Association between endotoxemia and blood no in the portal circulation of cirrhotic patients: results of a pilot study.

Pathophysiology of portal vein thrombosis (PVT) in cirrhosis is still not entirely understood. Elevated levels of lipopolysaccharides (LPS) in portal circulation are significantly associated with hypercoagulation, increased platelet activation and endothelial dysfunction. The aim of the study was to investigate if LPS was associated with reduced portal venous flow, the third component of Virchow's triad, and the underlying mechanism. Serum nitrite/nitrate, as a marker of nitric oxide (NO) generation, and LPS were measured in the portal and systemic circulation of 20 patients with cirrhosis undergoing transjugular intrahepatic portosystemic shunt (TIPS) procedure; portal venous flow velocity (PVV) was also measured in each patient and correlated with NO and LPS levels. Serum nitrite/nitrate and LPS were significantly higher in the portal compared to systemic circulation; a significant correlation was found between LPS and serum nitrite/nitrate (R = 0.421; p < 0.01). Median PVV before and after TIPS was 15 cm/s (6-40) and 31 cm/s (14-79), respectively. Correlation analysis of PVV with NO and LPS showed a statistically significant negative correlation of PVV with portal venous NO concentration (R = - 0.576; p = 0.020), but not with LPS. In vitro study with endothelial cells showed that LPS enhanced endothelial NO biosynthesis, which was inhibited by L-NAME, an inhibitor of NO synthase, or TAK-242, an inhibitor of TLR4, the LPS receptor; this effect was accomplished by up-regulation of eNOS and iNOS. The study shows that in cirrhosis, endotoxemia may be responsible for reduced portal venous flow via overgeneration of NO and, therefore, contribute to the development of PVT.

Effects of Poly (ADP-ribose) Polymerase Inhibition on DNA Integrity and Gene Expression in Ovarian Follicular Cells in Mice with Endotoxemia

Background: A mouse model of lipopolysaccharide (LPS)-induced inflammation was used to investigate the effect of pharmacological inhibition of nuclear enzyme PARP-1 on oocyte maturation, apoptotic and necrotic death, as well as DNA integrity of follicular cells. Also, the relative expression of cumulus genes (HAS2, COX2, and GREM1) associated with oocyte developmental competence was assessed. Methods: Mice were treated with the PARP-1 inhibitor, 4-HQN, one hour before LPS administration. After 24 h, oocyte in vitro maturation was detected. Granulosa cell DNA damage was determined by the alkaline comet assay. Live, necrotic and apoptotic cells were identified using double vital staining by fluorescent dyes, Hoechst 33342 and propidium iodide. The expression levels of cumulus genes were assessed using reverse transcriptase PCR. Results: The administration of 4-HQN to LPS-treated mice ameliorated oocyte meiotic maturation and exerted a significant cytoprotective effect. 4-HQN attenuated LPS-induced DNA damage and favored cell survival by decreasing necrosis and apoptosis in granulosa cells. Exposure to 4-HQN increased mRNA expression levels for HAS2, COX2, and GREM1 in cumulus cells. Conclusion: The obtained results indicate the involvement of PARP-1 in the pathogenesis of ovarian dysfunction caused by LPS. We suppose that this enzyme can be an attractive target for the therapy of inflammatory disorders in ovary. The protective action of PARP-1 inhibition could at least partly be associated with the reduction of necrotic death of follicular cells and also in other cells. However, the detailed mechanisms of the favorable effect of PARP inhibitors on endotoxin-induced ovarian disorders need to be further explored.

Wearable Patch Heart Rate Variability Is an Early Marker of Systemic Inflammation During Experimental Human Endotoxemia.

INTRODUCTION: Early diagnosis and treatment can reduce the risk of organ failure and mortality in systemic inflammatory conditions. Heart rate variability (HRV) has potential for early identification of the onset of systemic inflammation, as it may detect changes in sympathetic nervous system activity resulting from the developing inflammatory response before clinical signs appear. With the use of new methodologies, we investigated the onset and kinetics of HRV changes as well as several inflammatory parameters and symptoms during experimental human endotoxemia, a model of systemic inflammation in humans in vivo. PATIENTS AND METHODS: Healthy volunteers were intravenously administered LPS (n = 15) or placebo (n = 15). HRV was determined using a wireless wearable device, and parameters low to high frequency (LF:HF) ratio, root mean square of the successive differences (RMSSD), and standard deviation of normal-to-normal R-R intervals (SDNN)were calculated through 1-min-rolling 6-min windows. Plasma cytokine levels and flu-like symptoms and vital signs were serially assessed. RESULTS: The increase in LF:HF ratio, reflecting sympathetic predominance, was more pronounced in the LPS group compared to the placebo group, with the difference becoming statistically significant 65 min following LPS administration (1.63 [1.42-1.83] vs. 1.28 [1.11-1.44], P = 0.005). Significant between-group differences in RMSSD and SDNN were observed from 127 to 140 min post-LPS administration onwards, respectively. Plasma cytokine levels showed significant between-group differences staring 60 min post-LPS. For symptom score, heart rate, temperature, and diastolic blood pressure, significant differences compared with the placebo group were observed at 90, 118, 120, and 124 min post-LPS, respectively. CONCLUSION: In a controlled human model of systemic inflammation, elevations in the LF:HF ratio followed very shortly after elevations in plasma cytokine levels and preceded onset of flu-like symptoms and alterations in vital signs. HRV may represent a promising non-invasive tool for early detection of a developing systemic inflammatory response.

Disruption of intestinal barrier and endotoxemia after traumatic brain injury: Implications for post-traumatic epilepsy.

OBJECTIVE: Traumatic brain injury (TBI) may lead to the disruption of the intestinal barrier (IB), and to the escape of products of commensal gut bacteria, including lipopolysaccharide (LPS), into the bloodstream. We examined whether lateral fluid percussion injury (LFPI) and post-traumatic epilepsy (PTE) are associated with the increased intestinal permeability and endotoxemia, and whether these events in turn are associated with PTE. METHODS: LFPI was delivered to adult male Sprague-Dawley rats. Before, 1 week, and 7 months after LFPI, the IB permeability was examined by measuring plasma concentration of fluorescein isothiocyanate-labeled dextran (FD4) upon its enteral administration. Plasma LPS concentration was measured in the same animals, using enzyme-linked immunosorbent assay. PTE was examined 7 months after LFPI, with use of video-EEG (electroencephalography) monitoring. RESULTS: One week after LFPI, the IB disruption was detected in 14 of 17 and endotoxemia - in 10 of 17 rats, with a strong positive correlation between FD4 and LPS levels, and between plasma levels of each of the analytes and the severity of neuromotor deficit. Seven months after LFPI, IB disruption was detected in 13 of 15 and endotoxemia in 8 of 15 rats, with a strong positive correlation between plasma levels of the two analytes. Five of 15 LFPI rats developed PTE. Plasma levels of both FD4 and LPS were significantly higher in animals with PTE than among the animals without PTE. The analysis of seven rats, which were examined repeatedly at 1 week and at 7 months, confirmed that late IB disruption and endotoxemia were not due to lingering of impairments occurring shortly after LFPI. SIGNIFICANCE: LFPI leads to early and remote disruption of IB and a secondary endotoxemia. Early and late perturbations may occur in different subjects. Early changes reflect the severity of acute post-traumatic motor dysfunction, whereas late changes are associated with PTE.

Cardiac and Brainstem Neuroinflammatory Pathways Account for Androgenic Incitement of Cardiovascular and Autonomic Manifestations in Endotoxic Male Rats.

ABSTRACT: Inconsistent reports are available on the role of testosterone in end-organ damage caused by endotoxemia. Here, pharmacologic, surgical, and molecular studies were employed to assess the testosterone modulation of cardiovascular, autonomic, and peripheral and central inflammatory derangements caused by endotoxemia. Studies were performed in conscious male rats preinstrumented with femoral indwelling catheters for the measurement of blood pressure and subjected to castration or pharmacologic interventions that interrupt the biosynthetic cascade of testosterone. Compared with the effects of lipopolysaccharide (10 mg/kg intravenously) in sham operated rats, 2-week castration reduced the lipopolysaccharide-evoked (1) falls in blood pressure, (2) decreases in time- and frequency-domain indices of heart rate variability, (3) shifts in spectral measures of cardiac sympathovagal balance toward parasympathetic dominance, and (4) increases in protein expressions of toll-like receptor-4 and monocyte chemoattractant protein-1 in heart and medullary neurons of the nucleus tractus solitarius and rostral ventrolateral medulla. While the ameliorating actions of castration on endotoxic cardiovascular manifestations were maintained after testosterone replacement, the concomitant inflammatory signals were restored to near-sham levels. The favorable influences of castration on inflammatory and cardiovascular abnormalities of endotoxemia were replicated in intact rats pretreated with degarelix (gonadotropin-releasing hormone receptor blocker) or finasteride (5α-reductase inhibitor) but not formestane (aromatase inhibitor). The data signifies the importance of androgens and its biosynthetic enzymes in cardiovascular and autonomic insults induced by the endotoxic inflammatory response. Clinically, the interruption of testosterone biosynthesis could offer a potential strategy for endotoxemia management.

Silencing IFNγ inhibits A1 astrocytes and attenuates neurogenesis decline and cognitive impairment in endotoxemia.

Cognitive impairment, acute or long-term, is a common complication in patients with severe bacterial infection. However, the underlying mechanisms are not fully verified and effective medicine is not available in clinics. Interferon gamma (IFNγ) is a pivotal cytokine against infection and is believed to be a tune in homeostasis of cognitive function. Here, we collected blood and cerebrospinal fluid (CF) from human subjects and mice, and found that plasma and CF levels of IFNγ were significantly increased in septic patients and endotoxin-challenged mice when compared with healthy controls. IFNγ signaling was boosted in the hippocampus of mice after a challenge of lipopolysaccharide (LPS), which was accompanied with cognitive impairment and decline of neurogenesis. Deficiency of IFNγ or its receptor (IFNγR) dramatically attenuated microglia-induced A1 astrocytes and consequently restored neurogenesis and cognitive function in endotoxemia mice model. Using primary microglia, astrocytes and neurons, we found that IFNγ remarkably increased LPS-mediated release of TNFα and IL-1α in microglia and consequently induced the transformation of astrocyte to A1 subtype, which ultimately resulted in neuron damage. Thus, IFNγ promotes cognitive impairment in endotoxemia by enhancing microglia-induced A1 astrocytes. Targeting IFNγ would be a novel strategy for preventing or treating cognitive dysfunction in patients with Gram-negative infection.

Endotoxemia coupled with heightened inflammation predicts future depressive symptoms.

OBJECTIVE: Cross-sectional data have linked gut barrier abnormalities and endotoxemia with depression, even among those without gastrointestinal symptoms. This study examined longitudinal associations between endotoxemia markers and depressive symptoms, as well as the role of inflammation in this relationship. DESIGN: At three annual visits, 315 women (n=209 breast cancer survivors, n = 106 non-cancer patient controls, M=55 years old) completed the Center for Epidemiological Studies Depression questionnaire (CES-D) and provided blood samples to assess inflammatory markers - interleukin-6, tumor necrosis factor-alpha, and C-reactive protein - and endotoxemia markers - lipopolysaccharide-binding protein (LBP), soluble CD14 (sCD14), and their ratio. RESULTS: Adjusting for key demographic variables, health behaviors, visit 1 depressive symptoms, and cancer status and treatment, women with higher visit 1 LBP and LBP/sCD14 had more depressive symptoms at the two subsequent annual visits. Illustrating the notable impact, a woman at the 75th percentile for LBP or LBP/sCD14 at visit 1 was 18 % more likely to report clinically significant depressive symptoms (CES-D ≥16) at follow-up than a woman in the lowest quartile. Cancer status and treatment type did not modulate this relationship. In contrast, visit 1 depressive symptoms did not predict endotoxemia at follow-up. A significant interaction between LBP/sCD14 and inflammatory burden suggested that visit 1 endotoxemia fueled depressive symptoms only in the context of elevated inflammation. CONCLUSION: These results suggest that endotoxemia, combined with systemic inflammation, can drive depressive symptoms. These findings may implicate bacterial endotoxin translocation from the gut to the bloodstream in depression etiology. Interventions that reduce endotoxemia and inflammation may lessen the risk of depression.

Identification of a brainstem locus that inhibits tumor necrosis factor.

In the brain, compact clusters of neuron cell bodies, termed nuclei, are essential for maintaining parameters of host physiology within a narrow range optimal for health. Neurons residing in the brainstem dorsal motor nucleus (DMN) project in the vagus nerve to communicate with the lungs, liver, gastrointestinal tract, and other organs. Vagus nerve-mediated reflexes also control immune system responses to infection and injury by inhibiting the production of tumor necrosis factor (TNF) and other cytokines in the spleen, although the function of DMN neurons in regulating TNF release is not known. Here, optogenetics and functional mapping reveal cholinergic neurons in the DMN, which project to the celiac-superior mesenteric ganglia, significantly increase splenic nerve activity and inhibit TNF production. Efferent vagus nerve fibers terminating in the celiac-superior mesenteric ganglia form varicose-like structures surrounding individual nerve cell bodies innervating the spleen. Selective optogenetic activation of DMN cholinergic neurons or electrical activation of the cervical vagus nerve evokes action potentials in the splenic nerve. Pharmacological blockade and surgical transection of the vagus nerve inhibit vagus nerve-evoked splenic nerve responses. These results indicate that cholinergic neurons residing in the brainstem DMN control TNF production, revealing a role for brainstem coordination of immunity.

High glucose load and endotoxemia among overweight and obese Arab women with and without diabetes: An observational study.

Dietary intake influences gut microbiota activity. Nevertheless, there is a lack of evidence available that illustrates the acute effects of high glucose meal on metabolic endotoxemia. The present study assessed the acute impact of high glucose meal on endotoxemia and other clinical parameters in Saudi females with varying degrees of glycemia.The subjects were 64 consenting pre-menopausal women, grouped into 3: control [n = 14 lean, non-T2DM, BMI = 22.2 ±â€Š2.2 kg/m]; overweight [n = 16, non-T2DM, BMI = 28.5 ±â€Š1.5 kg/m] and T2DM [n = 34, BMI = 35.2 ±â€Š7.7 kg/m]. After an overnight fast, all subjects were given a standardized high-glucose (75 g) meal. Anthropometrics were taken and blood samples were withdrawn at baseline and postprandial (0, 2 and 4-hours), serum glucose, endotoxin and lipid profile were quantified.At baseline, total cholesterol, LDL-cholesterol, triglycerides and serum glucose levels were significantly higher (P values <.01) whereas significantly lower HDL-cholesterol levels (P < .01) were observed in T2DM subjects compared to other groups. Baseline endotoxin levels were highest in the overweight group (3.2 ±â€Š1.1 mmol/L) as compared to control (2.0 ±â€Š0.5 mmol/L) and T2DM (2.7 ±â€Š1.2 mmol/L) (P = .046). HDL-cholesterol, LDL-cholesterol and triglycerides, significantly decreased in the T2DM group after 2 hours (P values <.05), whereas unremarkable changes observed in other groups. Lastly, endotoxin levels significantly increased only in the overweight group (3.2 ±â€Š1.1 vs 4.2 ±â€Š1.4 mmol/L; P < .05), 4 hours postprandial.High glucose meal elevates endotoxemia only among overweight subjects and impairs dysbiosis.

Nicotine uncovers endotoxic-like cardiovascular manifestations in female rats: Estrogen and nitric oxide dependency.

Endotoxic manifestations are diminished in female populations due to immune boosting actions of sex steroids. Considering that tobacco constituents including nicotine inhibit estrogen synthesis, we tested the hypothesis that nicotine exposure unveils cardiovascular anomalies of endotoxemia in female rats. Studies were undertaken in conscious female rats treated with i.v. lipopolysaccharide (LPS, 10 mg/kg) in absence and presence of nicotine. In contrast to no effects for LPS when used alone, dose-related decreases in blood pressure (BP) and serum estrogen were noted in endotoxic rats treated consequently with nicotine (25, 50, or 100 µg/kg i.v.). Signs of cardiac autonomic dysfunction appeared in LPS/nicotine-treated rats such as (i) decreased time-domain indices of heart rate variability (HRV), e.g. standard deviation of R-R intervals (SDNN) and root mean square of successive differences in R-R interval durations (rMSSD), and (ii) reduced total power of the frequency spectrum and shifted cardiac sympathovagal balance toward sympathetic dominance. Nicotine reversed the LPS-evoked modest rises in serum TNFα and IL-1ß while had no effect on associated arterial baroreflex dysfunction, inferring no roles for inflammation or baroreflexes in LPS-nicotine interaction. Estrogen or aminoguanidine (iNOS inhibitor), but not pentoxifylline (TNFα inhibitor), abolished LPS/nicotine hypotension. Together, nicotine acts probably via reducing estrogen availability to uncover nitric oxide-dependent hypotension and autonomic dysregulation in endotoxic female rats.

Inhibition of CPT2 exacerbates cardiac dysfunction and inflammation in experimental endotoxaemia.

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.

Effect of sedation with dexmedetomidine or propofol on gastrointestinal motility in lipopolysaccharide-induced endotoxemic mice.

BACKGROUND: Sepsis often accompanies gastrointestinal motility disorder that contributes to the development of sepsis in turn. Propofol and dexmedetomidine, as widely used sedatives in patients with sepsis, are likely to depress gastrointestinal peristalsis. We queried whether propofol or dexmedetomidine, at sedative doses, aggravated sepsis-induced ileus. METHODS: Sedative/Anesthetic Scores and vital signs of lipopolysaccharide (LPS)-induced endotoxemic mice were measured during sedation with propofol or dexmedetomidine. Endotoxemic mice were divided into 10% fat emulsion, propofol, saline, and dexmedetomidine group. The gastric emptying, small intestinal transit, tests of colonic motility, gastrointestinal transit and whole gut transit were evaluated at 15 mins and 24 h after intraperitoneal injection of sedatives/vehicles respectively. RESULTS: 40 mg·kg- 1propofol and 80 µg·kg- 1 dexmedetomidine induced a similar depth of sedation with comparable vital signs except that dexmedetomidine strikingly decreased heart rate in endotoxemic mice. Dexmedetomidine markedly inhibited gastric emptying (P = 0.006), small intestinal transit (P = 0.006), colonic transit (P = 0.0006), gastrointestinal transit (P = 0.0001) and the whole gut transit (P = 0.034) compared with the vehicle, whereas propofol showed no depression on all parts of gastrointestinal motility 15 mins after administration. The inhibitive effects of dexmedetomidine in these tests vanished 24 h after the administration. CONCLUSIONS: Deep sedation with dexmedetomidine, but not propofol, significantly inhibited gastrointestinal peristalsis in endotoxemic mice while the inhibitory effect disappeared 24 h after sedation. These data suggested that both propofol and dexmedetomidine could be applied in septic patients while dexmedetomidine should be used cautiously in patients with cardiac disease or ileus.

Early-Life Maternal Deprivation Predicts Stronger Sickness Behaviour and Reduced Immune Responses to Acute Endotoxaemia in a Pig Model.

Early-life adversity may have programming effects on neuroendocrine and immune adaptation mechanisms in humans and socially living animals. Using a pig model, we investigated the effect of daily 2-h maternal and littermate deprivation from postnatal days 2-15, either alone (DA) or in a group of littermates (DG) on the neuroendocrine, immunological and behavioural responses of piglets challenged with the bacterial endotoxin lipopolysaccharide (LPS) on day 42. LPS increased plasma concentrations of cortisol, tumour necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and interleukin-10 (IL-10) and induced typical signs of sickness in all piglets. DA+DG piglets showed stronger signs of sickness compared to control (C) piglets. Plasma TNF-α concentrations were significantly lower in DA+DG males. In addition, the TNF-α/IL-10 ratio was significantly lower in DA than in DG and C males. Gene expression analyses showed lower hypothalamic TNF-α mRNA expression and diminished mRNA expression of the mineralocorticoid receptor (MR) and IL-10 in the amygdala of DA+DG piglets in response to LPS. Interestingly, males showed a higher MR- and a lower IL-10 mRNA expression in the amygdala than females. The present data suggest that repeated maternal deprivation during early life may alter neuroendocrine and immune responses to acute endotoxaemia in a sex-specific manner.

Use of perfusion index to detect hemodynamic changes in endotoxemic pigs.

OBJECTIVE: The perfusion index (PI) derived from plethysmographic signals provides a noninvasive indication of peripheral perfusion. This study aimed to investigate changes in PI and other hemodynamic variables in pigs subjected to endotoxemia. DESIGN: Prospective experimental study. SETTING: University teaching hospital. ANIMALS: Twelve healthy pigs weighing a mean (± standard deviation [SD]) of 31.7 ± 2.0 kg. INTERVENTIONS: Pigs were divided into control and endotoxin groups (n = 6 each). Endotoxemia was induced by IV infusion of lipopolysaccharide. Heart rate, mean arterial pressure, cardiac index (CI), central venous pressure, systemic vascular resistance index (SVRI), extravascular lung water index (ELWI), Global end-diastolic volume (GEDV) index, and pulmonary permeability index were measured using a transpulmonary thermodilution monitor in all pigs. PI was measured using a pulse oximeter probe attached to the tail. Pao2 , Paco2 , and plasma lactate concentration were measured by blood gas analysis. Measurements were taken at baseline (T0 ). Saline or lipopolysaccharide was then administered for 30 min to all pigs (control or endotoxemia group, respectively), and each parameter was measured every 30 min up to 270 min. Data were analyzed by analysis of variance and Student's t-tests. MEASUREMENTS AND MAIN RESULTS: There were no significant changes in any variables in the control group, but CI, SVRI, PI, ELWI, blood lactate concentration, and Pao2 changed significantly from baseline in the endotoxin group (P < 0.001, P = 0.0048, P < 0.001, P = 0.0064, P < 0.001, and P = 0.0220, respectively). In the endotoxin group, mean (± SD) %PI increased from T0 to 154 ± 34% at T60 (P = .001) and 135 ± 50% at T90 (P =0 .004), which mirrored significant changes in %CI and %SVRI. CONCLUSION: The PI may be useful to detect changes in CI and SVRI.

Microbiota and Hypertension: Role of the Sympathetic Nervous System and the Immune System.

There are numerous studies indicating a direct association between hypertension and gut microbiota in both animal models and humans. In this review, we focused on the imbalance in the gut microbiota composition relative to healthy state or homeostasis, termed dysbiosis, associated with hypertension and discuss the current knowledge regarding how microbiota regulates blood pressure (BP), involving the sympathetic nervous system and the immune system. The profile of ecological parameters and bacterial genera composition of gut dysbiosis in hypertension varies according to the experimental model of hypertension. Recent evidence supports that gut microbiota can protect or promote the development of hypertension by interacting with gut secondary lymph organs and altering T helper 17/regulatory T cells polarization, with subsequent changes in T cells infiltration in vascular tissues. Here, we also describe the bidirectional communication between the microbiome and the host via the sympathetic nervous system and its role in BP regulation. Dysbiosis in hypertension is mainly associated with reduced proportions of short-chain fatty acid-producing bacteria, mainly acetate- and butyrate-producing bacteria, and an increased enrichment of the genes for lipopolysaccharide biosynthesis and export, lending to moderate endotoxemia. The role of these metabolic and structural products in both immune and sympathetic system regulation and vascular inflammation was also analyzed. Overall, gut microbiota is now recognized as a well-established target to dietary interventions with prebiotics or probiotics to reduce BP.

Structural and Morphological Changes in the Liver Due to Intestinal Endotoxins.

BACKGROUND: Under normal physiological conditions, endotoxin (ET) released during self-renewal of the colibacillus pool is an obligate stimulus for the formation of the immune system and homeostasis of the body. Violation of the barrier function of the intestinal wall and the mechanisms of neutralization of endotoxin lead to systemic endotoxemia of intestinal origin. Its development is facilitated by stress, intoxication, a decrease in nonspecific resistance of the body, as well as damage to the intestinal mucosa and dysbiosis, where the mucous membrane is more vulnerable and permeable to endotoxin. PURPOSE OF THE RESEARCH: The aim of this study is to compare and assess the severity and nature of hepatocyte damage from endotoxin exposure and the degree of manifestation of stress due to oxidation, to determine the characteristics of structural changes in hepatocytes and to assess the oxidation stress during endotoxin intoxication in the experiment with biochemical markers. MATERIALS AND METHODS: The experiments were conducted on 40 non-linear rats, divided into two groups of 20 animals. Group 1 animals received intraperitoneal injections of ET of Escherichia coli drug (Sigma USA K-235) for seven days at a rate of 0.1 mg/kg of the body weight. Animals of the second group served as the control group. Character and stage of liver damage were studied using morphological methods, including electron and light microscopy. In studying oxidizing stress, biochemical methods were used to define the changes, such as conjugated dienes and dienketones, spontaneous oxidizing modification of proteins. RESULTS AND CONCLUSION: 1. The severity and depth of morphological changes in the liver during endotoxin intoxication were correlated with the dynamics of the content of lipid oxidation products (CD and DK, MDA) and proteins. There was a tendency for a more significant increase in the oxidative modification of proteins in serum. This confirms the data on the primary damage of proteins by free radicals. 2. When exposed to intestinal microflora endotoxin, pronounced dyscirculatory changes, fatty and hydropic degeneration of hepatocytes with signs of toxic damage to their nuclei were determined, but at the same time, the increased hyperplastic activity of sinusoidal cells remained associated with the effects of endotoxin. These changes are associated with both the direct toxic effect of endotoxin, and the effects of oxidative stress, in which endotoxin is a potent inducer.

Simvastatin attenuated sickness behavior and fever in a murine model of endotoxemia.

AIMS: During illnesses caused by infectious disease, a suite of brain-mediated responses called sickness syndrome occurs, triggering behavioral and physiological (fever) changes. Simvastatin is widely used as a lipid-lowering medication that has beneficial immunomodulatory properties. This study investigated the effects of simvastatin in a mouse model of sickness syndrome by systemic administration of lipopolysaccharide (LPS). MAIN METHODS: Male mice were pretreated with vehicle or simvastatin (40 mg/kg, p.o.) for 7 days and received LPS (200 µg/kg, i.p.) or sterile saline. We investigated the behavioral effects in male mice 2 h after LPS administration using tests screening for depressive-like behavior and locomotor activity alterations. Changes in body temperature were measured by biotelemetry probe preimplanted in the peritoneal cavity to evaluate the effect of simvastatin on the thermoregulatory response during immunological challenge. KEY FINDINGS: Pretreatment with simvastatin blunted most of the assessed parameters related to sickness syndrome, including depressive-like behavior and depressed locomotor activity, and attenuated LPS-induced fever. These data are consistent with simvastatin promoting alterations in peripheral febrigenic signaling (plasma levels of TNF-α, IL-1ß, and IL-10). SIGNIFICANCE: Our data provide further evidence of the capacity of simvastatin to attenuate sickness behavior and fever induced by immunological challenge through a mechanism related to changes in the profile of cytokine production.

Maresin conjugates in tissue regeneration 1 prevents lipopolysaccharide-induced cardiac dysfunction through improvement of mitochondrial biogenesis and function.

Mitochondrial dysfunction is increasingly considered as the center of pathophysiology in sepsis-induced cardiac dysfunction. Maresin conjugates in tissue regeneration 1 (MCTR1) is a newly identified specialized pro-resolving mediator (SPM) and has been shown to accelerate tissue regeneration and exert positive inotropic effects. Our present study aims to investigate the effect of MCTR1 on lipopolysaccharide (LPS)-induced cardiac dysfunction and explore its potential mechanisms. Mice were treated with LPS to generate LPS-induced cardiac dysfunction. H9C2 cells were used to verify the effect of MCTR1 in vitro. LPS injection triggered cardiac dysfunction and increased mRNA expression of inflammation cytokines, which were significantly attenuated by post-treatment of MCTR1. Mechanistically, we found that MCTR1 ameliorated LPS-mediated reduction of protein expression of mitochondrial biogenesis factors and silent information regulator 1 (Sirt1), accompanied by enhancement of mitochondrial biogenesis and function. Besides, Sirt1 inhibitor EX527 inhibited effects of MCTR1 on mitochondrial biogenesis and function, blunted the protective effect of MCTR1 on cardiac function, and prevented enhancement of survival rate. MCTR1 protected against LPS-induced cardiac dysfunction through improvement of mitochondrial biogenesis and function in a Sirt1-dependent manner. Our studies showed that MCTR1 might represent a novel therapeutic strategy for cardiac dysfunction caused by sepsis.

Selective abolition of Mayer waves in conscious endotoxemic rats.

The relation between vascular sympathetic tone and the amplitude of arterial pressure (AP) Mayer waves was examined by analyzing 60-min recordings of AP and renal sympathetic nerve activity (RSNA) obtained in conscious rats before and after lipopolysaccharide administration, which results in strong sympathoexcitation. Mayer waves completely disappeared together with accompanying oscillations of RSNA. Meanwhile, the gain of the sympathetic baroreceptor reflex was increased, thus suggesting that abolition of Mayer waves resulted from the previously reported reduction of vascular reactivity to α-adrenoceptor stimulation. In conclusion, the amplitude of Mayer waves cannot be used indiscriminately as an index of vascular sympathetic tone.

Resuscitation with PEGylated carboxyhemoglobin preserves renal cortical oxygenation and improves skeletal muscle microcirculatory flow during endotoxemia.

PEGylated carboxyhemoglobin (PEGHbCO), which has carbon monoxide-releasing properties and plasma expansion and oxygen-carrying properties, may improve both skeletal microcirculatory flow and renal cortical microcirculatory Po2 (CµPo2) and, subsequently, limit endotoxemia-induced acute kidney injury. Anesthetized, ventilated Wistar albino rats (n = 44) underwent endotoxemic shock. CµPo2 was measured in exposed kidneys using a phosphorescence-quenching method. Rats were randomly assigned to the following five groups: 1) unresuscitated lipopolysaccharide (LPS), 2) LPS + Ringer's acetate (RA), 3) LPS + RA + 0.5 µg·kg·-1min-1 norepinephrine (NE), 4) LPS + RA + 320 mg/kg PEGHbCO, and 5) LPS + RA + PEGHbCO + NE. The total volume was 30 mL/kg in each group. A time control animal group was used. Skeletal muscle microcirculation was assessed by handheld intravital microscopy. Kidney immunohistochemistry and myeloperoxidase-stained leukocytes in glomerular and peritubular areas were analyzed. Endotoxemia-induced histological damage was assessed. Plasma levels of IL-6, heme oxygenase-1, malondialdehyde, and syndecan-1 were assessed by ELISA. CµPo2 was higher in the LPS + RA + PEGHbCO-resuscitated group, at 35 ± 6mmHg compared with 21 ± 12 mmHg for the LPS+RA group [mean difference: -13.53, 95% confidence interval: (-26.35; -0.7156), P = 0.035]. The number of nonflowing, intermittent, or sluggish capillaries was smaller in groups infused with PEGHbCO compared with RA alone (P < 0.05), while the number of normally perfused vessels was greater (P < 0.05). The addition of NE did not further improve CµPo2 or microcirculatory parameters. Endotoxemia-induced kidney immunohistochemistry and histological alterations were not mitigated by PEGHbCO 1 h after resuscitation. Renal leukocyte infiltration and plasma levels of biomarkers were similar across groups. PEGHbCO enhanced CµPo2 while restoring skeletal muscle microcirculatory flow in previously nonflowing capillaries. PEGHbCO should be further evaluated as a resuscitation fluid in mid- to long-term models of sepsis-induced acute kidney injury.