Protective Effect of Electroacupuncture on the Barrier Function of Intestinal Injury in Endotoxemia through HO-1/PINK1 Pathway-Mediated Mitochondrial Dynamics Regulation.

Background and Aims: Endotoxemia (ET) is a common critical illness in patients receiving intensive care and is associated with high mortality and prolonged hospital stay. The intestinal epithelial cell dysfunction is regarded as the "engine" of deteriorated ET. Although electroacupuncture (EA) can mitigate endotoxin-induced intestinal epithelial cell dysfunction in ET, the mechanism through which EA improves endotoxin-induced intestinal injury for preventing ET deterioration needs further investigation. Methods: An in vivo ET model was developed by injecting lipopolysaccharide (LPS) in wild-type and PINK1-knockout mice. An in vitro model was also established by incubating epithelial cells in the serum samples obtained from both groups of mice. Hemin and zinc protoporphyrin IX (ZnPP) were applied to activate or inhibit heme oxygenase 1 (HO-1) production. EA treatment was performed for 30 min consecutively for 5 days before LPS injection, and on the day of the experiment, EA was performed throughout the process. Samples were harvested at 6 h after LPS induction for analyzing tissue injury, oxidative stress, ATP production, activity of diamine oxidase (DAO), and changes in the levels of HO-1, PTEN-induced putative kinase 1 (PINK1), mitochondrial fusion and fission marker gene, caspase-1, and interleukin 1 beta (IL-1ß). Results: In the wild-type models (both in vivo and vitro), EA alleviated LPS-induced intestinal injury and mitochondrial dysfunction, as indicated by decreased reactive oxygen species (ROS) production and oxygen consumption rate (OCR) and reduced levels of mitochondrial fission proteins. EA treatment also boosted histopathological morphology, ATP levels, DAO activity, and levels of mitochondrial fusion proteins in vivo and vitro. The effect of EA was enhanced by hemin but suppressed by Znpp. However, EA + AP, Znpp, or hemin had no effects on the LPS-induced, PINK1-knocked out mouse models. Conclusion: EA may improve the HO-1/PINK1 pathway-mediated mitochondrial dynamic balance to protect the intestinal barrier in patients with ET.

[Parasympathetic innervation contributes to the increase of survival rate and anti-inflammatory effect of electroacupuncture at "Ciliao"(BL32) in rats with lethal endotoxemia].

OBJECTIVE: To observe the effect of electroacupuncture (EA) at "Ciliao" (BL32) on the survival rate and serum inflammatory cytokine levels in rats with lethal endotoxemia, and to explore its parasympathetic mechanism in suppressing severe systemic inflammation. METHODS: A total of 82 male SD rats were used in the present study. In the first part of this study, 40 rats were randomized into model and EA-BL32 groups (n=20/group). The endotoxemia model was established by intraperitoneal injection of lethal amount of lipopolysaccharide (LPS, 10 mg/kg). EA (30 Hz, 6 mA) was applied to bilateral BL32 for 30 min before and after LPS injection. The survival rate in 7 days was then recorded. In the second part of this study, 42 rats were randomized into normal control, model, EA-BL32, EA-BL32+cervical vagotomy, EA-BL32+truncal (subdiagrammatical) vagotomy and EA-BL32+pelvic neurectomy groups (n=7/group). The endotoxemia model was established by intraperitoneal injection of LPS (6 mg/kg) 30 min after the neurectomy. Rats of the control group received intraperitoneal injection of 6 mg/kg saline. EA with the same parameters mentioned above was applied to bilateral BL32 for 30 min before and after LPS injection. Blood sample was collected from the abdominal aorta 3 h after LPS injection for detecting the levels of TNF-α, IL-1ß and IL-6 by ELISA. RESULTS: ① The EA survival rate was 25% in the model group and 60% in the EA -BL32group, being significantly improved after EA (P<0.05). ② The contents of serum TNF-α, IL-1ß and IL-6 were significantly higher in the model group than those in the control group (P<0.000 1). After EA intervention, and compared with the model group, the levels of TNF-α, IL-1ß and IL-6 were significantly decreased in the EA-BL32, EA-BL32+cervical vagotomy, EA-BL32+truncal vagotomy and EA-BL32+pelvic neurectomy groups (P<0.000 1，P<0.01). After neurectomy and compared to the EA-BL32 group, the contents of TNF-α and IL-6 in the EA+cervical vagotomy and EA+pelvic neurectomy groups, IL-1ß in the EA+pelvic neurotomy group were significantly higher (P<0.0000 1, P<0.05), suggesting an elimination of EA effects after neurectomy. No significant differences were found among the 3 neurectomy groups in the levels of TNF-α, IL-1ß and IL-6 (P>0.05). CONCLUSION: EA of BL32 can improve the survival rate and attenuate the level of inflammatory cytokines in rats with lethal endotoxemia, which is closely related to the intact of parasympathetic pathway including the vagus nerve and pelvic nerve.

Effect of probiotic supplementation along with calorie restriction on metabolic endotoxemia, and inflammation markers in coronary artery disease patients: a double blind placebo controlled randomized clinical trial.

PURPOSE: Alterations in the gut microbiome (dysbiosis) has been associated with increased microbial translocation, leading to chronic inflammation in coronary artery disease (CAD). It has been proposed that modulation of gut microbiota by probiotic might modify metabolic endotoxemia. Therefore, the purpose of this study was to examine the effects of Lactobacillus rhamnosus GG (LGG) on endotoxin level, and biomarkers of inflammation in CAD participants. METHODS: This study was a 12-weeks randomized, double-blind, and intervention on 44 patients with CAD. Patients were randomly allocated to receive either one LGG capsule 1.6 × 109 colony-forming unit (CFU) or the placebo capsules for 12 weeks. In addition, all the participants were also prescribed a calorie-restricted diet. Serum levels of interleukin-1ß (IL-1ß), Toll-like receptor 4 (TLR4), interleukin-10 (IL-10), and lipopolysaccharide (LPS), were assessed before and after the intervention. RESULTS: A significant decrease in IL1-Beta concentration (- 1.88 ± 2.25, vs. 0.50 ± 1.58 mmol/L, P = 0.027), and LPS levels (- 5.88 ± 2.70 vs. 2.96+ 5.27 mg/L, P = 0.016), was observed after the probiotic supplementation compared with the placebo. Participants who had ≥2.5 kg weight loss showed significantly improved cardiovascular-related factors, compared to patients with < 2.5 kg weight reduction, regardless of the supplement they took. CONCLUSION: These data provide preliminary evidence that probiotic supplementation has beneficial effects on metabolic endotoxemia, and mega inflammation in participants with CAD.

Splenic Nerve Neuromodulation Reduces Inflammation and Promotes Resolution in Chronically Implanted Pigs.

Neuromodulation of the immune system has been proposed as a novel therapeutic strategy for the treatment of inflammatory conditions. We recently demonstrated that stimulation of near-organ autonomic nerves to the spleen can be harnessed to modulate the inflammatory response in an anesthetized pig model. The development of neuromodulation therapy for the clinic requires chronic efficacy and safety testing in a large animal model. This manuscript describes the effects of longitudinal conscious splenic nerve neuromodulation in chronically-implanted pigs. Firstly, clinically-relevant stimulation parameters were refined to efficiently activate the splenic nerve while reducing changes in cardiovascular parameters. Subsequently, pigs were implanted with a circumferential cuff electrode around the splenic neurovascular bundle connected to an implantable pulse generator, using a minimally-invasive laparoscopic procedure. Tolerability of stimulation was demonstrated in freely-behaving pigs using the refined stimulation parameters. Longitudinal stimulation significantly reduced circulating tumor necrosis factor alpha levels induced by systemic endotoxemia. This effect was accompanied by reduced peripheral monocytopenia as well as a lower systemic accumulation of CD16+CD14high pro-inflammatory monocytes. Further, lipid mediator profiling analysis demonstrated an increased concentration of specialized pro-resolving mediators in peripheral plasma of stimulated animals, with a concomitant reduction of pro-inflammatory eicosanoids including prostaglandins. Terminal electrophysiological and physiological measurements and histopathological assessment demonstrated integrity of the splenic nerves up to 70 days post implantation. These chronic translational experiments demonstrate that daily splenic nerve neuromodulation, via implanted electronics and clinically-relevant stimulation parameters, is well tolerated and is able to prime the immune system toward a less inflammatory, pro-resolving phenotype.

Nutritional Management of Metabolic Endotoxemia: A Clinical Review.

Context • Diet-induced, metabolic endotoxemia is emerging as an important contributory factor to the development of a wide range of chronic diseases, including cardiometabolic, autoimmune, psychiatric, and neurodegenerative illnesses. Emerging human clinical studies have demonstrated that diet and dietary components are potent modifiers of circulating endotoxins and can be used to reduce plasma levels significantly and improve metabolic health. Objective • The aim of the current study was to explore briefly the concept of metabolic endotoxemia and its relationship to disease development, to examine the influence of diet and dietary components on circulating endotoxins, and, finally, discuss the clinical relevance of nutritional interventions for management of metabolic endotoxemia. Design • The researcher performed a literature review of dietary and nutritional interactions with metabolic endotoxemia with a focus on studies relevant to clinical practice. Setting • The study took place at the UK College of Nutrition and Health (London, England). Results • Improving dietary quality, optimizing the intake of phytonutrient-rich foods, improving micronutrient status, consuming fermented foods, manipulating the gut microflora with prebiotics and probiotics, and using specific nutritional supplements, such as glutamine, lactoferrin, resveratrol, and berberine, have been shown to be effective in targeting metabolic endotoxemia. Conclusions • Diet, dietary components, and nutritional supplements, including prebiotics and probiotics, have demonstrated the ability to provide clinically important reductions in circulating endotoxins and improve related sequels, such as inflammation and other negative health markers. The development of personalized nutritional interventions for the management of metabolic endotoxemia is a promising area for future research due to the potential of such interventions to improve multiple aspects of human health and mitigate a wide range of chronic diseases.

Transfusion of 35-day stored red blood cells does not result in increase of plasma non-transferrin bound iron in human endotoxemia.

BACKGROUND: Transfusion of a single unit of stored red blood cells (RBCs) has been hypothesized to induce supra-physiological levels of non-transferrin bound iron (NTBI), which may enhance inflammation and act as a nutrient for bacteria. We investigated the relation between RBC storage time and iron levels in a clinically relevant "two-hit" human transfusion model. STUDY DESIGN AND METHODS: Eighteen healthy male volunteers (ages 18-35 years) were infused with 2 ng lipopolysaccharide (LPS)/kg to induce systemic inflammatory response syndrome. Two hours later, each participant received either 1 unit of 2-day stored (2D) autologous RBCs, 35-day stored (35D) autologous RBCs, or an equal volume of saline. Every 2 hours up to 8 hours after LPS infusion, hemoglobin, hemolysis parameters, and iron parameters, including NTBI, were measured. RESULTS: Transfusion of both 2D and 35D RBCs caused increases in hemoglobin, plasma iron, and transferrin saturation; whereas levels remained stable in the saline group. Transfusion of 35D RBCs did not result in hemolysis nor did it lead to increased levels of NTBI compared with 2D RBCs or saline. LPS induced increases in ferritin, haptoglobin, bilirubin, and lactate dehydrogenase that were similar in all three groups. CONCLUSION: We conclude that 35D autologous RBCs do not cause hemolysis or increased levels of NTBI during human endotoxemia.

Long-term anti-endotoxin/E. coli efficacy in mice transfected with AAV2/1-muBPI25 -muFcγ1.

Bactericidal/permeability increasing (BPI) is an antibiotic protein which kills Gram-negative bacteria and neutralizes endotoxin. We have previously developed a recombinant adeno-associated virus which contains human BPI amino acid residues 1-199 and Fc fragment of human IgG1 gene (AAV-hBPI-Fc) and shown that the recombinant virus can protect mice from lethal endotoxemia. However, whether AAV-hBPI-Fc can be used in vivo for the long term remains unclear. To address this, we established an adeno-associated virus-containing mouse BPI and Fc fragment genes (muBPI-Fc) and compared antigenicity of these recombinant proteins in murine models. Immunohistochemistry showed the expression of both fusion proteins at injected sites. ELISA and Western blotting showed that the muBPI-Fc protein was detected in serum up to 8 weeks after injection, without generation of autoantibodies against muBPI-Fc. In contrast, expressed hBPI-Fc protein was only detected on the 2nd week, whereas the autoantibody against hBPI-Fc protein occurred in serum from the 4th week to the end of study. muBPI-Fc also reduced production of proinflammatory cytokines and protected mice from endotoxemia and bacteremia. Our data showed that AAV-muBPI-Fc has potential long-term efficacy as an anti-endotoxin and has anti-bacterial activity in mice, suggesting the potential clinical application of AAV-hBPI-Fc, such as in endotoxin shock.

The role of outcome expectancies for a training program consisting of meditation, breathing exercises, and cold exposure on the response to endotoxin administration: a proof-of-principle study.

Expectancies play a major role for the treatment outcome of a broad variety of immune-mediated conditions and may strengthen or mimic the effects of regular long-term therapies. This study adds to a recently published study of Kox et al. (PNAS 111:7379-7384, 2014) on the ability to voluntarily influence the physiological stress response in healthy men after a training program consisting of meditation, breathing techniques, and exposure to cold, which found highly promising results on the clinical, autonomic, and immune response to experimentally induced inflammation (using the experimental human endotoxemia model). Within this project, a number of variables were included to assess the role of generalized (optimism, neuroticism) and specific outcome expectancies (related to the effects of the training on health) on the response to endotoxin administration after training. Indications were found that especially the generalized outcome expectancy optimism is a potential determinant of the autonomic (epinephrine: rho = 0.76, p < .01) and immune response (interleukin-10: rho = 0.60, p < .05) to induced inflammation after training, whereas more specific expectations with regard to the effects of the training could be especially relevant for the clinical symptom report (flu-like symptoms: rho = -0.71, p < .01). This proof-of-principle study provides first indications for potential innovative treatments to change immune-modulating responses by means of psychological mechanisms. If replicated, these findings may be used for predicting training responses and potentiate their effects by means of optimism-inducing interventions in patients with immune-mediated rheumatic conditions.

The effects of co-administration of probiotics with herbal medicine on obesity, metabolic endotoxemia and dysbiosis: a randomized double-blind controlled clinical trial.

BACKGROUND & AIMS: Probiotics help maintain balance in composition of the gut microbiota, and have been considered as a potential treatment for obesity. This study was conducted in order to assess the effects of probiotics when combined with herbal medicine in treatment of obesity. Probiotics were tested for the ability to modulate gut microbiota, gut permeability, and endotoxin level, which may have correlation with factors involved in obesity. METHODS: A randomized, double-blind, placebo controlled study was conducted, in which patients with higher BMI (>25 kg/m(2)) and waist circumference (>85 cm) were enrolled and randomly assigned to receive Bofutsushosan with either probiotics or placebo capsules for a period of eight weeks. Assessment of body composition parameters, metabolic biomarkers, endotoxin level, gut permeability, and fecal bacteria in stool was performed at baseline and at week 8. The study was registered at the Clinical Research Information Service, approved by the Korea National Institute of Health (KCT0000386). RESULTS: Although both groups showed a significant reduction in weight and waist circumference (p = 0.000), no significant differences in body composition and metabolic markers were observed. In correlation analysis, change in body composition showed positive correlation with endotoxin level (r = 0.441, p < 0.05 for BW; and r = 0.350, p < 0.05 for fat mass) and the population of gut Lactobacillus plantarum (r = 0.425, p < 0.05 for BW; and r = 0.407, p < 0.05 for BMI). The Gram negative bacterial population in gut also exhibited positive correlation with changes in body composition (WC) and total cholesterol level (r = 0.359, and 0.393, for the former and later parameters, respectively, p < 0.05 for both). While, the profile of gut Bifidobacterium breve population showed negative correlation with endotoxin level (r = -0.350, p < 0.05). CONCLUSIONS: Correlations between gut microbiota and change in body composition indicate that probiotics may influence energy metabolism in obesity. Correlation between endotoxin level and weight reduction indicates that probiotics may play an important role in prevention of endotoxin production, which can lead to gut microbiota dysbiosis associated with obesity.

Effects of a diabetes-specific enteral nutrition on nutritional and immune status of diabetic, obese, and endotoxemic rats: interest of a graded arginine supply.

OBJECTIVE: Obese and type 2 diabetic patients present metabolic disturbance-related alterations in nonspecific immunity, to which the decrease in their plasma arginine contributes. Although diabetes-specific formulas have been developed, they have never been tested in the context of an acute infectious situation as can be seen in intensive care unit patients. Our aim was to investigate the effects of a diabetes-specific diet enriched or not with arginine in a model of infectious stress in a diabetes and obesity situation. As a large intake of arginine may be deleterious, this amino acid was given in graded fashion. DESIGN: Randomized, controlled experimental study. SETTING: University research laboratory. SUBJECTS: Zucker diabetic fatty rats. INTERVENTIONS: Gastrostomized Zucker diabetic fatty rats were submitted to intraperitoneal lipopolysaccharide administration and fed for 7 days with either a diabetes-specific enteral nutrition without (G group, n=7) or with graded arginine supply (1-5 g/kg/day) (GA group, n=7) or a standard enteral nutrition (HP group, n=10). MEASUREMENTS AND MAIN RESULTS: Survival rate was better in G and GA groups than in the HP group. On day 7, plasma insulin to glucose ratio tended to be lower in the same G and GA groups. Macrophage tumor necrosis factor-α (G: 5.0±1.1 ng/2×106 cells·hr⁻¹; GA: 3.7±0.8 ng/2×106 cells·hr⁻¹; and HP: 1.7±0.6 ng/2×106 cells·hr⁻¹; p<.05 G vs. HP) and nitric oxide (G: 4.5±1.1 ng/2×106 cells·hr⁻¹; GA: 5.1±1.0 ng/2×106 cells·hr⁻¹; and HP: 1.0±0.5 nmol/2×106 cells·hr⁻¹; p<.05 G and GA vs. HP) productions were higher in the G and GA groups compared to the HP group. Macrophages from the G and GA groups exhibited increased arginine consumption. CONCLUSIONS: In diabetic obese and endotoxemic rats, a diabetes-specific formula leads to a lower mortality, a decreased insulin resistance, and an improvement in peritoneal macrophage function. Arginine supplementation has no additional effect. These data support the use of such disease-specific diets in critically ill diabetic and obese patients.

Electroacupuncture improves survival in rats with lethal endotoxemia via the autonomic nervous system.

BACKGROUND: Recent advances have indicated a complex interplay between the autonomic nervous system and the innate immune system. Targeting neural networks for the treatment of sepsis is being developed as a therapeutic strategy. Because electroacupuncture at select acupoints can modulate activities of the autonomic nervous system, we tested the hypothesis that electroacupuncture at specific acupoints could modulate systemic inflammatory responses and improve survival via its impact on the autonomic nervous system in a rat model of sepsis. METHODS: Sprague-Dawley male rats received electroacupuncture for 45 min before and at 1, 2, or 4 h after a lethal dose of intraperitoneal lipopolysaccharide injection (6 mg/kg). Outcomes included survival and systemic cytokine responses. Also, the possible roles of neural circuitry, including the hypothalamic-pituitary-adrenal axis and the autonomic nervous system, were evaluated. RESULTS: Electroacupuncture pretreatment at the Hegu acupoints significantly attenuate systemic inflammatory responses and improve survival rate from 20% to 80% in rats with lethal endotoxemia. Such a site-specific effect requires the activation of muscarinic receptors in the central nervous system, but not increasing central sympathetic tone. In the periphery synergistic, rather than independent, action of the sympathetic and parasympathetic systems is also necessary. CONCLUSIONS: Electroacupuncture pretreatment has a dramatic survival-enhancing effect in rats with lethal endotoxemia, which involves the activation of efferent neural circuits of the autonomic nervous system (e.g., cholinergic antiinflammatory pathway). This approach could be developed as a prophylactic treatment for sepsis or perioperative conditions related to excessive inflammation.

Effects of hyperbaric oxygen treatment on horses with experimentally induced endotoxemia.

OBJECTIVE: To determine the effectiveness of preinduction hyperbaric oxygen treatment (HBOT) in ameliorating signs of experimentally induced endotoxemia in horses. ANIMALS: 18 healthy adult horses. PROCEDURES: Horses were randomly assigned to 1 of 3 equal-sized treatment groups to receive normobaric ambient air and lipopolysaccharide (LPS), HBOT and LPS, or HBOT and physiologic saline (0.9% NaCl) solution. Horses were physically examined, and blood was obtained for a CBC and to determine concentration or activity of plasma tissue necrosis factor-α, blood lactate, and blood glucose before the horses were treated with HBOT and then intermittently for 6 hours after administration of LPS or physiologic saline solution. RESULTS: All LPS-treated horses developed signs and biochemical and hematologic changes consistent with endotoxemia. Treatment with HBOT significantly ameliorated the effect of LPS on clinical endotoxemia score but did not significantly improve other abnormalities associated with endotoxemia. CONCLUSIONS AND CLINICAL RELEVANCE: The protective effect of HBOT was minimal, and results did not support its use as a treatment for horses prior to development of endotoxemia.

Electro-acupuncture at 'Neiguan' (PC6) attenuates liver injury in endotoxaemic rats.

BACKGROUND: Intravenous injection of lipopolysaccharide (LPS) stimulates macrophages to release proinflammatory cytokines and nitric oxide (NO). This results in hypotension, vascular hyporeactivity and multiple organ failure (eg, liver injury) in rats. In rats with endotoxin shock, electro-acupuncture (EA) of 'Neiguan' (PC6) retrieved blood pressure and reduced plasma concentrations of NO. The authors evaluated whether EA at PC6 could alleviate the development of liver injury and dysfunction in endotoxic rats. METHODS: A total of 28 male adult Wistar rats were included in this study. Rats received intravenous LPS (10 mg/kg for 4 h) or saline for 4 h followed by EA at PC6 acupuncture point. RESULTS: Elevated biochemical parameters of liver injury and marked infiltration of neutrophils into liver tissues caused by LPS were significantly attenuated by EA. However, hypotension, tachycardia and raised production of plasma NO were not suppressed by EA at PC6. CONCLUSIONS: These results indicate that EA at PC6 should be further investigated as a possible adjuvant therapy for endotoxin-induced liver dysfunction. Its mechanism of action needs further investigation.

[Effect of electroacupuncture of auricular concha on inflammatory reaction in endotoxaemia rats].

OBJECTIVE: To evaluate the effect of electroacupuncture (EA) of the auricular concha (EA-AC) on serum cytokines contents and pulmonary transcription factor nuclear factor-kappaB (NF-kappaB) expression in lipopolysaccharide (LPS) induced endotoxaemia rats so as to study its mechanism underlying cholinergic anti-inflammatory efficacy. METHODS: Male SD rats were randomized into normal control, model (LPS), simple EA-AC, EA-AC + LPS, vagal nerve stimulation (VNS) + LPS, and EA-Zusanli (ST 36) + LPS groups (n = 12/group). Endotoxaemia model was duplicated by intravenous (tail vein) injection of LPS (0.5 mL/kg). Two intradermal needles were inserted into the central sites of the cavity of concha and cymba of auricular concha respectively on each side and stimulated electrically by using an electrical stimulator (i.e, EA-AC). VNS was applied to the left cervical vagal nerve, and EA (1 mA, 10 Hz, pulse-width 1 ms) was also applied to bilateral "Zusanli" (ST 36). Serum cytokines (TNF-alpha IL-6) contents 2 h after modeling were determined by using enzyme linked immunosorbent assay (ELISA), and pulmonary NF-kappaB p 65 expression 2 h after modeling was detected by using western blotting. RESULTS: Compared with the normal control group, serum TNF-alpha and IL-6 contents, and pulmonary NF-kappaB p65 expression level in the model group were increased significantly (P < 0.01). In comparison with the model group, serum TNF-alpha contents in the simple EA-AC, EA-AC + LPS, VNS+ LPS and ST 36 + LPS groups, and serum IL-6 contents and pulmonary NF-kappaB p 65 expression levels in the simple EA-AC, EA-AC + LPS and VNS + LPS groups were down-regulated considerably (P < 0.05, P < 0.01). Compared with the VNS + LPS group, serum TNF-alpha -28) and IL-6 contents, and pulmonary NF-kappaB p 65 expression level in the ST 36 + LPS group were increased significantly (P < 0.05, P < 0.01). In comparison with the EA-AC + LPS group, pulmonary NF-kappaB p 65 expression level in the ST 36 + creased remarkably (P < 0.05). CONCLUSION: Both EA of auricular concha and vagus nerve stimulation can serum TNF-alpha and IL-6 contents, and down-regulate pulmonary NF-kappaB p 65 expression level in endotoxaemia similar cholinergic anti-inflammatory mechanism between them.

Voluntarily produced increases in heart rate variability modulate autonomic effects of endotoxin induced systemic inflammation: an exploratory study.

Exposure of healthy people to lipopolysaccharide (LPS; endotoxin) produces a pro-inflammatory response, subjective symptoms, and decreased heart rate variability (HRV). Given the efficacy of HRV biofeedback (BF) for treating asthma, the large autonomic effects of HRV BF, and the link between vagus nerve activity and inflammation, we hypothesized that HRV BF would dampen the acute manifestations of systemic inflammation induced by LPS challenge. Healthy participants age 18-40 were randomly assigned to four-one-hour training sessions of either HRV BF (n = 6) or a control 15/min paced breathing condition (n = 5) prior to acute experimentally induced LPS exposure. Participants were coached to do the procedures for 10 min each at five hourly time points after LPS injection, and then 2 h later. Subjective symptoms, HRV parameters, and plasma cytokine levels were measured at each time point, 2 h afterward, and the following morning. Participants were able to perform the procedures both during four pre-exposure training sessions and while experiencing LPS-induced symptoms. The HRV BF group showed significant attenuation of the LPS-induced decline in HRV for the 6 h following LPS exposure, suggesting that HRV BF decreased autonomic dysfunction produced by LPS-induced inflammation. HRV BF also reduced symptoms of headache and eye sensitivity to light, but did not affect LPS-induced levels of pro-inflammatory cytokines or symptoms of nausea, muscle aches, or feverishness. Further evaluation of HRV BF appears to be warranted among patients with inflammatory conditions.

Administration of Chlorella sp. microalgae reduces endotoxemia, intestinal oxidative stress and bacterial translocation in experimental biliary obstruction.

RATIONALE: Endotoxemia has long been documented in obstructive jaundice, and altered intestinal barrier function is considered to be one of the important mechanisms for this phenomenon. The aim of this study was to investigate the role of different microalgae (Chlorella sp. and Spirulina sp.) extracts in intestinal barrier function and oxidative stress in experimentally jaundiced rats. METHODS: A total of 60 male wistar rats were randomly divided into four groups of 15 each: I, sham operated; II, bile duct ligation (BDL); III, BDL+Chlorella sp.; IV, BDL+Spirulina sp. Rats were fed rat chow or microalgae extracts supplemented enteral diet ten days after sham operation or BDL. Main outcome measures were endotoxin concentrations in plasma, evidence of bacterial translocation (BT) in mesenteric lymph nodes (MLNs) and liver, oxidative stress, and histology. RESULTS: Compared to the group I, a significant increase in contamined MLNs, liver, and spleen samples and increased endotoxemia were noted in group II (P<0.01) but were significant reduced in group III (P<0.05). There was no significant difference in BT rate between the group II and group IV (P>0.05). Moreover, Chlorella sp. administration protected in jaundiced rats against oxidative stress, as demonstrated by reduction of intestinal lipid peroxidation, increase of the antioxidant reduced glutathione (GSH), and decrease of the oxidized glutathione (GSSG). The intestinal mucosa in control rats was atrophic with significantly decreased villous density and total mucosal thickness. Chlorella sp. caused a significant reduction in villous atrophy compared with controls. CONCLUSIONS: Chlorella sp. microalgae supplemented enteral diet has significant protective effects on intestinal mucosa barrier in obstructive jaundice, and reduces intestinal translocation of bacteria and endotoxin.

Polyphenols in the prevention and treatment of sepsis syndromes: rationale and pre-clinical evidence.

Sepsis is the overwhelming systemic response to infection of a normally sterile body compartment. Despite advances in elucidating its pathophysiology, severe sepsis remains a leading cause of death in the critically ill. Polyphenols are a family of chemicals found in food and beverages derived from plants, such as cocoa, green tea, turmeric, and soya, as well as in medicinal herbs. These phytochemicals exhibit anti-inflammatory and vasculoprotective properties in clinical and preclinical studies. The oral or systemic administration of polyphenols protects rodents from endotoxinemia and microbial sepsis. Under these circumstances, polyphenols reproducibly attenuate microvascular hyperpermeability, tissue infiltration by leukocytes, oxidative and nitrosative stress, tissue injury, organ dysfunction, shock and vasoplegia, lactate production, and mortality. Importantly, efficacy is maintained in some cases even when treatment is initiated hours after the onset of sepsis. The inhibition of nuclear factor-kappaB activation and subsequent expression of inducible nitric oxide synthase, adhesion molecules, and tumor necrosis factor-alpha by polyphenols is operative in ameliorating the sequelae of sepsis. Enhancement of the endogenous antioxidant capacity probably also contributes to the effectiveness of the polyphenols. Because several of the polyphenols reviewed in this article appear to be safe and to exert anti-inflammatory effects in humans, clinical trials assessing their efficacy in the critically ill are indicated. Whether delivered alone or in combination with nutritional formulas, polyphenols may help to prevent and treat sepsis.

[Criteria for intoxication in the evaluation of severity of endotoxicosis, the efficiency of ozone therapy and traditional treatment in patients with diabetes mellitus complicated by pyonecrotic lesions of the lower extremities].

The severity of endotoxicosis was evaluated in 128 patients with type 2 diabetes mellitus complicated by pyonecrotic lesions of the lower extremities. There was evidence for a reduction in serum albumin concentration, which led to diminished detoxication capacities of the body. Concurrently, the effective albumin concentration and the binding capacity of both albumin and plasma became lower, which suggested higher blood toxicity. There was imbalance between the formation, accumulation and binding, utilization and elimination of toxic products, as confirmed by a rise in calculated intoxication criteria. Traditional therapy did not cause a significant reduction, which requires special detoxication therapy. Ozone therapy, an oxidative detoxication method substantially diminishes the severity of endogenous intoxication, as supported by an increase in the total concentration of albumin and its functional properties.

Pharmacologic levels of dietary arginine in CB6F1 mice increase serum ammonia in the healthy state and serum nitrite in endotoxemia.

BACKGROUND: Therapeutic or pharmacologic doses of arginine are used to enhance blood flow and immune function despite the lack of dose-response studies and the potential for adverse effects. This study determined the optimal level of oral arginine supplementation required to elevate serum arginine concentrations yet limit adverse effects in healthy and endotoxemic mice. METHODS: Male CB6F1 mice were fed one of the following diets: The standard AIN93G (3 g arginine/100 g of protein) or this diet modified to provide 10 g, 20 g, or 30 g arginine/100 g of protein. On day 14, mice were injected with lipopolysaccharide (endotoxemic) or saline (healthy) and 4 hours later were exsanguinated. RESULTS: Weight gain was reduced 50% in the group fed the 30 g arginine vs standard diet. Serum arginine, ornithine, citrulline, histidine, lysine, serine, threonine, tyrosine, and phenylalanine were greater and glutamate levels were lower in healthy supplemented mice; lipopolysaccharide treatment negated these changes. Serum ammonia concentration was 52% greater in healthy mice fed the 30 g arginine vs standard diet. Serum nitrite and urea were unaffected by supplementation in healthy mice. Serum nitrite was 37% greater in endotoxemic mice fed 30 g vs 10 g arginine, and serum urea was 27% greater in mice fed 20 g or 30 g vs 10 g arginine. CONCLUSIONS: Changes in serum arginine or its metabolites were observed with all of the modified diets; however, a 30-g arginine diet was associated with an initial impairment of growth and potential adverse effects.