Ethanol misuse is frequently associated with a multitude of profound medical conditions, contributing to health-, individual- and social-related damage. A particularly dangerous threat from this classification is coined as alcoholic liver disease (ALD), a liver condition caused by prolonged alcohol overconsumption, involving several pathological stages induced by alcohol metabolic byproducts and sustained cellular intoxication. Molecular, pathological mechanisms of ALD principally root in the innate immunity system and are especially associated with enhanced functionality of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway. NF-κB is an interesting and convoluted DNA transcription regulator, promoting both anti-inflammatory and pro-inflammatory gene expression. Thus, the abundancy of studies in recent years underlines the importance of NF-κB in inflammatory responses and the mechanistic stimulation of inner molecular motifs within the factor components. Hereby, in the following review, we would like to put emphasis on the correlation between the NF-κB inflammation signaling pathway and ALD progression. We will provide the reader with the current knowledge regarding the chronic and acute alcohol consumption patterns, the molecular mechanisms of ALD development, the involvement of the NF-κB pathway and its enzymatic regulators. Therefore, we review various experimental in vitro and in vivo studies regarding the research on ALD, including the recent active compound treatments and the genetic modification approach. Furthermore, our investigation covers a few human studies.

Polytrauma and concomitant hemorrhagic shock can lead to intestinal damage and subsequent multiple organ dysfunction syndrome. The intestinal fatty acid-binding protein (I-FABP) is expressed in the intestine and appears quickly in the circulation after intestinal epithelial cell damage. This porcine animal study investigates the I-FABP dynamics in plasma and urine after polytrauma. Furthermore, it evaluates to what extent I-FABP can also act as a marker of intestinal damage in a porcine polytrauma model. Eight pigs (Sus scrofa) were subjected to polytrauma which consisted of lung contusion, tibial fracture, liver laceration, and hemorrhagic shock followed by blood and fluid resuscitation and fracture fixation with an external fixator. Eight sham animals were identically instrumented but not injured. Afterwards, intensive care treatment including mechanical ventilation for 72 h followed. I-FABP levels in blood and urine were determined by ELISA. In addition, immunohistological staining for I-FABP, active caspase-3 and myeloperoxidase were performed after 72 h. Plasma and urine I-FABP levels were significantly increased shortly after trauma. I-FABP expression in intestinal tissue showed significantly lower expression in polytraumatized animals vs. sham. Caspase-3 and myeloperoxidase expression in the immunohistological examination were significantly higher in the jejunum and ileum of polytraumatized animals compared to sham animals. This study confirms a loss of intestinal barrier after polytrauma which is indicated by increased I-FABP levels in plasma and urine as well as decreased I-FABP levels in immunohistological staining of the intestine.

Traumatic brain injury (TBI) may cause damage to distant organs. Acute ethanol intoxication (EI) induces complex local and systemic anti-inflammatory effects and influences the early outcomes of traumatized patients. Here, we evaluated its effects on the BI-induced expression of local inflammatory mediators in the trauma-remote organs the lungs and liver. Male mice were exposed to ethanol as a single oral dose (5g·kg^–1, 32%) before inducing a moderate blunt TBI. Sham groups underwent the same procedures without TBI. Ether 3 or 6h after the TBI, the lung and liver were collected. The gene expression of HMGB1, IL-6, MMP9, IL-1β, and TNF as well as the homogenate protein levels of receptor for advanced glycation end products (RAGE), IL-6, IL-1β, and IL-10 were analyzed. Liver samples were immunohistologically stained for HMGB1. EI decreased the gene expressions of the proinflammatory markers HMGB1, IL-6, and MMP9 in the liver upon TBI. In line with the reduced gene expression, the TBI-induced protein expression of IL-6 in liver tissue homogenates was significantly reduced by EI at 3h after TBI. While the histological HMGB1 expression was enhanced by TBI, the RAGE protein expression in the liver tissue homogenates was diminished after TBI. EI reduced the histological HMGB1 expression and enhanced the hepatic RAGE protein expression at 6h post TBI. With regard to the lungs, EI significantly reduced the gene expressions of HMGB1, IL-6, IL-1β, and TNF upon TBI, without significantly affecting the protein expression levels of inflammatory markers (RAGE, IL-6, IL-1β, and IL-10). At the early stage of TBI-induced inflammation, the gene expression of inflammatory mediators in both the lungs and liver is susceptible to ethanol-induced remote effects. Taken together, EI may alleviate the TBI-induced pro-inflammatory response in the trauma-distant organs, the lungs and liver, via the HMGB1-RAGE axis.

The incidence of cholangiocellular carcinoma (CCA) is rising worldwide. As there are no specific early symptoms or specific markers of CCA, it is often diagnosed in later inoperable stages. Accumulating evidence underlines the importance of radiation therapy in the induction of antitumor immunity. The surface protein composition on extracellular vesicles (EVs) relates to originating cells and thus may play a role in vesicle function. We assessed immune profiles of EVs and their immune origin in patients with inoperable CCA prior and after selective internal radiotherapy (SIRT). A total of 47 CCA patients receiving SIRT and 12 healthy volunteers (HV) were included. Blood was withdrawn before therapy (pre T) and after T. EVs were purified from plasma by cluster of differentiation (CD)9-, CD63-, and CD81-immunobead isolation. To detect differently abundant surface markers, dynamic range and EVs input quality were assessed. A total of 37 EVs surface markers were measured by flow cytometry and correlated either with the administered activity dose (MBq) or with the interval until death (month). EVs phenotyping identified lymphocytes, B cells, NK cells, platelets, endothelial cells, leukocyte activation, B cell activation, T and B cell adhesion markers, stem/progenitor cells, and antigen-presenting cells (APC) as EVs-parenteral cells. CD4 and CD8 significantly declined, while other markers significantly increased in CCA patients pre T vs. HV. Platelets-deriving EVs significantly decreased, normalizing to levels of HV but still significantly increasing vs. HV post SIRT. B cells-deriving EVs significantly increased pre T vs. HV, positively correlating with administered activity dose. MHCII and CD40 EVs significantly increased pre SIRT and negatively correlated with administered activity dose, while EVs from antigen presenting cells and CD49e pre SIRT positively correlated with survival time after therapy. Increased levels of CD24 and CD44 in cancer pre T were significantly decreased post T. Among the heterogeneity of EVs that was demonstrated, in particular, B cells-deriving, MHCII, and CD40 positive or APC-deriving EVs need to be further studied for their diagnostic or prognostic relevance in clinical scenarios.

Background. In several preclinical and in vitro models of acute inflammation, alcohol (ethanol, EtOH) has been described as an immunomodulatory agent. Similarly, in different pathologies, clinical observations have confirmed either pro- or anti-inflammatory effects of EtOH. The liver plays an important role in immunity and alcohol metabolism; therefore, we analysed dose- and time-dependent effects of EtOH on the inflammatory response of human liver cells in an in vitro model of acute inflammation. Methods. HepG2 cells were stimulated with IL-1β and subsequently exposed to EtOH in a low or high dose (85mM, LoD or 170mM, HiD) for 1h (acute exposure) or 72h (prolonged exposure). IL-6 and TNF-α release was determined by ELISA. Cell viability, adhesion of isolated neutrophils to HepG2 monolayers, their ICAM-1 expression, and the activation of stress-induced protein kinase/c-Jun N-terminal kinase (SAPK/JNK) or signal transducer and activator of transcription 3 (STAT3) were analysed. Results. In this experimental design, EtOH did not markedly change the cell viability. Acute and prolonged exposure to EtOH significantly reduced dose-independent IL-1β-induced IL-6 and TNF-α release, as well as adhesion capacity to pretreated HepG2 cells. Acute exposure to EtOH significantly decreased the percentage of ICAM-1-expressing cells. IL-1β stimulation notably increased the activation of SAPK/JNK. However, low-dose EtOH exposure reduced this activation considerably, in contradiction to high-dose EtOH exposure. Acute exposure to LoD EtOH significantly diminished the IL-1β-induced STAT3 activation, whereas an acute exposure of cells to either HiD EtOH or in a prolonged setting showed no effects on STAT3 activation. Conclusion. EtOH exerts anti-inflammatory potential in this in vitro model of hepatic inflammation. These effects are associated with the reduced activation of JNK/STAT3 by EtOH, particularly in the condition of acute exposure to low-dose EtOH.

Femoral fractures and severe bleeding frequently occur in old patients showing a delayed healing. As there are no studies investigating the combined effect of high age and severe blood loss on fracture healing, this was examined radiographically and biomechanically in this study. Therefore, young and old male mice were randomly assigned to three operation groups. In the fracture group (Fx), external fixator and osteotomy were applied to the femur. The combined trauma group (THFx) additionally received a pressure-controlled hemorrhage. Sham animals were only implanted with arterial catheter and external fixator. Sacrifice was performed after three weeks and bone healing was evaluated radiologically via µCT, as well as biomechanically using a three-point bending test. A decreased share of callus/total bone volume was observed in old mice with blood loss compared to old Fx. Hemorrhagic shock also reduced the trabecular number in old mice compared to Fx and young THFx. Moreover, a lower elastic limit in old Sham mice without fracture was revealed. Fracture combined with a high loss of blood further reduced the elastic limit in old mice compared to isolated Fx in old animals. In conclusion, this study showed that severe blood loss has a higher negative effect in old mice compared to young ones.