Thirty-eight-negative-kinase 1 (TNK1) is a major mediator of trauma induced intestinal injury and multi-organ failure
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE118023 | GEO | 2021/08/01
REPOSITORIES: GEO
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Project description: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.
| S-EPMC6205400 | biostudies-literature
Project description:Thirty-eight-negative-kinase 1 (TNK1) is a major mediator of trauma induced intestinal injury and multi-organ failure
| PRJNA484022 | ENA
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.
| S-EPMC7479097 | biostudies-literature
Project description:BACKGROUND: Both trauma-induced coagulopathy (TIC) and transfusion strategies influence early outcome in hemorrhagic trauma patients. Their impact on late outcome is less well characterized. This study systematically reviews risk factors for TIC- and transfusion-associated multiple organ failure (MOF) in severely injured trauma patients. MATERIALS AND METHODS: A systematic search was conducted in PubMed and Embase. Studies published from 1986 to 2013 on adult trauma patients with an injury severity score ?16, investigating TIC or transfusion strategies with MOF as primary or secondary outcome, were eligible for inclusion. Results of the included studies were evaluated with meta-analyses of pooled data. RESULTS: In total, 50 studies were included with a total sample size of 63,586 patients. Due to heterogeneity of the study populations and outcome measures, results from 7 studies allowed for pooling of data. Risk factors for TIC-associated MOF were hypocoagulopathy, hemorrhagic shock, activated protein C, increased histone levels, and increased levels of markers of fibrinolysis on admission. After at least 24?h after admission, the occurrence of thromboembolic events was associated with MOF. Risk factors for transfusion-associated MOF were the administration of fluids and red blood cell units within 24?h post-injury, the age of red blood cells (>14?days) and a ratio of FFP:RBC???1:1 (OR 1.11, 95% CI 1.04-1.19). CONCLUSION: Risk factors for TIC-associated MOF in severely injured trauma patients are early hypocoagulopathy and hemorrhagic shock, while a hypercoagulable state with the occurrence of thromboembolic events later in the course of trauma predisposes to MOF. Risk factors for transfusion-associated MOF include administration of crystalloids and red blood cells and a prolonged storage time of red blood cells. Future prospective studies investigating TIC- and transfusion-associated risk factors on late outcome are required.
| S-EPMC4408845 | biostudies-other
Project description:ObjectivesSmoking is declining, but it is unevenly distributed among population groups. Our aim was to examine the socio-economic differences in smoking during 1978-2016 in Finland, a country with a history of strict tobacco control policy.MethodsAnnual population-based random sample data of 25-64-year-olds from 1978 to 2016 (N = 104,315) were used. Response rate varied between 84 and 40%. In addition to logistic regression analysis, absolute and relative educational differences in smoking were examined.ResultsSmoking was more prevalent among the less educated but declined in all educational groups during the study period. Both absolute and relative differences in smoking between the less and highly educated were larger at the end of the study period than at the beginning. Cigarette price seemed to have a larger effect on the smoking among the less educated.ConclusionsSocio-economic differences in smoking among the Finnish adult population have increased since the 1970s until 2016. Further actions are needed, especially focusing on lower socio-economic positions, to tackle inequalities in health. They should include support for smoking cessation and larger cigarette tax increases.
| S-EPMC6614163 | biostudies-literature
Project description:Percutaneous absorption is highly variable between chemicals but also within chemicals depending on exposure conditions and experimental set up. We tested a larger number of organic solvents with the same experimental set up, using skin from new-born piglets and static diffusion cells. Thirty-six common organic solvents were studied neat (and 31 of them also in water dilution): acetone, acetonitrile, n-butanol 2-butanone 2-butoxyethanol, 1-butoxy-2-propanol, n-butyl acetate, butyl acrylate, cyclohexane, cyclohexanone, 1,2-dichloroethane, dichloromethane, ethanol, 2-ethoxyethanol, ethyl acetate, ethyl acrylate, ethylbenzene, furfuryl alcohol, n-hexane, 2-hexanone, 2-isopropoxyethanol, methanol, 1-methoxy-2-propanol, methyl acrylate, 3-methyl-1-butanol, methyl tertiary butyl ether, 4-metyl-2-pentanol, methyl methacrylate, 2-propanol, 2-propen-1-ol, 2-propoxyethanol, 1-propoxy-2-propanol, styrene, trichloromethane, toluene and m-xylene. In addition, a mixture of 2-methylbutyl acetate and n-pentyl acetate was tested. For most of the solvents, little or no percutaneous absorption data have been published. Lag times, steady-state fluxes and apparent permeability coefficients were obtained from the time courses of solvent appearance in the receptor medium, as measured by gas chromatography. The use of the same methodology and kind of skin resulted in small variability within experiments, underlining the need for consistent methodology for useful results for developing predictive models. Furthermore, a comparison of the neat and diluted data shows that water dilution affects all these variables and that the direction and magnitude of the effects vary between chemicals. This comparison strongly supports that prediction of percutaneous absorption of neat and water diluted chemicals requires different models.
| S-EPMC6209206 | biostudies-literature
Project description:RNAseq of chronic lymphocytic leukaemia (CLL) subsets comprising of Unmutated CLL and Mutated CLL. Mutated CLL cases were further subdivided based on B cell receptor signalling capacity.
2023-05-11 | E-MTAB-12023 | biostudies-arrayexpress
Project description:BackgroundThe nature of multiple organ dysfunction syndrome (MODS) after traumatic injury is evolving as resuscitation practices advance and more patients survive their injuries to reach critical care. The aim of this study was to characterize contemporary MODS subtypes in trauma critical care at a population level.MethodsAdult patients admitted to major trauma centre critical care units were enrolled in this 4-week point-prevalence study. MODS was defined by a daily total Sequential Organ Failure Assessment (SOFA) score of more than 5. Hierarchical clustering of SOFA scores over time was used to identify MODS subtypes.ResultsSome 440 patients were enrolled, of whom 245 (55·7 per cent) developed MODS. MODS carried a high mortality rate (22·0 per cent versus 0·5 per cent in those without MODS; P < 0·001) and 24·0 per cent of deaths occurred within the first 48 h after injury. Three patterns of MODS were identified, all present on admission. Cluster 1 MODS resolved early with a median time to recovery of 4 days and a mortality rate of 14·4 per cent. Cluster 2 had a delayed recovery (median 13 days) and a mortality rate of 35 per cent. Cluster 3 had a prolonged recovery (median 25 days) and high associated mortality rate of 46 per cent. Multivariable analysis revealed distinct clinical associations for each form of MODS; 24-hour crystalloid administration was associated strongly with cluster 1 (P = 0·009), traumatic brain injury with cluster 2 (P = 0·002) and admission shock severity with cluster 3 (P = 0·003).ConclusionContemporary MODS has at least three distinct types based on patterns of severity and recovery. Further characterization of MODS subtypes and their underlying pathophysiology may lead to future opportunities for early stratification and targeted interventions.
| S-EPMC7078999 | biostudies-literature
Project description:BACKGROUND/AIM:Multiple organ dysfunction syndrome (MODS) is the leading cause of late posttraumatic mortality. This study analyzed the prognostic values of osteoprotegerin (OPG) and neutrophil gelatinase-associated lipocalin (NGAL/lipocalin 2) compared to interleukin-6 (IL-6) in multiply injured patients. PATIENTS AND METHODS:A retrospective observational cohort study on multiply injured patients with an injury severity score (ISS) of ≥16 was performed. OPG, NGAL and IL-6 blood concentrations were measured. Statistical analysis comprised receiver-operating-characteristic (ROC) analysis with the corresponding area under the curve (AUC). RESULTS:Thirty-nine patients with a mean ISS of 34±11 were included. Fourteen patients (36%) developed MODS and 8 patients (21%) died. Plasma levels of NGAL, OPG, and IL-6 were significantly elevated in the MODS+ group. Each biomarker positively correlated with MODS score and diagnosis of MODS. CONCLUSION:NGAL and OPG might be indicative of MODS and could have the potential to be biomarkers in the early detection of patients at risk of posttraumatic MODS.
| S-EPMC6754992 | biostudies-other
Project description:DNA methylation arrays of chronic lymphocytic leukaemia (CLL) subsets comprising of Unmutated CLL and Mutated CLL. Mutated CLL cases were further subdivided based on B cell receptor signalling capacity.
2023-05-11 | E-MTAB-12018 | biostudies-arrayexpress