This review aims to briefly discuss a short list of a broad variety of inflammatory cytokines. Numerous studies have implicated that inflammatory cytokines exert important effects with regard to various inflammatory diseases, yet the reports on their specific roles are not always consistent. They can be used as biomarkers to indicate or monitor disease or its progress, and also may serve as clinically applicable parameters for therapies. Yet, their precise role is not always clearly defined. Thus, in this review, we focus on the existing literature dealing with the biology of cytokines interleukin (IL)-6, IL-1, IL-33, tumor necrosis factor-alpha (TNF-α), IL-10, and IL-8. We will briefly focus on the correlations and role of these inflammatory mediators in the genesis of inflammatory impacts (e.g., shock, trauma, immune dysregulation, osteoporosis, and/or critical illness).

The Masquelet induced membrane technique for reconstructing large diaphyseal defects has been shown to be a promising clinical treatment, yet relatively little is known about the cellular, histological and biochemical make-up of these membranes and how they produce this positive clinical outcome. We compared cellular make-up, histological changes and growth factor expression in membranes induced around femur bone defects and in subcutaneous pockets at 2, 4 and 6 weeks after induction, and to the periosteum. We found that membranes formed around bone defects were similar to those formed in subcutaneous pockets; however, both were significantly different from periosteum with regard to structural characteristics, location of blood vessels and overall thickness. Membranes induced at the femur defect (at 2 weeks) and in periosteum contain mesenchymal stem cells (MSCs; STRO-1 ) which were not found in membranes induced subcutaneously. BMP-2, TGFβ and VEGF were significantly elevated in membranes induced around femur defects in comparison to subcutaneously induced membranes, whereas SDF-1 was not detectable in membranes induced at either site. We found that osteogenic and neovascular activity had mostly subsided by 6 weeks in membranes formed at both sites. It was conclude that cellular composition and growth factor content in induced membranes depends on the location where the membrane is induced and differs from periosteum. Osteogenic and neovascular activity in the membranes is maximal between 2 and 4 weeks and subsides after 6. Based on this, better and quicker bone healing might be achieved if the PMMA cement were replaced with a bone graft earlier in the Masquelet technique. Copyright © 2013 John Wiley & Sons, Ltd.

The mechanisms leading to prostate cancer metastasis are not understood completely. Although there is evidence that the CXC chemokine receptor (CXCR) 4 and its ligand CXCL12 may regulate tumor dissemination, their role in prostate cancer is controversial. We examined CXCR4 expression and functionality, and explored CXCL12-triggered adhesion of prostate tumor cells to human endothelium or to extracellular matrix proteins laminin, collagen, and fibronectin. Although little CXCR4 was expressed on LNCaP and DU-145 prostate tumor cells, CXCR4 was still active, enabling the cells to migrate toward a CXCL12 gradient. CXCL12 induced elevated adhesion to the endothelial cell monolayer and to immobilized fibronectin, laminin, and collagen. Anti-CXCR4 antibodies or CXCR4 knock out significantly impaired CXCL12-triggered tumor cell binding. The effects observed did not depend on CXCR4 surface expression level. Rather, CXCR4-mediated adhesion was established by alpha5 and beta3 integrin subunits and took place in the presence of reduced p38 and p38 phosphorylation. These data show that chemoattractive mechanisms are involved in adhesion processes of prostate cancer cells, and that binding of CXCL12 to its receptor leads to enhanced expression of alpha5 and beta3 integrins. The findings provide a link between chemokine receptor expression and integrin-triggered tumor dissemination.

In 1994, the "danger model" argued that adaptive immune responses are driven rather by molecules released upon tissue damage than by the recognition of "strange" molecules. Thus, an alternative to the "self versus non-self recognition model" has been provided. The model, which suggests that the immune system discriminates dangerous from safe molecules, has established the basis for the future designation of damage-associated molecular patterns (DAMPs), a term that was coined by Walter G. Land, Seong, and Matzinger. The pathological importance of DAMPs is barely somewhere else evident as in the posttraumatic or post-surgical inflammation and regeneration. Since DAMPs have been identified to trigger specific immune responses and inflammation, which is not necessarily detrimental but also regenerative, it still remains difficult to describe their "friend or foe" role in the posttraumatic immunogenicity and healing process. DAMPs can be used as biomarkers to indicate and/or to monitor a disease or injury severity, but they also may serve as clinically applicable parameters for optimized indication of the timing for, i.e., secondary surgeries. While experimental studies allow the detection of these biomarkers on different levels including cellular, tissue, and circulatory milieu, this is not always easily transferable to the human situation. Thus, in this review, we focus on the recent literature dealing with the pathophysiological importance of DAMPs after traumatic injury. Since dysregulated inflammation in traumatized patients always implies disturbed resolution of inflammation, so-called model of suppressing/inhibiting inducible DAMPs (SAMPs) will be very briefly introduced. Thus, an update on this topic in the field of trauma will be provided.

Chest trauma has a significant relevance on outcome after severe trauma. Clinically, impaired lung function typically occurs within 72 hours after trauma. However, the underlying pathophysiological mechanisms are still not fully elucidated. Therefore, we aimed to establish an experimental long-term model to investigate physiological, morphologic and inflammatory changes, after severe trauma. Male pigs (sus scrofa) sustained severe trauma (including unilateral chest trauma, femur fracture, liver laceration and hemorrhagic shock). Additionally, non-injured animals served as sham controls. Chest trauma resulted in severe lung damage on both CT and histological analyses. Furthermore, severe inflammation with a systemic increase of IL-6 (p = 0.0305) and a local increase of IL-8 in BAL (p = 0.0009) was observed. The pO2/FiO2 ratio in trauma animals decreased over the observation period (p < 0.0001) but not in the sham group (p = 0.2967). Electrical Impedance Tomography (EIT) revealed differences between the traumatized and healthy lung (p < 0.0001). In conclusion, a clinically relevant, long-term model of blunt chest trauma with concomitant injuries has been developed. This reproducible model allows to examine local and systemic consequences of trauma and is valid for investigation of potential diagnostic or therapeutic options. In this context, EIT might represent a radiation-free method for bedside diagnostics.

BACKGROUND AND PURPOSEHaemorrhagic shock and resuscitation (H/R) induces hepatic injury, strong inflammatory changes and death. Alcohol intoxication is assumed to worsen pathophysiological derangements after H/R. Here, we studied the effects of acute alcohol intoxication on survival, liver injury and inflammation after H/R, in rats. EXPERIMENTAL APPROACHRats were given a single oral dose of ethanol (5 g·kg -1 , 30%) or saline (control), 12 h before they were haemorrhaged for 60 min and resuscitated (H/R). Sham groups received the same procedures without H/R. Measurements were made 2, 24 and 72 h after resuscitation. Survival was assessed 72 h after H/R. KEY RESULTSEthanol increased survival after H/R three-fold and also induced fatty changes in the liver. H/R-induced liver injury was amplified by ethanol at 2 h but inhibited 24 h after H/R. Elevated serum IL-6 levels as well as hepatic IL-6 and TNF-a gene expression 2 h after H/R were reduced by ethanol. Ethanol enhanced serum IL-1b at 2 h, but did not affect increased hepatic IL-1b expression at 72 h after H/R. Local inflammatory markers, hepatic infiltration with polymorphonuclear leukocytes and intercellular adhesion molecule 1 expression decreased after ethanol compared with saline, following H/R. Ethanol reduced H/R-induced IkBa activation 2 h after H/R, and NF-kB-dependent gene expression of MMP9. CONCLUSIONS AND IMPLICATIONSEthanol reduced H/R-induced mortality at 72 h, accompanied by a suppression of proinflammatory changes after H/R in ethanol-treated animals. Binge-like ethanol exposure modulated the inflammatory response after H/R, an effect that was associated with NF-kB activity. AbbreviationsALT, alanine aminotransferase; BAC, blood alcohol concentrations; H/R:, haemorrhagic shock and resuscitation; ICAM-1, intercellular adhesion molecule 1; MODS, multiple organ dysfunction syndrome; MOF, multiple organ failure; PMNL, polymorphonuclear leukocytes IntroductionAlcohol consumption is associated with one-third of all traumatic injury deaths each year (Li et al., 1997;Rehm et al., 2003). Almost 50% of trauma victims have positive blood alcohol concentrations (BACs), among them 35% with a BAC greater than 1 mg·mL -1 (Reyna et al., 1985;Rivara et al., 1993;Madan et al., 1999;Hadfield et al., 2001). Alcohol-intoxicated BJP British Journal of Pharmacology DOI:10.1111DOI:10. /j.1476DOI:10. -5381.2011 1188 British Journal of Pharmacology (2012) 165 1188-1199The Authors British Journal of Pharmacology © 2011 The British Pharmacological Society trauma victims have an increased risk for subsequent complications such as pneumonia, sepsis or multiple organ failure (MOF); some studies report a greater morbidity and mortality in these patients (Faunce et al., 1997;Bagby et al., 1998;Ruiz et al., 1999;Boe et al., 2001;Messingham et al., 2002;Zhang et al., 2002). Other studies report divergent results showing that acute alcohol intoxication does not affect the outcome and is even associated with decreased 24 h mortality after trauma (own unpublished data). The source ...

Hepatocellular carcinoma (HCC) is one of major health concerns worldwide and one of leading causes of cancer death after lung and gastric cancers. Simvastatin is a cholesterol-lowering drug which inhibits 3-hydroxy-3-methylglutarylcoenzyme CoA (HMG-CoA) reductase. Simvastatin exhibits numerous pleiotropic effects including anti-cancer activity. Yet, the anticancer effects in HCC remain poorly characterized. Therefore, in this study, we investigated the effects of simvastatin on tumor cell growth, apoptosis and cell cycle. HepG2 and Huh7 cell lines were treated with simvastatin (32 and 64 µM) for different time periods. Tumor cell growth was assessed using MTT assay. Apoptosis and cell cycle analysis were also evaluated. Analysis of cell cycle proteins involved in simvastatin-induced manipulation was performed by Western blot and quantitative RT-PCR analyses. Simvastatin induced a reduction of tumor cell growth. In both cell lines, simvastatin induced apoptosis and impaired cell cycle progression as depicted by the greater rates of G0/G1-phase cells than the rates of S-phase cells. Protein expression levels of cell cycle regulating proteins CDK1, CDK2, CDK4, cyclin D1, cyclin E, p19 and p27 were markedly altered by simvastatin. Moreover, CDC2, CCND1 and CDCN2D mRNA expressions were also altered by drug treatment. Collectively, these results suggest that simvastatin induces apoptosis in tumor cells and its anti-proliferative activity was accompanied by inhibition of cyclin-dependent kinases and cyclins, whereas CDK inhibitors p19 and p27 were enhanced. These results may provide novel insights into simvastatin tumor-suppressive action.

This review summarizes a short list of currently discussed trauma-induced danger-associated molecular patterns (DAMP). Due to the bivalent character and often pleiotropic effects of a DAMP, it is difficult to describe its “friend or foe” role in post-traumatic inflammation and regeneration, both systemically as well locally in tissues. DAMP can be used as biomarkers to indicate or monitor disease or injury severity, but also may serve as clinically applicable parameters for better indication and timing of surgery. Due to the inflammatory processes at the local tissue level or the systemic level, the precise role of DAMP is not always clear to define. While in vitro and experimental studies allow for the detection of these biomarkers at the different levels of an organism—cellular, tissue, circulation—this is not always easily transferable to the human setting. Increased knowledge exploring the dual role of DAMP after trauma, and concentrating on their nuclear functions, transcriptional targets, release mechanisms, cellular sources, multiple functions, their interactions and potential therapeutic targeting is warranted.