The Journal of clinical investigation, 2018-11, Vol.128 (11), p.5056-5072
- 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
2018
Details
- Autor(en) / Beteiligte
- 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
- Titel
- Thirty-eight-negative kinase 1 mediates trauma-induced intestinal injury and multi-organ failure
- Ist Teil von
- The Journal of clinical investigation, 2018-11, Vol.128 (11), p.5056-5072
- Ort / Verlag
- United States: American Society for Clinical Investigation
- Erscheinungsjahr
- 2018
- Link zum Volltext
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0021-9738eISSN: 1558-8238DOI: 10.1172/jci97912Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6205400
- Format
- –
- Schlagworte
- Animal models, Animals, Apoptosis, Colitis, Colorectal diseases, Cytokines, Digestive system, Digestive tract, Disease Models, Animal, Female, Fetal Proteins - genetics, Fetal Proteins - metabolism, Gangrene, Gastrointestinal diseases, Gastrointestinal tract diseases, Immunomodulation, Inflammation, Inflammatory bowel disease, Inflammatory bowel diseases, Inflammatory Bowel Diseases - enzymology, Inflammatory Bowel Diseases - etiology, Inflammatory Bowel Diseases - genetics, Inflammatory Bowel Diseases - pathology, Inflammatory diseases, Interleukin 6, Interleukin-6 - genetics, Interleukin-6 - metabolism, Intestine, Intestines - enzymology, Intestines - pathology, Ischemia, Kinases, Large intestine, Liver, Mice, Mucosa, Multiple Organ Failure - enzymology, Multiple Organ Failure - etiology, Multiple Organ Failure - genetics, Multiple Organ Failure - pathology, Multiple Trauma - complications, Multiple Trauma - enzymology, Multiple Trauma - genetics, Multiple Trauma - pathology, Nuclear transport, Permeability, Phosphorylation, Phosphotransferases, Physiology, Prevention, Protein-Tyrosine Kinases - genetics, Protein-Tyrosine Kinases - metabolism, Risk factors, Rodents, Sepsis, Septic shock, Stat3 protein, STAT3 Transcription Factor - genetics, STAT3 Transcription Factor - metabolism, Stem cells, Swine, Systemic inflammatory response syndrome, Systemic Inflammatory Response Syndrome - enzymology, Systemic Inflammatory Response Syndrome - etiology, Systemic Inflammatory Response Syndrome - pathology, Transcription Factor RelA - genetics, Transcription Factor RelA - metabolism, Trauma, Tumor Necrosis Factor-alpha - genetics, Tumor Necrosis Factor-alpha - metabolism, Tumor necrosis factor-α, Tumors, Vascular endothelial growth factor, Wounds and injuries