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Sangeeta S. Chavan - One of the best experts on this subject based on the ideXlab platform.
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Image_1_Forebrain Cholinergic Signaling Regulates Innate Immune Responses and Inflammation.jpg
2019Co-Authors: Kurt R. Lehner, Sangeeta S. Chavan, Harold A. Silverman, Meghan E. Adorissio, Ashbeel Roy, Mohammed A. Al-onaizi, Yaakov Levine, Peder S. Olofsson, Robert Gros, Neil M. NathansonAbstract:The brain regulates physiological functions integral to survival. However, the insight into brain neuronal regulation of peripheral immune function and the neuromediator systems and pathways involved remains limited. Here, utilizing selective genetic and pharmacological approaches, we studied the role of forebrain cholinergic signaling in the regulation of peripheral immune function and inflammation. Forebrain-selective genetic ablation of acetylcholine release and vagotomy abolished the suppression of serum TNF by the centrally-acting cholinergic drug galantamine in murine Endotoxemia. Selective stimulation of acetylcholine action on the M1 muscarinic acetylcholine receptor (M1 mAChR) by central administration of the positive allosteric modulator benzyl quinolone carboxylic acid (BQCA) suppressed serum TNF (TNFα) levels in murine Endotoxemia. This effect was recapitulated by peripheral administration of the compound. BQCA also improved survival in murine Endotoxemia and these effects were abolished in M1 mAChR knockout (KO) mice. Selective optogenetic stimulation of basal forebrain cholinergic neurons innervating brain regions with abundant M1 mAChR localization reduced serum TNF in endotoxemic mice. These findings reveal that forebrain cholinergic neurons regulate innate immune responses and inflammation, suggesting the possibility that in diseases associated with cholinergic dysfunction, including Alzheimer's disease this anti-inflammatory regulation can be impaired. These results also suggest novel anti-inflammatory approaches based on targeting forebrain cholinergic signaling in sepsis and other disorders characterized by immune dysregulation.
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Single-Pulse and Unidirectional Electrical Activation of the Cervical Vagus Nerve Reduces Tumor Necrosis Factor in Endotoxemia
Bioelectronic Medicine, 2015Co-Authors: Peder S. Olofsson, Sangeeta S. Chavan, Yaakov A. Levine, April Caravaca, Valentin A. Pavlov, Michael Faltys, Kevin J. TraceyAbstract:The inflammatory reflex is a neural circuit defined by action potentials transmitted in the vagus nerve that regulate cytokine production in the spleen. Detailed mechanistic studies implicate the vagus nerve, the splenic nerve, a T-cell subset that produces acetylcholine under the control of adrenergic signals, and alpha7 nicotinic acetylcholine receptors (α7nAChR). expressed on macrophages. This study defines the vagus nerve fibers that transmit the efferent signal in this pathway, a motor arc of the inflammatory reflex. Mice and rats were subjected to electrical cervical vagus nerve stimulation or sham surgery. Cytokine levels in serum were measured in endotoxemic animals or in endotoxin-exposed blood samples. Evoked potentials were measured in the vagus nerve and a portion of the vagus nerve was anesthetized using local application of lidocaine before stimulation. The lowest threshold subdiaphragmatic fibers in the rat vagus nerve have conduction velocities consistent with that of myelinated B fibers. The stimulation current threshold for significant suppression of serum TNF levels was similar in mice and rats (≤500 µA). Blockade of the fibers caudal to the site of vagus nerve stimulation impaired the inhibition of TNF release. A single suprathreshold pulse stimulation was sufficient to suppress TNF release in Endotoxemia. These results indicate that single-pulse and unidirectional electrical activation of the cervical vagus nerve reduce TNF in Endotoxemia.
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modulation of tnf release by choline requires α7 subunit nicotinic acetylcholine receptor mediated signaling
Molecular Medicine, 2008Co-Authors: William R. Parrish, Margot Gallowitschpuerta, Kanta Ochani, Mauricio Rosasballina, Laqueta Hudson, Sarah M Johnson, Nirav Patel, Mahendar Ochani, Lihong Yang, Sangeeta S. ChavanAbstract:The α7 subunit-containing nicotinic acetylcholine receptor (α7nAChR) is an essential component in the vagus nerve-based cholinergic anti-inflammatory pathway that regulates the levels of TNF, high mobility group box 1 (HMGB1), and other cytokines during inflammation. Choline is an essential nutrient, a cell membrane constituent, a precursor in the biosynthesis of acetylcholine, and a selective natural α7nAChR agonist. Here, we studied the anti-inflammatory potential of choline in murine Endotoxemia and sepsis, and the role of the α7nAChR in mediating the suppressive effect of choline on TNF release. Choline (0.1–50 mM) dose-dependently suppressed TNF release from endotoxin-activated RAW macrophage-like cells, and this effect was associated with significant inhibition of NF-κB activation. Choline (50 mg/kg, intraperitoneally (i.p.)) treatment prior to endotoxin administration in mice significantly reduced systemic TNF levels. In contrast to its TNF suppressive effect in wild type mice, choline (50 mg/kg, i.p.) failed to inhibit systemic TNF levels in α7nAChR knockout mice during Endotoxemia. Choline also failed to suppress TNF release from endotoxin-activated peritoneal macrophages isolated from α7nAChR knockout mice. Choline treatment prior to endotoxin resulted in a significantly improved survival rate as compared with saline-treated endotoxemic controls. Choline also suppressed HMGB1 release in vitro and in vivo, and choline treatment initiated 24 h after cecal ligation and puncture (CLP)-induced polymicrobial sepsis significantly improved survival in mice. In addition, choline suppressed TNF release from endotoxin-activated human whole blood and macrophages. Collectively, these data characterize the anti-inflammatory efficacy of choline and demonstrate that the modulation of TNF release by choline requires α7nAChR-mediated signaling.
Jürgen Birnbaum - One of the best experts on this subject based on the ideXlab platform.
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effects of n acetylcysteine and tirilazad mesylate on intestinal functional capillary density leukocyte adherence mesenteric plasma extravasation and cytokine levels in experimental Endotoxemia in rats
Clinical Hemorheology and Microcirculation, 2008Co-Authors: Jürgen Birnbaum, C Lehmann, Edda Klotz, Vargas O Hein, A Blume, F Jubin, N Polze, D Luther, Claudia SpiesAbstract:Abstract The study's objective was to determine the effects of the administration of N-acetylcysteine (NAC) and of tirilazad mesylate (TM) on intestinal functional capillary density, mesenteric plasma extravasation, leukocyte adherence and on cytokine release during experimental Endotoxemia in rats. In a prospective, randomized, controlled animal study, 80 male Wistar rats were examined in 2 test series. Both series were divided into 4 groups. Group 1 served as control group (CON group). Group 2 (LPS group), group 3 (NAC group) and group 4 (TM group) received endotoxin infusions (10 mg/kg over 2 h). In NAC group 150 mg/kg body weight NAC was administered after the first 30 minutes of Endotoxemia intravenously. In TM group, 10 mg/kg body weight TM was administered after the first 30 minutes of Endotoxemia intravenously. Animals of the series 1 underwent studies of leukocyte adherence on submucosal venular endothelium of the small bowel wall and intestinal functional capillary density (FCD) in the intestinal mucosa and the circular as well as the longitudinal muscle layer by intravital fluorescence microscopy (IVM). Plasma levels of interleukin 1beta (IL-1beta), interferone gamma (IFN-gamma) and soluble intercellular adhesion molecule1 (s-ICAM 1) as well as white blood cell count (WBC) were estimated. In the animals of the series 2 mesenteric plasma extravasation was determined by IVM and plasma levels of tumor necrosis factor alpha (TNF-alpha), IL-4, IL-6, IL-10 and malondialdehyde (MDA) were estimated. After LPS administration, FCD in the villi intestinales was unchanged and in the longitudinal muscularis layer it was increased. There was no effect of NAC or TM administration on FCD.Although the plasma extravasation was not significantly influenced by LPS administration, TM administration resulted in a lower plasma extravasation in the TM group compared to the other groups. After endotoxin challenge, the firmly adherence of leukocytes to vascular endothelium as a parameter of leukocyte activation in Endotoxemia was increased but NAC or TM administration had no influence on leukocyte adherence. The plasma levels of IL-1beta, IL-6, IL-10, TNF-alpha, IFN-gamma and sICAM-1 were increased in the endotoxemic groups (LPS group, NAC group and TM group) and the WBC was decreased compared to controls. IL-4 levels were unchanged during observation period. Plasma MDA levels were not influenced by LPS administration compared to controls. The administration of NAC resulted in lower sICAM-1 and MDA levels compared to the LPS group. The IL-1beta, IL-6, IL-10, TNF-alpha and IFN-gamma plasma levels were not influenced by NAC or TM administration. In this posttreatment sepsis model in rats, NAC administration resulted in lower sICAM-1 and MDA levels compared to the LPS treated animals. TM administration reduced the plasma extravasation in this model.
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Reduction in intestinal leukocyte adherence in rat experimental Endotoxemia by treatment with the 21-aminosteroid U-74389G.
Intensive Care Medicine, 2001Co-Authors: Christian Lehmann, Alexander Georgiew, Mathias Weber, Jürgen BirnbaumAbstract:Objectives: To investigate leukocyte adherence in intestinal venules in experimental Endotoxemia after treatment with the 21-aminosteroid U-74389G. Design and setting: Prospective, randomized, controlled animal study in an experimental laboratory. Subjects: Twenty-one male Wistar rats weighing 190±40 g. Interventions: The rats were divided equally into three groups: (a) control group, (b) Endotoxemia (5 mg/kg lipopolysacharide from Escherichia coli O55:B5), and (c) Endotoxemia and U-74389G administration 30 min before (3 mg/kg) and 60 min after endotoxin challenge (1.5 mg/kg). Measurements and main results: The distal small intestine of the animals was examined using intravital fluorescence videomicroscopy 2 h after endotoxin challenge. Leukocytes were stained in vivo by means of rhodamine 6G. In the endotoxemic animals we observed a fourfold increase in the count of firmly adherent leukocytes in submucosal postcapillary and collecting venules. Treatment with the 21-aminosteroid U-74389G significantly attenuated the count of sticking leukocytes in the collecting venules (control, 61±10 cells/mm2; lipopolysaccharide, 237±42 cells/mm2; U-74389G 125±9 cells/mm2; p
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reduction in intestinal leukocyte adherence in rat experimental Endotoxemia by treatment with the 21 aminosteroid u 74389g
Intensive Care Medicine, 2001Co-Authors: Christian Lehmann, Alexander Georgiew, Mathias Weber, Jürgen BirnbaumAbstract:Objectives: To investigate leukocyte adherence in intestinal venules in experimental Endotoxemia after treatment with the 21-aminosteroid U-74389G. Design and setting: Prospective, randomized, controlled animal study in an experimental laboratory. Subjects: Twenty-one male Wistar rats weighing 190±40 g. Interventions: The rats were divided equally into three groups: (a) control group, (b) Endotoxemia (5 mg/kg lipopolysacharide from Escherichia coli O55:B5), and (c) Endotoxemia and U-74389G administration 30 min before (3 mg/kg) and 60 min after endotoxin challenge (1.5 mg/kg). Measurements and main results: The distal small intestine of the animals was examined using intravital fluorescence videomicroscopy 2 h after endotoxin challenge. Leukocytes were stained in vivo by means of rhodamine 6G. In the endotoxemic animals we observed a fourfold increase in the count of firmly adherent leukocytes in submucosal postcapillary and collecting venules. Treatment with the 21-aminosteroid U-74389G significantly attenuated the count of sticking leukocytes in the collecting venules (control, 61±10 cells/mm2; lipopolysaccharide, 237±42 cells/mm2; U-74389G 125±9 cells/mm2; p<0.05). In these venules leukocyte rolling behavior was comparable to that in the control group without endotoxin challenge. Conclusions: Administration of U-74389G, which has radical scavenging properties, attenuates leukocyte adherence in selected populations of intestinal venules which is found increased during Endotoxemia. Thus, 21-aminosteroids may have an impact in the treatment of endotoxin-induced intestinal injury.
Christian Lehmann - One of the best experts on this subject based on the ideXlab platform.
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Reduction in intestinal leukocyte adherence in rat experimental Endotoxemia by treatment with the 21-aminosteroid U-74389G.
Intensive Care Medicine, 2001Co-Authors: Christian Lehmann, Alexander Georgiew, Mathias Weber, Jürgen BirnbaumAbstract:Objectives: To investigate leukocyte adherence in intestinal venules in experimental Endotoxemia after treatment with the 21-aminosteroid U-74389G. Design and setting: Prospective, randomized, controlled animal study in an experimental laboratory. Subjects: Twenty-one male Wistar rats weighing 190±40 g. Interventions: The rats were divided equally into three groups: (a) control group, (b) Endotoxemia (5 mg/kg lipopolysacharide from Escherichia coli O55:B5), and (c) Endotoxemia and U-74389G administration 30 min before (3 mg/kg) and 60 min after endotoxin challenge (1.5 mg/kg). Measurements and main results: The distal small intestine of the animals was examined using intravital fluorescence videomicroscopy 2 h after endotoxin challenge. Leukocytes were stained in vivo by means of rhodamine 6G. In the endotoxemic animals we observed a fourfold increase in the count of firmly adherent leukocytes in submucosal postcapillary and collecting venules. Treatment with the 21-aminosteroid U-74389G significantly attenuated the count of sticking leukocytes in the collecting venules (control, 61±10 cells/mm2; lipopolysaccharide, 237±42 cells/mm2; U-74389G 125±9 cells/mm2; p
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reduction in intestinal leukocyte adherence in rat experimental Endotoxemia by treatment with the 21 aminosteroid u 74389g
Intensive Care Medicine, 2001Co-Authors: Christian Lehmann, Alexander Georgiew, Mathias Weber, Jürgen BirnbaumAbstract:Objectives: To investigate leukocyte adherence in intestinal venules in experimental Endotoxemia after treatment with the 21-aminosteroid U-74389G. Design and setting: Prospective, randomized, controlled animal study in an experimental laboratory. Subjects: Twenty-one male Wistar rats weighing 190±40 g. Interventions: The rats were divided equally into three groups: (a) control group, (b) Endotoxemia (5 mg/kg lipopolysacharide from Escherichia coli O55:B5), and (c) Endotoxemia and U-74389G administration 30 min before (3 mg/kg) and 60 min after endotoxin challenge (1.5 mg/kg). Measurements and main results: The distal small intestine of the animals was examined using intravital fluorescence videomicroscopy 2 h after endotoxin challenge. Leukocytes were stained in vivo by means of rhodamine 6G. In the endotoxemic animals we observed a fourfold increase in the count of firmly adherent leukocytes in submucosal postcapillary and collecting venules. Treatment with the 21-aminosteroid U-74389G significantly attenuated the count of sticking leukocytes in the collecting venules (control, 61±10 cells/mm2; lipopolysaccharide, 237±42 cells/mm2; U-74389G 125±9 cells/mm2; p<0.05). In these venules leukocyte rolling behavior was comparable to that in the control group without endotoxin challenge. Conclusions: Administration of U-74389G, which has radical scavenging properties, attenuates leukocyte adherence in selected populations of intestinal venules which is found increased during Endotoxemia. Thus, 21-aminosteroids may have an impact in the treatment of endotoxin-induced intestinal injury.
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inhibition of tumor necrosis factor alpha release in rat experimental Endotoxemia by treatment with the 21 aminosteroid u 74389g
Critical Care Medicine, 1999Co-Authors: Christian Lehmann, Alexander Georgiew, Karl Egerer, Mathias Weber, Tilman GruneAbstract:OBJECTIVE: To determine the effect of the 21-aminosteroid U-74389G on tumor necrosis factor (TNF)-alpha release in experimental Endotoxemia. DESIGN: Prospective, randomized, controlled animal study. SETTING: Experimental laboratory. SUBJECTS: Twenty-one male Wistar rats weighing 190+/-40 g. INTERVENTIONS: The rats were divided equally into 3 groups: a) control; b) Endotoxemia (5 mg/kg lipopolysaccharide [LPS] from Escherichia coli 055:B5); and c) Endotoxemia and U-74389G administration 30 mins before (3 mg/kg) and 60 mins after (1.5 mg/kg) endotoxin challenge. MEASUREMENTS AND MAIN RESULTS: At 0, 120, and 240 mins, serum levels of TNF-alpha were measured using a specific rat TNF-alpha ELISA kit. U-74389G-treated endotoxemic animals showed significantly reduced TNF-alpha release 120 mins after endotoxin challenge (control, 2.5+/-2.1 pg/mL; LPS, 4041+/-871 pg/mL; U-74389G, 1627+/-474 pg/mL [p < .05]). Two hundred forty minutes after LPS administration, TNF-alpha levels decreased, whereas values in the untreated LPS group remained twice as high as those in the U-74389G group (LPS, 863+/-182 pg/mL; U-74389G, 369+/-54 pg/mL [p < .05]). CONCLUSIONS: The study demonstrated that administration of U-74389G, which has radical-scavenging and membrane-stabilizing properties, decreased TNF-alpha release during Endotoxemia. Thus, 21-aminosteroids may lend themselves to evaluation in the treatment of septic states.
Tilman Grune - One of the best experts on this subject based on the ideXlab platform.
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inhibition of tumor necrosis factor alpha release in rat experimental Endotoxemia by treatment with the 21 aminosteroid u 74389g
Critical Care Medicine, 1999Co-Authors: Christian Lehmann, Alexander Georgiew, Karl Egerer, Mathias Weber, Tilman GruneAbstract:OBJECTIVE: To determine the effect of the 21-aminosteroid U-74389G on tumor necrosis factor (TNF)-alpha release in experimental Endotoxemia. DESIGN: Prospective, randomized, controlled animal study. SETTING: Experimental laboratory. SUBJECTS: Twenty-one male Wistar rats weighing 190+/-40 g. INTERVENTIONS: The rats were divided equally into 3 groups: a) control; b) Endotoxemia (5 mg/kg lipopolysaccharide [LPS] from Escherichia coli 055:B5); and c) Endotoxemia and U-74389G administration 30 mins before (3 mg/kg) and 60 mins after (1.5 mg/kg) endotoxin challenge. MEASUREMENTS AND MAIN RESULTS: At 0, 120, and 240 mins, serum levels of TNF-alpha were measured using a specific rat TNF-alpha ELISA kit. U-74389G-treated endotoxemic animals showed significantly reduced TNF-alpha release 120 mins after endotoxin challenge (control, 2.5+/-2.1 pg/mL; LPS, 4041+/-871 pg/mL; U-74389G, 1627+/-474 pg/mL [p < .05]). Two hundred forty minutes after LPS administration, TNF-alpha levels decreased, whereas values in the untreated LPS group remained twice as high as those in the U-74389G group (LPS, 863+/-182 pg/mL; U-74389G, 369+/-54 pg/mL [p < .05]). CONCLUSIONS: The study demonstrated that administration of U-74389G, which has radical-scavenging and membrane-stabilizing properties, decreased TNF-alpha release during Endotoxemia. Thus, 21-aminosteroids may lend themselves to evaluation in the treatment of septic states.
David J Klein - One of the best experts on this subject based on the ideXlab platform.
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polymyxin b hemoperfusion a mechanistic perspective
Critical Care, 2014Co-Authors: Claudio Ronco, David J KleinAbstract:Direct hemoperfusion therapy with polymyxin B immobilized fiber cartridge (PMX-DHP) is an established strategy in the treatment of septic shock in Japan and parts of Western Europe. PMX-DHP is currently the subject of a pivotal North American randomized controlled trial (EUPHRATES) in patients with septic shock and confirmed Endotoxemia, as measured by the endotoxin activity assay. The major mechanism of action of this therapy is the removal of circulating endotoxin. High affinity binding of circulating endotoxin by the PMX-DHP column may decrease circulating endotoxin levels by up to 90% after two standard treatments. Basic research has shown reductions in circulating cytokine levels and in renal tubular apoptosis. Clinical research has shown that PMX-DHP therapy results in hemodynamic improvements, improvements in oxygenation, renal function, and reductions in mortality. Further research is needed to further define additional patient populations with Endotoxemia that may benefit from PMX-DHP therapy as well as to further elucidate dosing, timing, and additional information on mechanisms of action. This review will present the mechanistic rationale for this targeted strategy of endotoxin removal using PMX-DHP in endotoxemic septic patients, highlighting both the specific effects of the therapy and the evidence accumulated so far of clinical improvement following this therapy in terms of recovery of organ function.
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Endotoxemia related to cardiopulmonary bypass is associated with increased risk of infection after cardiac surgery a prospective observational study
Critical Care, 2011Co-Authors: David J Klein, Alexander D. Romaschin, Francoise Briet, Rosane Nisenbaum, David C MazerAbstract:Introduction Previous studies have documented a high frequency of Endotoxemia associated with cardiopulmonary bypass (CPB). Endotoxemia may be responsible for some of the complications associated with cardiac surgery. The purpose of the study was to examine the prevalence of Endotoxemia during cardiopulmonary bypass supported aortocoronary bypass grafting surgery (ACB) using a new assay, the Endotoxin Activity Assay (EAA), and explore the association between Endotoxemia and post-operative infection.