Month: July 2020

NKT-cell-deficient mice were protected from acute toxic liver injury, in well agreement with our previous and the current study. Possibly, these data might indicate that hepatic NKT cells are especially relevant in Th1 prone inflammatory conditions. Taken together, our study provides experimental evidence that targeting the chemokine CXCL16 is a promising strategy in fatty liver diseases. The extent of hepatic inflammation, macrophage activation and steatosis Staurosporine development in experimental metabolic injury. Future studies should address the optimal dose and administration schedule and should aim at translating these findings into novel approaches for human NAFLD. Despite advances in critical care, systemic inflammatory response syndrome and sepsis syndrome with subsequent multi-organ failure still contribute to overall mortality in critically ill patients, equalling the number of deaths caused by acute myocardial infarction. Besides specific treatment of the underlying cause of systemic inflammation, early diagnosis based on clinical findings and laboratory testing is of paramount importance to enable successful therapy. The kinetics of biomarkers reflecting changes in the inflammatory condition can be helpful to identify patients at high risk for complications. At present, procalcitonin is regarded as the best available laboratory tool for the diagnosis of infection and systemic inflammation in combination with clinical symptoms and has been introduced as a variable in the diagnostic criteria for sepsis in the recently updated Surviving Sepsis Campaign guidelines. PCT has the advantage of an earlier peak level upon infection, a better specificity and correlation to disease severity and clinical outcome as compared to routine biomarkers such as white blood cell count or C-reactive protein. Activation of acid sphingomyelinase, a C-type phosphodiesterase leads to generation of ceramide from biological inert sphingomyelin derived from the cell membrane. Generation of ceramide at the outer leaflet of cell membranes induces changes in composition and spatial arrangement in terms of forming ceramide-enriched membrane lipid rafts, leading to receptor clustering and apoptosis signalling and modification of the cellular response to stress stimuli. Clinical data concerning the potential role of acid sphingomyelinase serum activity is infrequent. In a retrospective study of 12 patients with severe sepsis, Claus et al. showed that elevated ASM levels can be observed after the onset of sepsis, and that a further increase may be associated with worse outcome. On the other hand, recent animal studies suggest a protective role of ASM secretion during the early host response as a first line of defence. Due to its pathophysiological properties in the early host response, determination of ASM may also be used as an early diagnostic marker before the onset of systemic inflammation. The aim of our pilot study was to evaluate the role of ASM in a mixed intensive care unit population at risk for the development of systemic inflammation.

Where a clinically reliable discrimination between survivors and nonsurvivors can be derived. Other pro- and anti-inflammatory cytokines like Interleukin IL-8, IL-6, IL-1b, or Tumor necrosis factor-a were shown to hold similar AUC. Thus, it is most likely that the one particular biomarker for predicting outcome of patients with systemic inflammation may not exist due to the complexity of the immune response. One may speculate that ASM increases as a result of inflammation, as various inflammatory stimuli lead to activation of ASM mediated lipid signalling, including oxidative stress, induction by or of cytokines, platelet activating-factor -mediated pulmonary oedema formation during acute lung injury and ceramide accumulation in ischemia/reperfusion injury in mitochondria. Due to the various pathophysiological properties of ASM in mediation of inflammation and apoptosis, we may also speculate that non-declining or continuously increased ASM in critically ill patients with systemic inflammation plays a putative causative role with respect to adverse outcome. Our study has some limitations which have to be mentioned. The main limitation is the low number of patients included and that it was conducted as a single FDA-approved Compound Library inhibitor center study. Therefore, our results should be interpreted with caution as there is a high likelihood of a type II error. However, this study should be regarded in the context of a single center, pilot study aiming to gain more insight into the clinical usefulness of ASM kinetics in the course of systemic inflammation. A further limitation is that we did not perform consecutive ASM measurements in the ICU patients without systemic inflammation. This was due to financial restraints of this pilot study. Measurements of ASM are not yet comparable with established laboratory for PCT or CRP that are easier and cheaper to conduct. It is also likely that the time interval at which ASM was measured did not accurately capture an early change in ASM kinetics. Future studies on ASM kinetics may address this potential limitation choosing an even closer measurement interval. Lastly, the potential of using ASM as a prognostic marker after systemic inflammation in clinical practice warrants further improvement of the assay to become more widely available. Conclusions Our study showed that patients who underwent uncomplicated surgery exhibited a significant post-operative increase in ASM. In a mixed ICU population, ASM was significantly higher compared to these patients. While ASM did not indicate the onset of systemic inflammation earlier than PCT in our group of patients, it was able to predict ICU mortality in patients after systemic inflammation in the presence of low PCT level. ASM may hold potential as a tool for risk stratification of these patients, but the clinical value has to be further evaluated in larger studies. SPIDIA is a European Commission funded, four-year, integrated project aimed at the standardization and improvement of preanalytical procedures for in vitro diagnostics.

In contrast, mice that received hMSC treatment showed decreased lesion size, which is associated with decreased astrocyte and microglia activation. In agreement with these results, we described in a recent paper that MSC treatment resolves the glial scar as Iba1 and GFAP Bortezomib Proteasome inhibitor positive fluorescence significantly decreases over time, returning to sham level at 18 days following treatment. Reactive astrocytes contribute to a process called glial scar formation, which forms a physical and chemical barrier that prevents inflammation from spreading through the tissue, thus restricting the progression of the injury. However, a downside of scar formation is that it also inhibits growth cone motility, thereby impairing axon regeneration. This may be one of the reasons underlying impaired neurogenesis following a HI insult in the neonatal brain. Hence, our data suggest that hMSCinduced reduction in astrocyte activation is crucial for repair of the lesion after HI brain damage. The decrease in astrocyte and microglia activity may be mediated by anti-inflammatory cytokines secreted by the hMSCs. We and others have previously shown that MSCs secrete IL-10, which is known to suppress the pro-inflammatory phenotype of both microglia and astrocytes. Interestingly, the effect of MSCs on GFAP positive cells is apparently restricted to reactive astrocytes involved in astrogliosis, as GFAP expression can still be observed in the hippocampus following repair and the staining strongly resembles the hippocampus of sham-operated animals. Future studies should focus on the mechanisms underlying MSC-mediated reduction of astrocytic scar in brain lesions, which may be crucial in promoting a proneurogenic microenvironment that supports tissue repair. Besides showing the potential of hMSCs to repair the HI injured brain, we also provide new insight into factors that may be involved in MSC migration from the nose to the injury site. Our results show that expression of the integrin beta 2 protein is upregulated at 10 days after HI. Itgb-2 together with the Intercellular Adhesion Molecule 1 mediates the migration of leukocytes along endothelial cells and may be involved in the migration of MSCs through blood vessels and regulate transmigration into the brain tissue. The results from the PCR array show that CXCL10 is the chemotactic factor with the highest fold change at 10 days following HI. Interestingly, at 17 days after HI, the expression level of this chemokine has returned to sham level. We also show that the expression of the CXCL10 receptor, CXCR3, increases following co-culture of hMSCs with brain extract from 10 days after HI. Together these results suggest that CXCL10 may play an important role in regulating homing of MSCs to the lesion site. We also found that Ccl5 significantly decreases at 17 days following HI, which also suggests a role for this chemokine in MSC homing to lesion.

Thereby emerging as potential attractive targets for future therapeutic approaches. Work from our laboratory has recently identified a yet unrecognized pathway promoting inflammation in experimental steatohepatitis in mice. Using mice either deficient for the chemokine receptor CXCR6 or transgenic for a fluorescent protein in one of the CXCR6 alleles, the accumulation of natural killer T cells was identified as a rapid response to hepatocyte injury. Cxcr62/2 mice lacking type-I NKT cells were protected against acute- and chronic liver failure in two independent models of liver fibrosis, showed significantly attenuated hepatic inflammation and reduced levels of pro-inflammatory cytokines like tumor necrosis factor, monocyte chemoattractant protein-1 and interferon-c. The adoptive transfer of wildtype NKT cells into Cxcr6-deficient mice in a model of steatohepatitis restored inflammation and liver fibrosis. Our experimental data indicated that hepatic NKT cells specifically utilize its receptor CXCR6 for the rapid accumulation in injured livers, where they produce and release cytokines like interleukin 4 and IFNc that act on macrophages and possibly other hepatic cell compartments to initiate and perpetuate inflammation. We thus reasoned that inhibiting the cognate ligand for CXCR6, CXCL16, might hold therapeutic potential in steatohepatitis. Whereas in human inflamed livers CXCR6 is expressed by CD4 as well as CD8 T cells, NK cells and NKT cells the chemokine CXCL16 exists in a soluble and transmembrane form and is expressed by liver sinusoids, possibly allowing NKT cells to patrol hepatic vessels. CXCL16 is also expressed by hepatic macrophages, likely favoring interactions between NKT and Kupffer cells. Importantly, CXCL16 expression is up-regulated in acute or chronic liver injury in mice, but also in chronic liver diseases in humans. In this study, we investigated the pharmacological inhibition of CXCL16 using a monoclonal antibody as a novel therapeutic approach in experimental steatohepatitis in mice. Non-alcoholic fatty liver disease is a raising health burden in Western countries, which affect about 30% of the general adult population, is associated with an increased mortality and promote several medical complications like hepatocarcinogenesis in humans. Within the liver, hepatocyte apoptosis, ER stress and oxidative stress are key contributors to hepatocellular injury. Moreover, lipotoxic mediators and danger signals activate the hepatic macrophage pool, mainly Kupffer cells, which are critical for the initiation and perpetuation of the inflammatory response and release several inflammatory mediators. Such mediators, mainly cytokines and chemokines, attract inflammatory cells and activate parenchymal as well as non-parenchymal liver cells during NAFLD progression. In our study, we provide experimental Reversine evidence that interfering with the CXCR6-CXCL16 pathway might hold therapeutic potential in NAFLD. The administration of an anti-CXCL16 antibody blocked the rapid accumulation of patrolling hepatic NKT cells.

We studied the prevalence of high blood ASP1517 pressure in a longitudinal cohort study of children with NAFLD from pediatric centers across the United States. Children with NAFLD had a high rate of high blood pressure both at baseline and again at 48 weeks. The odds of having high blood pressure at baseline and high blood pressure that persisted at 48 weeks were associated with BMI, LDL-cholesterol and uric acid. Hepatic steatosis was associated with high blood pressure at baseline. The rates of high blood pressure in children with NAFLD exceeded what would be expected based upon the contribution of obesity alone. Population-based cohort studies estimate the prevalence of high blood pressure in obese, Although most children with NAFLD are overweight or obese, our finding that more than one of every three children with NAFLD had high blood pressure at baseline indicates that children with NAFLD are at particularly increased risk for high blood pressure. A previous single center study in overweight and obese children with biopsy-confirmed NAFLD demonstrated that mean systolic and diastolic blood pressure were significantly higher compared to overweight and obese controls without evidence of NAFLD. Similarly, studies in children have shown that hepatic steatosis, independent of degree of obesity, is associated with cardiac dysfunction., Notably, in our cohort, children with NAFLD who had high blood pressure at baseline had higher degrees of hepatic steatosis. Data are extremely limited on the persistence of high blood pressure in children. In our study, the prevalence of 21.4% for persistent high blood pressure over 48 weeks in children with NAFLD was much higher than reported for other groups of children with longitudinal data available. For example, in the National Heart, Lung, and Blood Institute Growth and Health Study, the rate of persistent high blood pressure over 18 months in girls was 0.6% overall and 3% in obese girls. NAFLD and high blood pressure share pathophysiologic factors such as systemic oxidative stress and vascular and adipose tissue inflammation, which can produce vascular endothelial dysfunction. In the setting of hepatic steatosis, liver endothelial dysfunction can occur even prior to development of hepatic inflammation and fibrosis. While it is not yet clear whether hypertension is a cause or consequence of endothelial dysfunction, exogenous infusion of endothelium-derived nitric oxide synthase inhibitors can produce hypertension in humans. Our finding that elevated serum levels of LDL-cholesterol and uric acid were associated with increased odds for both baseline and persistent high blood pressure in this cohort also supports a possible role for underlying endothelial dysfunction. High levels of LDL cholesterol have been shown to alter the activity of endothelial-derived nitric oxide synthase. Oxidized LDL is also associated with endothelial dysfunction and activation of the renin-angiotensin system., Likewise, elevated uric acid has been functionally linked to decreased endothelial nitric oxide synthase activity and nitric oxide production and in turn endothelial dysfunction.