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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-?. A TNF-? 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.

SUBMITTER: Armacki M

PROVIDER: S-EPMC6205400 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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

Armacki Milena M Trugenberger Anna Katharina AK Ellwanger Ann K AK Eiseler Tim T Schwerdt Christiane C Bettac Lucas L Langgartner Dominik D Azoitei Ninel N Halbgebauer Rebecca R Groß Rüdiger R Barth Tabea T Lechel André A Walter Benjamin M BM Kraus Johann M JM Wiegreffe Christoph C Grimm Johannes J Scheffold Annika A Schneider Marlon R MR Peuker Kenneth K Zeißig Sebastian S Britsch Stefan S Rose-John Stefan S Vettorazzi Sabine S Wolf Eckhart E Tannapfel Andrea A Steinestel Konrad K Reber Stefan O SO Walther Paul P Kestler Hans A HA Radermacher Peter P Barth Thomas Fe TF Huber-Lang Markus M Kleger Alexander A Seufferlein Thomas T

The Journal of clinical investigation 20181015 11

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 pa ...[more]

PMID: 30320600

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Project description:Trauma represents a major socioeconomic burden worldwide. After a severe injury, hemorrhagic shock (HS) as a frequent concomitant aspect is a central driver of systemic inflammation and organ damage. The kidney is often strongly affected by traumatic-HS, and acute kidney injury (AKI) poses the patient at great risk for adverse outcome. Recently, thirty-eight-negative kinase 1 (TNK1) was proposed to play a detrimental role in organ damage after trauma/HS. Therefore, we aimed to assess the role of TNK1 in HS-induced kidney injury in a murine and a post hoc analysis of a non-human primate model of HS comparable to the clinical situation. Mice and non-human primates underwent resuscitated HS at 30 mmHg for 60 min. 5 h after the induction of shock, animals were assessed for systemic inflammation and TNK1 expression in the kidney. In vitro, murine distal convoluted tubule cells were stimulated with inflammatory mediators to gain mechanistic insights into the role of TNK1 in kidney dysfunction. In a translational approach, we investigated blood drawn from either healthy volunteers or severely injured patients at different time points after trauma (from arrival at the emergency room and at fixed time intervals until 10 days post injury; identifier: NCT02682550, https://clinicaltrials.gov/ct2/show/NCT02682550). A pronounced inflammatory response, as seen by increased IL-6 plasma levels as well as early signs of AKI, were observed in mice, non-human primates, and humans after trauma/HS. TNK1 was found in the plasma early after trauma-HS in trauma patients. Renal TNK1 expression was significantly increased in mice and non-human primates after HS, and these effects with concomitant induction of apoptosis were blocked by therapeutic inhibition of complement C3 activation in non-human primates. Mechanistically, in vitro data suggested that IL-6 rather than C3 cleavage products induced upregulation of TNK1 and impaired barrier function in renal epithelial cells. In conclusion, these data indicate that C3 inhibition in vivo may inhibit an excessive inflammatory response and mediator release, thereby indirectly neutralizing TNK1 as a potent driver of organ damage. In future studies, we will address the therapeutic potential of direct TNK1 inhibition in the context of severe tissue trauma with different degrees of additional HS.

Project description:ObjectivesTo assess psychopathology and medical traumatic stress in children with intestinal failure (IF) and identify associated risk factors.MethodsTwo-center study, performed from September 2019 until April 2022 (partly during COVID-19 pandemic), including children (1.5-17y) with IF, dependent on parenteral nutrition (PN) or weaned off PN, treated by a multidisciplinary IF-team. Psychopathology in children was evaluated with a semi-structured interview assessing psychiatric classifications and validated questionnaires assessing emotional (internalizing) and behavioral (externalizing) problems. Medical traumatic stress was assessed with a validated questionnaire. Problem scores were compared with normative data. Associations between clinical characteristics and outcomes were analyzed with linear regression analyses.ResultsForty-one (of 111 eligible) children were included (median age 8.9y (IQR 5.5-11.8), 54% female, 73% born preterm). Median PN-duration was 17.3 months (IQR 6.9-54.0); 17 children (41%) were still PN-dependent. One third of the children met criteria for at least one psychiatric classification (compared with 14% in age-matched general population). Anxiety disorders and attention deficit hyperactivity disorder were most common. In school-aged children (n=29, 6-17y), significantly increased emotional problems were consistently reported by children (p=0.011), parents (p<0.001) and teachers (p=0.004). In preschool children (n=12, 1.5-5y), no significant differences with normative data were found. Subclinical or clinical emotional problems were reported in 19 children (46%). Medical traumatic stress was present in 14%, and 22% of children had received psychological help for trauma before. Lower gastrointestinal related quality of life was associated with more emotional problems, but not PN-duration.ConclusionsChildren with IF, particularly school-aged children, are at risk for psychological problems which is reflected by the high rate of received psychotherapy and the high rate of emotional problems and psychiatric classifications.

Project description:Acute liver failure (ALF) is a syndrome characterized by an intense systemic inflammatory response (SIRS) and multi-organ system failure (MOSF). Platelet-derived microparticles increase in proportion to the severity of the SIRS and MOSF, and are associated with poor outcome. We investigated whether patients with ALF develop thrombocytopenia in proportion to the SIRS, MOSF, and poor outcome.In a retrospective study, we collected data on the post-admission platelet counts of 1598 patients included in the ALF Study Group Registry from 1998 through October 2012. We investigated correlations between platelet counts and clinical features of ALF, laboratory test results, and outcomes. Of the patients studied, 752 (47%) survived without liver transplantation, 390 (24%) received liver transplants, and 517 (32%) died.In patients with SIRS, platelet counts decreased 2 to 7 days after admission, compared with patients without SIRS (P ? .001). Patients with abnormal levels of creatinine, phosphate, lactate, or bicarbonate had significantly lower platelet counts than patients with normal levels of these laboratory values (all P ? .001). The decrease in platelets during days 1 to 7 after admission was proportional to the grade of hepatic encephalopathy and requirement for vasopressor and renal replacement therapy. Although platelet numbers decreased after admission in the overall population, platelets were significantly lower 2 to 7 days after admission in patients with outcomes of death or liver transplantation than in patients who made spontaneous recoveries and survived. In contrast, international normalized ratios over time were not associated with SIRS, laboratory test results associated with poor outcomes, grade of hepatic encephalopathy, or requirement for renal replacement therapy.The development of thrombocytopenia in patients with ALF is associated with the development of MOSF and poor outcome. We speculate that SIRS-induced activation of platelets, yielding microparticles, results in clearance of platelet remnants and subsequent thrombocytopenia.

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

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

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