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Thirty-eight-negative kinase 1 mediates trauma-induced intestinal injury and multi-organ failure.
Armacki, Milena; Trugenberger, Anna Katharina; Ellwanger, Ann K; Eiseler, Tim; Schwerdt, Christiane; Bettac, Lucas; Langgartner, Dominik; Azoitei, Ninel; Halbgebauer, Rebecca; Groß, Rüdiger; Barth, Tabea; Lechel, André; Walter, Benjamin M; Kraus, Johann M; Wiegreffe, Christoph; Grimm, Johannes; Scheffold, Annika; Schneider, Marlon R; Peuker, Kenneth; Zeißig, Sebastian; Britsch, Stefan; Rose-John, Stefan; Vettorazzi, Sabine; Wolf, Eckhart; Tannapfel, Andrea; Steinestel, Konrad; Reber, Stefan O; Walther, Paul; Kestler, Hans A; Radermacher, Peter; Barth, Thomas Fe; Huber-Lang, Markus; Kleger, Alexander; Seufferlein, Thomas.
Afiliación
  • Armacki M; Department of Internal Medicine I, University Hospital Ulm, Ulm, Germany.
  • Trugenberger AK; Department of Internal Medicine I, University Hospital Ulm, Ulm, Germany.
  • Ellwanger AK; Department of Internal Medicine I, University Hospital Ulm, Ulm, Germany.
  • Eiseler T; Department of Internal Medicine I, University Hospital Ulm, Ulm, Germany.
  • Schwerdt C; Waldkrankenhaus "Rudolph Elle" Eisenberg, Lehrstuhl für Orthopädie Uniklinik Jena, Jena, Germany.
  • Bettac L; Department of Internal Medicine I, University Hospital Ulm, Ulm, Germany.
  • Langgartner D; Laboratory for Molecular Psychosomatics, Clinic for Psychosomatic Medicine and Psychotherapy, and.
  • Azoitei N; Department of Internal Medicine I, University Hospital Ulm, Ulm, Germany.
  • Halbgebauer R; Institute of Clinical and Experimental Trauma Immunology, University Hospital Ulm, Ulm, Germany.
  • Groß R; Department of Internal Medicine I, University Hospital Ulm, Ulm, Germany.
  • Barth T; Department of Internal Medicine I, University Hospital Ulm, Ulm, Germany.
  • Lechel A; Department of Internal Medicine I, University Hospital Ulm, Ulm, Germany.
  • Walter BM; Department of Internal Medicine I, University Hospital Ulm, Ulm, Germany.
  • Kraus JM; Institute of Medical Systems Biology and.
  • Wiegreffe C; Institute of Molecular and Cellular Anatomy, Ulm University, Ulm, Germany.
  • Grimm J; Institute of Pathology and.
  • Scheffold A; Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany.
  • Schneider MR; Gene Center, LMU Munich, Munich, Germany.
  • Peuker K; Center for Regenerative Therapies Dresden, TU Dresden, Dresden, Germany.
  • Zeißig S; Center for Regenerative Therapies Dresden, TU Dresden, Dresden, Germany.
  • Britsch S; Institute of Molecular and Cellular Anatomy, Ulm University, Ulm, Germany.
  • Rose-John S; Institute of Biochemistry, CA University Kiel, Kiel, Germany.
  • Vettorazzi S; Institute of Comparative Molecular Endocrinology, Ulm University, Ulm, Germany.
  • Wolf E; Gene Center, LMU Munich, Munich, Germany.
  • Tannapfel A; Institute of Pathology, Ruhr University Bochum, Bochum, Germany.
  • Steinestel K; Institute of Pathology and Molecular Pathology, Bundeswehrkrankenhaus Ulm, Ulm, Germany.
  • Reber SO; Laboratory for Molecular Psychosomatics, Clinic for Psychosomatic Medicine and Psychotherapy, and.
  • Walther P; Central Facility for Electron Microscopy, University of Ulm, Ulm, Germany.
  • Kestler HA; Institute of Medical Systems Biology and.
  • Radermacher P; Institute of Anesthesiological Pathophysiology and Process Engineering, Ulm University, Ulm, Germany.
  • Barth TF; Institute of Pathology and.
  • Huber-Lang M; Institute of Clinical and Experimental Trauma Immunology, University Hospital Ulm, Ulm, Germany.
  • Kleger A; Department of Internal Medicine I, University Hospital Ulm, Ulm, Germany.
  • Seufferlein T; Department of Internal Medicine I, University Hospital Ulm, Ulm, Germany.
J Clin Invest ; 128(11): 5056-5072, 2018 11 01.
Article en En | MEDLINE | ID: mdl-30320600
Dysregulated intestinal epithelial apoptosis initiates gut injury, alters the intestinal barrier, and can facilitate bacterial translocation leading to a systemic inflammatory response syndrome (SIRS) and/or multi-organ dysfunction syndrome (MODS). A variety of gastrointestinal disorders, including inflammatory bowel disease, have been linked to intestinal apoptosis. Similarly, intestinal hyperpermeability and gut failure occur in critically ill patients, putting the gut at the center of SIRS pathology. Regulation of apoptosis and immune-modulatory functions have been ascribed to Thirty-eight-negative kinase 1 (TNK1), whose activity is regulated merely by expression. We investigated the effect of TNK1 on intestinal integrity and its role in MODS. TNK1 expression induced crypt-specific apoptosis, leading to bacterial translocation, subsequent septic shock, and early death. Mechanistically, TNK1 expression in vivo resulted in STAT3 phosphorylation, nuclear translocation of p65, and release of IL-6 and TNF-α. A TNF-α neutralizing antibody partially blocked development of intestinal damage. Conversely, gut-specific deletion of TNK1 protected the intestinal mucosa from experimental colitis and prevented cytokine release in the gut. Finally, TNK1 was found to be deregulated in the gut in murine and porcine trauma models and human inflammatory bowel disease. Thus, TNK1 might be a target during MODS to prevent damage in several organs, notably the gut.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Tirosina Quinasas / Traumatismo Múltiple / Enfermedades Inflamatorias del Intestino / Síndrome de Respuesta Inflamatoria Sistémica / Proteínas Fetales / Intestinos / Insuficiencia Multiorgánica Tipo de estudio: Etiology_studies / Prognostic_studies Límite: Animals Idioma: En Revista: J Clin Invest Año: 2018 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Tirosina Quinasas / Traumatismo Múltiple / Enfermedades Inflamatorias del Intestino / Síndrome de Respuesta Inflamatoria Sistémica / Proteínas Fetales / Intestinos / Insuficiencia Multiorgánica Tipo de estudio: Etiology_studies / Prognostic_studies Límite: Animals Idioma: En Revista: J Clin Invest Año: 2018 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Estados Unidos