xCT mRNA was constitutively expressed in the brain, thymus, and spleen, and that the expression of xCT mRNA was strongly up-regulated in thymus and spleen by the administration of a sublethal dose of LPS. In addition to brain, thymus, and spleen, xCT mRNA was detected also in the bronchiolar epithelium of the lung by the administration of the lethal dose of LPS. xCT is induced in some specific tissues by the
Authors: Birnbaum, J. , Lehmann, Ch. , Klotz, E. , Hein, O. Vargas , Blume, A. , Jubin, F. , Polze, N. , Luther, D. , Spies, C.D. Article Type: Research Article Abstract: Introduction: The studys objective was to determine the effects of the administration of N-acetylcysteine (NAC) and of tirilazad mesylate (TM) on intestinal functional capillary density, mesenteric plasma extravasation, leukocyte adherence and on cytokine release during experimental endotoxemia in rats. Methods: In a prospective, randomized, controlled animal study, 80 male Wistar rats were examined in 2 test series. Both series were divided into 4 groups. Group 1 served as control group (CON group). Group 2 (LPS group), group 3 (NAC group) and group 4 (TM group) received endotoxin infusions (10 mg/kg over 2 h). In NAC group 150 mg/kg body …weight NAC was administered after the first 30 minutes of endotoxemia intravenously. In TM group, 10 mg/kg body weight TM was administered after the first 30 minutes of endotoxemia ...
Authors: Birnbaum, J. , Lehmann, Ch. , Klotz, E. , Hein, O. Vargas , Blume, A. , Jubin, F. , Polze, N. , Luther, D. , Spies, C.D. Article Type: Research Article Abstract: Introduction: The studys objective was to determine the effects of the administration of N-acetylcysteine (NAC) and of tirilazad mesylate (TM) on intestinal functional capillary density, mesenteric plasma extravasation, leukocyte adherence and on cytokine release during experimental endotoxemia in rats. Methods: In a prospective, randomized, controlled animal study, 80 male Wistar rats were examined in 2 test series. Both series were divided into 4 groups. Group 1 served as control group (CON group). Group 2 (LPS group), group 3 (NAC group) and group 4 (TM group) received endotoxin infusions (10 mg/kg over 2 h). In NAC group 150 mg/kg body …weight NAC was administered after the first 30 minutes of endotoxemia intravenously. In TM group, 10 mg/kg body weight TM was administered after the first 30 minutes of endotoxemia ...
Nitric oxide (NO) has been reported to have a protective function in attenuating hepatic injury during endotoxemia or sepsis. As a result, the role of NO in attenuating the hepatic microcirculatory alterations associated with endotoxemia was investigated in mice by in vivo microscopy. The livers were examined 2 h after intravenous injection of Escherichia coli 0111:B4 lipopolysaccharide (LPS) alone or in combination with inhibitors of the synthesis of NO, NG-nitro-L-arginine methyl ester or NG-monomethyl-L-arginine. In the animals treated with the combination of NO synthase inhibitors and LPS, leukocyte adherence was increased threefold above that in animals treated with LPS alone. This was accompanied by a 33% reduction in sinusoidal blood flow. Simultaneous administration of L-arginine, but not D-arginine, eliminated these microcirculatory disturbances. The results demonstrate that inhibition of LPS-stimulated NO production results in an early hepatic microvascular inflammatory response to a dose of
TY - JOUR. T1 - Endotoxemia is associated with acute coronary syndrome in patients with end stage kidney disease. AU - Hsu, Chien Chin. AU - Wei, Tsui Shan. AU - Huang, Chien Cheng. AU - Chen, Yi Ming. PY - 2017/7/12. Y1 - 2017/7/12. N2 - Background: Cardiovascular disease is the major cause of death in patients with end-staged kidney disease (ESRD). Most ESRD patients have systemic inflammation, and increasing the risk of cardiovascular event. Endotoxin derived from lipopolysaccharide of Gram negative bacteria accounts for 70% of intestinal bacteria, leading to release of proinflammatory cytokines and negative cardiovascular effect. Impaired intestinal barriers have been found in some ESRD patients, and may lead to bacteria translocation from gastrointestinal tract. We aim to investigate the association of endotoxemia in ESRD patients and acute coronary syndrome (ACS). Methods: We collected serum from adult ESRD patients who presented to emergency department (ED) with ACS (30 patients) or ...
TY - JOUR. T1 - Acute ethanol intoxication and endotoxemia after trauma. AU - Woodman, George E.. AU - Fabian, Timothy C.. AU - Croce, Martin A.. AU - Proctor, Kenneth G.. PY - 1996/7/1. Y1 - 1996/7/1. N2 - To determine actions of acute intoxication on pathophysiologic responses to trauma, anesthetized and ventilated mongrel pigs received a 20% solution of ethanol (EtOH) by an intravenous (IV group; 2 g/kg, n = 8) or an oral (PO group; 3 g/kg, n = 12 x 60 minutes) route of administration, or the lactated Ringers vehicle (LR group; n = 12). After 60 minutes, all were subjected to soft tissue injury and 30 to 35% hemorrhage, 60-minute shock, and then resuscitation, with shed blood plus supplemental LR. After 3 days, host defense was challenged with Escherichia coli lipopolysaccharide (LPS); (1 μg/kg x 30-minutes IV). The supplemental resuscitation was identical (50-53 mL/kg/hours), but posttraumatic acidosis was observed in the IV group and the PO group (base deficit = 4.4 ± 1.3 and 5.5 ± 0.9 ...
TY - JOUR. T1 - Detection of interleukin 1α and 1β in rabbit tissues during endotoxemia using sensitive radioimmunoassays. AU - Clark, B. D.. AU - Bedrosian, I.. AU - Schindler, R.. AU - Cominelli, F.. AU - Cannon, Joseph Gerard. AU - Shaw, A. R.. AU - Dinarello, C. A.. PY - 1991/12/1. Y1 - 1991/12/1. N2 - Interleukin 1 (IL-1) is a primary mediator of a wide variety of immunologic and inflammatory responses, including reactions to microbial infections. To study this cytokine in an animal model, we have developed specific and sensitive radioimmunoassays for the quantitation of rabbit IL- 1α and IL-1β. The sensitivity (limit of detection at 95% confidence level) of our assay for IL-1α and 1β was 20-40 and 40-80 pg/ml, respectively. Recovery of IL-1 from tissues ranged from 75 to 107%, with a mean of 95% for IL-1α and 89% (range 19-98) for IL-1β. We employed these assays in in vivo and in vitro studies. In an in vivo model, we measured the amount of rabbit IL-1α and 1β protein present in ...
Disordered coagulation contributes to death in sepsis and lacks effective treatments. Existing markers of disseminated intravascular coagulation (DIC) reflect its sequelae rather than its causes, delaying diagnosis and treatment. Here we show that disruption of the endothelial Tie2 axis is a sentinel event in septic DIC. Proteomics in septic DIC patients revealed a network involving inflammation and coagulation with the Tie2 antagonist, angiopoietin-2 (Angpt-2), occupying a central node. Angpt-2 was strongly associated with traditional DIC markers including platelet counts, yet more accurately predicted mortality in 2 large independent cohorts (combined N = 1,077). In endotoxemic mice, reduced Tie2 signaling preceded signs of overt DIC. During this early phase, intravital imaging of microvascular injury revealed excessive fibrin accumulation, a pattern remarkably mimicked by Tie2 deficiency even without inflammation. Conversely, Tie2 activation normalized prothrombotic responses by inhibiting ...
Disordered coagulation contributes to death in sepsis and lacks effective treatments. Existing markers of disseminated intravascular coagulation (DIC) reflect its sequelae rather than its causes, delaying diagnosis and treatment. Here we show that disruption of the endothelial Tie2 axis is a sentinel event in septic DIC. Proteomics in septic DIC patients revealed a network involving inflammation and coagulation with the Tie2 antagonist, angiopoietin-2 (Angpt-2), occupying a central node. Angpt-2 was strongly associated with traditional DIC markers including platelet counts, yet more accurately predicted mortality in 2 large independent cohorts (combined N = 1,077). In endotoxemic mice, reduced Tie2 signaling preceded signs of overt DIC. During this early phase, intravital imaging of microvascular injury revealed excessive fibrin accumulation, a pattern remarkably mimicked by Tie2 deficiency even without inflammation. Conversely, Tie2 activation normalized prothrombotic responses by inhibiting ...
Disturbed homeostasis as a result of tissue stress can provoke leukocyte responses enabling recovery. Since mild hypothermia displays specific clinically relevant tissue-protective properties and interleukin (IL)-22 promotes healing at host/environment interfaces, effects of lowered ambient temperature on IL-22 were studied. We demonstrate that a 5h exposure of endotoxemic mice to 4°C reduces body temperature by 5.0 degrees and enhances splenic and colonic il22 gene expression. In contrast, tumor necrosis factor (TNF)-a and IL-17A were not increased. In vivo data on IL-22 were corroborated using murine splenocytes and human peripheral blood mononuclear cells (PBMC) cultured upon 33°C and polyclonal T cell activation. Upregulation by mild hypothermia of largely T-cell-derived IL-22 in PBMC required monocytes and associated with enhanced nuclear T-cell NFATc2. Notably, nuclear factor of activated T cells (NFAT) antagonism by cyclosporine A or FK506 impaired IL-22 upregulation at normothermia and
The present study tested whether aging alters endotoxin-induced myocardial dysfunction in a sublethal model of endotoxemia in rats. The main findings were the following: 12 hours after LPS injection (0.5 mg/kg), a marked reduction in myocardial contractility was observed in the isolated perfused senescent heart; in contrast with septic cardiac dysfunction in young rats, myofilament Ca2+ sensitivity of left ventricular skinned fibers was not reduced in senescent rats; and NO production, oxidative stress, and antioxidant enzymes activities were not different between young adult and senescent LPS groups. Thus, despite similar alterations in potential mediators, cellular mechanisms responsible for this contractile dysfunction are different between young adult and senescent rats. More specifically, myofilament Ca2+ responsiveness remains unaltered in the senescent heart. This may have clinical implications for management of elderly septic patients.. Nonlethal models of endotoxemia have allowed ...
Cardiovascular dysfunction is common in severe sepsis or septic shock. Although functional alterations are often described, the elevated serum levels of cardiac proteins and autopsy findings of myocardial immune cell infiltration, edema, and damaged mitochondria suggest that structural changes to the heart during severe sepsis and septic shock may occur and may contribute to cardiac dysfunction. We explored the available literature on structural (versus functional) cardiac alterations during experimental and human endotoxemia and/or sepsis. Limited data suggest that the structural changes could be prevented, and myocardial function improved by (pre-)treatment with platelet-activating factor, cyclosporin A, glutamine, caffeine, simvastatin, or caspase inhibitors. ...
In this paper we discuss approaches for integrating biological information reflecting diverse physiologic levels. In particular we explore statistical and model-based methods for integrating transcriptomic, proteomic and metabolomics data. Our case studies reflect responses to a systemic inflammatory stimulus and in response to an anti-inflammatory treatment. Our paper serves partly as a review of existing methods and partly as a means to demonstrate, using case studies related to human endotoxemia and response to methylprednisolone treatment, how specific question may require appropriate methods, thus emphasizing the non-uniqueness of the approaches. Finally, we explore novel ways for integrating -omics information with PKPD models, towards the development of more integrated pharmacology models.
Lectins are a family of glycoproteins (a complex protein containing a carbohydrate combined with a simple protein) found in the plant kingdom, including grains, legumes and solanacous plants (tomatoes, potatoes, eggplants and peppers)21, 27. Lectins also have the ability to bind sugar containing molecules. They were first studied for their ability to agglutinate (cause to adhere) red blood cells by binding to their cell membranes. Many lectins present in other foods are harmless, but some lectins found in grains, legumes and solanaceous plants have been shown to be harmful to human physiology28. Lectins are resistant to heat (unless cooked by pressure cooking)29 and digestive enzymes38, and therefore arrive intact when they reach the intestinal epithelium, passing through the intestinal barrier into peripheral circulation. Lectins are able to bind peripheral tissues, producing many deleterious health effects21. Furthermore, lectins disrupt intestinal barrier and immunological function when they ...
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This study demonstrates that a systems biology approach (correlation-network analysis) can be used to identify key linkages between the microbiome, inflammatory milieu, endotoxemia, and cognition in patients with HE. The IL-23 system was highly correlated with several bacterial families in patients within the HE group, and there was a direct correlation between cognition, Porphyromonadaceae, and Alcaligeneceae. We found significant differences between the microbial flora of age-matched healthy controls to the cirrhotic population with a higher degree of difference in patients with HE. The study showed that there was no significant difference in the stool flora between patients with HE on lactulose compared with those additionally on rifaximin. The results also indicate that a systematic withdrawal of lactulose therapy had minimal effect on the gut microflora abundance.. To date, it has been difficult to identify significant differences between control and disease groups using classic ...
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Human in vivo models of systemic inflammation are used to study the physiological mechanisms of inflammation and the effect of drugs and nutrition on the imm...