Репозиторий Университета

© 2018 Elsevier Ltd An excessive inflammatory response is frequently associated with cellular dysfunction and cell death. The latter may cause single and multiple organ failure. The most susceptible organs are liver, lung, kidney, heart and intestine. This review will focus on the liver as a target organ for an excessive inflammatory response. It is commonly accepted that organ failure is caused by the action of inflammatory cytokines released in excess during the inflammatory response. It has been suggested that inflammation mediated liver failure is not due to an increased death rate of parenchymal cells, but due to an intracellular metabolic disorder. This metabolic disorder is associated with mitochondrial and endoplasmic reticulum (ER) dysfunction during the acute phase response elicited by systemic inflammation. An overproduction of acute phase proteins in the liver as well as elevated reactive oxygen species (ROS) generation induce ER stress, triggering the unfolded protein response (UPR), which may initiate or aggravate inflammation. It is known that certain inflammatory mediators, such as the pro-inflammatory cytokines IL-1β, IL-6 and TNF-α induce ER stress. These findings suggest that ER stress and the subsequent UPR on the one hand, and the inflammatory response on the other create a kind of feed forward loop, which can be either beneficial (e.g., elimination of the pathogen and restoration of tissue homeostasis) or deleterious (e.g., excessive cell dysfunction and cell death). This review aims to unfurl the different pathways contributing to this loop and to highlight the relevance of UPR signaling (IRE1α, ATF6, and PERK) and mediators of the inflammatory response (NF-κB, STAT3, IL-1β, IL-6, TLR) which have a particular role as pathophysiological triggers in the liver.

© 2018 Media Sphera Publishing Group. All rights reserved. Aim. To perform a comparative analysis of anemia of chronic disease (ACD) and iron-deficiency anemia (IDA) in late middle-aged and elderly patients with chronic heart failure (CHF) by ferrokinetic parameters, inflammation indexes, and their associations. Materials and methods. 65 patients with ischemic heart disease were evaluated, including 35 patients with CHF and ACD, 10 patients with CHF and IDA, and 20 patients without CHF, ACD, and IDA (control group, CG). Results. Patients with CHF and IDA had true iron deficiency whereas 54% of patients with CHF and ACD had functional iron deficiency, and 46% of patients had no iron deficiency. Levels of acute phase proteins, ferritin and hepcidin, C-reactive protein (CRP), and interIeukin-6 (IL-6) were highly sig-nificantly different in patients with CHF and ACD and patients with CHF and IDA; positive and significant correlations were found for levels of IL-6 and ferritin, IL-6 and CRP, and CRP and hepcidin. In patients with CHF and IDA, levels of acute phase proteins, ferritin and hepcidin, CRP, and IL-6 were low and correlations of IL-6 with ferritin, IL-6 with CRP, and CRP with hepcidin were non-significant. Concentrations of erythropoietin were significantly higher in patients with CHF and ACD and patients with CHF and IDA compared to the control group; however, significant differences between them were absent.

© 2018 Ima-Press Publishing House. All rights reserved.  The clinical efficacy and safety of interleukin-6 (IL-6) receptor blockade have been well studied, but the data on the impact of therapeutic inhibition of IL-6 on B cells are scarce and contradictory. Preliminary reports have shown that B cell function and a humoral immune response may be modulated by an IL-6 receptor inhibitor. Objective: to assess the effect of 12-month tocilizumab (TCZ) therapy on B-cell phenotype and gene expression in RA and to analyze the association between B-cell subsets and RA activity. Subjects and methods. Examinations were made in 24 active RA patients (20 women and 4 men) (median age, 55 [49; 64] years; disease duration, 72 [24; 108] months; DAS28 5.8 [5.3; 6.3]; the patients were seropositive for rheumatoid factor (RF) (100%) and for anti-cyclic citrullinated peptide antibodies (87.3%). The patients received TCZ 8 mg/kg every 4 weeks. After 12 months of therapy, 54% of patients were categorized as good responders, 46% as moderate responders according to the EULAR response criteria. A control group consisted of 29 volunteers (21 women and 8 men; median age, 58.5 [53.0; 62.0] years). Peripheral blood lymphocytes were immunophenotyped at the time of enrollment and after 12 months. The absolute and relative counts of CD19+B lymphocytes, memory B cells (CD19+CD27+), non-switched memory B cells (CD19+IgD+CD27+), switched memory B cells (CD19+IgDCD27+), naive (CD19+IgD+CD27-), double-negative (CD19+IgD-CD27-), transitional (CD19+IgD+CD10+CD38++CD27) B cells, plasma cells (CD19+CD38+), and plasmablasts (CD19+CD38+++IgD-CD27+CD20-) were estimated using multicolor flow cytometry. Results and discussion. The relative and absolute counts of memory B cells (CD19+CD27+) (1.3 [0.9; 1.7]%, 0015 [0.001; 0.003]•10 9 /l), switched memory B cells (CD19+IgD-CD27+) (6.8 [3.6; 11.6]%, 0.01 [0.005; 0.02]•10 9 /l), and the absolute number of transitional B cells (CD19+CD38++CD10+IgD+CD27-) (0.00009 [0; 0.00028]•10 9 /l) were found to be lower in RA patients than in donors: 2.2 [1.1; 3.0]%, 0.003 [0.001; 0.007]•10 9 /l; 12.8 [9.3; 17.0]%, 0.02 [0.01; 0.04]•10 9 /l; 0.0001 [0; 0.0003]•10 9 /l, respectively (p<0.05 for all cases). After 12 months of TCZ therapy initiation, there were decreases in the relative and absolute counts of plasmablasts (CD19+CD38+++CD27+IgD-CD20-) from 0.15 [0.1; 0.3] to 0.1 [0.01; 0.1]% and from 0.0003 [0.00007; 0.004]•10 9 /l to 0.0001 [0; 0.0003]•10 9 /l, respectively (p<0.05). At the same time, the relative and absolute counts of memory B cells (CD19+CD27+) and switched memory B cells (CD19+CD27+IgD-) remained lower in RA patients than in donors: 1.0 [0.7; 1.2] and 2.2 [1.1; 3.0]%; 0.001 [0.006; 0.003]•10 9 /l and 0.003 [0.001; 0.007]•10 9 /l; 3.1 [1.1; 4.2] and 12.8 [9.3; 17.0]%; 0.003 [0.002; 0.006]•10 9 /l and 0.02 [0.01; 0.04]•10 9 /l, respectively (p<0.05 for all cases). Following 12 months of TCZ therapy, the numbers of other B-cell subpopulations were not considerably altered. When included in the study, the patients with RA showed correlations between the absolute count of memory B cells (CD19+CD27+) and the level of C-reactive protein (r=0.50; p<0.05); between the absolute count of plasmablasts (CD19+CD38+++CD27+IgD-CD20-) and the level of RF (r=0.41 and r=0.52; p<0.05). There were no correlations of B cell subsets with clinical and laboratory findings after 12 months of TCZ initiation. Conclusion. Immunophenotyping of peripheral blood B lymphocyte subsets showed the lower relative and absolute counts of memory B cells (CD19+CD27+) and switched memory B cells (CD19+CD27+IgD-) in RA patients than in healthy donors. The found correlations between the counts of memory B cells and plasmablasts and the values of laboratory parameters in patients with high RA activity may suggest that B lymphocytes are involved in the pathogenesis of RA. There was a decline in plasmablast levels after 12 months of TCZ therapy.

© Ima-Press Publishing House. All rights reserved. Interleukin 6 (IL-6) plays an important role in the pathogenesis of ischemic stroke (IS), exerting a modulating effect on a number of processes that determine the outcome of this disease. Objective: to investigate the peripheral blood levels of IL-6 in patients in the acute period of different IS pathogenetic subtypes and its effect on recovery rates. Patients and methods. The study enrolled 155 patients (74 men and 81 women; mean age, 63.8 years). A control group consisted of 28 people without IS. Pathogenetic subtype II was established in accordance with the TOAST (Trial of Org 10172 in Acute Stroke Treatment) criteria on the basis of their clinical picture and the data of computed tomography or magnetic resonance imaging and ultrasonography of the main arteries of the head. The severity of a patient's condition and a focal neurological defect and the time course of clinical changes after stroke were determined using the National Institutes of Health Stroke Scale (NIHSS). An enzyme immunoassay (EIA) was used to measure IL-6 levels on days 1, 7, and 21 after onset of IS. An enzyme immunoassay (EIA) was used to measure IL-6 levels on days 1, 7, and 21 after onset of IS. Results. In the acute period of IS, there were significantly elevated levels of IL-6. The latter reached its highest values on day 7 in patients with the atherothrombotic pathogenetic subtype of IS. On day 7 of the study, the peak concentration of IL6 was typical for patients with all subtypes of IS, except for lacunar stroke. After its increase on day 1 of the study, the IL6 level in patients with lacunar stroke did not change significantly in all other periods. In acute IS, the concentration of IL-6 was significantly influenced by the following cardiovascular risk factors: hypercholesterolemia of days 1, 7 (p<0.01) and 21 (p<0.05), hypertension in day 1 (p<0.05), diabetes mellitus on days 1 and 7 (p<0.05), and coronary heart disease in all the study periods (p<0.01). The IL-6 concentration significantly correlated with the severity of neurological defect, but did not significantly affect the rate of recovery in the patient with acute IS. Conclusion. IL-6 was established to be of prognostic value for the outcome of acute IS on day 7. The rate of recovery can be used to identify targets for therapeutic intervention.

Exposure to benzene and its inevitable metabolites can result in deleterious effects on human health, including lymphocytopenia, hematotoxicity and cancer. However, the duration of exposure might alter the effects including immune consequences. The aim of this study was to determine whether benzene could modulate lymphocyte proliferation induced by the T cell mitogen concanavalin A, in rats, at different exposure durations. 386 Wistar rats were assigned into control and treatment groups which were subdivided into groups for 45, 90 and 135days for 0,6mL/kg of drinking water mixed benzene treatment. The percentage of CD3+, CD4+, CD8+ spleen lymphocytes was defined using the flow cytometer. Interleukin (IL)-4, IL-6, IL-10 and interferon-gamma, in supernatants of splenocyte cultures stimulated with Concanavalin A, were assessed by enzyme-linked immunosorbent assay (ELISA) technique. The decrease in the total lymphocyte and T cell counts were associated with increased benzene exposure duration. Th2-type cytokine, IL-4 significantly increased, whereas IL-6, CD4+T cells, CD4+/CD8+ ratio and CD3+ T cells decreased. Despite the positive correlation between benzene toxicity and indicated increased immune responses, 45-day exposure to benzene appeared to be the most sensitive time point for evaluating benzene cytotoxicity.

Exposure to benzene and its inevitable metabolites can result in deleterious effects on human health, including lymphocytopenia, hematotoxicity and cancer. However, the duration of exposure might alter the effects including immune consequences. The aim of this study was to determine whether benzene could modulate lymphocyte proliferation induced by the T cell mitogen concanavalin A, in rats, at different exposure durations. 386 Wistar rats were assigned into control and treatment groups which were subdivided into groups for 45, 90 and 135days for 0,6mL/kg of drinking water mixed benzene treatment. The percentage of CD3+, CD4+, CD8+ spleen lymphocytes was defined using the flow cytometer. Interleukin (IL)-4, IL-6, IL-10 and interferon-gamma, in supernatants of splenocyte cultures stimulated with Concanavalin A, were assessed by enzyme-linked immunosorbent assay (ELISA) technique. The decrease in the total lymphocyte and T cell counts were associated with increased benzene exposure duration. Th2-type cytokine, IL-4 significantly increased, whereas IL-6, CD4+T cells, CD4+/CD8+ ratio and CD3+ T cells decreased. Despite the positive correlation between benzene toxicity and indicated increased immune responses, 45-day exposure to benzene appeared to be the most sensitive time point for evaluating benzene cytotoxicity.