Post-operative infection and sepsis in humans is associated with deficient gene expression of γc cytokines and their apoptosis mediators (original) (raw)
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Shock, 2006
Patient response to acute bacterial infection is highly variable. Differing outcomes in this setting may be related to variations in the immune response to an infectious insult. Using quantitative real-time polymerase chain reaction, we quantified gene expression of the tumor necrosis factor !(TNF!), interferon + (IFN+), and interleukin 10 (IL10), IL12p35, and IL4 genes in 3 patient groups. These groups consisted of an intensive care unit (ICU) cohort who presented with severe sepsis or septic shock, a group of noncritically ill ward patients with documented Gram-negative bacteremia, and a group of healthy controls. Greater interleukin 10 messenger RNA (mRNA) levels were detected in the ICU group in comparison with both the bacteremic and control groups (P G 0.0001). More TNF-! mRNA was detected in the ICU group when compared with the control group (P G 0.0001). However, TNF-! mRNA was most abundant in the bacteremic group (P = 0.0007). Lesser IFN-+ mRNA levels were detected in the ICU group when compared with both the bacteremic and control groups (P G 0.0003). Cytokine mRNA levels were not associated with the occurrence of shock upon admission to ICU. On the seventh day of ICU stay, the presence of shock was associated with lesser IFN-+ mRNA (P = 0.0004) and lesser TNF-! mRNA (P = 0.001). Survivors had greater TNF-! mRNA copy numbers on day 7 of ICU stay than nonsurvivors (P = 0.002). We conclude that a proinflammatory response is the appropriate response in the setting of infection and is associated with lesser requirements for inotropes and lesser mortality. Quantitative real-time polymerase chain reaction can be used to predict infection outcome in clinically relevant situations where enzyme-linked immunosorbent assay testing has proved disappointing.
Cytokine Profile and Microbiological Screening in Postoperative Sepsis
Critical Care Medicine, 2004
Introduction: Hyperchloremic metabolic acidosis is a common feature of sepsis. Often the source of acidosis is partly iatrogenic, because saline solution resuscitaion if often used to treat shock. It is unknown if the acidosis itself has an effect on the levels of inflammatory mediators. Hypothesis: Hyperchloremic acidosis induced by dilute HCl infusion has a significant effect on circulating levels of inflammatory mediators in an experimental model of severe sepsis in the rat. Methods: We included 20 adult, male, Sprague-Dawley rats in this study. Eighteen hours after inducing lethal sepsis by cecal ligation and puncture, animals were randomized and classified in three groups. In group-2 and 3, we began an IV infusion of 0.1 HCl to reduce the standard base excess (SBE) by 5 to 10 mEq/L and 10 to 15 mEq/L respectively. In group-1 we infused a similar volume of lactated Ringer solution. In all groups infusion continued 8 hours or until the animal died. we measured arterial blood gases, electrolytes, tumor necrosis factor (TNF)-α, interleukine (IL)-6, and IL-10 levels at 0h, 4h and 8h. Results: all measured cytokines showed steady trend of elevation at 4 and 8 h. this was true for IL-6 (rose from 106 ± 26 to 244 ±81 at 4h and 234±57 at 8h in group1 and from 36±12 to 345±125 at 4h and to 254 ±74 at 8h in group2 and from 56±5 to 400±97 at 4h and 581± 118 at 8h in goup3). Similar results obtained for IL-10 (rose from 23±4 to 92±20 at 4h and to 101±23 at 8h for group1 and from 28±8 to 165±24 at 4h and to 124±14 at 8h for group2 and from 25±4 to 278± 67 at 4h and to 175±32 at 8h. TNF-α showed similar fashion of increase (Rose from 3.6±3.6 to 43±25 at 4h and 19±8 at 8h. for group 1 and from 7.8± 7.8 to 64±18 at 4h and to 14.2±3.7 at 8h for group 2 and from 41.6±31 to 108±18 at 4h and 31±12 at 8h for group3. Conclusions: moderate (SBE of −5to −10) and severe (SBE of −10 to −15) acidosis, induced by HCl infusion may increase circulating levels of IL-6, IL-10, and TNF-α in septic rats.
Characterising Cytokine Gene Expression Signatures in Patients with Severe Sepsis
Mediators of Inflammation, 2013
Introduction. Severe sepsis in humans may be related to an underlying profound immune suppressive state. We investigated the link between gene expression of immune regulatory cytokines and the range of illness severity in patients with infection and severe sepsis.Methods. A prospective observational study included 54 ICU patients with severe sepsis, 53 patients with infection without organ failure, and 20 healthy controls. Gene expression in peripheral blood mononuclear cells (PBMC) was measured using real-time polymerase chain reaction.Results. Infection differed from health by decreased expression of the IL2, and IL23 and greater expression of IL10 and IL27. Severe sepsis differed from infection by having decreased IL7, IL23, IFNγ, and TNFαgene expression. An algorithm utilising mRNA copy number for TNFα, IFNγ, IL7, IL10, and IL23 accurately distinguished sepsis from severe sepsis with a receiver operator characteristic value of 0.88. Gene expression was similar with gram-positive...
Understanding the Inflammatory Cytokine Response in Pneumonia and Sepsis
Archives of Internal Medicine, 2007
Background: Severe sepsis is common and frequently fatal, and community-acquired pneumonia (CAP) is the leading cause. Although severe sepsis is often attributed to uncontrolled and unbalanced inflammation, evidence from humans with infection syndromes across the breadth of disease is lacking. In this study we describe the systemic cytokine response to pneumonia and determine if specific patterns, including the balance of proinflammatory and anti-inflammatory markers, are associated with severe sepsis and death.
Decreased Cytokine Expression in Peripheral Blood Leukocytes of Patients With Severe Sepsis
2002
Background: High levels of tumor necrosis factor (TNF) messenger RNAs and interleukin (IL) 8 have been reported in leukocytes of patients with sepsis. Hypothesis: Assessment of leukocyte intracytoplas- mic levels of proinflammatory and anti-inflammatory cy- tokines might be clinically more relevant to determine prognosis in patients with severe sepsis. Design: Cohort study. Setting: Surgical intensive care units of a university
Daru : journal of Faculty of Pharmacy, Tehran University of Medical Sciences, 2010
sepsis is one of the most widespread and lethal disease in Intensive Care Units (ICU). Based on pathophisyology of sepsis, it seems that routine laboratory tests combined with analysis of pro-inflammatory cytokines plasma levels, help clinicians to have more information about disease progress and its correct management. This was a prospective observational study to determine the predictive role of Tumor Necrosis Factor alpha (TNF-α), Interleukin (IL)-1β and IL-6 as three main pro-inflammatory cytokines and Acute Physiology and Chronic Health Evaluation (APACHE II) and Sequential Organ Failure Assessment (SOFA) as two scoring systems in mortality of critically ill patients with severe sepsis. Fifty and five patients with criteria of severe sepsis were included in this study. An exclusion criterion was post Cardiopulmonary Resuscitation (CPR) status. Cytokines (TNF-α, IL-1β and IL-6) were assayed in the first, third and seventh days in blood of patients. Among three measured cytokines...
Serial cytokine levels in patients with severe sepsis
Inflammation Research, 2009
Objective and design The serial or dynamic changes of cytokine levels in severely septic patients, between shock and no shock, survivors and non-survivors are still unclear. Methods Seventy-six patients with severe sepsis were enrolled to our study. Plasma levels of interferon-c, interleukin (IL)-6, IL-10, IL-12 and transforming growth factor-b1 from day 1 to day 7 were determined. Results IL-6 level in non-survivors was higher than that in survivors on day 1. IL-10 level in non-survivors was higher than that in survivors on day 1, 2, and 3. IL-6 level in shock patients was higher than that in non-shock patients on day 1, 2, 6 and 7. IL-10 level in shock patients was higher than that in non-shock patients from day 1 to day 7. Plasma time-course curves of IL-6 and IL-10 were different between survivors and non-survivors. Plasma timecourse curve of IL-6 was different between patients with shock and without shock. Regression analysis found that IL-6 was correlated with IL-10 and shock. IL-10 was correlated with IL-6 and mortality. Conclusion IL-6 and IL-10 were the key cytokines in the pathogenesis of severe sepsis. IL-6 was comparatively more associated with septic shock and IL-10 was comparatively more associated with mortality.
Proinflammatory versus anti-inflammatory response in sepsis patients: looking at the cytokines
Critical Care, 2014
Introduction: During the course of systemic inflammation, most of the immune cell types get activated to a certain degree as part of, or contributing to, the cascade of physiopathological events. Whether for some cells, classically phagocytes of the innate immune system, it is clear that direct sensing of pathogen-associated molecular patterns leads to activation initiating systemic inflammation, the picture is not so clear for natural killer (NK) cells. While NK cells have been shown to express toll-like receptors (TLR), the role of these receptors on NKs during systemic inflammation has not been directly addressed. Methods: To directly assess the role of TLR expression on NK cells we used an adoptive transfer model in which NKs purified from the spleens of WT, TLR4KO and TLR2/4DKO mice were transferred intravenously to RAG2 -/γc -/-(devoid of T, B and NK cells). Five days after reconstitution the mice were challenged intraperitoneally with conventional or TLR-grade lipopolysaccharide (LPS). Immune cell activation and production of IFNγ by NK cells was determined after 6 hours by FACS analysis. Results: We observed no differences in reconstitution of the recipient mice with NK cells from different backgrounds suggesting no difference in trafficking and survival of the transferred cells. At 6 hours after LPS challenge, WT, TLR4KO or TLR2/4DKO NK cells recovered from the spleen and lungs of RAG2 -/γc -/mice showed comparable levels of CD69 activation marker expression. Intracellular labeling for IFNγ in NK cells also revealed no significant differences. Conclusion: Whether there is a role for direct TLR signaling on NK cells remains the objective of further investigations; however, our data show that in the course of a systemic inflammatory process, like endotoxinemia, the expression of TLR2 and TLR4 by NK cells makes no difference in terms of their activation and secretion of IFNγ
Cytokine profiles as markers of disease severity in sepsis: a multiplex analysis
Critical Care, 2007
Introduction The current shortage of accurate and readily available, validated biomarkers of disease severity in sepsis is an important limitation when attempting to stratify patients into homogeneous groups, in order to study pathogenesis or develop therapeutic interventions. The aim of the present study was to determine the cytokine profile in plasma of patients with severe sepsis by using a multiplex system for simultaneous detection of 17 cytokines. Methods This was a prospective cohort study conducted in four tertiary hospitals. A total of 60 patients with a recent diagnosis of severe sepsis were included. Plasma samples were collected for measurement of cytokine concentrations. A multiplex analysis was performed to evaluate levels of 17 cytokines (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17, interferon-γ, granulocyte colony-stimulating factor [G-CSF], granulocyte-macrophage colony-stimulating factor, monocyte chemoattractant protein [MCP]-1, macrophage inflammatory protein-1 and tumour necrosis factor-α). Cytokine concentrations were related to the presence of severe sepsis or septic shock, the severity and evolution of organ failure, and early and late mortality. Results Concentrations of IL-1β, IL-6, IL-7, IL-8, IL-10, IL-13, interferon-γ, MCP-1 and tumour necrosis factor-α were significantly higher in septic shock patients than in those with severe sepsis. Cytokine concentrations were associated with severity and evolution of organ dysfunction. With regard to the severity of organ dysfunction on day 1, IL-8 and MCP-1 exhibited the best correlation with Sequential Organ Failure Assessment score. In addition, IL-6, IL-8 and G-CSF concentrations during the first 24 hours were predictive of worsening organ dysfunction or failure of organ dysfunction to improve on day three. In terms of predicting mortality, the cytokines IL-1β, IL-4, IL-6, IL-8, MCP-1 and G-CSF had good accuracy for predicting early mortality (< 48 hours), and IL-8 and MCP-1 had the best accuracy for predicting mortality at 28 days. In multivariate analysis, only MCP-1 was independently associated with prognosis. Conclusion In this exploratory analysis we demonstrated that use of a multiple cytokine assay platform allowed identification of distinct cytokine profiles associated with sepsis severity, evolution of organ failure and death.