Thirty-eight-negative kinase 1 mediates trauma-induced intestinal injury and multi-organ failure
Milena Armacki, … , Alexander Kleger, Thomas Seufferlein
Milena Armacki, … , Alexander Kleger, Thomas Seufferlein
Published October 15, 2018
Citation Information: J Clin Invest. 2018;128(11):5056-5072. https://doi.org/10.1172/JCI97912.
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Research Article Gastroenterology Inflammation

Thirty-eight-negative kinase 1 mediates trauma-induced intestinal injury and multi-organ failure

Abstract

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.

Authors

Milena Armacki, Anna Katharina Trugenberger, Ann K. Ellwanger, Tim Eiseler, Christiane Schwerdt, Lucas Bettac, Dominik Langgartner, Ninel Azoitei, Rebecca Halbgebauer, Rüdiger Groß, Tabea Barth, André Lechel, Benjamin M. Walter, Johann M. Kraus, Christoph Wiegreffe, Johannes Grimm, Annika Scheffold, Marlon R. Schneider, Kenneth Peuker, Sebastian Zeißig, Stefan Britsch, Stefan Rose-John, Sabine Vettorazzi, Eckhart Wolf, Andrea Tannapfel, Konrad Steinestel, Stefan O. Reber, Paul Walther, Hans A. Kestler, Peter Radermacher, Thomas F.E. Barth, Markus Huber-Lang, Alexander Kleger, Thomas Seufferlein

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Figure 4

TNK1-expressing mice show liver, pancreas, and lung damage.

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TNK1-expressing mice show liver, pancreas, and lung damage. The liver is...
The liver is grossly enlarged (A and B) and shows discoloration (A) due to fat deposits (D). TNK1-expressing mice also show histopathological changes in the liver (n = 10 per group). (A–E) Hepatocyte ballooning, degeneration, and cell death besides inflammatory infiltrates are observed in murine liver samples 24 hours after doxycycline administration. Representative images of H&E- and cC3-stained liver are shown (A). (F–H) TNK1-expressing mice exhibit signs of mild edematous pancreatitis (F, left panels) with localized areas of tissue apoptosis (F, middle panels) (n = 10 per group). There is also an increase and apical accumulation of zymogen granules in acinar cells (F, right panel, electron micrograph). (G and H) Application of a pancreatitis score confirms higher interstitial edema (G) and inflammatory infiltrates (H). (I and J) Signs of emphysema, pulmonary edema, congestion, and cell death accompanied by inflammation are observed in lungs after 24 hours of doxycycline exposure (n = 10 per group). The corresponding chart depicts scoring of the lung damage. (K) Recombinant TNK1 is not expressed in the lung, as compared with high expression in the intestine. Representative Western blot is shown (n = 3). All experimental procedures were conducted 24 hours after exposure of mice to saline or doxycycline. Data are expressed as mean ± SEM. Differences were tested by parametric 2-tailed, unpaired Student’s t tests (*P = 0.01–0.05; **P = 0.001–0.01; ***P = 0.0001–0.001; ****P < 0.0001). Scale bars: 100 μm.