369 results on '"Wehner, Sven"'
Search Results
102. Expression of type I interferon by splenic macrophages suppresses adaptive immunity during sepsis
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Schwandt, Timo, primary, Schumak, Beatrix, additional, Gielen, Gerrit H, additional, Jüngerkes, Frank, additional, Schmidbauer, Patricia, additional, Klocke, Katrin, additional, Staratschek-Jox, Andrea, additional, van Rooijen, Niko, additional, Kraal, Georg, additional, Ludwig-Portugall, Isis, additional, Franken, Lars, additional, Wehner, Sven, additional, Kalff, Jörg C, additional, Weber, Olaf, additional, Kirschning, Carsten, additional, Coch, Christoph, additional, Kalinke, Ulrich, additional, Wenzel, Jörg, additional, Kurts, Christian, additional, Zawatzky, Rainer, additional, Holzmann, Bernhard, additional, Layland, Laura, additional, Schultze, Joachim L, additional, Burgdorf, Sven, additional, den Haan, Joke MM, additional, Knolle, Percy A, additional, and Limmer, Andreas, additional
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- 2011
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103. Preoperative short-term parenteral administration of polyunsaturated fatty acids ameliorates intestinal inflammation and postoperative ileus in rodents
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Wehner, Sven, primary, Meder, Katharina, additional, Vilz, Tim O., additional, Alteheld, Birgit, additional, Stehle, Peter, additional, Pech, Thomas, additional, and Kalff, Joerg C., additional
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- 2011
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104. Anastomotic healing in the context of inhibited macrophage function and sepsis
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Pantelis, Dimitrios, primary, Beissel, Anke, additional, Vilz, Tim O., additional, Wehner, Sven, additional, and Kalff, Joerg C., additional
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- 2011
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105. Effects of immunosuppressive therapy after experimental small bowel transplantation in rats
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Pech, Thomas, primary, Fujishiro, Jun, additional, Finger, Tobias, additional, von Websky, Martin, additional, Stoffels, Burkhard, additional, Wehner, Sven, additional, Abu-Elmagd, Kareem, additional, Kalff, Joerg C., additional, and Schaefer, Nico, additional
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- 2011
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106. Hemin induction of HO-1 protects against LPS-induced sepsis and ileus
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Overhaus, Marcus, primary, Bortscher, Stephan, additional, Chang, Johannes, additional, Schaefer, Nico, additional, Wehner, Sven, additional, and Kalff, Joerg C., additional
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- 2011
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107. Downstream TLR-signaling contributes to inflammatory events within the postsurgical gut wall
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Stoffels, Burkhard, primary, Kalff, Joerg C., additional, and Wehner, Sven, additional
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- 2011
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108. Isolation of T cells and dendritic cells from peripheral intestinal tissue, Peyer’s Patches and mesenteric lymph nodes in mice after intestinal manipulation
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Koscielny, Arne, primary, Koscielny, Arne, additional, Wehner, Sven, additional, Engel, Daniel Robert, additional, Kurts, Christian, additional, and Kalff, Joerg, additional
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- 2011
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109. Humanoid Gait Optimization Based on Human Data
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Wehner, Sven, primary and Bennewitz, Maren, additional
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- 2011
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110. Measurement of gastrointestinal and colonic transit in mice
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Wehner, Sven, primary
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- 2011
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111. Mechanical stretch aggravates lipopolysaccharide-induced inflammatory pathways in intestinal smooth muscle cells and macrophages
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Wehner, Sven, primary, Rocke, Anatol, additional, Schuchtrup, Silke, additional, Vilz, Tim, additional, Hirner, Andreas, additional, and Kalff, Joerg C., additional
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- 2009
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112. Parenteral immunonutrition with omega-3 fatty acids prevents intestinal inflammation and postoperative ileus in rodents
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Wehner, Sven, primary, Meder, Katharina P., additional, Straesser, Stefan, additional, Vilz, Tim O., additional, Hirner, Andreas, additional, and Kalff, Joerg C., additional
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- 2009
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113. Preoperative application of CPSI-2364 per os attenuates inflammatory reactions in the tunica muscularis and prevents postoperative ileus in swine
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Vilz, Tim O., primary, Sommer, Nils, additional, Wehner, Sven, additional, Hirner, Andreas, additional, and Kalff, Joerg C., additional
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- 2009
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114. Reply
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Kalff, Joerg C., primary and Wehner, Sven, additional
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- 2009
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115. Inhibition of p38 Mitogen-Activated Protein Kinase Pathway as Prophylaxis of Postoperative Ileus in Mice
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Wehner, Sven, primary, Straesser, Stefan, additional, Vilz, Tim O., additional, Pantelis, Dimitrios, additional, Sielecki, Thais, additional, de la Cruz, Vidal F., additional, Hirner, Andreas, additional, and Kalff, Joerg C., additional
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- 2009
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116. Inhibition of p38 MAP kinase as a target for prophylaxis of postoperative ileus
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Wehner, Sven, primary, Straesser, Stefan, additional, Lysson, Mariola, additional, Hirner, Andreas, additional, and Kalff, Joerg C., additional
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- 2008
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117. Intestinal dendritic cells (DC) and CCR7 are centrally involved in the gastrointestinal field effect
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Koscielny, Arne J., primary, Engel, Daniel, additional, Wehner, Sven, additional, Kurts, Christian, additional, and Kalff, Jörg, additional
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- 2006
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118. Postoperative ileus: Mechanical activation of intestinal macrophages and smooth muscle cells
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Wehner, Sven, primary, Schuchtrup, Silke, additional, Rocke, Anatol, additional, Hirner, Andreas, additional, and Kalff, Joerg, additional
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- 2006
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119. Effects of sphingosine‐1‐phosphate and ceramide‐1‐phosphate on rat intestinal smooth muscle cells: implications for postoperative ileus
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Dragusin, Mihaela, primary, Wehner, Sven, additional, Kelly, Samuel, additional, Wang, Elaine, additional, Merrill, Alfred H., additional, Kalff, Jörg C., additional, Echten‐Deckert, Gerhild, additional, Dragusin, Mihaela, additional, and Merrill, Alfred, additional
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- 2006
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120. Depletion and inactivation of intestinal muscularis macrophages prevent postoperative ileus
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Behrendt, Florian F., primary, Wehner, Sven, additional, Lysson, Mariola, additional, Bauer, Anthony J., additional, Hirner, Andreas, additional, and Kalff, Joerg C., additional
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- 2004
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121. Cytoprotective function of sAPPα in human keratinocytes
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Wehner, Sven, primary, Siemes, Christina, additional, Kirfel, Gregor, additional, and Herzog, Volker, additional
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- 2004
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122. sAPP as a regulator of dendrite motility and melanin release in epidermal melanocytes and melanoma cells
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Quast, Thomas, primary, Wehner, Sven, additional, Kirfel, Gregor, additional, Jaeger, Klaus, additional, De Luca, Michele, additional, and Herzog, Volker, additional
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- 2003
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123. A role for 12/15‐lipoxygenase‐derived proresolving mediators in postoperative ileus: protectin DX‐regulated neutrophil extravasation
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Stein, Kathy, Stoffels, Melissa, Lysson, Mariola, Schneiker, Bianca, Dewald, Oliver, Krönke, Gerhard, Kalff, Jörg C., and Wehner, Sven
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Resolution of POI involves monocytotic 12/15‐LOX activity and generation of PDX, resulting in reduction of neutrophil infiltration into the postoperative bowel wall. Resolution of inflammation is an active counter‐regulatory mechanism involving polyunsaturated fatty acid‐derived proresolving lipid mediators. Postoperative intestinal motility disturbances, clinically known as postoperative ileus, occur frequently after abdominal surgery and are mediated by a complex inflammation of the intestinal muscularis externa. Herein, we tested the hypothesis that proresolving lipid mediators are involved in the resolution of postoperative ileus. In a standardized experimental model of postoperative ileus, we detected strong expression of 12/15‐lipoxygenase within the postoperative muscularis externa of C57BL/6 mice, predominately located within CX3CR1+/Ly6C+infiltrating monocytes rather than Ly6G+neutrophils. Mass spectrometry analyses demonstrated that a 12/15‐lipoxygenase increase was accompanied by production of docosahexaenoic acid‐derived lipid mediators, particularly protectin DX and resolvin D2, and their common precursor 17‐hydroxy docosahexaenoic acid. Perioperative administration of protectin DX, but not resolvin D2 diminished blood‐derived leukocyte infiltration into the surgically manipulated muscularis externa and improved the gastrointestinal motility. Flow cytometry analyses showed impaired Ly6G+/Ly6C+neutrophil extravasation after protectin DX treatment, whereas Ly6G‐/Ly6C+monocyte numbers were not affected. 12/15‐lipoxygenase‐deficient mice, lacking endogenous protectin DX synthesis, demonstrated increased postoperative leukocyte levels. Preoperative intravenous administration of a docosahexaenoic acid‐rich lipid emulsion reduced postoperative leukocyte infiltration in wild‐type mice but failed in 12/15‐lipoxygenase‐deficient mice mice. Protectin DX application reduced leukocyte influx and rescued 12/15‐lipoxygenase‐deficient mice mice from postoperative ileus. In conclusion, our results show that 12/15‐lipoxygenase mediates postoperative ileus resolution via production of proresolving docosahexaenoic acid‐derived protectin DX. Perioperative, parenteral protectin DX or docosahexaenoic acid supplementation, as well as modulation of the 12/15‐lipoxygenase pathway, may be instrumental in prevention of postoperative ileus.
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- 2016
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124. Expression of type I interferon by splenic macrophages suppresses adaptive immunity during sepsis.
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Schwandt, Timo, Schumak, Beatrix, Gielen, Gerrit H, Jüngerkes, Frank, Schmidbauer, Patricia, Klocke, Katrin, Staratschek-Jox, Andrea, van Rooijen, Niko, Kraal, Georg, Ludwig-Portugall, Isis, Franken, Lars, Wehner, Sven, Kalff, Jörg C, Weber, Olaf, Kirschning, Carsten, Coch, Christoph, Kalinke, Ulrich, Wenzel, Jörg, Kurts, Christian, and Zawatzky, Rainer
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GENE expression ,INTERFERONS ,MACROPHAGES ,SPLEEN ,SEPSIS ,CYTOKINES ,INFLAMMATION ,SEPTIC shock - Abstract
Early during Gram-negative sepsis, excessive release of pro-inflammatory cytokines can cause septic shock that is often followed by a state of immune paralysis characterized by the failure to mount adaptive immunity towards secondary microbial infections. Especially, the early mechanisms responsible for such immune hypo-responsiveness are unclear. Here, we show that TLR4 is the key immune sensing receptor to initiate paralysis of T-cell immunity after bacterial sepsis. Downstream of TLR4, signalling through TRIF but not MyD88 impaired the development of specific T-cell immunity against secondary infections. We identified type I interferon (IFN) released from splenic macrophages as the critical factor causing T-cell immune paralysis. Early during sepsis, type I IFN acted selectively on dendritic cells (DCs) by impairing antigen presentation and secretion of pro-inflammatory cytokines. Our results reveal a novel immune regulatory role for type I IFN in the initiation of septic immune paralysis, which is distinct from its well-known immune stimulatory effects. Moreover, we identify potential molecular targets for therapeutic intervention to overcome impairment of T-cell immunity after sepsis. [ABSTRACT FROM AUTHOR]
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- 2012
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125. Expression and Potential Function of β-Amyloid Precursor Proteins during Cutaneous Wound Repair
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Kummer, Christiane, Wehner, Sven, Quast, Thomas, Werner, Sabine, and Herzog, Volker
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AMYLOID beta-protein precursor , *KERATINOCYTES , *GENE expression - Abstract
sAPP, the secretory domain of the β-amyloid precursor protein (APP), exerts a growth promoting and motogenic activity on keratinocytes. Here we report on the expression of APP and its homologue, the amyloid precursor like protein 2 (APLP2), during cutaneous wound repair using a full-thickness excisional wound healing model in mice. In unwounded skin APP was predominantly expressed in the basal cell layer. During wound healing increased suprabasal expression of APP was observed in all cell layers of the hyperproliferative epithelium at the wound margin. APP mRNA was increased up to 2.3-fold, whereas the APLP2 mRNA was decreased. Immunocytochemically, all proliferation competent keratinocytes of the normal as well as the wound site epidermis showed increased expression of APP but not of APLP2. Using culture models of keratinocyte differentiation the release of sAPP was found to be significantly higher in proliferating cells, i.e., when cultured at subconfluency or at low [Ca2+], than in quiescent, partially differentiated keratinocytes cultured at confluency or at high [Ca2+]. Our results suggest that sAPP secretion is presumably also increased in proliferation competent keratinocytes of the wound margin and that sAPP due to its growth promoting and motogenic function might participate in the control of epidermal wound repair. [Copyright &y& Elsevier]
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- 2002
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126. State-of-the-art colorectal disease: postoperative ileus.
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Sommer, Nils P., Schneider, Reiner, Wehner, Sven, Kalff, Jörg C., and Vilz, Tim O.
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FLUID therapy , *MEDICAL personnel , *BOWEL obstructions , *MINIMALLY invasive procedures , *EPIDURAL catheters , *EPIDURAL analgesia - Abstract
Purpose: Postoperative Ileus (POI) remains an important complication for patients after abdominal surgery with an incidence of 10–27% representing an everyday issue for abdominal surgeons. It accounts for patients' discomfort, increased morbidity, prolonged hospital stays, and a high economic burden. This review outlines the current understanding of POI pathophysiology and focuses on preventive treatments that have proven to be effective or at least show promising effects. Methods: Pathophysiology and recommendations for POI treatment are summarized on the basis of a selective literature review. Results: While a lot of therapies have been researched over the past decades, many of them failed to prove successful in meta-analyses. To date, there is no evidence-based treatment once POI has manifested. In the era of enhanced recovery after surgery or fast track regimes, a few approaches show a beneficial effect in preventing POI: multimodal, opioid-sparing analgesia with placement of epidural catheters or transverse abdominis plane block; μ-opioid-receptor antagonists; and goal-directed fluid therapy and in general the use of minimally invasive surgery. Conclusion: The results of different studies are often contradictory, as a concise definition of POI and reliable surrogate endpoints are still absent. These will be needed to advance POI research and provide clinicians with consistent data to improve the treatment strategies. [ABSTRACT FROM AUTHOR]
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- 2021
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127. AIM2 inflammasome-derived IL-1β induces postoperative ileus in mice.
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Hupa, Kristof Johannes, Stein, Kathy, Schneider, Ralf, Lysson, Mariola, Schneiker, Bianca, Hornung, Veit, Latz, Eicke, Iwakura, Yoichiro, Kalff, Jörg C., and Wehner, Sven
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Postoperative ileus (POI) is an intestinal dysmotility frequently occurring after abdominal surgery. An orchestrated neuroimmune response within the muscularis externa (ME) involves activation of resident macrophages, enteric glia and infiltration of blood-derived leukocytes. Interleukin-1 receptor type-I (IL1R1) signalling on enteric glia has been shown to be involved in POI development. Herein we investigated the distinct role of the IL1R1 ligands interleukin (IL) -1α and IL-1β and focused on the mechanism of IL-1β production. IL-1α and IL-1β deficient mice were protected from POI. Bone-marrow transplantation studies indicated that IL-1α originated from radio-resistant cells while IL-1β was released from the radio-sensitive infiltrating leukocytes. Mouse strains deficient in inflammasome formation identified the absent in melanoma 2 (AIM2) inflammasome to be crucial for IL-1β production in POI. Mechanistically, antibiotic-treated mice revealed a prominent role of the microbiome in IL-1β production. Our study provides new insights into distinct roles of IL-1α and IL-1β signalling during POI. While IL-1α release is most likely an immediate passive response to the surgical trauma, IL-1β production depends on AIM2 inflammasome formation and the microbiome. Selective interaction in this pathway might be a promising target to prevent POI in surgical patients. [ABSTRACT FROM AUTHOR]
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- 2019
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128. Non‐invasive transcutaneous auricular vagus nerve stimulation prevents postoperative ileus and endotoxemia in mice.
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Hong, Gun‐Soo, Zillekens, Anne, Schneiker, Bianca, Pantelis, Dimitrios, Jonge, Wouter J., Schaefer, Nico, Kalff, Joerg C., and Wehner, Sven
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VAGUS nerve ,STRETCH reflex ,NEURAL stimulation - Abstract
Background: The cholinergic anti‐inflammatory pathway comprises the perception of peripheral inflammation by afferent sensory neurons and reflex activation of efferent vagus nerve activity to regulate inflammation. Activation of this pathway was shown to reduce the inflammatory response and improve outcome of postoperative ileus (POI) and sepsis in rodents. Herein, we tested if a non‐invasive auricular electrical transcutaneous vagus nerve stimulation (tVNS) affects inflammation in models of POI or endotoxemia. Methods: Mice underwent tVNS or sham stimulation before and after induction of either POI by intestinal manipulation (IM) or endotoxemia by lipopolysaccharide administration. Some animals underwent a preoperative right cervical vagotomy. Neuronal activation of the solitary tract nucleus (NTS) and the dorsal motor nucleus of the vagus nerve (DMV) were analyzed by immunohistological detection of c‐fos+ cells. Gene and protein expression of IL‐6, MCP‐1, IL‐1β as well as leukocyte infiltration and gastrointestinal transit were analyzed at different time points after IM. IL‐6, TNFα, and IL‐1β serum levels were analyzed 3 hours after lipopolysaccharide administration. Results: tVNS activated the NTS and DMV and reduced intestinal cytokine expression, reduced leukocyte recruitment to the manipulated intestine segment, and improved gastrointestinal transit after IM. Endotoxemia‐induced IL‐6 and TNF‐α release was also reduced by tVNS. The protective effects of tVNS on POI and endotoxemia were abrogated by vagotomy. Conclusion: tVNS prevents intestinal and systemic inflammation. Activation of the DMV indicates an afferent to efferent central circuitry of the tVNS stimulation and the beneficial effects of tVNS depend on an intact vagus nerve. tVNS may become a non‐invasive approach for treatment of POI. Activation of the cholinergic anti‐inflammatory pathway was shown to reduce the inflammatory response and improve outcome of postoperative ileus (POI) and sepsis in rodents. Herein, we tested if a non‐invasive auricular electrical transcutaneous vagus nerve stimulation (tVNS) affects inflammation in models of POI or endotoxemia. [ABSTRACT FROM AUTHOR]
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- 2019
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129. International Consensus Based Review and Recommendations for Minimum Reporting Standards in Research on Transcutaneous Vagus Nerve Stimulation (Version 2020)
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Farmer, Adam D., Strzelczyk, Adam, Finisguerra, Alessandra, Gourine, Alexander V., Gharabaghi, Alireza, Hasan, Alkomiet, Burger, Andreas M., Jaramillo, Andrés M., Mertens, Ann, Majid, Arshad, Verkuil, Bart, Badran, Bashar W., Ventura-Bort, Carlos, Gaul, Charly, Beste, Christian, Warren, Christopher M., Quintana, Daniel S., Hämmerer, Dorothea, Freri, Elena, Frangos, Eleni, Tobaldini, Eleonora, Kaniusas, Eugenijus, Rosenow, Felix, Capone, Fioravante, Panetsos, Fivos, Ackland, Gareth L., Kaithwas, Gaurav, O'Leary, Georgia H., Genheimer, Hannah, Jacobs, Heidi I. L., Van Diest, Ilse, Schoenen, Jean, Redgrave, Jessica, Fang, Jiliang, Deuchars, Jim, Széles, Jozsef C., Thayer, Julian F., More, Kaushik, Vonck, Kristl, Steenbergen, Laura, Vianna, Lauro C., McTeague, Lisa M., Ludwig, Mareike, Veldhuizen, Maria G., De Couck, Marijke, Casazza, Marina, Keute, Marius, Bikson, Marom, Andreatta, Marta, D'Agostini, Martina, Weymar, Mathias, Betts, Matthew, Prigge, Matthias, Kaess, Michael, Roden, Michael, Thai, Michelle, Schuster, Nathaniel M., Montano, Nicola, Hansen, Niels, Kroemer, Nils B., Rong, Peijing, Fischer, Rico, Howland, Robert H., Sclocco, Roberta, Sellaro, Roberta, Garcia, Ronald G., Bauer, Sebastian, Gancheva, Sofiya, Stavrakis, Stavros, Kampusch, Stefan, Deuchars, Susan A., Wehner, Sven, Laborde, Sylvain, Usichenko, Taras, Polak, Thomas, Zaehle, Tino, Borges, Uirassu, Teckentrup, Vanessa, Jandackova, Vera K., Napadow, Vitaly, and Koenig, Julian
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610 Medicine & health ,3. Good health - Abstract
Given its non-invasive nature, there is increasing interest in the use of transcutaneous vagus nerve stimulation (tVNS) across basic, translational and clinical research. Contemporaneously, tVNS can be achieved by stimulating either the auricular branch or the cervical bundle of the vagus nerve, referred to as transcutaneous auricular vagus nerve stimulation(VNS) and transcutaneous cervical VNS, respectively. In order to advance the field in a systematic manner, studies using these technologies need to adequately report sufficient methodological detail to enable comparison of results between studies, replication of studies, as well as enhancing study participant safety. We systematically reviewed the existing tVNS literature to evaluate current reporting practices. Based on this review, and consensus among participating authors, we propose a set of minimal reporting items to guide future tVNS studies. The suggested items address specific technical aspects of the device and stimulation parameters. We also cover general recommendations including inclusion and exclusion criteria for participants, outcome parameters and the detailed reporting of side effects. Furthermore, we review strategies used to identify the optimal stimulation parameters for a given research setting and summarize ongoing developments in animal research with potential implications for the application of tVNS in humans. Finally, we discuss the potential of tVNS in future research as well as the associated challenges across several disciplines in research and clinical practice.
130. Glial cell-derived soluble factors increase the metastatic potential of pancreatic adenocarcinoma cells and induce epithelial-to-mesenchymal transition.
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García-Reyes, Balbina, Kuzmanov, Ivan, Schneider, Reiner, Schneiker, Bianca, Efferz, Patrik, Kalff, Jörg C., and Wehner, Sven
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EPITHELIAL-mesenchymal transition , *SCHWANN cells , *NEUROGLIA , *INHIBITION of cellular proliferation , *PANCREATIC duct - Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive types of cancer, characterized by the spreading of highly metastatic cancer cells, including invasion into surrounding nerves and perineural spaces. Nerves, in turn, can invade the tumor tissue and, through the secretion of neurotrophic factors, chemokines, and cytokines, contribute to PDAC progression. However, the contribution of the nerve-associated glial cells to PDAC progression is not well characterized. Methods: Two murine PDAC cell lines were cultured with the conditioned media (CM) of primary enteric glial cells or IMS32 Schwann cells (SCs). Different properties of PDAC cells, such as invasiveness, migratory capacity, and resistance to gemcitabine, were measured by RT-qPCR, microscopy, and MTT assays. Using a neuronal cell line, the observed effects were confirmed to be specific to the glial lineage. Results: Compared to the control medium, PDAC cells in the glial cell-conditioned medium showed increased invasiveness and migratory capacity. These cells showed reduced E-cadherin and increased N-cadherin and Vimentin levels, all markers of epithelial–mesenchymal transition (EMT). Primary enteric glial cell CM inhibited the proliferation of PDAC cells but preserved their viability, upregulated transcription factor Snail, and increased their resistance to gemcitabine. The conditioned medium generated from the IMS32 SCs produced comparable results. Conclusion: Our data suggest that glial cells can increase the metastatic potential of PDAC cells by increasing their migratory capacity and inducing epithelial-to-mesenchymal transition, a re-programming that many solid tumors use to undergo metastasis. Glial cell-conditioned medium also increased the chemoresistance of PDAC cells. These findings may have implications for future therapeutic strategies, such as targeting glial cell-derived factor signaling in PDAC. [ABSTRACT FROM AUTHOR]
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- 2023
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131. β-adrenergic signaling triggers enteric glial reactivity and acute enteric gliosis during surgery.
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Leven, Patrick, Schneider, Reiner, Schneider, Linda, Mallesh, Shilpashree, Vanden Berghe, Pieter, Sasse, Philipp, Kalff, Jörg C., and Wehner, Sven
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OPTOGENETICS , *SYMPATHETIC nervous system , *ENTERIC nervous system , *ADRENERGIC receptors , *GLIOSIS , *ADRENERGIC agonists - Abstract
Background: Enteric glia contribute to the pathophysiology of various intestinal immune-driven diseases, such as postoperative ileus (POI), a motility disorder and common complication after abdominal surgery. Enteric gliosis of the intestinal muscularis externa (ME) has been identified as part of POI development. However, the glia-restricted responses and activation mechanisms are poorly understood. The sympathetic nervous system becomes rapidly activated by abdominal surgery. It modulates intestinal immunity, innervates all intestinal layers, and directly interfaces with enteric glia. We hypothesized that sympathetic innervation controls enteric glia reactivity in response to surgical trauma. Methods: Sox10iCreERT2/Rpl22HA/+ mice were subjected to a mouse model of laparotomy or intestinal manipulation to induce POI. Histological, protein, and transcriptomic analyses were performed to analyze glia-specific responses. Interactions between the sympathetic nervous system and enteric glia were studied in mice chemically depleted of TH+ sympathetic neurons and glial-restricted Sox10iCreERT2/JellyOPfl/+/Rpl22HA/+ mice, allowing optogenetic stimulation of β-adrenergic downstream signaling and glial-specific transcriptome analyses. A laparotomy model was used to study the effect of sympathetic signaling on enteric glia in the absence of intestinal manipulation. Mechanistic studies included adrenergic receptor expression profiling in vivo and in vitro and adrenergic agonism treatments of primary enteric glial cell cultures to elucidate the role of sympathetic signaling in acute enteric gliosis and POI. Results: With ~ 4000 differentially expressed genes, the most substantial enteric glia response occurs early after intestinal manipulation. During POI, enteric glia switch into a reactive state and continuously shape their microenvironment by releasing inflammatory and migratory factors. Sympathetic denervation reduced the inflammatory response of enteric glia in the early postoperative phase. Optogenetic and pharmacological stimulation of β-adrenergic downstream signaling triggered enteric glial reactivity. Finally, distinct adrenergic agonists revealed β-1/2 adrenoceptors as the molecular targets of sympathetic–driven enteric glial reactivity. Conclusions: Enteric glia act as early responders during post-traumatic intestinal injury and inflammation. Intact sympathetic innervation and active β-adrenergic receptor signaling in enteric glia is a trigger of the immediate glial postoperative inflammatory response. With immune-activating cues originating from the sympathetic nervous system as early as the initial surgical incision, adrenergic signaling in enteric glia presents a promising target for preventing POI development. [ABSTRACT FROM AUTHOR]
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- 2023
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132. RESIDENT MACROPHAGES WITHIN THE INTESTINAL MUSCULARIS PLAY A KEY ROLE IN THE INITIATION AND MANIFESTATION OF ACUTE REJECTION IN ALLOGENEIC RODENT SMALL BOWEL TRANSPLANTATION (SBTx).
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Schaefer, Nico, Tahara, Kazunori, Websky, Martin Von, Wehner, Sven, Koscielny, Arne, Abu-Elmagd, Kareem, Kalff, Jorg, Hirner, Andreas, and Turler, Andreas
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- 2006
133. Sympathetic activity regulates epithelial proliferation and wound healing via adrenergic receptor α2A.
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ten Hove, Anne S., Mallesh, Shilpashree, Zafeiropoulou, Konstantina, de Kleer, Janna W. M., van Hamersveld, Patricia H. P., Welting, Olaf, Hakvoort, Theodorus B. M., Wehner, Sven, Seppen, Jurgen, and de Jonge, Wouter J.
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ADRENERGIC receptors , *SYMPATHETIC nervous system , *ANTIMICROBIAL peptides , *HEALING , *SYNTHETIC receptors - Abstract
Innervation of the intestinal mucosa by the sympathetic nervous system is well described but the effects of adrenergic receptor stimulation on the intestinal epithelium remain equivocal. We therefore investigated the effect of sympathetic neuronal activation on intestinal cells in mouse models and organoid cultures, to identify the molecular routes involved. Using publicly available single-cell RNA sequencing datasets we show that the α2A isoform is the most abundant adrenergic receptor in small intestinal epithelial cells. Stimulation of this receptor with norepinephrine or a synthetic specific α2A receptor agonist promotes epithelial proliferation and stem cell function, while reducing differentiation in vivo and in intestinal organoids. In an anastomotic healing mouse model, adrenergic receptor α2A stimulation resulted in improved anastomotic healing, while surgical sympathectomy augmented anastomotic leak. Furthermore, stimulation of this receptor led to profound changes in the microbial composition, likely because of altered epithelial antimicrobial peptide secretion. Thus, we established that adrenergic receptor α2A is the molecular delegate of intestinal epithelial sympathetic activity controlling epithelial proliferation, differentiation, and host defense. Therefore, this receptor could serve as a newly identified molecular target to improve mucosal healing in intestinal inflammation and wounding. [ABSTRACT FROM AUTHOR]
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- 2023
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134. BQ788 reveals glial ETB receptor modulation of neuronal cholinergic and nitrergic pathways to inhibit intestinal motility: Linked to postoperative ileus.
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Mazzotta, Elvio, Grants, Iveta, Villalobos‐Hernandez, Egina, Chaudhuri, Samhita, McClain, Jonathon L., Seguella, Luisa, Kendig, Derek M., Blakeney, Bryan A., Murthy, Srinivasa K., Schneider, Reiner, Leven, Patrick, Wehner, Sven, Harzman, Alan, Grider, John R., Gulbransen, Brian D., and Christofi, Fedias L.
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BOWEL obstructions , *EFFERENT pathways , *INTESTINES , *MUSCARINIC receptors , *GENE expression , *WESTERN immunoblotting - Abstract
Background and Purpose: ET‐1 signalling modulates intestinal motility and inflammation, but the role of ET‐1/ETB receptor signalling is poorly understood. Enteric glia modulate normal motility and inflammation. We investigated whether glial ETB signalling regulates neural‐motor pathways of intestinal motility and inflammation. Experimental Approach: We studied ETB signalling using: ETB drugs (ET‐1, SaTX, BQ788), activity‐dependent stimulation of neurons (high K+‐depolarization, EFS), gliotoxins, Tg (Ednrb‐EGFP)EP59Gsat/Mmucd mice, cell‐specific mRNA in Sox10CreERT2;Rpl22‐HAflx or ChATCre;Rpl22‐HAflx mice, Sox10CreERT2::GCaMP5g‐tdT, Wnt1Cre2::GCaMP5g‐tdT mice, muscle tension recordings, fluid‐induced peristalsis, ET‐1 expression, qPCR, western blots, 3‐D LSM‐immunofluorescence co‐labelling studies in LMMP‐CM and a postoperative ileus (POI) model of intestinal inflammation. Key Results: In the muscularis externa ETB receptor is expressed exclusively in glia. ET‐1 is expressed in RiboTag (ChAT)‐neurons, isolated ganglia and intra‐ganglionic varicose‐nerve fibres co‐labelled with peripherin or SP. ET‐1 release provides activity‐dependent glial ETB receptor modulation of Ca2+ waves in neural evoked glial responses. BQ788 reveals amplification of glial and neuronal Ca2+ responses and excitatory cholinergic contractions, sensitive to L‐NAME. Gliotoxins disrupt SaTX‐induced glial‐Ca2+ waves and prevent BQ788 amplification of contractions. The ETB receptor is linked to inhibition of contractions and peristalsis. Inflammation causes glial ETB up‐regulation, SaTX‐hypersensitivity and glial amplification of ETB signalling. In vivo BQ788 (i.p., 1 mg·kg−1) attenuates intestinal inflammation in POI. Conclusion and Implications: Enteric glial ET‐1/ETB signalling provides dual modulation of neural‐motor circuits to inhibit motility. It inhibits excitatory cholinergic and stimulates inhibitory nitrergic motor pathways. Amplification of glial ETB receptors is linked to muscularis externa inflammation and possibly pathogenic mechanisms of POI. [ABSTRACT FROM AUTHOR]
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- 2023
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135. Microbiota-dependent presence of murine enteric glial cells requires myeloid differentiation primary response protein 88 signaling.
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Enderes, Jana, Neuhaus, Hannah, Basic, Marijana, Schneiker, Bianca, Lysson, Mariola, Kalff, Jörg C, and Wehner, Sven
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Enteric glial cells (EGCs) were shown to maintain the barrier integrity and immune homeostasis of the bowel. Postnatally, EGCs develop from progenitor cells located in the myenteric plexus and are continuously replenished through adulthood. Both, murine EGC development and replenishment were shown to depend on the microbiome. The underlying mechanisms are still unknown, and we hypothesized that the myeloid differentiation primary response protein 88 (Myd88) or toll-like receptor signaling pathways may be involved. Adult and neonatal C57BL/6 wild-type (wt) and Myd88−/− mice were housed under specific pathogen-free (SPF) or germ-free (GF) conditions. GF mice were further conventionalized by gavaging stools from, and cohousing with, SPF mice having intact microbiomes. The small bowels were harvested at various time points, and immunohistochemistry and qPCR analysis of EGC markers in the muscularis externa and mucosa were performed. In wt mice, after conventionalization, the glial cell-specific markers, glial fibrillary acidic protein (GFAP) and S100 calcium-binding protein β (S100β), were upregulated in the mucosa and muscularis externa. In Myd88−/− mice, this upregulation did not occur. Importantly, GFAP (only in the mucosa) and S100β (in both the mucosa and muscularis externa) were significantly reduced in conventionalized Myd88−/− mice compared with the conventionalized wt mice. In neonatal mice, the gene expressions of GFAP and S100β increased between the day of birth (P0) and postnatal day 15 (P15) in the mucosa and muscularis externa of both wt and Myd88−/− mice. Notably, in the mucosa but not the muscularis externa, at P15, the gene expressions of GFAP and S100β were significantly reduced in Myd88−/−. Our data demonstrated that postnatal development and replenishment of EGCs require intestinal microbiota and depend on Myd88. The specific upstream mechanisms may involve toll-like-receptor recognition of the microbiota and will be the subject of further research. [ABSTRACT FROM AUTHOR]
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- 2023
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136. INTESTINAL DENDRITIC CELLS (DC) AND CCR7 ARE CENTRALLY INVOLVED IN THE GASTROINTESTINAL FIELD EFFECT.
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Koscielny, Arne J, Engel, Daniel, Schaefer, Nico, Wehner, Sven, Kurts, Christian, and Kalff, Joerg C
- Published
- 2006
137. IL-1-dependent enteric gliosis guides intestinal inflammation and dysmotility and modulates macrophage function.
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Schneider, Reiner, Leven, Patrick, Mallesh, Shilpashree, Breßer, Mona, Schneider, Linda, Mazzotta, Elvio, Fadda, Paola, Glowka, Tim, Vilz, Tim O., Lingohr, Philipp, Kalff, Jörg C., Christofi, Fievos L., and Wehner, Sven
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GLIOSIS , *MACROPHAGE activation , *NEUROGLIA , *MACROPHAGES , *INTESTINES - Abstract
Muscularis Externa Macrophages (ME-Macs) and enteric glial cells (EGCs) are closely associated cell types in the bowel wall, and important interactions are thought to occur between them during intestinal inflammation. They are involved in developing postoperative ileus (POI), an acute, surgery-induced inflammatory disorder triggered by IL-1 receptor type I (IL1R1)-signaling. In this study, we demonstrate that IL1R1-signaling in murine and human EGCs induces a reactive state, named enteric gliosis, characterized by a strong induction of distinct chemokines, cytokines, and the colony-stimulating factors 1 and 3. Ribosomal tagging revealed enteric gliosis as an early part of POI pathogenesis, and mice with an EGC-restricted IL1R1-deficiency failed to develop postoperative enteric gliosis, showed diminished immune cell infiltration, and were protected from POI. Furthermore, the IL1R1-deficiency in EGCs altered the surgery-induced glial activation state and reduced phagocytosis in macrophages, as well as their migration and accumulation around enteric ganglia. In patients, bowel surgery also induced IL-1-signaling, key molecules of enteric gliosis, and macrophage activation. Together, our data show that IL1R1-signaling triggers enteric gliosis, which results in ME-Mac activation and the development of POI. Intervention in this pathway might be a useful prophylactic strategy in preventing such motility disorders and gut inflammation. IL1R1-signaling triggers enteric glia reactivity, resulting in enteric gliosis, macrophage activation and the development of postoperative ileus. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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138. Transcutaneous vagal nerve simulation to reduce a systemic inflammatory response syndrome and the associated intestinal failure: study protocol of a prospective, two-armed, sham-controlled, double-blinded trial in healthy subjects (the NeuroSIRS-Study).
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van Beekum, Cornelius J., von Websky, Martin W., Willis, Maria A., Panknin, Christina, Coenen, Martin, Fimmers, Rolf, Kalff, Jörg C., Wehner, Sven, and Vilz, Tim O.
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SYSTEMIC inflammatory response syndrome , *NEURAL stimulation , *VAGUS nerve stimulation , *RESEARCH protocols , *SHORT bowel syndrome , *INTESTINES , *THERAPEUTICS - Abstract
Purpose: Surgery initiates pro-inflammatory mediator cascades leading to a variably pronounced sterile inflammation (SIRS). SIRS is associated with intestinal paralysis and breakdown of intestinal barrier and might result in abdominal sepsis. Technological progress led to the development of a neurostimulator for transcutaneous auricular vagal nerve stimulation (taVNS), which is associated with a decline in inflammatory parameters and peristalsis improvement in rodents and healthy subjects via activation of the cholinergic anti-inflammatory pathway. Therefore, taVNS might be a strategy for SIRS prophylaxis. Methods: The NeuroSIRS-Study is a prospective, randomized two-armed, sham-controlled, double-blind clinical trial. The study is registered at DRKS00016892 (09.07.2020). A controlled endotoxemia is used as a SIRS-mimicking model. 2 ng/kg bodyweight lipopolysaccharide (LPS) will be administered after taVNS or sham stimulation. The primary objective is a reduction of clinical symptoms of SIRS after taVNS compared to sham stimulation. Effects of taVNS on release of inflammatory cytokines, intestinal function, and vital parameters will be analyzed. Discussion: TaVNS is well-tolerated, with little to no side effects. Despite not fully mimicking postoperative inflammation, LPS challenge is the most used experimental tool to imitate SIRS and offers standardization and reproducibility. The restriction to healthy male volunteers exerts a certain bias limiting generalizability to the surgical population. Still, this pilot study aims to give first insights into taVNS as a prophylactic treatment in postoperative inflammation to pave the way for further clinical trials in patients at risk for SIRS. This would have major implications for future therapeutic approaches. [ABSTRACT FROM AUTHOR]
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- 2022
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139. Author Correction: AIM2 inflammasome-derived IL-1β induces postoperative ileus in mice.
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Hupa, Kristof Johannes, Stein, Kathy, Schneider, Reiner, Lysson, Mariola, Schneiker, Bianca, Hornung, Veit, Latz, Eicke, Iwakura, Yoichiro, Kalff, Jörg C., and Wehner, Sven
- Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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140. Myocardial maladaptation to pressure overload in CB2 receptor-deficient mice.
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Duerr, Georg D., Heinemann, Jan C., Kley, Julian, Eichhorn, Lars, Frede, Stilla, Weisheit, Christina, Wehner, Sven, Bindila, Laura, Lutz, Beat, Zimmer, Andreas, and Dewald, Oliver
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MYOSIN , *AORTIC stenosis , *CELL analysis , *CARDIAC hypertrophy , *MICE , *IMMUNOREGULATION - Abstract
Adaptation to aortic valve stenosis leads to myocardial hypertrophy, which has been associated with inflammation, fibrosis and activation of the endocannabinoid system. Since the endocannabinoid system and the CB2 receptor provide cardioprotection and modulate immune response in experimental ischemia, we investigated the role of CB2 in a mouse model of cardiac pressure overload. Transverse aortic constriction was performed in CB2 receptor-deficient (Cnr2−/−) mice and their wild-type littermates (Cnr2+/+). After echocardiography and Millar left heart catheter hemodynamic evaluation hearts were processed for histological, cellular and molecular analyses. The endocannabinoid system showed significantly higher anandamide production and CB2 receptor expression in Cnr2+/+ mice. Histology showed non-confluent, interstitial fibrosis with rare small areas of cardiomyocyte loss in Cnr2+/+ mice. In contrast, extensive cardiomyocyte loss and confluent scar formation were found in Cnr2−/− mice accompanied by significantly increased apoptosis and left ventricular dysfunction when compared with Cnr2+/+ mice. The underlying cardiac maladaptation in Cnr2−/− mice was associated with significantly reduced expression of myosin heavy chain isoform beta and less production of heme oxygenase-1. Cnr2−/− hearts presented after 7 days with stronger proinflammatory response including significantly higher TNF-alpha expression and macrophage density, but lower density of CD4+ and B220+ cells. At the same time, we found increased apoptosis of macrophages and adaptive immune cells. Higher myofibroblast accumulation and imbalance in MMP/TIMP-regulation indicated adverse remodeling in Cnr2−/− mice. Our study provides mechanistic evidence for the role of the endocannabinoid system in myocardial adaptation to pressure overload in mice. The underlying mechanisms include production of anandamide, adaptation of contractile elements and antioxidative enzymes, and selective modulation of immune cells action and apoptosis in order to prevent the loss of cardiomyocytes. • The endocannabinoid system is involved in adaptation to pressure overload. • CB2 receptor modulates contractile elements and oxidative stress in cardiomyocytes. • Apoptosis of macrophages and adaptive immune cells is regulated via CB2 receptor. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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141. Effect of transcutaneous vagus nerve stimulation on muscle activity in the gastrointestinal tract (transVaGa): a prospective clinical trial.
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Hong, Gun-Soo, Pintea, Bogdan, Lingohr, Philipp, Coch, Christoph, Randau, Thomas, Schaefer, Nico, Wehner, Sven, Kalff, Joerg C., and Pantelis, Dimitrios
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VAGUS nerve , *GASTROINTESTINAL system , *NEURAL stimulation , *CLINICAL trials , *ADVERSE health care events , *CERVICAL plexus - Abstract
Purpose: Postoperative ileus (POI) is a common complication after abdominal surgery. Invasive stimulation of the cervical vagus nerve is known to reduce inflammatory response and ameliorated POI after surgery in a mouse model. However, the transcutaneous vagus nerve stimulation (tVNS) is a possible non-invasive approach. In this clinical study, we aimed to investigate the effect of tVNS on the activation of the stomach muscle in humans. Methods: Patients requiring open laparotomy were screened for this prospective proof of concept clinical study. After open laparotomy, muscle activity of the stomach was measured by a free running electromyography (EMG) before and during tVNS on the ear. Frequency and amplitude of compound gastric action potentials were the electrophysiological parameters we assessed to reveal the changes in electro motor gastric activity. Gastrin levels as a surrogate marker for vagus nerve activation was analyzed before, 1 and 3 h after tVNS. Results: Fourteen patients were included, no severe adverse events and no medical device related adverse events occurred. tVNS led to significant reduction of action potential frequency and significant elevation of action potential amplitude in the stomach compared to control. Gastrin levels were significantly elevated 3 h after tVNS compared to levels before tVNS. Conclusion: Application of tVNS is a safe and feasible procedure during surgical intervention. Our results provide evidence that tVNS activates efferent visceral vagal fibers. Therefore, this low risk and easy to perform method could be useful to prevent postoperative ileus. Clinical trial register number: DRKS00013340. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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142. Advantages of laparoscopic compared to conventional surgery are not related to an innate immune response of peritoneal immune activation: an animal study in rats.
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Lingohr, Philipp, Dohmen, Jonas, Matthaei, Hanno, Schwandt, Timo, Stein, Kathy, Hong, Gun-Soo, Steitz, Julia, Longerich, Thomas, Bölke, Edwin, Wehner, Sven, and Kalff, Jörg
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ABDOMINAL surgery , *LAPAROSCOPIC surgery , *IMMUNE response , *NATURAL immunity , *POSTOPERATIVE care , *HEALTH outcome assessment - Abstract
Purpose: Laparoscopic surgery (LS) has proved superior compared to conventional surgery (CS) regarding morbidity, length of hospital stay, rate of wound infection and time until recovery. An improved preservation of the postoperative immune function is assumed to contribute to these benefits though the role of the local peritoneal immune response is still poorly understood. Our study investigates the peritoneal immune response subsequent to abdominal surgery and compares it between laparoscopic and conventional surgery to find an immunological explanation for the clinically proven benefits of LS. Methods: Wistar rats ( N = 140) underwent laparoscopic cecum resection (LCR; N = 28), conventional cecum resection (CCR; N = 28), laparoscopic sham operation (LSO; N = 28), conventional sham operation (CSO; N = 28), or no surgical treatment (CTRL; N = 28). Postoperatively, peritoneal lavages were performed, leukocytes isolated and analyzed regarding immune function and phagocytosis activity. Results: Immune function was inhibited postoperatively in animals undergoing LCR or CCR compared to CTRL reflected by a lower TNF-α (CTRL 3956.65 pg/ml, LCR 2018.48 pg/ml ( p = 0.023), CCR 2793.78 pg/ml (n.s.)) and IL-6 secretion (CTRL 625.84 pg/ml, LCR 142.84 pg/ml ( p = 0.009), CCR 169.53 pg/ml ( p = 0.01)). Phagocytosis was not affected in rats undergoing any kind of surgery compared to CTRL. Neither cytokine secretion nor phagocytosis activity differed significantly between laparoscopic and conventional surgery. Conclusions: According to our findings the benefits associated with LS compared to CS cannot be explained by differences in the postoperative peritoneal innate immune response. Further studies are needed to elucidate the causes for a more favorable postoperative outcome in patients after LS compared to CS. [ABSTRACT FROM AUTHOR]
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- 2017
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143. Establishing a biomarker for postoperative ileus in humans — Results of the BiPOI trial.
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Vilz, Tim O., Roessel, Lisa, Chang, Johannes, Pantelis, Dimitrios, Schwandt, Timo, Koscielny, Arne, Wehner, Sven, and Kalff, Joerg C.
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BOWEL obstructions , *ABDOMINAL surgery , *BIOMARKERS , *SURGICAL complications , *ACQUISITION of data , *CLINICAL trials - Abstract
Aims Postoperative ileus (POI) is a frequent complication after abdominal surgery, resulting from an inflammation of the muscularis externa (ME). So far no valid biomarker for occurrence, duration or intensity of POI exists. Extravasation of monocytes and neutrophils from blood circulating into the postoperative ME is well known as a hallmark of POI. In a previous study we demonstrated that a low abundant subset of T H 1 cells, activated by IL-12, can be detected in the peripheral blood of a small subset of patients in response to abdominal surgery. The aim of the present study was to investigate if these specific T H 1 cells, IL-12 or circulating leukocyte levels could act as a valid marker for POI occurrence. Main methods At different time points, blood samples of patients undergoing abdominal or extraabdominal surgery were collected. Serum levels of IL-12 or T H 1 cells as well as neutrophils and monocytes were analyzed. Data were compared between both groups and correlated with clinical signs of POI. Key findings Time until first flatus and defecation as well as solid food tolerances are delayed after abdominal compared to extraabdominal surgery. Circulating IL-12 levels and numbers of T H 1 cells, neutrophils and monocytes did not differ between both groups. Significance While previous experiments indicated that specific T H 1 cells play a crucial role in POI dissemination, our present data from a larger human cohort demonstrate that they do not seem to be suitable to distinguish between abdominal and extraabdominal surgery. Furthermore neither T H 1 cells nor leukocytes or serum IL-12 levels are appropriate biomarkers for POI in a clinical setting. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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144. CB2 receptor-mediated effects of pro-inflammatory macrophages influence survival of cardiomyocytes.
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Heinemann, Jan C., Duerr, Georg D., Keppel, Katharina, Breitbach, Martin, Fleischmann, Bernd K., Zimmer, Andreas, Wehner, Sven, Welz, Armin, and Dewald, Oliver
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HEART cells , *CANNABINOID receptors , *INFLAMMATION , *MACROPHAGES , *IMMUNOHISTOCHEMISTRY , *IN vitro studies - Abstract
Aims The endocannabinoid system and cannabinoid receptor 2 (CB2 receptor) have been associated with modulation of inflammatory response and myocardial adaptation after ischemic injury. In order to elucidate CB2 receptor-related effects during cellular interactions, we investigated cardiomyocyte survival and macrophage function in vitro . Main methods Murine embryonic (eCM) and adult (CM) cardiomyocytes, murine macrophages (MO), and their subtypes M1 (M1-MO) and M2 (M2-MO) were derived from wildtype- (WT) and CB2 receptor-deficient (Cnr2 −/− ) mice. Cells were cultured separately or in co-culture under normoxia or hypoxia (2% O 2 ) and pro-inflammatory stimulation using interferon (IFN)γ. Besides immunohistochemistry, we also measured mRNA expression (Taqman®) and performed FACS-analysis of cardiomyocytes. Macrophage migration was assessed using Boyden chamber assay. Key findings We found a significant induction of CB2 receptor mRNA and protein in murine eCM as well as M1- and M2-MO in vitro following cultivation under hypoxia or stimulation with IFNγ. A significantly higher amount of apoptotic Cnr2 −/− -CMs was found after incubation under hypoxia when compared to WT-CMs. We observed a significantly stronger migration potential in Cnr2 −/− -M1-MOs towards the supernatant of apoptotic CM, than in corresponding WT-cells. Co-culture revealed a significantly higher loss of eCMs and induction of their apoptosis after cultivation with Cnr2 −/− -M1-MOs. Production of TNF-α in M1-MOs was dependent on CB2 receptor stimulation by anandamide. Significance Our data provide novel insights into CB2 receptor-mediated protection of cardiomyocytes during hypoxia and pro-inflammatory stimulation. We show CB2 receptor-dependent effects on migration and function of M1-MOs in interaction with cardiomyocytes, thereby influencing their survival. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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145. Enteric Glial Cells: A New Frontier in Neurogastroenterology and Clinical Target for Inflammatory Bowel Diseases
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Suren Soghomonyan, Sven Wehner, Fernando Ochoa-Cortes, Rosario Cuomo, Fabio Turco, Andrómeda Liñán-Rico, Emmett E. Whitaker, Fievos L. Christofi, Ochoa Cortes, Fernando, Turco, Fabio, Linan Rico, Andromeda, Soghomonyan, Suren, Whitaker, Emmett, Wehner, Sven, Cuomo, Rosario, and Christofi, Fievos L.
- Subjects
0301 basic medicine ,Cell signaling ,Central nervous system ,reactive hEGC phenotype ,Inflammation ,tipartite synapse ,Cell Communication ,Biology ,calcium signaling ,Enteric Nervous System ,postoperative ileus ,03 medical and health sciences ,chemistry.chemical_compound ,human enteric glial cell ,GI infection ,neuroglial communication ,medicine ,Immunology and Allergy ,Humans ,Future Directions and Methods for IBD Research ,Palmitoylethanolamide ,Inflammatory Bowel Disease ,Gastroenterology ,Purinergic signalling ,Neurogastroenterology ,Inflammatory Bowel Diseases ,Prognosis ,gliotransmission ,3. Good health ,030104 developmental biology ,medicine.anatomical_structure ,enteric glial cells ,chemistry ,motility ,Cytoprotection ,Immunology ,Neuroglia ,Enteric nervous system ,medicine.symptom ,Enteric Glia ,Neuroscience ,purinergic signaling ,Signal Transduction - Abstract
Article first Published online 18 December 2015, The word “glia” is derived from the Greek word “γλοια,” glue of the enteric nervous system, and for many years, enteric glial cells (EGCs) were believed to provide mainly structural support. However, EGCs as astrocytes in the central nervous system may serve a much more vital and active role in the enteric nervous system, and in homeostatic regulation of gastrointestinal functions. The emphasis of this review will be on emerging concepts supported by basic, translational, and/or clinical studies, implicating EGCs in neuron-to-glial (neuroglial) communication, motility, interactions with other cells in the gut microenvironment, infection, and inflammatory bowel diseases. The concept of the “reactive glial phenotype” is explored as it relates to inflammatory bowel diseases, bacterial and viral infections, postoperative ileus, functional gastrointestinal disorders, and motility disorders. The main theme of this review is that EGCs are emerging as a new frontier in neurogastroenterology and a potential therapeutic target. New technological innovations in neuroimaging techniques are facilitating progress in the field, and an update is provided on exciting new translational studies. Gaps in our knowledge are discussed for further research. Restoring normal EGC function may prove to be an efficient strategy to dampen inflammation. Probiotics, palmitoylethanolamide (peroxisome proliferator-activated receptor–α), interleukin-1 antagonists (anakinra), and interventions acting on nitric oxide, receptor for advanced glycation end products, S100B, or purinergic signaling pathways are relevant clinical targets on EGCs with therapeutic potential.
- Published
- 2015
146. Extracellular matrix substrates differentially influence enteric glial cell homeostasis and immune reactivity.
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Schneider L, Schneider R, Hamza E, and Wehner S
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- Animals, Mice, Enteric Nervous System metabolism, Enteric Nervous System immunology, Cells, Cultured, Drug Combinations, Collagen metabolism, Mice, Inbred C57BL, Proteoglycans metabolism, Extracellular Matrix metabolism, Neuroglia metabolism, Neuroglia immunology, Homeostasis, Laminin metabolism
- Abstract
Introduction: Enteric glial cells are important players in the control of motility, intestinal barrier integrity and inflammation. During inflammation, they switch into a reactive phenotype enabling them to release inflammatory mediators, thereby shaping the inflammatory environment. While a plethora of well-established in vivo models exist, cell culture models necessary to decipher the mechanistic pathways of enteric glial reactivity are less well standardized. In particular, the composition of extracellular matrices (ECM) can massively affect the experimental outcome. Considering the growing number of studies involving primary enteric glial cells, a better understanding of their homeostatic and inflammatory in vitro culture conditions is needed., Methods: We examined the impact of different ECMs on enteric glial culture purity, network morphology and immune responsiveness. Therefore, we used immunofluorescence and brightfield microscopy, as well as 3' bulk mRNA sequencing. Additionally, we compared cultured cells with in vivo enteric glial transcriptomes isolated from Sox10
iCreERT2 Rpl22HA/+ mice., Results: We identified Matrigel and laminin as superior over other coatings, including poly-L-ornithine, different lysines, collagens, and fibronectin, gaining the highest enteric glial purity and most extended glial networks expressing connexin-43 hemichannels allowing intercellular communication. Transcriptional analysis revealed strong similarities between enteric glia on Matrigel and laminin with enrichment of gene sets supporting neuronal differentiation, while cells on poly-L-ornithine showed enrichment related to cell proliferation. Comparing cultured and in vivo enteric glial transcriptomes revealed a 50% overlap independent of the used coating substrates. Inflammatory activation of enteric glia by IL-1β treatment showed distinct coating-dependent gene expression signatures, with an enrichment of genes related to myeloid and epithelial cell differentiation on Matrigel and laminin coatings, while poly-L-ornithine induced more gene sets related to lymphocyte differentiation., Discussion: Together, changes in morphology, differentiation and immune activation of primary enteric glial cells proved a strong effect of the ECM. We identified Matrigel and laminin as pre-eminent substrates for murine enteric glial cultures. These new insights will help to standardize and improve enteric glial culture quality and reproducibility between in vitro studies in the future, allowing a better comparison of their functional role in enteric neuroinflammation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Schneider, Schneider, Hamza and Wehner.)- Published
- 2024
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147. IL-1R signaling drives enteric glia-macrophage interactions in colorectal cancer.
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van Baarle L, De Simone V, Schneider L, Santhosh S, Abdurahiman S, Biscu F, Schneider R, Zanoletti L, Siqueira de Mello R, Verbandt S, Hu Z, Stakenborg M, Ke BJ, Stakenborg N, Salvador Laureano R, García-Reyes B, Henn J, Toma M, Vanmechelen M, Boeckxstaens G, De Smet F, Garg AD, Ibiza S, Tejpar S, Wehner S, and Matteoli G
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- Animals, Humans, Mice, Macrophages metabolism, Macrophages immunology, Receptors, Interleukin-1 metabolism, Receptors, Interleukin-1 genetics, Tumor-Associated Macrophages immunology, Tumor-Associated Macrophages metabolism, Interleukin-6 metabolism, Monocytes metabolism, Monocytes immunology, Mice, Inbred C57BL, Cell Communication, Cell Differentiation, Cell Line, Tumor, Female, Colorectal Neoplasms pathology, Colorectal Neoplasms immunology, Colorectal Neoplasms metabolism, Colorectal Neoplasms genetics, Tumor Microenvironment immunology, Neuroglia metabolism, Signal Transduction
- Abstract
Enteric glia have been recently recognized as key components of the colonic tumor microenvironment indicating their potential role in colorectal cancer pathogenesis. Although enteric glia modulate immune responses in other intestinal diseases, their interaction with the colorectal cancer immune cell compartment remains unclear. Through a combination of single-cell and bulk RNA-sequencing, both in murine models and patients, here we find that enteric glia acquire an immunomodulatory phenotype by bi-directional communication with tumor-infiltrating monocytes. The latter direct a reactive enteric glial cell phenotypic and functional switch via glial IL-1R signaling. In turn, tumor glia promote monocyte differentiation towards pro-tumorigenic SPP1
+ tumor-associated macrophages by IL-6 release. Enteric glia cell abundancy correlates with worse disease outcomes in preclinical models and colorectal cancer patients. Thereby, our study reveals a neuroimmune interaction between enteric glia and tumor-associated macrophages in the colorectal tumor microenvironment, providing insights into colorectal cancer pathogenesis., (© 2024. The Author(s).)- Published
- 2024
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148. Sympathetic activity regulates epithelial proliferation and wound healing via adrenergic receptor α 2A .
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Ten Hove AS, Mallesh S, Zafeiropoulou K, de Kleer JWM, van Hamersveld PHP, Welting O, Hakvoort TBM, Wehner S, Seppen J, and de Jonge WJ
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- Animals, Mice, Cell Proliferation, Intestinal Mucosa, Receptors, Adrenergic, Receptors, Adrenergic, alpha-2 genetics, Wound Healing physiology, Epithelial Cells, Intestines
- Abstract
Innervation of the intestinal mucosa by the sympathetic nervous system is well described but the effects of adrenergic receptor stimulation on the intestinal epithelium remain equivocal. We therefore investigated the effect of sympathetic neuronal activation on intestinal cells in mouse models and organoid cultures, to identify the molecular routes involved. Using publicly available single-cell RNA sequencing datasets we show that the α
2A isoform is the most abundant adrenergic receptor in small intestinal epithelial cells. Stimulation of this receptor with norepinephrine or a synthetic specific α2A receptor agonist promotes epithelial proliferation and stem cell function, while reducing differentiation in vivo and in intestinal organoids. In an anastomotic healing mouse model, adrenergic receptor α2A stimulation resulted in improved anastomotic healing, while surgical sympathectomy augmented anastomotic leak. Furthermore, stimulation of this receptor led to profound changes in the microbial composition, likely because of altered epithelial antimicrobial peptide secretion. Thus, we established that adrenergic receptor α2A is the molecular delegate of intestinal epithelial sympathetic activity controlling epithelial proliferation, differentiation, and host defense. Therefore, this receptor could serve as a newly identified molecular target to improve mucosal healing in intestinal inflammation and wounding., (© 2023. Springer Nature Limited.)- Published
- 2023
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149. BQ788 reveals glial ET B receptor modulation of neuronal cholinergic and nitrergic pathways to inhibit intestinal motility: Linked to postoperative ileus.
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Mazzotta E, Grants I, Villalobos-Hernandez E, Chaudhuri S, McClain JL, Seguella L, Kendig DM, Blakeney BA, Murthy SK, Schneider R, Leven P, Wehner S, Harzman A, Grider JR, Gulbransen BD, and Christofi FL
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- Mice, Animals, Neuroglia, Neurons metabolism, Gastrointestinal Motility, Inflammation metabolism, Cholinergic Agents metabolism, Gliotoxin metabolism, Ileus drug therapy, Ileus etiology, Ileus metabolism
- Abstract
Background and Purpose: ET-1 signalling modulates intestinal motility and inflammation, but the role of ET-1/ET
B receptor signalling is poorly understood. Enteric glia modulate normal motility and inflammation. We investigated whether glial ETB signalling regulates neural-motor pathways of intestinal motility and inflammation., Experimental Approach: We studied ETB signalling using: ETB drugs (ET-1, SaTX, BQ788), activity-dependent stimulation of neurons (high K+ -depolarization, EFS), gliotoxins, Tg (Ednrb-EGFP)EP59Gsat/Mmucd mice, cell-specific mRNA in Sox10CreERT2 ;Rpl22-HAflx or ChATCre ;Rpl22-HAflx mice, Sox10CreERT2 ::GCaMP5g-tdT, Wnt1Cre2 ::GCaMP5g-tdT mice, muscle tension recordings, fluid-induced peristalsis, ET-1 expression, qPCR, western blots, 3-D LSM-immunofluorescence co-labelling studies in LMMP-CM and a postoperative ileus (POI) model of intestinal inflammation., Key Results: In the muscularis externa ETB receptor is expressed exclusively in glia. ET-1 is expressed in RiboTag (ChAT)-neurons, isolated ganglia and intra-ganglionic varicose-nerve fibres co-labelled with peripherin or SP. ET-1 release provides activity-dependent glial ETB receptor modulation of Ca2+ waves in neural evoked glial responses. BQ788 reveals amplification of glial and neuronal Ca2+ responses and excitatory cholinergic contractions, sensitive to L-NAME. Gliotoxins disrupt SaTX-induced glial-Ca2+ waves and prevent BQ788 amplification of contractions. The ETB receptor is linked to inhibition of contractions and peristalsis. Inflammation causes glial ETB up-regulation, SaTX-hypersensitivity and glial amplification of ETB signalling. In vivo BQ788 (i.p., 1 mg·kg-1 ) attenuates intestinal inflammation in POI., Conclusion and Implications: Enteric glial ET-1/ETB signalling provides dual modulation of neural-motor circuits to inhibit motility. It inhibits excitatory cholinergic and stimulates inhibitory nitrergic motor pathways. Amplification of glial ETB receptors is linked to muscularis externa inflammation and possibly pathogenic mechanisms of POI., (© 2023 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)- Published
- 2023
- Full Text
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150. Surgical site infections are independently associated with the development of postoperative acute-on-chronic liver failure in liver cirrhosis.
- Author
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Chang J, Hoffstall S, Gödiker J, Lehmann J, Schwind L, Lingohr P, Manekeller S, Wehner S, Strassburg CP, Chang P, and Praktiknjo M
- Subjects
- Humans, Surgical Wound Infection complications, Surgical Wound Infection diagnosis, Surgical Wound Infection epidemiology, Prognosis, Liver Cirrhosis complications, Liver Cirrhosis diagnosis, Liver Cirrhosis surgery, Acute-On-Chronic Liver Failure diagnosis, Acute-On-Chronic Liver Failure epidemiology, Acute-On-Chronic Liver Failure etiology, Liver Transplantation adverse effects, Bacterial Infections complications, Bacterial Infections epidemiology
- Abstract
Acute-on-chronic liver failure (ACLF) is associated with organ failure and high short-term mortality. Bacterial infections and surgery have been reported as major precipitants for ACLF. However, detailed characterization of postoperative infections after elective surgery in patients with liver cirrhosis and their impact on the development of ACLF have not been investigated yet. A total of 235 patients with cirrhosis without ACLF and proven bacterial infections undergoing elective surgery were included. The primary end point was the development of ACLF within 28 days after surgery, and secondary end points were infection development within 28 days and 3-month ACLF-related mortality. Cox regression analysis was used for identification of risk factors associated with ACLF development, infection development, and mortality. A total of 86 patients (37%) developed ACLF within 28 days after surgery. Patients with new postoperative infections had significantly higher rates of associated ACLF episodes within 28 days (51% vs. 24%, p < 0.001) and higher 3-month mortality ( p < 0.05) than patients without postoperative infections. New infections after surgery [HR: 2.43 (1.59-3.71), p < 0.001] and organ/space surgical site infections [HR: 2.46 (1.26-4.80), p = 0.01] in particular were independent risk factors associated with ACLF development 28 days after surgery. Extensive procedures were associated with the development of new postoperative infection episodes within 28 days. Infections treated with initial appropriate empirical antibiotic strategies showed significantly improved survival. This study characterizes and identifies bacterial infections in general and organ/space surgical site infection in particular as precipitating events for the development of ACLF after elective surgery in patients with cirrhosis. Postoperative ACLF combined with infections leads to higher postoperative short-term mortality than each condition separately, especially in extensive procedures. Interdisciplinary care, early identification of postoperative ACLF and infections, and adequate, broad, and early treatment strategies are needed to improve postoperative outcome., (Copyright © 2023 American Association for the Study of Liver Diseases.)
- Published
- 2023
- Full Text
- View/download PDF
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