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Endotoxaemia is an inflammatory condition which happens due to the presence of outer cell wall layer of Gram-negative bacteria in blood circulation, containing lipopolysaccharide commonly known as endotoxin. This condition causes high mortality in affected animals and sheep are highly suscepti-ble in this regard. Several researchers have emphasised the therapeutic regimens of endotoxaemia and its sequels in sheep. Furthermore, sheep are among the most commonly used animal species in ex-perimental studies on endotoxaemia, and for the past five decades, ovine models have been employed to evaluate different aspects of endotoxaemia. Currently, there are several studies on experimentally induced endotoxaemia in sheep, and information regarding novel therapeutic protocols in this species contributes to better understanding and treating the condition. This review aims to specifically intro-duce various treatment methods of endotoxaemia in sheep.

Purpose: Myocardial injury is a common complication in patients with endotoxaemia/sepsis, especially in children. Moreover, it develops through an unclear pathophysiological mechanism, and effective therapies are lacking. Recently, RNA modification, particularly N6-methyladenosine (m6A) modification, has been found to be involved in various physiological processes and to play important roles in many diseases. However, the role of m6A modification in endotoxaemia/sepsis-induced myocardial injury is still in its infancy. Therefore, we attempted to construct the m6A modification map of myocardial injury in a rat model treated by lipopolysaccharide (LPS) and explore the role of m6A modification in LPS-induced myocardial injury. Method: Myocardial injury adolescent rat model was constructed by intraperitoneal injection of LPS. m6A RNA Methylation Quantification Kit was used to detect overall level of m6A modification in rat cardiac tissue. m6A-specific methylated RNA immunoprecipitation followed by high-throughput sequencing (MeRIP-seq) and RNA sequencing (RNA-seq) were conducted to identify the altered m6A-modified genes and differentially expressed genes in cardiac tissue of rats treated by LPS and control rats (6 versus. 6). Bioinformatics was used to analyze the functions of differentially m6A modified genes, differentially expressed genes, and genes with both differential m6A modification and differential expression. qPCR was used to detect expression of m6A modification related enzymes. Result: We found that the overall level of m6A modification in cardiac tissue of the LPS group was up-regulated compared with that of the control group. MeRIP-seq and RNA-seq results showed that genes with differential m6A modification, genes with differential expression and genes with both differential m6A modification and differential expression were closely associated with inflammatory responses and apoptosis. In addition, we found that m6A-related enzymes (Mettl16, Rbm15, Fto, Ythdc2 and Hnrnpg) were differentially expressed in the LPS group versus. the control group. Conclusion: m6A modification is involved in the pathogenesis process of LPS-induced myocardial injury, possibly through the regulation of inflammatory response and apoptosis-related pathways. These results provide valuable information regarding the potential pathogenic mechanisms underlying LPS-induced myocardial injury. [ABSTRACT FROM AUTHOR]

Summary: The traditional approach to exertional heat illness (EHI) is based on the premise that external heat is the trigger and sole driver of the condition. During the last few decades, many researchers have suggested that climatic heat alone does not fully explain the pathophysiology of EHI, and a second pathway has been proposed which focuses on the gastrointestinal tract (GIT). The causal agent of EHI in Thoroughbred racehorses is the strenuous exercise of racing. The generation of metabolic heat is prodigious and can cause direct injury to the GIT. The associated redistribution of cardiac output to working muscles is most likely to subject the GIT to substantial hypo‐perfusion and if horses race under hot/humid conditions impairing thermoregulation this may exacerbate intestinal hyperthermia. Evidence in human athletes shows that the combination of intestinal hyperthermia and reduced blood flow causes a breakdown in the integrity of the mucosal barrier and leads to increased intestinal permeability, allowing leakage of endotoxin into the central circulation. Normally, protective immune mechanisms clear elevated endotoxin levels, but if there is immune dysfunction and the concentration of endotoxin exceeds a certain threshold, a systemic inflammatory response triggers a cytokine cascade with serious downstream consequences. It is argued that the cytokine inflammatory cascade, rather than core body hyperthermia contributes to the clinical progression of EHI when endotoxaemia is dominant. The authors have presented the current state of knowledge for human subjects and cited studies in racehorses which suggest its relevance. Acknowledgement of the gastrointestinal inflammatory pathway for EHI is important because it provides track veterinarians with a different perspective on prevention and treatment. [ABSTRACT FROM AUTHOR]

Rationale: Sepsis is a severe inflammatory response to infection that leads to long-lasting cognitive impairment and depression after resolution. The lipopolysaccharide (LPS)-induced endotoxaemia model is a well-established model of gram-negative bacterial infection and recapitulates the clinical characteristics of sepsis. However, whether LPS-induced endotoxaemia during adolescence can modulate depressive and anxiety-like behaviours in adulthood remains unclear. Objectives: To determine whether LPS-induced endotoxaemia in adolescence can modulate the stress vulnerability to depressive and anxiety-like behaviours in adulthood and explore the underlying molecular mechanisms. Methods: Quantitative real-time PCR was used to measure inflammatory cytokine expression in the brain. A stress vulnerability model was established by exposure to subthreshold social defeat stress (SSDS), and depressive- and anxiety-like behaviours were evaluated by the social interaction test (SIT), sucrose preference test (SPT), tail suspension test (TST), force swimming test (FST), elevated plus-maze (EPM) test, and open field test (OFT). Western blotting was used to measure Nrf2 and BDNF expression levels in the brain. Results: Our results showed that inflammation occurred in the brain 24 h after the induction of LPS-induced endotoxaemia at P21 but resolved in adulthood. Furthermore, LPS-induced endotoxaemia during adolescence promoted the inflammatory response and the stress vulnerability after SSDS during adulthood. Notably, the expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and BDNF in the mPFC were decreased after SSDS exposure in mice treated with LPS during adolescence. Activation of the Nrf2-BDNF signalling pathway by sulforaphane (SFN), an Nrf2 activator, ameliorated the effect of LPS-induced endotoxaemia during adolescence on stress vulnerability after SSDS during adulthood. Conclusions: Our study identified adolescence as a critical period during which LPS-induced endotoxaemia can promote stress vulnerability during adulthood and showed that this effect is mediated by impairment of Nrf2-BDNF signalling in the mPFC. [ABSTRACT FROM AUTHOR]

Abstract Background Endotoxaemia is believed to be a major cause of mortality and there are several therapeutic regimens for the treatment of this situation. Objectives The present experimental study was conducted to evaluate acute phase response, cardiovascular and hepatorenal damages following the treatment of Ovine experimental endotoxaemia model employing unfractionated heparin (UFH). Materials and Methods Twenty clinically healthy 1‐year‐old fat‐tailed ewes were randomly divided into four equal groups, comprising UFH 200, UFH 400, Ctrl+ and Ctrl‐. Lipopolysaccharide (LPS) from Escherichia coli serotype O55:B5 at 0.4 μg/kg was administered intravenously to the ewes. UFH (at 200 and 400 IU/kg) was administrated to the UFH 200 and UFH 400 groups, respectively. All the ewes were evaluated clinically before and 1.5, 3, 4.5, 6 and 24 hours after LPS injection. Blood samplings were also performed at those hours. We measured serum concentrations of haptoglobin, interferon‐gamma, total antioxidant status, malondialdehyde, cardiac lactate dehydrogenase, cardiac troponin‐I, total bilirubin, alanine transaminase and creatinine. Serum concentrations of acute phase response, cardiovascular, hepatic and renal biomarkers and clinical parameters increased significantly following the induction of endotoxaemia in the groups receiving LPS. Results The significantly lowest concentrations of these parameters at hours 4.5 and 6 among the treatment groups belonged to the UFH 400 sheep. Conclusions UFH could act as an anti‐inflammatory mediator by decreasing inflammatory cytokines and acute phase proteins, modulating oxidative stress biomarkers and reducing multiple organ dysfunction following endotoxaemia in a dose–dependent manner. Furthermore, the anti‐inflammatory effects of UFH at 400 IU/kg were significantly higher than another dose. This research examined the effect of two doses of UFH and higher doses may have more anti‐inflammatory effects that require further studies.

PurposeMyocardial injury is a common complication in patients with endotoxaemia/sepsis, especially in children. Moreover, it develops through an unclear pathophysiological mechanism, and effective therapies are lacking. Recently, RNA modification, particularly N6-methyladenosine (m6A) modification, has been found to be involved in various physiological processes and to play important roles in many diseases. However, the role of m6A modification in endotoxaemia/sepsis-induced myocardial injury is still in its infancy. Therefore, we attempted to construct the m6A modification map of myocardial injury in a rat model treated by lipopolysaccharide (LPS) and explore the role of m6A modification in LPS-induced myocardial injury.MethodMyocardial injury adolescent rat model was constructed by intraperitoneal injection of LPS. m6A RNA Methylation Quantification Kit was used to detect overall level of m6A modification in rat cardiac tissue. m6A-specific methylated RNA immunoprecipitation followed by high-throughput sequencing (MeRIP-seq) and RNA sequencing (RNA-seq) were conducted to identify the altered m6A-modified genes and differentially expressed genes in cardiac tissue of rats treated by LPS and control rats (6 versus. 6). Bioinformatics was used to analyze the functions of differentially m6A modified genes, differentially expressed genes, and genes with both differential m6A modification and differential expression. qPCR was used to detect expression of m6A modification related enzymes.ResultWe found that the overall level of m6A modification in cardiac tissue of the LPS group was up-regulated compared with that of the control group. MeRIP-seq and RNA-seq results showed that genes with differential m6A modification, genes with differential expression and genes with both differential m6A modification and differential expression were closely associated with inflammatory responses and apoptosis. In addition, we found that m6A-related enzymes (Mettl16, Rbm15, Fto, Ythdc2 and Hnrnpg) were differentially expressed in the LPS group versus. the control group.Conclusionm6A modification is involved in the pathogenesis process of LPS-induced myocardial injury, possibly through the regulation of inflammatory response and apoptosis-related pathways. These results provide valuable information regarding the potential pathogenic mechanisms underlying LPS-induced myocardial injury.

The effects of the human endotoxin challenge on tissue pharmacokinetics are unknown. In the present study, we aimed to assess the effect of the endotoxin challenge on interstitial fluid pharmacokinetics of tedizolid in healthy volunteers using intramuscular microdialysis. Eight healthy male subjects were treated with 200 mg of tedizolid phosphate for 6 days. On Day 6, an intravenous bolus of lipopolysaccharide (LPS) (2 ng/kg body weight) was administered. LPS infusion did not affect plasma pharmacokinetics of tedizolid. In contrast, following LPS infusion, median muscle tissue fAUC (0.83 [0.75–1.15] vs. 1.14 [1.11–1.43] mg × h/L, P =.0078) and muscle tissue fCmax (0.15 [0.14–0.19] vs. 0.19 [0.18–0.24] mg/L, P =.0078) were significantly increased by 38% and 24%, respectively. The human endotoxin challenge was associated with increased tissue concentrations of tedizolid, without affecting its plasma concentration–time profile. The human endotoxin challenge combined with microdialysis may be used to investigate the influence of systemic inflammation on tissue pharmacokinetics. [ABSTRACT FROM AUTHOR]

Background: According to the leaky gut concept, microbial products (e.g., lipopolysaccharide, LPS) enter the circulation and mediate pro-inflammatory immunological responses. Higher plasma LPS levels have been reported in patients with various cardiovascular diseases, but not specifically during early atrial fibrillation (AF). Methods: We studied data and blood samples from patients presenting with first-diagnosed AF (FDAF) (n = 80) and 20 controls. Results: Circulating biomarkers that are suggestive of mucosal inflammation (zonulin, mucosal adhesion molecule MAdCAM-1) and intestinal epithelium damage (intestinal fatty acid binding protein, IFABP) were increased in the plasma of patients with FDAF when compared to patients with chronic cardiovascular diseases but without AF. Surrogate plasma markers of increased intestinal permeability (LPS, CD14, LPS-binding protein, gut-derived LPS-neutralising IgA antibodies, EndoCAbs) were detected during early AF. A reduced ratio of IgG/IgM EndoCAbs titres indicated chronic endotoxaemia. Collagen turnover biomarkers, which corresponded to the LPS values, suggested an association of gut-derived low-grade endotoxaemia with adverse structural remodelling. The LPS concentrations were higher in FDAF patients who experienced a major adverse cardiovascular event. Conclusions: Intestinal barrier dysfunction and microbial translocation accompany FDAF. Improving gut permeability and low-grade endotoxaemia might be a potential therapeutic approach to reducing the disease progression and cardiovascular complications in FDAF. [ABSTRACT FROM AUTHOR]

Clinical studies in healthy volunteers challenged with lipopolysaccharide (LPS), a constituent of the cell wall of Gram‐negative bacteria, represent a key model to characterize the Toll‐like receptor 4 (TLR4)‐mediated inflammatory response. Here, we developed a mathematical modelling framework to quantitatively characterize the dynamics and inter‐individual variability of multiple inflammatory biomarkers in healthy volunteer LPS challenge studies. Data from previously reported LPS challenge studies were used, which included individual‐level time‐course data for tumour necrosis factor α (TNF‐α), interleukin 6 (IL‐6), interleukin 8 (IL‐8) and C‐reactive protein (CRP). A one‐compartment model with first‐order elimination was used to capture the LPS kinetics. The relationships between LPS and inflammatory markers was characterized using indirect response (IDR) models. Delay differential equations were applied to quantify the delays in biomarker response profiles. For LPS kinetics, our estimates of clearance and volume of distribution were 35.7 L h−1 and 6.35 L, respectively. Our model adequately captured the dynamics of multiple inflammatory biomarkers. The time delay for the secretion of TNF‐α, IL‐6 and IL‐8 were estimated to be 0.924, 1.46 and 1.48 h, respectively. A second IDR model was used to describe the induced changes of CRP in relation to IL‐6, with a delayed time of 4.2 h. The quantitative models developed in this study can be used to inform design of clinical LPS challenge studies and may help to translate preclinical LPS challenge studies to humans. [ABSTRACT FROM AUTHOR]

Background: Microcirculation is the essential link between macrocirculation and cellular metabolism., Objectives: To test our hypotheses that microcirculation variables will show a heterogeneous flow pattern during experimental endotoxaemia, and that fluid therapy and noradrenaline (NA) infusion will normalise altered microcirculation variables., Study Design: In vivo experiments., Methods: Six healthy adult horses were anaesthetised with dexmedetomidine, ketamine, and diazepam and were mechanically ventilated under isoflurane anaesthesia. Endotoxaemia was induced with 30 ng kg -1 Escherichia coli lipopolysaccharide intravenously. One hundred and twenty minutes later fluid bolus and noradrenaline (NA) infusion were administered to produce normotension. Pulse rate (PR) and mean arterial blood pressure (MAP) were measured and microcirculation variables were obtained by side-stream darkfield technique (de Backer density (DBD), perfused de Backer density (PDBD), proportion of perfused vessels, microvascular flow index (MFI), heterogeneity index (HI)), laser Doppler flowmetry (blood flow) and white light spectrometry (tissue oxygen saturation (tSO 2 )) in sublingual, jejunal and genital area. Measurements were obtained at baseline, after endotoxin, at 60 and 120 min and during the normotensive phase. Data were analysed by mixed model variance analysis and Tukey-Kramer., Results: The PPV decreased significantly over time by 30% (p < 0.001) at the jejunum. MFI decreased from baseline to ET60 and from baseline to ET120 in sublingual and genital mucosa (2.9 vs. 1.4, p < 0.001 and 2.8 vs. 1.9, p < 0.01), respectively. The sublingual HI increased from baseline to ET60, ET120 and NA (0.1 vs. 0.9, p = 0.02; vs. 0.6, p = 0.01; vs. 0.3, p = 0.01), respectively. The genital HI increased from baseline to ET120 (0.2 vs. 1.1, p ≤ 0.01) and NA (0.16 vs. 0.53, p < 0.05, respectively). Moderate agreement between observers for MFI assessment was present (kappa = 0.4). The PR significantly increased, and MAP significantly decreased from baseline over time., Main Limitations: The obtained data could be influenced by secretions, pressure artefacts, the experience of the examiner and the sampling location. Blood flow was not quantified and there was no control group., Conclusions: Overall, short-term experimental endotoxaemia did negatively alter MFI and HI; however, it did not alter tSO 2 , blood flow, DBD, PDBD or proportion of perfused vessels. Intravenous fluid therapy and NA did not restore MFI and HI to baseline values., (© 2025 The Author(s). Equine Veterinary Journal published by John Wiley & Sons Ltd on behalf of EVJ Ltd.)

Background: Endotoxaemia is a common condition in equids, frequently accompanied by alterations in haemostasis. Non-steroidal anti-inflammatory drugs, such as meloxicam, have been proven to alleviate some signs of endotoxaemia in donkeys. Neither the haemostatic response to induced endotoxaemia nor the effect of meloxicam in this regard have been described in donkeys., Objectives: (a) To characterise the haemostatic changes in response to induced endotoxaemia in healthy donkeys, and (b) to assess the effect of meloxicam in these animals., Study Design: In vivo experiments., Methods: Endotoxaemia was induced by LPS (20 ng/kg) infusion in six healthy adult Andalusian donkeys. All animals randomly received either an IV bolus of saline solution (untreated group) or meloxicam (0.6 mg/kg) after LPS infusion (PLI), with a 1-month washout period between trials. Samples were collected at -30, 0, 30, 60, 90, 120, 180 and 360 min PLI for clotting times, antithrombin III, anti-Xa activities, platelet and fibrinogen concentrations; and at -30, 90, 180 and 360 min PLI for viscoelastography (Sonoclot)., Results: LPS caused prothrombotic-specific viscoelastographic changes (short activated clot time and elongated clot rate formation) and lower antithrombin III activities compared with reference range for this species. Prolonged prothrombin times were also seen at late timepoints in the experiment. Meloxicam administration resulted in no significant differences between groups., Main Limitations: Short sampling duration, only Andalusian donkeys., Conclusions: Acute endotoxaemia induced hypercoagulability and initial signs of a consumptive coagulopathy in donkeys. Despite a more prolonged increase in anti-Xa activity, meloxicam did not ameliorate most of these haemostatic changes., (© 2025 EVJ Ltd.)

Background: Endotoxaemia causes untoward inflammatory‐mediated effects that might be attenuated by dexmedetomidine. Objectives: To evaluate the effects of a dexmedetomidine intravenous (IV) infusion on systemic and intestinal haemodynamics and arterial blood gas values in sevoflurane‐anaesthetised horses administered Escherichia coli O55:B5 lipopolysaccharides (LPS). Study design: Randomised controlled in vivo experiment. Methods: A total of 13 horses weighing 456 ± 86 kg (mean ± standard deviation) and aged 13.9 ± 9.0 years donated for euthanasia underwent ventral midline celiotomy using sevoflurane anaesthesia. Baseline physiological variables were recorded after a 90‐minute equilibration period. All horses were given 0.1 mcg/kg bwt LPS IV. Horses were randomly assigned to no further treatment (group LPS; seven horses) or IV administration of dexmedetomidine (loading dose 1.75 mcg/kg bwt followed by 1.75 mcg/kg bwt/h; group LPS–Dex; six horses) with concurrent target sevoflurane dose reduction of 50%. Cardiac index (CI; thermodilution), intestinal blood flow, arterial blood parameters and plasma dexmedetomidine concentration measurements were recorded every 30 minutes until euthanasia at 390 minutes. Data were compared between and within groups to baseline using a mixed model analysis (significance P <.05). Results: In LPS‐Dex horses, intestinal blood flow and CI were transiently decreased after the dexmedetomidine loading dose, but no significant differences were found compared with baseline during the infusion. Sevoflurane dose was reliably reduced by approximately 40%. Significant differences were identified in creatinine (115 umol/L LPS‐Dex; 195 umol/L LPS), bicarbonate (29.7 mmol/L LPS‐Dex; 23 mmol/L LPS) and base excess (2.0 mmol/L LPS‐Dex; −5.3 mmol/L LPS). Dexmedetomidine plasma concentrations were highest after the loading dose and stable during infusion dosing. Main limitations: Experimental conditions are not reflective of clinical colic management. Conclusions: A dexmedetomidine infusion with sevoflurane dose reduction attenuated some deleterious changes in anaesthetised horses administered LPS without sustained negative cardiovascular effects and may be beneficial during colic surgery. [ABSTRACT FROM AUTHOR]

Background: Endotoxaemia is believed to be a major cause of mortality and there are several therapeutic regimens for the treatment of this situation. Objectives: The present experimental study was conducted to evaluate acute phase response, cardiovascular and hepatorenal damages following the treatment of Ovine experimental endotoxaemia model employing unfractionated heparin (UFH). Materials and Methods: Twenty clinically healthy 1‐year‐old fat‐tailed ewes were randomly divided into four equal groups, comprising UFH 200, UFH 400, Ctrl+ and Ctrl‐. Lipopolysaccharide (LPS) from Escherichia coli serotype O55:B5 at 0.4 μg/kg was administered intravenously to the ewes. UFH (at 200 and 400 IU/kg) was administrated to the UFH 200 and UFH 400 groups, respectively. All the ewes were evaluated clinically before and 1.5, 3, 4.5, 6 and 24 hours after LPS injection. Blood samplings were also performed at those hours. We measured serum concentrations of haptoglobin, interferon‐gamma, total antioxidant status, malondialdehyde, cardiac lactate dehydrogenase, cardiac troponin‐I, total bilirubin, alanine transaminase and creatinine. Serum concentrations of acute phase response, cardiovascular, hepatic and renal biomarkers and clinical parameters increased significantly following the induction of endotoxaemia in the groups receiving LPS. Results: The significantly lowest concentrations of these parameters at hours 4.5 and 6 among the treatment groups belonged to the UFH 400 sheep. Conclusions: UFH could act as an anti‐inflammatory mediator by decreasing inflammatory cytokines and acute phase proteins, modulating oxidative stress biomarkers and reducing multiple organ dysfunction following endotoxaemia in a dose–dependent manner. Furthermore, the anti‐inflammatory effects of UFH at 400 IU/kg were significantly higher than another dose. This research examined the effect of two doses of UFH and higher doses may have more anti‐inflammatory effects that require further studies. [ABSTRACT FROM AUTHOR]

Background: According to the leaky gut concept, microbial products (e.g., lipopolysaccharide, LPS) enter the circulation and mediate pro-inflammatory immunological responses. Higher plasma LPS levels have been reported in patients with various cardiovascular diseases, but not specifically during early atrial fibrillation (AF). Methods: We studied data and blood samples from patients presenting with first-diagnosed AF (FDAF) (n = 80) and 20 controls. Results: Circulating biomarkers that are suggestive of mucosal inflammation (zonulin, mucosal adhesion molecule MAdCAM-1) and intestinal epithelium damage (intestinal fatty acid binding protein, IFABP) were increased in the plasma of patients with FDAF when compared to patients with chronic cardiovascular diseases but without AF. Surrogate plasma markers of increased intestinal permeability (LPS, CD14, LPS-binding protein, gut-derived LPS-neutralising IgA antibodies, EndoCAbs) were detected during early AF. A reduced ratio of IgG/IgM EndoCAbs titres indicated chronic endotoxaemia. Collagen turnover biomarkers, which corresponded to the LPS values, suggested an association of gut-derived low-grade endotoxaemia with adverse structural remodelling. The LPS concentrations were higher in FDAF patients who experienced a major adverse cardiovascular event. Conclusions: Intestinal barrier dysfunction and microbial translocation accompany FDAF. Improving gut permeability and low-grade endotoxaemia might be a potential therapeutic approach to reducing the disease progression and cardiovascular complications in FDAF.

Evidence suggests that immunosuppressant therapies protect against harmful effects of endotoxaemia. In this study, we tested whether calcineurin‐dependent (cyclosporine/tacrolimus) and ‐independent (sirolimus) immunosuppressants variably influence nephrotoxicity induced by endotoxaemia and whether this interaction is modulated by testosterone. We investigated the effects of immunosuppressants on renal histopathological, biochemical and inflammatory profiles in endotoxic male rats and the role of androgenic state in the interaction. Six‐hour treatment of rats with lipopolysaccharide (LPS, 3 mg/kg) increased (i) serum urea/creatinine, (ii) width of proximal/distal tubules, (iii) tubular degeneration and vacuolation, (iv) Western protein expressions of renal toll‐like receptor 4, monocyte chemoattractant protein‐1, and NADPH oxidase‐2, and (v) serum tumour necrosis factor‐α and myeloperoxidase. These endotoxic manifestations were intensified and eliminated upon concurrent exposure to cyclosporine and sirolimus, respectively. The cyclosporine actions appear to be a class rather than a drug effect because similar exacerbation of LPS nephrotoxicity was observed in rats treated with tacrolimus, another calcineurin inhibitor (CNI). Moreover, the deteriorated renal outcomes in LPS/tacrolimus‐treated rats were reduced after castration or androgen receptor blockade by flutamide. The data suggest opposite effects for calcineurin‐dependent (exaggeration) and ‐independent immunosuppressants (amelioration) on renal defects of endotoxaemia and implicate androgenic pathways in the worsened endotoxic renal profile induced by CNIs. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Gram-negative lipopolysaccharides are potent inducers of inflammation and have been shown to be present in patients with end-stage kidney disease. There are a variety of different manufacturers and assay types to quantify endotoxin levels; however, there is no standard methodology to demonstrate its presence in plasma. A control group consisting of haemodialysis and non-kidney disease was selected. Five sets of experiments were conducted to try and ascertain the best platform for plasma endotoxin testing. This included: testing of blank tubes; the effects of freezing, thawing and storage on recovery; the effect of different buffers; use of an endpoint assay and comparison of turbidimetric vs. chromogenic kinetic assays. No endotoxin was detected in the blood collection tubes. Freezing and thawing per se did not affect spike recovery rates. However, the sequencing of sample dilution relative to freezing had a significant effect on endotoxin recovery. Buffers increased spike recovery at all levels of dilution. No endotoxin was demonstrated with either the turbidimetric or chromogenic kinetic assay at two different dilutions in the haemodialysis controls. The endpoint assay at a 1:5 dilution did not achieve a valid standard curve. The findings of our study suggest that, when testing plasma samples, either a turbidimetric or chromogenic assay may be used and should be diluted with appropriate buffers to achieve optimal recovery. Studies looking to quantify the presence of plasma endotoxin need to internally validate their assays and specify their validation findings in their results. [ABSTRACT FROM AUTHOR]

Background: Immunosuppression after surgery is associated with postoperative complications, mediated in part by catecholamines that exert anti-inflammatory effects via the β-adrenergic receptor. Phenylephrine, generally regarded as a selective α-adrenergic agonist, is frequently used to treat perioperative hypotension. However, phenylephrine may impair host defence through β-adrenergic affinity.Methods: Human leukocytes were stimulated with lipopolysaccharide (LPS) in the presence or absence of phenylephrine and α- and β-adrenergic antagonists. C57BL/6J male mice received continuous infusion of phenylephrine (30-50 μg kg-1 min-1 i.v.) or saline via micro-osmotic pumps, before LPS administration (5 mg kg-1 i.v.) or caecal ligation and puncture (CLP). Twenty healthy males were randomised to a 5 h infusion of phenylephrine (0.5 μg kg-1 min-1) or saline before receiving LPS (2 ng kg-1 i.v.).Results: In vitro, phenylephrine enhanced LPS-induced production of the anti-inflammatory cytokine interleukin (IL)-10 (maximum augmentation of 93%) while attenuating the release of pro-inflammatory mediators. These effects were reversed by pre-incubation with β-antagonists, but not α-antagonists. Plasma IL-10 levels were higher in LPS-challenged mice infused with phenylephrine, whereas pro-inflammatory mediators were reduced. Phenylephrine infusion increased bacterial counts after CLP in peritoneal fluid (+42%, P=0.0069), spleen (+59%, P=0.04), and liver (+35%, P=0.09). In healthy volunteers, phenylephrine enhanced the LPS-induced IL-10 response (+76%, P=0.0008) while attenuating plasma concentrations of pro-inflammatory mediators including IL-8 (-15%, P=0.03).Conclusions: Phenylephrine exerts potent anti-inflammatory effects, possibly involving the β-adrenoreceptor. Phenylephrine promotes bacterial outgrowth after surgical peritonitis. Phenylephrine may therefore compromise host defence in surgical patients and increase susceptibility towards infection.Clinical Trial Registration: NCT02675868 (Clinicaltrials.gov). [ABSTRACT FROM AUTHOR]

Objectives: The study aimed to explore the anti-inflammatory effect, underlying mechanism, and chemistry of Halodule pinifolia extract. Methods: The ethyl acetate (EHP) and methanol (MHP) extracts of Halodule pinifolia were screened for pro-inflammatory cytokine inhibition effect under various in vitro (LPSand crystal-induced inflammation) and in vivo models (LPS-induced endotoxaemia model, carrageenan-induced paw oedema model, and oxalate-induced renal nephropathy model of inflammation). The effect of EHP on the expression of inflammatory markers using western blot analysis (in vitro) was investigated. Chemical constituents of bioactive EHP were isolated through chromatography and characterised using NMR spectroscopy. Furthermore, EHP was standardised for rosmarinic acid, vanillic acid, and ethyl protocatechuate using HPLC. Also, total phytosterols, phenolic, and flavonoid content of EHP were determined by UV spectroscopy. Key findings: EHP was comparatively more effective than MHP in inhibiting cytokines secretions under LPS-induced in vitro models. Furthermore, EHP was screened under endotoxaemia in vivo model, EHP (250 mg/kg) reduced plasma IL-6, TNF-α, and IL-1β levels by 88.3%, 78.2%, and 74.5%, respectively. In the carrageenan-induced oedema model, EHP (200 mg/kg) reduced paw volume and release of TNF-α (69.3%) and IL-1β (43.1%). EHP (200 mg/kg) further controlled renal nephropathy by inhibiting plasma IL-1β and BUN levels. Also, a significant reduction of mRNA expressions of TNF-α and IL-1β and KIM-1 in renal tissues was observed. Through western blot, EHP was identified to regulate the expression of pro-form as well as mature-form of IL-1β and caspase-1. EHP constituted rosmarinic acid (RA), vanillic acid (VA), ethyl protocatechuate (EP), sitosterol, stigmasterol, campesterol, and dihydrobrassicasterol. It was determined that 4.6 mg/g of RA, 2.92 mg/g of VA, 0.76 mg/g of EP, 21.7 mg/g of total phenolics, 29.8 mg/g of total flavonoids, and 48.2 mg/g of total phytosterols were present in dry EHP. The presence of anti-inflammatory constituents such as RA, VA, and PE in EHP corroborated the in vitro and in vivo anti-inflammatory activity of EHP. Conclusion: The anti-inflammatory property of EHP and its action through attenuation of pan-cytokines suggest that it can be developed into an oral pharmaceutical drug. [ABSTRACT FROM AUTHOR]

Summary: Nonsteroidal anti‐inflammatory drugs (NSAIDs) are commonly used to manage a wide variety of conditions in horses, including management of colic. Flunixin meglumine is by far the most commonly used drug in the control of colic pain and inflammation and has become a go‐to for not only veterinarians but also horse‐owners and nonmedical equine professionals. NSAID use, however, has always been controversial in critical cases due to a high risk of adverse effects associated with their potent cyclo‐oxygenase (COX) inhibition. There are two important COX isoenzymes: COX‐1 is generally beneficial for normal renal and gastrointestinal functions and COX‐2 is associated with the pain and inflammation of disease. Newer selective NSAIDs can target COX‐2‐driven pathology while sparing important COX‐1‐driven physiology, which is of critical importance in horses with severe gastrointestinal disease. Emerging research suggests that firocoxib, a COX‐2‐selective NSAID labelled for use in horses, may be preferable for use in colic cases in spite of the decades‐long dogma that flunixin saves lives. [ABSTRACT FROM AUTHOR]

The suppression of energy metabolism is one of cornerstones of cardiac dysfunction in sepsis/endotoxaemia. To investigate the role of fatty acid oxidation (FAO) in the progression of inflammation‐induced cardiac dysfunction, we compared the effects of FAO‐targeting compounds on mitochondrial and cardiac function in an experimental model of lipopolysaccharide (LPS)‐induced endotoxaemia. In LPS‐treated mice, endotoxaemia‐induced inflammation significantly decreased cardiac FAO and increased pyruvate metabolism, while cardiac mechanical function was decreased. AMP‐activated protein kinase activation by A769662 improved mitochondrial FAO without affecting cardiac function and inflammation‐related gene expression during endotoxaemia. Fatty acid synthase inhibition by C75 restored both cardiac and mitochondrial FAO; however, no effects on inflammation‐related gene expression and cardiac function were observed. In addition, the inhibition of carnitine palmitoyltransferase 2 (CPT2)‐dependent FAO by aminocarnitine resulted in the accumulation of FAO intermediates, long‐chain acylcarnitines, in the heart. As a result, cardiac pyruvate metabolism was inhibited, which further exacerbated inflammation‐induced cardiac dysfunction. In conclusion, although inhibition of CPT2‐dependent FAO is detrimental to cardiac function during endotoxaemia, present findings show that the restoration of cardiac FAO alone is not sufficient to recover cardiac function. Rescue of cardiac FAO should be combined with anti‐inflammatory therapy to ameliorate cardiac dysfunction in endotoxaemia. [ABSTRACT FROM AUTHOR]

Objectives: The aim of the study was to explore the inhibition efficacy of new synthetic coumarinolignans (SCLs) against the secretion of pro-inflammatory cytokines in two in vivo models of inflammation. Methods: Four SCLs 1–4 were screened for their pro-inflammatory cytokine inhibitory potential through oral administration at a dose of 50 mg/kg body weight in lipopolysaccharide-induced mouse endotoxaemia and carrageenan-induced mouse paw oedema models. Levels of pro-inflammatory cytokines (IL-1β, TNFα and IL-6) in blood and paw tissue samples were estimated using ELISA. Paw oedema was measured using a plethysmometer. Results were compared with a natural coumarinolignan, cleomiscosin A (5), and the structure–activity relationship (SAR) was interpreted. Results and discussion: Compound 2 had the greatest potential in the endotoxaemia model, exhibiting 66.41%, 62.56% and 43.15% inhibition of plasma IL-1β, TNFα and IL-6 secretions, respectively. Further dose-dependent study revealed its anti-inflammatory potential even at dose of 10 mg/kg body weight with 24.42% decline in the level of IL-1β. Nevertheless, SCLs 1, 3 and 4 showed marked inhibitory activity with 57.54%, 51.48% and 62.46% reduction in the levels of IL-1β, respectively. Moreover, compound 2 decreased the plasma TNFα and IL-1β levels to 50.03% and 36.58% along with the reduction of paw oedema volume in the local inflammation induced by carrageenan. All compounds including cleomiscosin A (5) were more effective against IL-1β. By studying SAR, the presence of dihydroxyl groups in the phenyl ring of lignans was identified to be essential for the activity. Also, esterification of lignans and presence of a 4-methyl substituent in the coumarin nucleus were found to play some role in enhancing the activity. Conclusion: All four SCLs, especially compound 2, have shown vast potential to emerge out as promising anti-inflammatory drugs. [ABSTRACT FROM AUTHOR]

Endotoxaemia is one of the most severe and ubiquitous disease processes in horses; and delayed gastric emptying is one of the most clinically significant manifestations of endotoxaemia. Current information suggests that oxidative damage plays a key role in the systemic effects induced by endotoxin and this raises the possibility that antioxidants, such as dimethyl sulfoxide (DMSO), might have a protective effect. No study has yet evaluated the efficacy of DMSO in ameliorating delayed gastric emptying caused by endotoxaemia in horses. We hypothesized that DMSO would ameliorate delayed gastric emptying caused by intravenous lipopolysaccharide (LPS) administration. Horses were randomly assigned to one of 4 groups; of 6 horses each: Normosol (Abbott Laboratories, Abbott Park, Illinois, USA) + LPS (0.2µg/kg bwt, i.v.); DMSO (1g/kg bwt, i.v.) + Saline; High-dose DMSO (1g/kg bwt, i.v.) + LPS; Low-dose DMSO (20 mg/kg bwt, i.v.) + LPS. All horses in all groups received acetaminophen (20 mg/kg reconstituted in one liter of warm tap water) by nasogastric intubation. Data for acetaminophen concentrations in the blood as a measure of gastric emptying were examined for the effect of treatment using a repeated-measures mixed-model ANOVA. A value of P < 0.05 was considered significant. Delayed gastric emptying occurred in all horses receiving LPS, as indicated by the lower concentrations of acetaminophen in these groups along the study period. DMSO did not ameliorate the effect of LPS on gastric emptying. Low-dose DMSO actually exacerbated the LPS-induced delay in gastric emptying. In this study, DMSO did not have any protective effect against LPS-induced delayed gastric emptying in horses. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Mechanical ventilation (MV) can save the lives of patients with sepsis. However, MV in both animal and human studies has resulted in ventilator‐induced diaphragm dysfunction (VIDD). Sepsis may promote skeletal muscle atrophy in critically ill patients. Elevated high‐mobility group box‐1 (HMGB1) levels are associated with patients requiring long‐term MV. Ethyl pyruvate (EP) has been demonstrated to lengthen survival in patients with severe sepsis. We hypothesized that the administration of HMGB1 inhibitor EP or anti‐HMGB1 antibody could attenuate sepsis‐exacerbated VIDD by repressing HMGB1 signalling. Male C57BL/6 mice with or without endotoxaemia were exposed to MV (10 mL/kg) for 8 hours after administrating either 100 mg/kg of EP or 100 mg/kg of anti‐HMGB1 antibody. Mice exposed to MV with endotoxaemia experienced augmented VIDD, as indicated by elevated proteolytic, apoptotic and autophagic parameters. Additionally, disarrayed myofibrils and disrupted mitochondrial ultrastructures, as well as increased HMGB1 mRNA and protein expression, and plasminogen activator inhibitor‐1 protein, oxidative stress, autophagosomes and myonuclear apoptosis were also observed. However, MV suppressed mitochondrial cytochrome C and diaphragm contractility in mice with endotoxaemia (P < 0.05). These deleterious effects were alleviated by pharmacologic inhibition with EP or anti‐HMGB1 antibody (P < 0.05). Our data suggest that EP attenuates endotoxin‐enhanced VIDD by inhibiting HMGB1 signalling pathway. [ABSTRACT FROM AUTHOR]

Summary: Background: Small intestinal strangulating obstruction (SISO) is associated with endotoxaemia which leads to an increased risk of death. Nonsteroidal anti‐inflammatory drugs (NSAIDs) are used to treat signs of endotoxaemia by inhibiting cyclo‐oxygenases (COX). COX‐1 is expressed constitutively and promotes gut barrier function, whereas COX‐2 is inducible and contributes to the signs of endotoxaemia. In preclinical SISO trials, intestinal barrier recovery was more complete with reductions in endotoxin permeability in horses treated with COX‐2 selective NSAIDs as compared with horses treated with flunixin meglumine. Objectives: We hypothesised that treatment of post‐surgical SISO horses with firocoxib (COX‐2 selective) would reduce the signs of endotoxaemia to a greater extent than flunixin meglumine (nonselective COX inhibitor) while continuing to provide similar levels of pain control. Study design: Blinded randomised clinical trial. Methods: In addition to clinical monitoring, preoperative and 12‐, 24‐ and 48‐h post‐operative plasma samples were assessed for prostaglandin E2 (PGE2), thromboxane B2 (TXB2), TNF⍺ and soluble CD14 (sCD14). Results: In 56 recruited SISO horses, either flunixin meglumine (1.1 mg/kg, i.v., q12h) or firocoxib (0.3 mg/kg, i.v. loading dose; 0.1 mg/kg, i.v., q24h) was given in the post‐operative period in three university hospitals from 2015 to 2017. COX‐2 selectivity was confirmed by a relative lack of inhibition of the COX‐1 prostanoid TXB2 by firocoxib and significant inhibition by flunixin meglumine (P = 0.014). Both drugs inhibited the COX‐2 prostanoid PGE2. There were no significant differences in pain scores between groups (P = 0.2). However, there was a 3.23‐fold increased risk (P = 0.04) of increased plasma sCD14 in horses treated with flunixin meglumine, a validated biomarker of equine endotoxaemia. Main limitations: Horses were all treated with flunixin meglumine prior to referral. In addition, many horses were treated with lidocaine, which has been shown to mitigate the deleterious effects of flunixin meglumine. Conclusions: In SISO cases, firocoxib reduced a biomarker of endotoxaemia as compared with flunixin meglumine while continuing to provide similar levels of pain control. [ABSTRACT FROM AUTHOR]

Summary: Early, non‐clinical studies support the use of hydroxocobalamin to treat sepsis‐induced hypotension, but there is no translational, large animal model. The objective of this study was to compare survival in a sepsis model where large swine had endotoxaemia induced with lipopolysaccharide (LPS) and were treated with intravenous hydroxocobalamin (HOC), noradrenaline (NA), or saline. Thirty swine (45–55 kg) were anaesthetized, intubated, and instrumented with continuous femoral and pulmonary artery pressure monitoring. Hypotension, predefined as 50% of baseline, was induced with LPS. Animals then received HOC, NA, or saline and monitored for 3 hours. The main outcome was survival to the conclusion of the study. Using a power of 80% and an alpha of 0.05, 10 animals were used per group. Secondary outcomes included: mean arterial pressure (MAP), systemic vascular resistance (SVR) and cardiac output (CO) along with several markers of sepsis. No differences were detected between groups at baseline or after hypotension. The survival distributions of the three groups were significantly different with more HOC animals surviving (10/10) compared with NA (8/10) or Saline (5/10) (log‐rank P < 0.03). MAP was found to be higher in both the HOC and NA groups and HOC achieved the highest SVR. In this large animal, translational study of an endotoxaemic model of sepsis, hydroxocobalamin improved survival when compared with saline. [ABSTRACT FROM AUTHOR]

Objective: Aim: The aim of this research is to clarify the potential effect of CDDO-EA against experimentally sepsis induced lung injury in mice., Patients and Methods: Materials and Methods: Mice have divided into four groups: Sham group CLP group, Vehicle-treatment group, CDDO-EA-treated group: mice in this group received CDDO-EA 2mg/kg intraperitoneally, 1hr before CLP, then the animals were sacrificed 24hr after CLP. After exsAngpuinations, tissue samples of lung were collected, followed by markers measurement including, TNF-α, IL-1β, VEGF, MPO, caspase11, Angp-1and Angp-2 by ELISA, gene expression of TIE2 and VE-cadherin by qRT-PCR, in addition to histopathological study., Results: Results: A significant elevation (p<0.05) in TNF-α, IL-1β, MPO, ANGP-2, VEGF, CASPASE 11 in CLP and vehicle groups when compared with sham group. CDDO-EA group showed significantly lower levels p<0.05, level of ANGP-1 was significantly lower p<0.05 in the CLP and vehicle groups as compared with the sham group. Quantitative real-time PCR demonstrated a significant decrement in mRNA expression of TIE2&ve-cadherin genes p<0.05 in sepsis & vehicle., Conclusion: Conclusions: CDDO-EA has lung protective effects due to its anti-inflammatory and antiAngpiogenic activity, additionally, CDDO-EA showes a lung protective effect as they affect tissue mRNA expression of TIE2 and cadherin gene. Furthermore, CDDO-EA attenuate the histopathological changes that occur during polymicrobial sepsis thereby lung protection effect.

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Summary: We reassessed data from a previous study on the transcerebral net exchange of large neutral amino acids (LNAAs) using a novel mathematical model of blood–brain barrier (BBB) transport. The study included twelve healthy volunteers who received a 4‐h intravenous lipopolysaccharide (LPS) infusion (total dose: 0·3 ng/kg), a human experimental model of the systemic inflammatory response during the early stages of sepsis. Cerebral blood flow and arterial‐to‐jugular venous LNAA concentrations were measured prior to and after LPS, and the BBB transport and brain extracellular concentrations of LNAAs were calculated. The arterial concentration and unidirectional cerebral influx of phenylalanine increased after LPS. The BBB transport of tyrosine was unaffected, while its concentration in the brain extracellular fluid increased. These findings suggest that LPS infusion leads to an increased cerebral uptake of phenylalanine, which is then metabolized to tyrosine. This may reflect a neuroprotective mechanism that ‘detoxifies’ excess intracerebral phenylalanine in the clinical setting of sepsis. [ABSTRACT FROM AUTHOR]

Sepsis is a systemic inflammatory disorder which often occurs during extremely stressful conditions such as trauma, burn, shock, and infection. This study investigated the curative effects of bone marrow-derived mesenchymal stem cells (BM-MSCs) against hepatic, renal, and pulmonary responses caused by a single administration of lipopolysaccharide (LPS) (10 mg/kg, i.p) in rats. Treatment with BM-MSCs (5 × 105 in 0.1 ml PBS, i.p.) 3 h after LPS antagonized the LPS-induced increment of the liver enzymes (ALT, AST) and kidney functions (BUN, sCr). BM-MSCs decreased tissue levels of P38-MAPK, NF-κB, STAT-3, TNF-α, IL-1β, iNOS, Bax together with elevation of the anti-inflammatory cytokine IL-10 and the anti-apoptotic biomarker Bcl-2. Meanwhile, rats exhibited marked reduction of the broncho-alveolar lavage fluid levels of TNF-α, IL-1β, and IFN-γ. Interestingly, BM-MSCs normalized both broncho-alveolar lavage fluid (BALF) neutrophils count and lung wet/dry ratios. Briefly, these findings may provide a preclinical platform for the management of LPS-induced sepsis using BM-MSCs via their ameliorative anti-inflammatory, anti-oxidant, and anti-apoptotic potentials. [ABSTRACT FROM AUTHOR]

Oestrogens have been reported to attenuate acute inflammation in sepsis. In this study, the effects of long-term oestrogen replacement with 17β-oestradiol (E2) on endotoxaemia-induced circulatory dysfunction and multiple organ dysfunction syndrome were evaluated in ovariectomized (Ovx) rats. E2 (50 μg/kg, s.c., 3 times/week) was administered for 8 weeks, followed by the induction of endotoxaemia by intravenous infusion of lipopolysaccharides (LPS; 30 mg/kg/4 hrs). Oestrogen deficiency induced by ovariectomy for 9 weeks augmented the LPS-induced damage, including endotoxic shock, myocardial contractile dysfunction, renal dysfunction and rhabdomyolysis. Cardiac levels of NF-κB p65, iNOS and oxidized glutathione, free radical production in skeletal muscles, myoglobin deposition in renal tubules, and plasma levels of plasminogen activator inhibitor-1, TNF-α, and IL-6 were more pronounced in the Ovx + LPS group than in the Sham + LPS group. Long-term treatment of E2 prevented this amplified damage in Ovx rats. Six hours after LPS initiation, activation of the autophagic process, demonstrated by increases in Atg12 and LC3B-II/LC3B-I ratios, and induction of haem oxygenase (HO)-1 and heat-shock protein (HSP) 70 protein expression in myocardium were increased significantly in the Ovx + E2 + LPS group. These results suggest that activation of autophagy and induction of HO-1 and HSP70 contribute to the protective effect of long-term E2 replacement on multiple organ dysfunction syndrome in endotoxaemia. [ABSTRACT FROM AUTHOR]

Sepsis is a severe and multifactorial disease with a high mortality rate. It represents a strong inflammatory response to an infection and is associated with vascular inflammation and oxidative/nitrosative stress. Here, we studied the underlying time responses in the widely used lipopolysaccharide (LPS)-induced endotoxaemia model in mice and rats. LPS (10 mg/kg; from Salmonella Typhosa) was intraperitoneally injected into mice and rats. Animals of every species were divided into five groups and sacrificed at specific points in time (0, 3, 6, 9, 12 h). White blood cells (WBC) decreased significantly in both species after 3 h and partially recovered with time, whereas platelet decrease did not recover. Oxidative burst and iNOS-derived nitrosyl-iron hemoglobin (HbNO) increased with time (maxima at 9 or 12 h). Immune cell infiltration (CD68 and F4/80 content) showed an increase with time, which was supported by increased vascular mRNA expression of VCAM-1, P-selectin, IL-6 and TNF-α. We characterized the time responses of vascular inflammation and oxidative/nitrosative stress in LPS-induced endotoxaemic mice and rats. The results of this study will help to interpret and compare data from different animal species in LPS-induced endotoxaemia models for the identification of new drug targets. [ABSTRACT FROM AUTHOR]

Bacterial endotoxin (lipopolysaccharide, LPS), is one of the most potent inducers of inflammatory signaling, yet it is abundant in the human gut and the modern diet. Small quantities of LPS routinely translocate from the gut lumen to the circulation (so-called metabolic endotoxaemia), and elevated plasma LPS concentrations are reported in a variety of chronic non-communicable diseases, including obesity, non-alcoholic fatty liver disease, atherosclerosis and type II diabetes. Murine models of experimentally-induced endotoxaemia and Toll-like receptor-4 deficiency suggest that endotoxin may promote the metabolic disturbances that underpin these diseases. However, as bioactive LPS is cleared rapidly from the circulation, and reported levels of endotoxin in human plasma vary widely, the potential relevance of metabolic endotoxaemia to human disease remains unclear. We here review insight into these questions gained from human and murine models of experimental endotoxaemia, focusing on the kinetics of LPS neutralization and its clearance from blood, the limitations of the widely used limulus assay and alternative methods for LPS quantitation. We conclude that although new methods for LPS measurement will be required to definitively quantify the extent of metabolic endotoxaemia in man, evidence from numerous approaches suggests that this molecule may play a key role in the development of diverse metabolic diseases. [ABSTRACT FROM PUBLISHER]

Endotoxaemia has been described in cases of Human African trypanosomiasis (HAT), but it is unclear if this phenomenon influences inflammatory pathology either in the periphery or central nervous system (CNS). We studied endotoxin concentrations in the plasma and cerebrospinal fluid (CSF) of Trypanosoma brucei rhodesiense patients using the chromogenic Limulus Amoebocyte lysate assay. The relationship of endotoxin concentration to the presentation of gross signs of inflammation and the inflammatory/counter-inflammatory cytokine profile of the relevant compartments were analysed. We demonstrate that HAT patients exhibit parasitaemia-independent plasma endotoxaemia, and that this is associated with splenomegaly and lymphadenopathy. Endotoxin concentrations normalize rapidly after treatment. There was no evidence of endotoxin release in the CNS. A rapid normalization of endotoxin levels after treatment and lack of association with parasitaemia suggest that gut leakage is the main source of endotoxin in the circulation. Low CSF endotoxin concentrations and a lack of any association with neuroinflammatory markers or neurological sequelae suggest that endotoxin does not play a role in the pathogenesis of the disease in the CNS. [ABSTRACT FROM PUBLISHER]

Postprandial inflammation and endotoxaemia are determinants of cardiovascular and metabolic disease risk which are amplified by high fat meals. We aimed to examine the determinants of postprandial inflammation and endotoxaemia in older and younger adults following a high fat mixed meal. In a randomised cross-over trial, healthy participants aged 20-25 and 60-75 years (n = 15/group) consumed a high-fat breakfast and a low-fat breakfast. Plasma taken at baseline and post-meal for 5 h was analysed for circulating endotoxin, cytokines (monocyte chemotactic protein-1 (MCP-1), interleukin (IL)-1β, IL-6, and tumour necrosis factor-alpha (TNF-α)), lipopolysaccharide binding protein (LBP), and inflammatory gene expression in peripheral blood mononuclear cells (PBMC). Older subjects had lower baseline PBMC expression of glutathione peroxidase 1 (GPX-1) but greater insulin-like growth factor-binding protein 3 (IGFBP3) and circulating MCP-1 compared to younger subjects. After either meal, there were no age differences in plasma, chylomicron endotoxin, or plasma LBP concentrations, nor in inflammatory cytokine gene and protein expression (MCP-1, IL-1β, and TNF-α). Unlike younger participants, the older group had decreased superoxide dismutase (SOD)-2 expression after the meals. After a high-fat meal, older adults have no increased inflammatory or endotoxin response, but an altered oxidative stress gene response compared with younger adults. Healthy older adults, without apparent metabolic dysfunction, have a comparable postprandial inflammatory and endotoxaemia response to younger adults. [ABSTRACT FROM AUTHOR]

Sepsis is a systemic inflammatory response triggered by microbial infection that can cause cardiovascular collapse, insufficient tissue perfusion and multi-organ failure. The cation channel transient receptor potential vanilloid 4 (TRPV4) is expressed in vascular endothelium and causes vasodilatation, but excessive TRPV4 activation leads to profound hypotension and circulatory collapse - key features of sepsis pathogenesis. We hypothesised that loss of TRPV4 signaling would protect against cardiovascular dysfunction in a mouse model of sepsis (endotoxaemia). Multi-parameter monitoring of conscious systemic haemodynamics (by radiotelemetry probe), mesenteric microvascular blood flow (laser speckle contrast imaging) and blood biochemistry (iSTAT blood gas analysis) was carried out in wild type (WT) and TRPV4 knockout (KO) mice. Endotoxaemia was induced by a single intravenous injection of lipopolysaccharide (LPS; 12.5 mg/kg) and systemic haemodynamics monitored for 24 h. Blood flow recording was then conducted under terminal anaesthesia after which blood was obtained for haematological/biochemical analysis. No significant differences were observed in baseline haemodynamics or mesenteric blood flow. Naïve TRPV4 KO mice were significantly acidotic relative to WT counterparts. Following induction of sepsis, all mice became significantly hypotensive, though there was no significant difference in the degree of hypotension between TRPV4 WT and KO mice. TRPV4 KO mice exhibited a higher sepsis severity score. While septic WT mice became significantly hypernatraemic relative to the naïve state, this was not observed in septic KO mice. Mesenteric blood flow was inhibited by topical application of the TRPV4 agonist GSK1016790A in naïve WT mice, but enhanced 24 h following LPS injection. Contrary to the initial hypothesis, loss of TRPV4 signaling (either through gene deletion or pharmacological antagonism) did not attenuate sepsis-induced cardiovascular dysfunction: in fact, pathology appeared to be modestly exaggerated in mice lacking TRPV4. Local targeting of TRPV4 signalling may be more beneficial than global inhibition in sepsis treatment.

• Culture broth extract of Penicillium polonicum (endophytic fungi of P. nigrum fruit) was found to inhibit pro-inflammatory cytokines. • Three phenolics (1, 2 and 4) and one indole derivative (3) were isolated from the extract and explored as IL-1β, TNF-α, IL-6 and iNOS inhibitors. • The effect of pure compounds (1–4) and their combinations C1 (mixture of 1–4) and C2 (mixture of 1–4 & piperine) were studied through in vitro and in vivo methods. • Evaluation through mouse LPS-induced endotoxaemia and carrageenan-induced paw oedema models proved the anti-inflammation effect. • Compounds 1–4 and C1 attenuated inflammation by controlling the TNF-α, IL-6, IL-1β, iNOS, MPO and NO levels. • Compounds regulated the expression of pro-form and matured-form of IL-1β and NFκB. Overexpression of pro-inflammatory cytokines and iNOS have been found to be concomitant with several chronic inflammatory diseases and hence targeting their inhibition would be a useful therapy for inflammation. In view of this, study on discovery of natural pro-inflammatory cytokines inhibitory lead molecules from Penicillium polonicum , an endophytic fungus isolated from the fresh fruits of Piper nigrum was performed. When the culture broth extract of P. polonicum (EEPP) was subjected to LPS-induced cytokines expression (ELISA in RAW 264.7 cells), it exhibited inhibition of TNF-α, IL-6 and IL-1β and this encouraged us to do chemical investigation on EEPP to explore the bioactive components. Four compounds isolated and characterised as 3,5-di- tert -butyl-4-hydroxy-phenyl propionic acid (1), 2,4-di- tert -butyl phenol (2), indole 3-carboxylic acid (3) and tyrosol (4) were tested for their effect on the production of TNF-α, IL-1β and IL-6 in RAW 264.7 cells (ELISA). All the compounds exhibited a highly significant (P < 0.0001) inhibition effect, particularly against IL-1β (IC 50 : 4 –0.91 μM, 1 –2.81 μM, 3 –4.38 μM, and 2 –5.54 μM). Tyrosol (4) was most active with IC 50 values of 0.91, 2.67 and 4.60 μM against IL-1β, IL-6 and TNF-α, respectively. On observing the potential activity of the compounds, two compositions C1 and C2 were prepared by mixing equimolar concentrations of compounds 1 , 2 , 3 & 4 (C1) and compounds 1 , 2 , 3 , 4 & piperine (C2) in equal ratio. A synergistic effect was observed with C1 exhibiting potential suppression of IL-6 secretion (IC 50 1.91 μM) and C2 against IL-1β (IC 50 5.98 μM). Also, the individual compounds and C1 were effective in controlling iNOS expressions in RAW 264.7 cells (RTPCR). Further, the in vivo performance of the compounds and compositions were studied under two in vivo inflammatory models (LPS-induced endotoxaemia and carrageenan-induced paw oedema). Compounds 1 , 2 , 3 , 4 , C1 and C2 at 50 mg/kg oral dose showed a significant control over the LPS-stimulated TNF-α, IL-1β and IL-6 levels in plasma. C1 , C2 and 1 exhibited > 50% pan-cytokine inhibition effect. Under the carrageenan-induced anti-inflammatory model, a significant reduction in the paw oedema measured in terms of the difference in the paw thickness was observed. Further, attenuation of pro-inflammatory cytokines levels following ELISA and RT-PCR experiments in the paw tissue homogenate was in agreement with paw thickness results. All compounds and C1 decreased the iNOS gene expression levels, and also the MPO activity and NO production in the paw tissue homogenate with tyrosol (4) as the most active molecule. Further, the mechanism of action was explored by testing the effect of the compounds on the expression of inflammatory markers using western blot analysis (in vitro). They were found to regulate the expression of pro-form and matured-form of IL-1β by inhibiting NFκB. Also, the compounds reduced the translocation of the NF- κ B subunit p65 to the nucleus. Thus, compounds 3,5-di- tert -butyl-4-hydroxy-phenyl propionic acid (1), 2,4-di- tert -butyl phenol (2), indole 3-carboxylic acid (3) and tyrosol (4) are reported as new natural multiple pro-inflammatory cytokines inhibitory leads. The interesting results of C1 might lay a footing for the development of a new anti-inflammatory composition. [ABSTRACT FROM AUTHOR]

The exact mechanism linking the systemic inflammatory response associated with sepsis to changes in lung function remains to be determined. In a human experimental model of inflammation, we investigated how acute systemic and local pulmonary inflammation affects ventilatory capacity and pulmonary gas exchange. Fifteen volunteers received Escherichia coli lipopolysaccharide ( LPS) intravenously or endobronchially on two different study days. Blood samples were obtained hourly (t = 0-8 h) and spirometry was performed at baseline and after 8 h. Both interventions decreased ventilatory capacity compared to baseline (p < 0.01), and this was more pronounced after intravenous (forced expiratory volume in 1-s, FEV1; 0.6 L/12% reduction) compared to endobronchial ( FEV1; 0.32 L/7% reduction) administration (p < 0.05). Furthermore, the alveolar-arterial oxygen difference increased after intravenous but not after endobronchial endotoxin. These findings indicate that pulmonary gas exchange is impaired to a greater extent during endotoxin-induced systemic inflammation than during endotoxin-induced local pulmonary inflammation. [ABSTRACT FROM AUTHOR]

Aberrant microbiota composition and function have been linked to several pathologies, including type 2 diabetes. In animal models, prebiotics induce favourable changes in the intestinal microbiota, intestinal permeability (IP) and endotoxaemia, which are linked to concurrent improvement in glucose tolerance. This is the first study to investigate the link between IP, glucose tolerance and intestinal bacteria in human type 2 diabetes. In all, twenty-nine men with well-controlled type 2 diabetes were randomised to a prebiotic (galacto-oligosaccharide mixture) or placebo (maltodextrin) supplement (5·5 g/d for 12 weeks). Intestinal microbial community structure, IP, endotoxaemia, inflammatory markers and glucose tolerance were assessed at baseline and post intervention. IP was estimated by the urinary recovery of oral 51Cr-EDTA and glucose tolerance by insulin-modified intravenous glucose tolerance test. Intestinal microbial community analysis was performed by high-throughput next-generation sequencing of 16S rRNA amplicons and quantitative PCR. Prebiotic fibre supplementation had no significant effects on clinical outcomes or bacterial abundances compared with placebo; however, changes in the bacterial family Veillonellaceae correlated inversely with changes in glucose response and IL-6 levels (r−0·90, P=0·042 for both) following prebiotic intake. The absence of significant changes to the microbial community structure at a prebiotic dosage/length of supplementation shown to be effective in healthy individuals is an important finding. We propose that concurrent metformin treatment and the high heterogeneity of human type 2 diabetes may have played a significant role. The current study does not provide evidence for the role of prebiotics in the treatment of type 2 diabetes. [ABSTRACT FROM PUBLISHER]

Besides their well-established endocrine roles, vasopressin and oxytocin are also important regulators of immune functions, participating in a complex neuroendocrine-immune network. Herein, we asked whether and how vasopressin and oxytocin could modulate lipopolysaccharide (LPS)-induced nitric oxide (NO) production in a well-established model of experimental endotoxemia. Male Wistar rats were previously treated intravenously with vasopressin V1 or oxytocin receptor antagonists and then received an intravenous LPS injection to induce endotoxemia, or saline as control. The animals were divided into two groups: in the first, blood was collected at 2, 4 and 6 h after LPS injection; in the second, mean arterial blood pressure (MABP) and heart rate (HR) were recorded during 6 h. Plasma vasopressin and oxytocin values were higher in LPS- than in saline-injected animal at 2 and 4 h, but returned to basal levels at 6 h. NO levels exhibited an opposite pattern, showing a progressive increase over the entire period. The previous administration of a vasopressin V1 receptor antagonist significantly reduced NO plasma concentrations at 2 and 4 h, but not at 6 h. In contrast, oxytocin receptor agonist pre-treatment had no effect on NO plasma concentration. In relation to MABP, previous treatment with vasopressin V1 receptor antagonist reversed the LPS-induced hypotension at 4h, which was not the case in the oxytocin antagonist-treated animals. None of the antagonists affected HR. Our findings indicate that vasopressin, but not oxytocin has effects on NO production during endotoxemia in rats, but they do not lend support to proposed anti-inflammatory actions of vasopressin during endotoxemia. This article is protected by copyright. All rights reserved. [ABSTRACT FROM AUTHOR]

Background & objectives: Despite advances in therapy and overall medical care, acute lung injury (ALI)/ acute respiratory distress syndrome (ARDS) management remains a problem. Hence the objective of this study was to develop a rat model that mimics human ALI/ARDS. Methods: Four groups of Wistar rats, 48 per group were treated with (i) intratracheal (IT) lipopolysaccharide (LPS) (5 mg/kg) dissolved in normal saline (NS), (ii) intravenous (iv) oleic acid (OA) (250 μl/kg) suspension in bovine serum albumin (BSA), (iii) dual hit: IT LPS (2 mg/kg) dissolved in NS and iv OA (100 μl/kg) and (iv) control group: IT NS and iv BSA. From each group at set periods of time various investigations like chest X-rays, respiratory rate (RR), tidal volume (TV), total cell count, differential cell count, total protein count and cytokine levels in bronchoalveolar lavage fluid (BALF), lung wet/dry weight ratio and histopathological examination were done. Results: It was noted that the respiratory rate, and tumour necrosis factor-α (TNF-α) levels were significantly higher at 4 h in the dual hit group as compared to LPS, OA and control groups. Interleukin-6 (IL-6) levels were significantly higher in the dual hit group as compared to LPS at 8 and 24 h, OA at 8 h and control (at all time intervals) group. IL-1β levels were significantly higher in LPS and dual hit groups at all time intervals, but not in OA and control groups. The injury induced in dual hit group was earlier and more sustained as compared to LPS and OA alone. Interpretation & conclusions: The lung pathology and changes in respiration functions produced by the dual hit model were closer to the diagnostic criteria of ALI/ARDS in terms of clinical manifestations and pulmonary injury and the injury persisted longer as compared to LPS and OA single hit model. Therefore, the ARDS model produced by the dual hit method was closer to the diagnostic criteria of ARDS in terms of clinical manifestations and pulmonary injury. [ABSTRACT FROM AUTHOR]

Haemorrhagic septicaemia (HS) is an acute, septicaemic disease of cattle and buffalo of Asia and Africa caused by Pasteurella multocida B:2 or E:2. Buffaloes are believed to be more susceptible than cattle. In this study, 9 buffaloes of 8 months old were divided equally into 3 groups (Groups 1, 3, 5). Similarly, 9 cattle of 8 months old were equally divided into 3 groups (Groups 2, 4, 6). Animals of Groups 1 and 2 were inoculated with PBS while Groups 3 and 4 were inoculated subcutaneously with 10 5 cfu/ml of P. multocida B:2. Animals of Groups 5 and 6 were inoculated intranasally with the same inoculum. Both buffaloes and cattle that were inoculated subcutaneously succumbed to the infection at 16 h and 18 h, respectively. Two buffaloes that were inoculated intranasally (Group 5) succumbed at 68 h while the remaining cattle and buffaloes survived the 72-h study period. Endotoxin was detected in the blood of infected cattle (Group 4) and buffaloes (Groups 3 and 5) prior to the detection of P. multocida B:2 in the blood. The endotoxin was detected in the blood of buffaloes of Group 3 and cattle of Group 4 at 0.5 h post-inoculation while buffaloes of Group 5 and cattle of Group 6 at 1.5 h. On the other hand, bacteraemia was detected at 2.5 h in buffaloes of Group 3 and cattle of Group 4 and at 12 h in buffaloes of Group 5 and cattle of Group 6. Affected cattle and buffaloes showed lesions typical of haemorrhagic septicaemia. These included congestion and haemorrhages in the organs of respiratory, gastrointestinal and urinary tracts with evidence of acute inflammatory reactions. The severity of gross and histopathology lesions in cattle and buffalo calves that succumbed to the infection showed insignificant (p > 0.05) difference. However, inoculated buffalo and cattle that survived the infection showed significantly ( p < 0.05) less severe gross and histopathological changes than those that succumbed. In general, cattle are more resistant to intranasal infection by P. multocida B:2 than buffaloes. [ABSTRACT FROM AUTHOR]

The study aimed to determine circulatory endotoxin concentration, cytokine profile, and gastrointestinal symptoms of ultra-endurance runners (UER, n = 17) in response to a 24-h continuous ultra-marathon competition (total distance range: 122-208 km) conducted in temperate ambient conditions (0-20°C) in mountainous terrain. Body mass and body temperature were measured, and venous blood samples were taken before and immediately after competition. Samples were analysed for gram-negative bacterial endotoxin, C-reactive protein, cytokine profile, and plasma osmolality. Gastrointestinal symptoms were also monitored throughout competition. Mean exercise-induced body mass loss was (mean±SD) 1.7±1.8% in UER. Pre- and post-competition plasma osmolality in UER was 286±11 mOsmol⋅kg-1 and 286±9mOsmol⋅kg-1, respectively. Pre- to post-competition increases (p<0.05) were observed for endotoxin (37%), C-reactive protein (2832%), IL-6 (3436%), IL-β (332%), TNF-α (35%), IL-10 (511%), and IL-8 (239%) concentrations in UER, with no change in the control group (CON; n = 12) observed (p>0.05). Gastrointestinal symptoms were reported by 75% of UER, with no symptoms reported by CON. IL-10 (r=0.535) and IL-8 (r=0.503) were positively correlated with gastrointestinal symptoms. A 24-h continuous ultra-marathon competition in temperate ambient conditions resulted in a circulatory endotoxaemia and pro-inflammatory cytokinaemia, counteracted by a compensatory anti-inflammatory response. [ABSTRACT FROM AUTHOR]

Introduction: Medical conditions such as obesity and inflammatory bowel disease are associated with impaired luteal function, menstrual disturbance and infertility. It is proposed that the disturbance in gut wall integrity ('leaky gut') seen in these conditions may result in the passage of bacterial endotoxin (LPS) from the colonic lumen into the circulation that may initiate inflammation in the ovary and subsequently impair hormone production. Methods: Quantify the association between systemic levels of LBP, a marker of endotoxin exposure, and levels of inflammation in the ovary (follicular fluid IL-6), plus steroid hormone production in 45 women undergoing IVF treatment. Results: Endotoxaemia (LBP) were positively correlated with plasma CRP and inflammation within the ovary (follicular fluid IL-6). Furthermore, endotoxaemia was negatively correlated with progesterone production. Conclusion: The observed correlations, together with previously published animal studies linking endotoxin exposure to impaired luteal function, suggest that the translocation of bacterial endotoxin from the gut lumen into the circulation has the potential to interfere with progesterone production and result in luteal deficiency. [ABSTRACT FROM AUTHOR]