interleukin-8 and Sepsis

Neonatal sepsis (NS) is a life-threatening disorder and an important cause of morbidity and mortality in neonates. Previous studies showed that interleukin 8 (IL-8) may effectively and rapidly diagnose NS.. We conducted the systematic review and meta-analysis to investigate the diagnostic value of the IL-8 in NS.. The literature was searched in PUBMED, EMBASE, Cochrane Library, CNKI, VIP and other Chinese Medical Databases during October 1998 to January 2014 using set search criteria. Each included study was evaluated by quality assessment of diagnostic accuracy studies tool. Two investigators independently extracted the data and study characteristics, and disagreements, if any, were resolved by consensus. Meta-disc software was used to calculate the pooled sensitivity, specificity and summary diagnostic odds ratio (SDOR), I² or Cochrane Q to test heterogeneity, and meta-regression to investigate the source of heterogeneity. Funnel plots were used to test the potential presence of publication bias. False-positive report probability (FPRP) was calculated to confirm the significance of the results.. Eight studies (548 neonates) were included in this meta-analysis. The pooled sensitivity and specificity of IL-8 were 0.78 and 0.84, respectively, which had moderate accuracy in the diagnosis of NS. The pooled diagnostic odds ratio (DOR) and area under curve (AUC) was 21.64 and 0.8908 (Q*=0.8215), respectively. The diagnostic threshold analysis showed that there was no threshold effect. The meta-regression analysis showed the cut-off, QUADAS and onset time have no effect on the heterogeneity. The funnel plots showed the existence of publication bias.. Meta-analysis showed IL-8 had a moderate accuracy (AUC=0.8908) for the diagnosis of NS. IL-8 is a helpful biomarker for early diagnosis of NS. However, we should combine the results with clinical symptoms and signs, laboratory and microbial results.

Topics: Biomarkers; Humans; Infant, Newborn; Interleukin-8; Reproducibility of Results; Sensitivity and Specificity; Sepsis

Sepsis remains a major cause of morbidity and mortality in adult and pediatric intensive care units. Heterogeneity of demographics, comorbidities, biological mechanisms, and severity of illness leads to difficulty in determining which patients are at highest risk of mortality. Determining mortality risk is important for weighing the potential benefits of more aggressive interventions and for deciding whom to enroll in clinical trials. Biomarkers can be used to parse patients into different risk categories and can outperform current methods of patient risk stratification based on physiologic parameters. Here we review the Pediatric Sepsis Biomarker Risk Model that has also been modified and applied to estimate mortality risk in adult patients. We compare the two models and speculate on the biological implications of the biomarkers in patients with sepsis.

Topics: Adult; Biomarkers; Chemokine CCL3; Chemokine CCL4; Child; Decision Trees; Granzymes; HSP70 Heat-Shock Proteins; Humans; Intensive Care Units, Pediatric; Interleukin-1alpha; Interleukin-8; Matrix Metalloproteinase 8; Models, Theoretical; Prognosis; Risk Factors; Sepsis

Neonatal sepsis is a major cause of morbidity and mortality and its signs and symptoms are nonspecific, which makes the diagnosis difficult. The routinely used laboratory tests are not effective methods of analysis, as they are extremely nonspecific and often cause inappropriate use of antibiotics. Sepsis is the result of an infection associated with a systemic inflammatory response with production and release of a wide range of inflammatory mediators. Cytokines are potent inflammatory mediators and their serum levels are increased during infections, so changes from other inflammatory effector molecules may occur. Although proinflammatory and anti-inflammatory cytokines have been identified as probable markers of neonatal infection, in order to characterize the inflammatory response during sepsis, it is necessary to analyze a panel of cytokines and not only the measurement of individual cytokines. Measurements of inflammatory mediators bring new options for diagnosing and following up neonatal sepsis, thus enabling early treatment and, as a result, increased neonatal survival. By taking into account the magnitude of neonatal sepsis, the aim of this review is to address the role of cytokines in the pathogenesis of neonatal sepsis and its value as a diagnostic criterion.

Topics: Biomarkers; Cytokines; Humans; Infant, Newborn; Inflammation; Interleukin-10; Interleukin-1beta; Interleukin-6; Interleukin-8; Sepsis; Transforming Growth Factor beta; Treatment Outcome; Tumor Necrosis Factor-alpha

Sepsis, severe sepsis, and septic shock cause significant morbidity and mortality worldwide. Rapid diagnosis and therapeutic interventions are desirable to improve the overall mortality in patients with sepsis. However, gold standard laboratory diagnostic methods for sepsis, pose a significant challenge to rapid diagnosis of sepsis by physicians and laboratories. This article discusses the usefulness and potential of biomarkers and molecular test methods for a more rapid clinical and laboratory diagnosis of sepsis. Because new technologies are quickly emerging, physicians and laboratories must appreciate the key factors and characteristics that affect the clinical usefulness and diagnostic accuracy of these test methodologies.

Topics: Acute-Phase Proteins; Bacteremia; Biomarkers; C-Reactive Protein; Calcitonin; Calcitonin Gene-Related Peptide; Carrier Proteins; Clinical Laboratory Techniques; Humans; Interleukin-6; Interleukin-8; Laboratories; Membrane Glycoproteins; Nucleic Acid Amplification Techniques; Protein Precursors; Sepsis; Serum Amyloid P-Component; Vasopressins

The present review is aimed at elucidating the neonatal 'sepsis redox cycle'--the cascade of inflammatory and redox events involved in the pathogenesis of sepsis in neonates. While adult and neonatal sepses share some common features, there are some substantial differences: higher mortality rates occur in adult sepsis and worse long-term effects are evident in neonatal sepsis survivors. Such epidemiological data may be explained by the lower ability of IL6 and IL8 to activate NF-κB-regulated transcription in neonatal sepsis in comparison to TNF-α, which is involved in the mechanisms of adult sepsis. The activation of NF-κB in neonatal sepsis is further promoted by hydrogen peroxide and results in mitochondrial dysfunction and energy failure as septic neonates experience decreased O2 consumption as well as lower heat production and body temperature in comparison to healthy peers. In neonates, specific organs that are still under development are vulnerable to sepsis-provoked stress, which may lead to brain, lung, and heart injury, as well as vision and hearing impairments. In the light of the processes integrated here, it is clear that therapeutic approaches should also target specific steps in the neonatal 'sepsis redox cycle' in addition to the current therapeutic approach that is mainly focused on pathogen eradication.

Topics: Humans; Hydrogen Peroxide; Infant, Newborn; Interleukin-6; Interleukin-8; Mitochondria; NF-kappa B; Oxidation-Reduction; Sepsis; Tumor Necrosis Factor-alpha

It has been reported that various types of blood purification intended for the removal of humoral mediators, such as cytokines, were performed in patients with severe sepsis/septic shock. While high-volume hemofiltration, hemofiltration using high cut-off membrane filters, and direct hemoperfusion with a polymyxin-B immobilized column are widely used in the treatment of severe sepsis/septic shock, we perform continuous hemodiafiltration using a polymethylmethacrylate membrane hemofilter (PMMA-CHDF), which shows an excellent cytokine-adsorbing capacity, for the treatment of severe sepsis/septic shock. In our previous study, it was found that PMMA-CHDF could efficiently remove various pro-inflammatory cytokines such as TNFalpha, IL-6 and IL-8 from the bloodstream, resulting in early recovery from septic shock. Furthermore, PMMA-CHDF could remove anti-inflammatory cytokines such as IL-10 from bloodstream, suggesting that it might improve immunoparalysis as well. These findings suggest that PMMA-CHDF is useful for the treatment of patients with severe sepsis/septic shock as a cytokine modulator.

Topics: Cytokines; Hemodiafiltration; Humans; Interleukin-10; Interleukin-6; Interleukin-8; Membranes, Artificial; Polymethyl Methacrylate; Sepsis; Shock, Septic; Tumor Necrosis Factor-alpha

The pathophysiology of acute renal failure in sepsis is complex and includes intrarenal vasoconstriction, infiltration of inflammatory cells in the renal parenchyma, intraglomerular thrombosis, and obstruction of tubuli with necrotic cells and debris. Attempts to interfere pharmacologically with these dysfunctional pathways, including inhibition of inflammatory mediators, improvement of renal hemodynamics by amplifying vasodilator mechanisms and blocking vasoconstrictor mechanisms, and administration of growth factors to accelerate renal recovery, have yielded disappointing results in clinical trials. Interruption of leukocyte recruitment is a potential promising approach in the treatment of septic acute renal failure, but no data in humans are presently available. Activated protein C and steroid replacement therapy have been shown to reduce mortality in patients with sepsis and are now accepted adjunctive treatment options for sepsis in general.

Topics: Acute Kidney Injury; Anticoagulants; Antineoplastic Agents; Antithrombins; Endothelins; Growth Substances; Humans; Interleukin-8; Lipoproteins; Natriuretic Peptides; Nitric Oxide Synthase; Platelet Activating Factor; Protein C; Sepsis; Steroids; Tumor Necrosis Factor-alpha

Continuous hemofiltration currently represents standard renal replacement therapy in critically ill patients. Because higher ultrafiltration rates are related to better survival rates in experimental and clinical studies and hemofiltration results in fewer cardiovascular side effects than does conventional hemodialysis, the use of inflammatory mediator removal by this extracorporeal procedure has emerged. This article reviews clinically relevant principles of compound transport and the experimental and clinical effects of hemofiltration during sepsis. Hemofiltration did not have a major impact on plasma concentrations of prominent inflammatory cytokines (tumor necrosis factor-a and interleukins 1b, 6, and 8) and seems therefore not to be able to counterbalance endogenous cytokine production despite considerable cytokine removal in the filtrate. Contradictory results in the literature are discussed under the viewpoint of membrane-related sieving coefficients and plasma cytokine measurement. A significant reduction in plasma anaphylatoxin concentrations by hemofiltration is associated with impressive immunomodulatory and cardiodepressive ultrafiltrate effects. Thus far, however, the use of hemofiltration for nonrenal indications remains experimental and is not supported by controlled clinical trials. Modern strategies of blood purification that may be associated with a high degree of effectiveness for mediator removal (high-volume hemofiltration and heparin-induced extracorporeal lipoprotein-fibrinogen precipitation) are discussed.

Topics: Anaphylatoxins; Animals; Blood Component Removal; Endotoxemia; Hemofiltration; Humans; Inflammation Mediators; Interleukin-1; Interleukin-6; Interleukin-8; Multiple Organ Failure; Sepsis; Tumor Necrosis Factor-alpha

Topics: Biomarkers; Humans; Infant, Newborn; Infant, Premature; Interleukin-8; Sepsis

Topics: Animals; Chemokine CCL2; Clinical Trials as Topic; Colony-Stimulating Factors; Cytokines; Endotoxemia; Humans; Inflammation; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Interleukin-6; Interleukin-8; Sepsis; Sialoglycoproteins; Tumor Necrosis Factor-alpha

The systemic inflammatory response syndrome (SIRS) is an acute illness characterized by generalized activation of the endothelium. The most severe form of the syndrome is found in patients with shock due to gram-negative sepsis. We examined both animal and limited human data for the contribution of cytokines to this syndrome. Cytokines are endogenously produced proteins of small molecular weight and multiple biological effects. The cytokines interleukin 1 (IL-1) and tumor necrosis factor (TNF), as well as interferon-gamma and interleukin 8, are discussed. Laboratory investigations suggest that these cytokines play a critical role in SIRS by promoting the biochemical and clinical characteristics of SIRS. The biochemical changes induced by TNF and IL-1 include increased synthesis of nitric oxide, prostaglandins, platelet-activating factor, and endothelial cell adhesion molecules. Specific blockade of TNF using neutralizing antibodies or soluble receptors to TNF in animal models of SIRS reduces mortality and severity of disease. Similar results have been observed blocking IL-1 using soluble IL-1 receptors or IL-1 receptor antagonists. Preliminary clinical studies suggest that blockade may be useful in treating human SIRS. The various strategies for blocking IL-1 and TNF are presented; in addition, their mechanism(s) of action and safety in humans are discussed. We conclude that based on animal studies and preliminary clinical trials, strategies to block IL-1 or TNF may benefit patients with the syndrome, although thorough clinical trials have not been completed.

Topics: Animals; Cytokines; Humans; Immunotherapy; Inflammation; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Interleukin-8; Receptors, Interleukin-1; Sepsis; Sialoglycoproteins; Syndrome; Tumor Necrosis Factor-alpha

Methods containing only clinical information fail to meet the needs of prediction of acute lung injury (ALI) because of the relatively low positive predictive value. This study aimed to investigate the feasibility of using biomarkers as predictors of ALI in populations with severe sepsis/septic shock and to explore difference among biomarkers after adjustment for potential confounders.. Serum specimens were collected from patients with severe sepsis/septic shock (n = 172) presented to the emergency department. Patients should be ruled out from the study if they were already suffering from ALI or if they deteriorated into ALI within 6 hours after specimen collection. The development of ALI of the remaining patients was tracked.. Of all patients with severe sepsis/septic shock who encountered ALI more than 6 hours succeeding to specimen collection, 19 deteriorated into ALI. Elevation in serum interleukin 8 (IL-8) and Parkinson disease 7 (PARK7) levels had significant connection with higher risk of developing ALI (. Patients with PARK7 or IL-8 levels above normal are more vulnerable to ALI. Patients vulnerable to ALI can be distinguished with the combination of serum biomarkers and clinical prediction scores. In addition, the early rise in PARK7 emphasizes the importance of endothelial injury in the early pathogenesis of ALI.

Topics: Acute Lung Injury; Adult; Aged; Biomarkers; Clinical Decision Rules; Feasibility Studies; Female; Follow-Up Studies; Humans; Interleukin-8; Male; Middle Aged; Prognosis; Protein Deglycase DJ-1; Risk Assessment; Sepsis; Shock, Septic

Selecting participants for research based on their risk is an enrichment strategy with potential for enhancing clinical trials in sepsis. Adult Septic Shock Information and Stratification (ASSIST) is a tool for estimating mortality risk that incorporates a panel of biomarkers, age, lactate, and chronic health status. We assessed the utility of ASSIST as an enrichment strategy in a clinical trial testing the efficacy of a polyclonal antitumor necrosis factor-α fragment antibody (AZD9773) in adults with severe sepsis or septic shock. We hypothesized that the effects of AZD9773 are dependent on baseline mortality risk, as estimated by ASSIST.. This was a post hoc analysis of a recently completed trial of 300 subjects, randomized to placebo, low-dose AZD9773, or high-dose AZD9773. The study's primary endpoint was number of ventilator-free days. There were 286 subjects with available plasma samples from study entry. We measured the ASSIST biomarkers and assigned each subject to low, intermediate, and high-risk strata based on their ASSIST mortality probability. To mirror the study's original statistical plan, we estimated the least squares mean ventilator-free days for each study arm within risk strata.. The effect of study arm within ASSIST-based risk strata was significant (P = 0.017). Within the low-risk group, there was an increase in ventilator-free days for both drug arms. Within the intermediate-risk group, there was an increase in ventilator-free days among those in the low-dose arm, but a decrease in the high-dose arm. Among high-risk patients, there was a decrease of ventilator-free days in both drug arms. Analogous associations were observed when modeling 28-day mortality.. In this study, a beneficial effect of AZD9773 might have been observed if the trial selected low to intermediate-risk patients. ASSIST has the potential to serve as an enrichment tool for sepsis clinical trials.

Topics: Adult; Biomarkers; Chemokine CCL3; Chemokine CCL4; Female; Granzymes; HSP70 Heat-Shock Proteins; Humans; Immunoglobulin Fab Fragments; Interleukin-1alpha; Interleukin-8; Male; Randomized Controlled Trials as Topic; Sepsis

Excessive systemic inflammatory response remains as a major problem underlying severe burns. This study aimed to assess the effect of low-dose glucocorticoid treatment in downregulating systemic inflammation in severely burned patients.. A prospective study from 2001 to 2014 at our hospital was conducted to compare the patients who received low-dose glucocorticoid during the acute phase with those who did not. Patients with burns 70% or greater of their total body surface area were included, and their plasma levels of inflammatory cytokines and clinical outcomes were compared.. A total of 69 patients were included in this study, with 31 patients receiving glucocorticoid treatment and the others not. Patient demographics including age, burn size, and incidence of inhalation injury were similar in both groups. The incidence of pulmonary infection and stress ulcer (and/or hemorrhage) was 24.2% and 3.0% in the treatment group, respectively, significantly lower than 47.8% and 19.6% of the control group (P < .05). Length of hospital stay was almost 13 days shorter in the treatment group (P < .05), whereas there was no significant difference in the overall mortality, duration of mechanical ventilation, and incidence of sepsis between the 2 groups. The enzyme-linked immunosorbent assay results confirmed that the plasma levels of C-reactive protein, tumor necrosis factor-α, interleukin-6, and interleukin-8 were significantly lower in the treatment group (P < .05).. Low dose of glucocorticoid treatment during the acute phase could reduce the levels of proinflammatory cytokines in severely burned patients and subsequently decrease the incidence of pulmonary infection and stress ulcer, as well as the length of hospital stay.

Topics: Adult; Anti-Inflammatory Agents; Burns; C-Reactive Protein; Cytokines; Enzyme-Linked Immunosorbent Assay; Female; Glucocorticoids; Humans; Incidence; Inflammation; Interleukin-6; Interleukin-8; Length of Stay; Male; Middle Aged; Pneumonia; Prospective Studies; Sepsis; Stomach Ulcer; Treatment Outcome; Tumor Necrosis Factor-alpha

The inflammatory response induced by burn injury contributes to increased incidence of infections, sepsis, organ failure, and mortality. Thus, monitoring postburn inflammation is of paramount importance but, so far, there are no reliable biomarkers available to monitor and/or predict infectious complications after burn. As interleukin 8 (IL-8) is a major mediator for inflammatory responses, the aim of our study was to determine whether IL-8 expression can be used to predict postburn sepsis, infections, and mortality. Plasma cytokines, acute-phase proteins, constitutive proteins, and hormones were analyzed during the first 60 days after injury from 468 pediatric burn patients. Demographics and clinical outcome variables (length of stay, infection, sepsis, multiorgan failure [MOF], and mortality) were recorded. A cutoff level for IL-8 was determined using receiver operating characteristic analysis. Statistical significance is set at P < 0.05. Receiver operating characteristic analysis identified a cutoff level of 234 pg/mL for IL-8 for survival. Patients were grouped according to their average IL-8 levels relative to this cutoff and stratified into high (H) (n = 133) and low (L) (n = 335) groups. In the L group, regression analysis revealed a significant predictive value of IL-8 to percent of total body surface area burned and incidence of MOF (P < 0.001). In the H group, IL-8 levels were able to predict sepsis (P < 0.002). In the H group, elevated IL-8 was associated with increased inflammatory and acute-phase responses compared with the L group (P < 0.05). High levels of IL-8 correlated with increased MOF, sepsis, and mortality. These data suggest that serum levels of IL-8 may be a valid biomarker for monitoring sepsis, infections, and mortality in burn patients.

Topics: Adolescent; Biomarkers; Burns; Child; Child, Preschool; Female; Humans; Infections; Inflammation Mediators; Interleukin-8; Kaplan-Meier Estimate; Male; Multiple Organ Failure; Predictive Value of Tests; Prospective Studies; Sepsis

To determine the immunologic effects of oropharyngeal colostrum administration in extremely premature infants.. We conducted a double-blind, randomized, placebo-controlled trial involving 48 preterm infants born before 28 weeks' gestation. Subjects received 0.2 mL of their mother's colostrum or sterile water via oropharyngeal route every 3 hours for 3 days beginning at 48 to 96 hours of life. To measure concentrations of secretory immunoglobulin A, lactoferrin, and several immune substances, urine and saliva were obtained during the first 24 hours of life and at 8 and 15 days. Clinical data during hospitalization were collected.. Urinary levels of secretory immunoglobulin A at 1 week (71.4 vs 26.5 ng/g creatinine, P = .04) and 2 weeks (233.8 vs 48.3 ng/g creatinine, P = .006), and lactoferrin at 1 week (3.5 vs 0.9 μg/g creatinine, P = .01) were significantly higher in colostrum group. Urine interleukin-1β level was significantly lower in colostrum group at 2 weeks (55.3 vs 91.8 μg/g creatinine, P = .01). Salivary transforming growth factor-β1 (39.2 vs 69.7 μg/mL, P = .03) and interleukin-8 (1.2 vs 4.9 ng/mL, P = .04) were significantly lower at 2 weeks in colostrum group. A significant reduction in the incidence of clinical sepsis was noted in colostrum group (50% vs 92%, P = .003).. This study suggests that oropharyngeal administration of colostrum may decrease clinical sepsis, inhibit secretion of pro-inflammatory cytokines, and increase levels of circulating immune-protective factors in extremely premature infants. Larger studies to confirm these findings are warranted.

Topics: Colostrum; Creatinine; Double-Blind Method; Enteral Nutrition; Hospitals, University; Humans; Immunoglobulin A, Secretory; Infant, Extremely Low Birth Weight; Infant, Newborn; Interleukin-1beta; Interleukin-8; Lactoferrin; Republic of Korea; Saliva; Sepsis; Transforming Growth Factor beta1

ARDS is a heterogeneous syndrome that encompasses lung injury from both direct and indirect sources. Direct ARDS (pneumonia, aspiration) has been hypothesized to cause more severe lung epithelial injury than indirect ARDS (eg, nonpulmonary sepsis); however, this hypothesis has not been well studied in humans.. We measured plasma biomarkers of lung epithelial and endothelial injury and inflammation in a single-center study of 100 patients with ARDS and severe sepsis and in a secondary analysis of 853 patients with ARDS drawn from a multicenter randomized controlled trial. Biomarker levels in patients with direct vs indirect ARDS were compared in both cohorts.. In both studies, patients with direct ARDS had significantly higher levels of a biomarker of lung epithelial injury (surfactant protein D) and significantly lower levels of a biomarker of endothelial injury (angiopoietin-2) than those with indirect ARDS. These associations were robust to adjustment for severity of illness and ARDS severity. In the multicenter study, patients with direct ARDS also had lower levels of von Willebrand factor antigen and IL-6 and IL-8, markers of endothelial injury and inflammation, respectively. The prognostic value of the biomarkers was similar in direct and indirect ARDS.. Direct lung injury in humans is characterized by a molecular phenotype consistent with more severe lung epithelial injury and less severe endothelial injury. The opposite pattern was identified in indirect lung injury. Clinical trials of novel therapies targeted specifically at the lung epithelium or endothelium may benefit from preferentially enrolling patients with direct and indirect ARDS, respectively.

Topics: Adult; Aged; Angiopoietin-2; Biomarkers; Cohort Studies; Comorbidity; Endothelium; Female; Humans; Interleukin-6; Interleukin-8; Lung; Male; Middle Aged; Phenotype; Prognosis; Pulmonary Surfactant-Associated Protein D; Respiratory Distress Syndrome; Respiratory Mucosa; Sepsis; von Willebrand Factor

REsearching severe Sepsis and Organ dysfunction in children: A gLobal perspective (RESOLVE), a phase III trial of drotrecogin alfa (activated) in pediatric severe sepsis, examined biomarker changes in inflammation and coagulation. This report describes biomarker profiles in early severe sepsis and the pharmacodynamic assessment of drotrecogin alfa (activated) in RESOLVE.. Serial measurements of interleukin-1β, interleukin-6, interleukin-8, interleukin-10, tissue necrosis factor-α, procalcitonin, D-dimer, and thrombin-antithrombin complex were performed at baseline and daily over the first five study days. Protein C levels were performed at baseline and at the end of the 96-hr study drug infusion. Analysis of variance-based log-transformed data compared the treatment groups for each measured variable.. : One hundred four pediatric intensive care units in 18 countries.. Four hundred seventy-seven children between 38 wks corrected gestational age and 17 yrs with sepsis-induced cardiovascular and respiratory dysfunction.. Drotrecogin alfa (activated).. Pharmacodynamic activity of drotrecogin alfa (activated) compared with placebo was observed with reduction of D-dimer on day 1 (p < .01) and thrombin-antithrombin complex on days 1-4 (p < .05). There were no significant changes by treatment in multiple cytokines or procalcitonin. In the overall population, a median protein C difference was not observed (p > .05) with drotrecogin alfa (activated) administration compared with placebo, although a difference (median percentage change from baseline) in favor of drotrecogin alfa (activated) was observed in patients >1 yr old (p = .0449).. While children in the RESOLVE trial were similar to adults in that they showed a relationship between severity of coagulation and inflammation abnormalities and mortality, their pharmacodynamic response to drotrecogin alfa (activated) differed with respect to changes in protein C activity and systemic inflammation.

Topics: Adolescent; Anti-Infective Agents; Antithrombin III; Biomarkers; Blood Proteins; Calcitonin; Calcitonin Gene-Related Peptide; Child; Child, Preschool; Cytokines; Disseminated Intravascular Coagulation; Double-Blind Method; Female; Fibrin Fibrinogen Degradation Products; Humans; Infant; Infant, Newborn; Interleukin-10; Interleukin-1beta; Interleukin-6; Interleukin-8; Male; Peptide Hydrolases; Protein C; Protein Precursors; Recombinant Proteins; Respiratory Insufficiency; Sepsis; Survival Analysis; Time Factors; Tumor Necrosis Factor-alpha

Topics: Aged; Female; Filtration; Hemofiltration; Humans; Intensive Care Units; Interleukin-8; Male; Middle Aged; Prospective Studies; Sepsis

The aim of this study is to evaluate the impact of neutral microporous resin hemoperfusion on hemodynamic improvement, removal of inflammatory cytokines, and mortality in critical care patients with severe sepsis. Forty-four patients with severe sepsis or septic shock were randomized to HA type hemoperfusion treatment (N=24) or standard therapy (N=20). Those undergoing hemoperfusion treatment received HA330 hemoperfusion. We measured the plasma concentrations of IL-6 and IL-8 at the start of every hemoperfusion treatment, and the following parameters were compared between the control group and the hemoperfusion group on days 3, 7, and 14: hemodynamics (cardiac index, systemic vascular resistance index, heart rate, and mean arterial pressure); change of hematology and coagulation function; organ function; and the sequential organ failure assessment (SOFA) score. Hospital, 28-day, and ICU mortality were also observed. Patients treated with HA hemoperfusion showed a significant removal of plasma IL-6 and IL-8 over time while in the study. Patients in the HA group also demonstrated significant increases in cardiac index, systemic vascular resistant index, fast withdrawal of vasoactive agents and decreases in heart rate compared with the controls at days 3 and 7. Although there was no significant difference between the groups in organ dysfunction as assessed by SOFA scores from day 0 (baseline) to day 7, significant improvement can be demonstrated in the hemoperfusion group at day 14. There was no significant difference between the groups in 28-day mortality, hospital mortality, or length of hospital stay, but ICU mortality and the length of ICU stay in the HA group were markedly reduced. Hemoperfusion treatment using the HA type cartridge in sepsis is safe and it may improve organ dysfunction, ICU mortality, and shorten the length of ICU stay. Clinical significant removal of inflammatory cytokines such as IL-6 and IL-8 from circulation by hemoperfusion may contribute to improving a patient's outcome in an ICU.

Topics: Aged; Aged, 80 and over; Blood Pressure; Female; Heart Rate; Hemoperfusion; Hospital Mortality; Humans; Intensive Care Units; Interleukin-6; Interleukin-8; Length of Stay; Male; Middle Aged; Multiple Organ Failure; Sepsis; Severity of Illness Index; Shock, Septic; Survival; Time Factors

The present study is aimed to determine serum and urine interleukin-8 (IL-8) levels in premature infants with late onset sepsis (LOS) and to evaluate if urine IL-8 is a useful test for LOS diagnosis. Fifty-six premature infants admitted to the NICU over 1 year had serum and urine IL-8 determined by ELISA. They were divided into three groups: I definite sepsis, II probable sepsis and III non-infected. Results were expressed as mean or median. Differences between groups were assessed by ANOVA, Kruskal-Wallis ANOVA and Dunn's Method. Sensitivity, specificity and positive and negative predictive values were calculated and a receiver operator characteristic curve was constructed to determine serum and urine IL-8 accuracy. There were no differences between groups for birth weight, and gestational and post-natal age. Median serum and urine IL-8 levels were significantly higher in GI and GII: 929 x 906 x 625 pg/ml; P = 0.024, and 249 x 189 x 42 pg/mgCr; P < 0.001. Optimal cut-off point was 625 pg/ml for serum IL-8 with 69% sensitivity and 75 pg/mgCr for urine IL-8 with 92% sensitivity. IL-8 can be determined in urine from premature infants with LOS and is an accurate and feasible diagnosis method.

Topics: Analysis of Variance; Biomarkers; Humans; Infant, Newborn; Infant, Premature; Interleukin-8; ROC Curve; Sensitivity and Specificity; Sepsis

Despite abundant experimental studies of biomarker patterns in early severe sepsis and septic shock, human data are few. Further, the impact of the severity of global tissue hypoxia resulting from resuscitative strategies on these early biomarker patterns remains unknown.. The temporal patterns of interleukin-1 receptor antagonist, intercellular adhesion molecule-1, tumor necrosis factor-alpha, caspase-3, and interleukin-8 were serially examined over the first 72 hrs of hospitalization after early hemodynamic optimization strategies of early goal-directed vs. standard therapy for severe sepsis and septic shock patients. The relationship of these biomarker patterns to each hemodynamic optimization strategy, severity of global tissue hypoxia (reflected by lactate and central venous oxygen saturation), organ dysfunction, and mortality were examined.. Abnormal biomarker levels were present upon hospital presentation and modulated to distinct patterns within 3 hrs based on the hemodynamic optimization strategy. The temporal expression of these patterns over 72 hrs was significantly associated with the severity of global tissue hypoxia, organ dysfunction, and mortality.. In early severe sepsis and septic shock, within the first 3 hrs of hospital presentation, distinct biomarker patterns emerge in response to hemodynamic optimization strategies. A significant association exists between temporal biomarker patterns in the first 72 hrs, severity of global tissue hypoxia, organ dysfunction, and mortality. These findings identify global tissue hypoxia as an important contributor to the early inflammatory response and support the role of hemodynamic optimization in supplementing other established therapies during this diagnostic and therapeutic "window of opportunity."

Topics: Aged; Biomarkers; Caspase 3; Female; Humans; Immunoassay; Intercellular Adhesion Molecule-1; Interleukin-8; Male; Middle Aged; Receptors, Interleukin-1; Sepsis; Shock, Septic; Time Factors; Tumor Necrosis Factor-alpha

Children with cancer often develop febrile illnesses after cytotoxic chemotherapy. Determining which children have serious bacterial infections in this vulnerable period would be valuable. We evaluated the ability of a rapid and sensitive assay for the concentration of calcitonin precursors (CTpr) as a sensitive diagnostic marker for bacterial sepsis in febrile, neutropenic children and determined the utility of measuring cytokines to improve the predictive value of this approach.. Prospective cohort study.. Academic children's hospital.. Fifty-six children (aged 5 months to 17 yrs) with a known malignancy who presented with fever and neutropenia.. Serial blood samples were obtained (admission, 24 hrs, and 48 hrs), and concentrations of CTpr, interleukin-6, and interleukin-8 were determined. Demographic and laboratory data from the patients were collected from the medical record.. Sixteen (29%) of the children met the criteria for bacterial sepsis. Plasma levels of CTpr and interleukin-8, but not interleukin-6, were increased at all time points in children with sepsis compared with those without sepsis. CTpr at 24 and 48 hrs after admission were reliable markers for sepsis (area under the curve = 0.92 and 0.908, respectively). Logistic regression using CTpr at 24 hrs in addition to interleukin-8 at 48 hrs produced the best-fit models associated with sepsis. Using cutoff values of CTpr >500 pg/mL and interleukin-8 >20 pg/mL produced a screening test for sepsis with 94% sensitivity and 90% specificity.. Our data show the utility of a rapid and sensitive assay for CTpr combined with interleukin-8 as a highly sensitive and specific diagnostic marker of bacterial sepsis in febrile, neutropenic children. The use of these markers as a clinical tool may allow for better prognostication for clinicians and may eventually lead to more targeted therapies for this heterogeneous population.

Topics: Adolescent; Bacterial Infections; Calcitonin; Child; Child, Preschool; Female; Fever; Follow-Up Studies; Humans; Infant; Interleukin-6; Interleukin-8; Luminescent Measurements; Male; Neoplasms; Neutropenia; Prospective Studies; Protein Precursors; Sensitivity and Specificity; Sepsis

Despite recent advances in the prospective identification of the patient with sepsis who may benefit from anti-inflammatory or antithrombotic therapies, successful treatment regimens have been fairly modest. We have explored whether determination of several proinflammatory cytokine or mediator concentrations can complement physiologic scoring systems to identify patients with severe sepsis who will survive or expire within 28 days. The design of the study included an exploratory analysis performed in conjunction with a prospective, randomized, double-blind, placebo-controlled, multicenter, clinical trial and involved 33 academic institutions in the United States. One hundred twenty-four patients with severe sepsis with or without septic shock were included in this analysis. Blood samples were obtained at baseline and on days 1 through 4, and were evaluated for proinflammatory and anti-inflammatory cytokine concentrations, as well as for procalcitonin and total protein C levels. Baseline concentrations and changes in the concentrations of these mediators were evaluated in relationship to the Acute Physiology and Chronic Health Evaluation (APACHE) II and multiple organ dysfunction (MOD) scores, and 28-day all-cause mortality. Using univariate logistic regression analyses, APACHE II and MOD scores, age (but not gender), and baseline plasma interleukin (IL)-6 and soluble tumor necrosis factor receptor (sTNFR) 1 (log transformed) concentrations were all predictive of increased 28-day all-cause mortality (P < 0.01). Baseline total protein C, IL-8, IL-10, TNF-alpha, and procalcitonin concentrations, and the change in plasma cytokine concentrations from baseline over the initial 4 days were not useful in predicting outcome. Selected baseline proinflammatory cytokine concentrations and APACHE II score were correlated (P < 0.01). IL-6 concentration is a strong candidate for predicting clinical outcome in patients with severe sepsis alone, or when combined with the APACHE II or MOD scores. The potential usefulness of the combination of cytokine measurements and prognostic scores to identify patients who may benefit from treatment with anti-inflammatory or antithrombotic therapies should be further evaluated.

Topics: Aged; Calcitonin; Calcitonin Gene-Related Peptide; Cytokines; Double-Blind Method; Female; Humans; Inflammation; Interleukin-10; Interleukin-6; Interleukin-8; Male; Middle Aged; Placebos; Prognosis; Protein C; Protein Precursors; Receptors, Tumor Necrosis Factor; Regression Analysis; Respiratory Distress Syndrome; Risk; Sepsis; Time Factors; Treatment Outcome; Tumor Necrosis Factor-alpha

The objective of this study was to clarify the efficacy and mechanism of action of direct hemoperfusion with an immobilized polymyxin B fiber column (DHP-PMX) in patients with acute lung injury or acute respiratory distress syndrome caused by sepsis.. Thirty-six patients with sepsis were included. In each patient a thermodilution catheter was inserted, and the oxygen delivery index and oxygen consumption index were measured. DHP-PMX was performed in patients with a normal oxygen delivery index and oxygen consumption index (> 500 ml/minute per m2 and > 120 ml/minute per m2, respectively). The Acute Physiology and Chronic Health Evaluation II score was used as an index of the severity of sepsis, and survival was assessed after 1 month. The humoral mediators measured were the chemokine IL-8, plasminogen activator inhibitor-1, and neutrophil elastase (NE). These mediators were measured before DHP-PMX treatment, and at 24, 48, and 78 hours after the start of treatment. The arterial oxygen tension (PaO2)/fractional inspired oxygen (FiO2) ratio was measured before DHP-PMX treatment and at 24, 48, 72, 92, and 120 hours after the start of treatment.. All patients remained alive after 1 month. Before DHP-PMX treatment, the Acute Physiology and Chronic Health Evaluation II score was 24 +/- 2.0, the IL-8 level was 54 +/- 15.8 pg/ml, plasminogen activator inhibitor-1 was 133 +/- 28.1 ng/ml, and NE was 418 +/- 72.1 mug/l. These three humoral mediators began to decrease from 24 hours after DHP-PMX treatment, and the decline became significant from 48 hours onward. The PaO2/FiO2 ratio was 244 +/- 26.3 before DHP-PMX treatment but improved significantly from 96 hours onward. There were significant negative correlations between the PaO2/FiO2 ratio and blood levels of NE and IL-8.. The mechanism of action of DHP-PMX is still not fully understood, but we report the following findings. The mean blood levels of plasminogen activator inhibitor-1, NE, and IL-8 were significantly decreased from 48 hours after DHP-PMX treatment. The mean PaO2/FiO2 ratio was significantly improved from 96 hours after DHP-PMX treatment. Improvement in the PaO2/FiO2 ratio appeared to be related to the decreases in blood NE and IL-8 levels.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Biomarkers; Endothelial Cells; Female; Hemoperfusion; Humans; Interleukin-8; Leukocyte Elastase; Male; Middle Aged; Oxygen; Plasminogen Activator Inhibitor 1; Polymyxin B; Respiratory Distress Syndrome; Sepsis; Time Factors; Treatment Outcome

Bacterial infection represents a serious risk in neonates and critically ill paediatric patients. Current clinical practice is characterized by frequent antibiotic treatment despite low incidence of true infection. However, some patients escape early diagnosis and progress to septic shock. Many new markers, including cytokines, have been suggested to improve decision making, but the clinical efficacy of these techniques remains uncertain. Therefore, we will test the clinical efficacy of a previously validated diagnostic strategy to reduce antibiotic usage and nosocomial infection related morbidity.. All patients admitted to the multidisciplinary neonatal and paediatric intensive care unit of a university children's hospital will be included. Patients will be allocated either to routine sepsis work up or to the intervention strategy with additional cytokine measurements. Physicians will be requested to estimate the pre-test probability of sepsis and pneumonia at initial suspicion. In the treatment arm, physicians will receive raw cytokine results, the likelihood ratio and the updated post-test probability. A high post-test probability will suggest that immediate initiation of antibiotic treatment is appropriate, whereas a low post-test probability will be supportive of watchful waiting or discontinuing prophylactic empirical therapy. Physicians may overrule the suggestions resulting from the post-test probability.. This trial will ascertain the clinical efficacy of introducing new diagnostic strategies consisting of pre-test probability estimate, novel laboratory markers, and computer-generated post-test probability in infectious disease work up in critically ill newborns and children.

Topics: Anti-Bacterial Agents; Bacteriological Techniques; Biomarkers; Child; Child, Preschool; Cost-Benefit Analysis; Drug Utilization; Early Diagnosis; Granulocyte Colony-Stimulating Factor; Hospitals, Pediatric; Humans; Infant; Infant, Newborn; Intensive Care Units, Neonatal; Intensive Care Units, Pediatric; Interleukin-8; Multicenter Studies as Topic; Predictive Value of Tests; Randomized Controlled Trials as Topic; Sepsis; Switzerland

The diagnosis of sepsis in critically ill patients is challenging because traditional markers of infection are often misleading. The present study was conducted to determine the procalcitonin level at early diagnosis (and differentiation) in patients with systemic inflammatory response syndrome (SIRS) and sepsis, in comparison with C-reactive protein, IL-2, IL-6, IL-8 and tumour necrosis factor-alpha.. Thirty-three intensive care unit patients were diagnosed with SIRS, sepsis or septic shock, in accordance with the American College of Chest Physicians/Society of Critical Care Medicine consensus criteria. Blood samples were taken at the first and second day of hospitalization, and on the day of discharge or on the day of death. For multiple group comparisons one-way analysis of variance was applied, with post hoc comparison. Sensitivity, specificity and predictive values of PCT and each cytokine studied were calculated.. PCT, IL-2 and IL-8 levels increased in parallel with the severity of the clinical condition of the patient. PCT exhibited a greatest sensitivity (85%) and specificity (91%) in differentiating patients with SIRS from those with sepsis. With respect to positive and negative predictive values, PCT markedly exceeded other variables.. In the present study PCT was found to be a more accurate diagnostic parameter for differentiating SIRS and sepsis, and therefore daily determinations of PCT may be helpful in the follow up of critically ill patients.

Topics: Adult; Aged; Area Under Curve; Biomarkers; C-Reactive Protein; Calcitonin; Calcitonin Gene-Related Peptide; Critical Care; Female; Humans; Interleukin-2; Interleukin-6; Interleukin-8; Male; Middle Aged; Predictive Value of Tests; Protein Precursors; Sepsis; Shock, Septic; Systemic Inflammatory Response Syndrome; Tumor Necrosis Factor-alpha

Late-onset sepsis in the NICU is a major problem associated with high morbidity and mortality.. To determine if clinical characteristics, hematological parameters and serial measurements of serum IL-6 and IL-8 can detect late-onset sepsis in premature neonates prior to positive blood cultures.. The study was done in 2 phases. The first phase (S1) was a retrospective evaluation of clinical signs and timing of blood culture positivity in all neonates with late-onset cultures proven sepsis from 1991-1998. The second phase (S2) was a prospective study that enrolled infants > or = 72 hours old, suspected of sepsis based on the presence of criteria identified in S1. At that time (day 0), blood was drawn for a CBC with differential, blood culture, IL-6 and IL-8 levels; cytokine levels were repeated on day 1. Infants with positive cultures were diagnosed as confirmed sepsis; those with negative cultures, as no sepsis.. S1: Of the 48 episodes of culture proven, late-onset sepsis, 54% of the blood cultures were positive by 24 hours and 90% by 48 hours. The most common presenting signs were desaturations (50%) and increased gastric residuals (33%); I/T ratio > 0.16 differentiated between gram-positive, negative and fungal infections (p = 0.007). S2: 27 infants were enrolled. Eight (mean [SEM] gestational age of 28.2 [0.94] weeks; birth weight of 1.15 [0.11] kg) had positive blood cultures; 19 (gestational age of 27.7 [0.9] weeks; birth weight of 1.06 [0.13] kg) had no sepsis. Infants with sepsis were more likely to have apnea/bradycardia (p = 0.002); no differences in hematological profile, as compared to those with no sepsis. Seven (88%) infants had positive blood cultures by 48 hours. Median values of IL-6 (pg/ml) were higher in infants with sepsis vs. those with no sepsis on days 0 [40 vs. 13] (p = 0.03) and 1 [24 vs. 9] (p < 0.001). IL-8 levels were not significantly different.. In both S1 and S2, a majority of the blood cultures were positive by 48 hours. IL-6 levels on days 0 and 1 were significantly higher in infants with confirmed sepsis, prior to the blood culture being positive. IL-6 levels may be useful in the initiation as well as early termination of antibiotic therapy in late-onset neonatal sepsis.

Topics: Biomarkers; Cytokines; Female; Gestational Age; Humans; Infant, Newborn; Infant, Premature, Diseases; Interleukin-6; Interleukin-8; Leukocyte Count; Male; Neutrophils; Prospective Studies; Retrospective Studies; Sepsis; Thrombocytopenia; Time

To investigate the influence of continuous renal replacement therapy (CRRT) on the plasma levels of endotoxin and cytokines in severely burned patients with sepsis.. Ten burn patients who received CRRT and another 10 without CRRT were investigated in terms of the changes in their plasma concentrations of endotoxin and some cytokines (TNFalpha, IL-1beta, IL-6, IL-8).. The plasma concentrations of endotoxin and all the cytokines (TNFalpha, IL-1beta, IL-6, IL-8) after CRRT treatment were significantly lower than those before the treatment (P < 0.01), and the plasma levels of the above factors at all the time points after CRRT treatment than those in patients were evidently lower by routine treatment (P < 0.05 - 0.01).. CRRT treatment could effectively lower the plasma levels of endotoxin and some cytokines (TNFalpha, IL-1beta, IL-6, IL-8).

Topics: Burns; Endotoxins; Humans; Interleukin-1beta; Interleukin-6; Interleukin-8; Renal Replacement Therapy; Sepsis; Tumor Necrosis Factor-alpha

Expression of inflammatory mediators is controlled in part at the transcriptional level via nuclear factor-kappa B. Inhibition of nuclear factor-kappa B activation may be beneficial in critically ill patients. N-acetylcysteine is an antioxidant that inhibits nuclear factor-kappa B activation in vitro. In this pilot study we investigated the effect of N-acetylcysteine on nuclear factor-kappa B activation and circulating cytokine and adhesion molecules in patients with sepsis.. Prospective, randomized, double blind, placebo-controlled pilot trial.. Eight-bed intensive care unit in a university teaching hospital.. Twenty consecutive patients within 12 hrs of fulfilling the consensus criteria for sepsis.. A bolus of 150 mg/kg N-acetylcysteine in 100 mL of 0.9% saline over 15 mins, then 50 mg/kg in 100 mL of 0.9% saline over 4 hrs as a loading dose, and then a maintenance infusion of 50 mg/kg in 200 mL of 0.9% saline over each 24-hr period for a total of 72 hrs, or an equivalent volume of saline.. Nuclear factor-kappa B activation was measured in mononuclear leukocytes using electrophoretic mobility shift assay, at baseline and 24, 48, 72, and 96 hrs later. Activation decreased significantly in patients treated with N-acetylcysteine (p =.016) but not placebo and was significantly reduced at 72 hrs compared with both preinfusion values (p =.028) and patients receiving placebo (p =.01). Plasma interleukin-6, interleukin-8, and soluble intercellular adhesion molecule-1 concentrations were measured using enzyme immunoassay. Interleukin-6 concentrations were high initially and then decreased in all patients, regardless of whether they received N-acetylcysteine or placebo. Interleukin-8 decreased significantly only in those who received N-acetylcysteine (p =.0081). Soluble intercellular adhesion molecule-1 concentrations remained unchanged in all patients.. Administration of N-acetylcysteine results in decreased nuclear factor-kappa B activation in patients with sepsis, associated with decreases in interleukin-8 but not interleukin-6 or soluble intercellular adhesion molecule-1. These pilot data suggest that antioxidant therapy with N-acetylcysteine may be useful in blunting the inflammatory response to sepsis. Further studies are warranted.

Topics: Acetylcysteine; Adult; Aged; Aged, 80 and over; Double-Blind Method; Female; Free Radical Scavengers; Humans; Infusions, Intravenous; Intercellular Adhesion Molecule-1; Interleukin-6; Interleukin-8; Male; Middle Aged; NF-kappa B; Sepsis

The first objective of this article was to determine the diagnostic accuracy of tumor necrosis factor-alpha, interleukin-6 (IL-6), and interleukin-8 (IL-8) in differentiating infected from noninfected neonates during the first 24 hours of suspected sepsis and to compare them to the currently used laboratory parameters: C-reactive protein (CRP), immature-to-total neutrophil ratio, and leukocyte and platelet count. The secondary objective was to compare the cytokine levels in subpopulations of neonates. Seventy-five premature and 30 term infants were enrolled. Blood samples for the "currently used laboratory tests" and the cytokine levels were obtained at the first suspicion of sepsis ("0-hour") and 18 to 30 hours later ("24-hours"). Patients were classified as septic (48) or nonseptic (57). Thirty-two septic patients had positive blood cultures and 16 showed clinical signs of sepsis. Twenty septic patients had early-onset and 28 had late-onset sepsis. Sensitivity, specificity, and positive and negative predictive values (PPV and NPV) were calculated for each test. Receiver-operating characteristic curves were analyzed to determine the optimal thresholds. A combination of CRP > 10 pg/mL plus IL-6 > 18 pg/mL (sensitivity = 89%, specificity = 73%, PPV = 70%, NPV = 90%) was the best "0-hour" test, and CRP (sensitivity = 78%, specificity = 94%) was the best "24-hours" test. Lower IL-6 at 0-hour (p = 0.018) and IL-8 at 24 hours (p = 0.023) were detected among the patients infected with coagulase-negative staphylococci then with other bacteria. In conclusion, a combination of CRP + IL-6 provided additional diagnostic accuracy for differentiation between septic and nonseptic patients during the first 24 hours of suspected sepsis.

Topics: Biomarkers; C-Reactive Protein; Cytokines; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Inflammation; Interleukin-6; Interleukin-8; Prospective Studies; Reference Values; ROC Curve; Sensitivity and Specificity; Sepsis; Tumor Necrosis Factor-alpha

To study the effect of early and continuous venovenous hemofiltration (CVVH) on the plasma concentrations of several humoral mediators of inflammation and subsequent organ dysfunction in septic patients.. Randomized, controlled trial.. Intensive care unit of a tertiary hospital.. Twenty-four patients with early septic shock or septic organ dysfunction.. Random allocation to receive 48 hrs of isovolemic CVVH at 2 L/hr of fluid exchange or no hemofiltration.. We measured the plasma concentrations of complement fractions C3a and C5a, interleukins 6, 8, and 10, and tumor necrosis factor alpha at baseline and 2, 24, 26, 48, and 72 hrs. A multiple organ dysfunction score (MODS) was calculated daily for each patient until death or discharge from the intensive care unit. The concentrations of most mediators decreased between baseline and 72 hrs. Some significant falls in concentration could be identified between specific time points, but CVVH was not associated with an overall reduction in any plasma cytokine concentrations. There was also no difference between the mean cumulative MODS for control survivors (43.3 +/- 19.7) and CVVH survivors (33.2 +/- 19.0; p = .30), and no difference between the average MODS calculated for all controls (4.1 +/- 1.9) and all CVVH subjects (3.3 +/- 1.7; p = .26). CVVH did not improve oxygenation, lower the platelet count, or reduce the duration of vasopressor support and mechanical ventilation.. Early use of CVVH at 2 L/hr did not reduce the circulating concentrations of several cytokines and anaphylatoxins associated with septic shock, or the organ dysfunction that followed severe sepsis. CVVH using current technology cannot be recommended as an adjunct to the treatment of septic shock unless severe acute renal failure is present.

Topics: Aged; Aged, 80 and over; Anaphylatoxins; Complement C3a; Complement C5a; Female; Hemofiltration; Humans; Interleukin-10; Interleukin-6; Interleukin-8; Male; Middle Aged; Sepsis; Tumor Necrosis Factor-alpha

Conventional outcomes research provides only percentage risk of such end points as mortality rate, utilization of resources, and/or broad groupings of multiple organ system dysfunction. These prognostications generally are not applicable to individual patients. The purpose of the present study was to determine whether the Systemic Mediator Associated Response Test (SMART) methodology could identify interactions among demographics, physiologic variables, standard hospital laboratory tests, and circulating cytokine concentrations that predicted continuous and dichotomous dependent clinical variables, in advance, in individual patients with severe sepsis and septic shock, and whether these independent variables could be integrated into prospectively validated predictive models.. Data review and multivariate stepwise logistic regression.. University research laboratory.. Three hundred three patients with severe sepsis or septic shock who comprised the placebo arm of a multiple-institution clinical trial, who were randomly separated into a model building training cohort (n = 200) and a predictive cohort (n = 103).. None.. From baseline data and baseline plus serial input, including patient demographics, hospital laboratory tests, and plasma concentrations of interleukin-6, interleukin-8, and granulocyte colony stimulating factor, multiple regression models were developed that predicted clinically important continuous dependent variables quantitatively, in individual patients. Multivariate stepwise logistic regression was used to develop models that prognosticated dichotomous dependent end points. Data from individual patients in the predictive cohort were inserted into each predictive model for each day, with prospective validation accomplished by simple linear regression of individual predicted vs. observed values for continuous dependent variables, and by establishing the receiver operator characteristics area under the curve for logistic regression models that predicted dichotomous end points. Of SMART models for continuous dependent variables, 100 of 143 (70%) were validated at r values >.7 through day 3, and 184 of 259 (71%) above r =.5 through day 5. SMART predictions of dichotomous end points achieved receiver operator characteristics areas under the curve >.7 for up to 84% of the equations in the first week. Many SMART models for both continuous and dichotomous dependent variables were validated at clinically useful levels of accuracy as far as 28 days after baseline.. SMART integration of demographics, bedside physiology, hospital laboratory tests, and circulating cytokines predicts organ failure and physiologic function indicators in individual patients with severe sepsis and septic shock.

Topics: Clinical Laboratory Techniques; Granulocyte Colony-Stimulating Factor; Humans; Interleukin-6; Interleukin-8; Logistic Models; Models, Theoretical; Multiple Organ Failure; Prognosis; Sepsis; Shock, Septic

Antithrombin III (AT III) is an important inhibitor of thrombin activity, as well as of many other proteases of the coagulation system. AT III administration showed beneficial effects on septic multiple organ dysfunction in clinical and experimental studies. It was the aim of this study to determine whether continuous long-term AT III supplementation alters the systemic inflammatory response in patients with severe sepsis. In a prospective study, 29 surgical patients with severe sepsis were randomly assigned to receive either conventional intensive care treatment (n = 15, control group) or additional AT III supplementation to achieve a plasma AT III activity >120% during a 14 day study period (n = 14, AT III group). Plasma concentrations of interleukin (IL)-6 and IL-8 and of the circulating soluble adhesion molecules sICAM-1 and sE-selectin, as well as of PMN elastase, were determined daily. Additionally, total leukocyte count and C-reactive protein (CRP) were measured daily, and body temperature was registered. Compared to control patients, a down-regulation of plasma IL-6 was observed in the AT III group (p < or = .01). AT III supplementation prevented the continuous increase in sICAM-1 plasma concentration observed in control patients and led to a significant fall in soluble sE-selectin and CRP concentration (p < or = .01). This fall corresponded to a down-regulation of body temperature over time (p < or = .01). There was no AT III effect on IL-8, PMN-elastase concentration, or total leukocyte count. Our results show that long-term AT III supplementation attenuates the systemic inflammatory response in patients with severe sepsis. The down-regulation of IL-6 may also explain the fall in endothelium-derived adhesion molecules and may represent the molecular basis by which AT III exerts its beneficial effects on organ function.

Topics: Adult; Aged; Anticoagulants; Antithrombin III; C-Reactive Protein; Critical Care; E-Selectin; Female; Humans; Inflammation; Intercellular Adhesion Molecule-1; Interleukin-6; Interleukin-8; Leukocyte Count; Male; Middle Aged; Multiple Organ Failure; Prospective Studies; Sepsis

To define the influence of interleukin-1 activity on coagulation and fibrinolytic system activation and the release of proinflammatory mediators in the early human response to severe infection.. All patients with severe sepsis syndrome who were enrolled from two surgical centers that were participating in a randomized, double-blind, placebo controlled, multicenter, multinational trial of recombinant human interleukin-1 receptor antagonist in the treatment of sepsis syndrome.. Twenty-six patients with sepsis syndrome received an intravenous loading dose of recombinant human interleukin-1 receptor antagonist (100 mg) or placebo followed by a continuous 72-hour infusion of recombinant human interleukin-1 receptor antagonist (1.0 [n = 9] or 2.0 [n = 8] mg/kg per hour) or placebo (n = 9).. Responses up to 72 hours after initiation of treatment.. Plasma levels of the anaphylatoxin C3a and thrombin-antithrombin III complexes were reduced in the high-dose recombinant human interleukin-1 receptor antagonist treatment group after 72 hours (P < .05). Similarly, parameters of fibrinolysis, tissue-type plasminogen activator, and plasminogen activator inhibitor type 1 but not plasmin-alpha 2-antiplasmin complexes, were also significantly reduced (P < .05) after 72 hours of treatment with a high dose of recombinant human interleukin-1 receptor antagonist. Neutrophil elastase-alpha 1-antitrypsin complexes and phospholipase A2 levels were also significantly reduced in the high-dose recombinant human interleukin-1 receptor antagonist treatment group after 72 hours.. The results confirm that activation of the coagulation and fibrinolytic systems and release of soluble inflammatory mediators are consistently observed in patients with severe sepsis syndrome. Interleukin-1 activity contributes to activation of these processes as documented by the reduction in surrogate activation markers during recombinant human interleukin-1 receptor antagonist treatment.

Topics: Adult; Blood Coagulation; Complement Activation; Double-Blind Method; Fibrinolysis; Hemostasis; Humans; Interleukin 1 Receptor Antagonist Protein; Interleukin-6; Interleukin-8; Neutrophil Activation; Phospholipases A; Phospholipases A2; Receptors, Interleukin-1; Sepsis; Sialoglycoproteins

Neonatal sepsis accounts for 0.97% of all disability-adjusted life years worldwide. Interleukin-6 has been used in sepsis diagnosis, but cut-off values are missing.. Neonates admitted to the neonatal wards with measurements of serum interleukin-6 born between September 2015 and September 2019 were retrospectively analysed. Mean serum interleukin-6 values of patients who never had increased laboratory parameters of infection nor died during their stay and mean interleukin-6 values on the day of blood sampling for a later positive culture in patients with culture-confirmed sepsis were analysed for each time period.. In all, 8.488 values in 1.695 neonates, including 752 very-preterm-infants and 701 very-low-birthweight infants, were analysed. The AUC for interleukin-6 was 0.84-0.91 in all neonates, 0.88-0.89 in very-preterm and 0.89-0.91 in very-low-birthweight infants. Using interleukin-6 cut-off values of 80 pg/ml on day of life 1, 40 pg/ml on day of life 2-7 and 30 pg/ml after day of life 7, a sensitivity of 75% and a specificity of 81% for culture-confirmed sepsis were achieved. In very-preterm infants, the corresponding values were 74% for sensitivity and 83% for specificity and in very-low-birthweight infants 74% and 86%, respectively.. Serum interleukin-6 has high accuracy for the detection of neonatal sepsis.. Serum interleukin-6 can be used with high accuracy to detect sepsis in neonates with the cut-off values of 80 pg/ml on day of life 1, 40 pg/ml on day of life 2-7 and 30 pg/ml after day of life 7. Serum interleukin-6 can be used with high accuracy to detect sepsis in neonates and very-preterm as well as very-low-birthweight infants. Interleukin-6 values display distinct cut-off values depending on the chronological age of the infant. Our article provides the first cut-off values for interleukin-6 in the first days of life in neonates.

Topics: Biomarkers; C-Reactive Protein; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Interleukin-6; Interleukin-8; Neonatal Sepsis; Retrospective Studies; Sensitivity and Specificity; Sepsis

Blood purification therapy is a method used to enable cytokine removal and to improve disturbed immune homeostasis in patients with sepsis or septic shock. This study aimed to evaluate the impact of HA 330 treatment on biochemical and hemodynamic parameters and cytokine levels in adult patients with septic shock.. Critically ill patients with septic shock who received continuous veno-venous hemodiafiltration and HA 330 treatment were included in this prospective observational study. Biochemical and hemodynamic parameters were followed throughout HA 330 treatment. Serum interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor (TNF)-α, high-mobility group box1 (HMGB-1) protein, IL-10 levels were analyzed by ELISA method, before and after each HA 330 session.. A total of 18 critically ill patients were included in this study. The median APACHE 2 score was 22.2 ± 7.49 and median SOFA score 9.6 ± 5.44 on intensive care unit admission. SOFA scores were significantly decreased on the 3rd day of HA 330 treatment, compared to 2nd day scores (p = 0.017). Median leukocyte value was significantly decreased (p = 0.027 and p = 0.024), while hemodynamic parameters remained unchanged throughout the HA 330 treatment. Median CRP and procalcitonin levels were significantly reduced at day 3 of HA 330 treatment compared to the baseline (p = 0.015 and p = 0.033, respectively). Serum IL-1 β, IL-6, IL-8, TNF-a, HMGB-1, and IL-10 levels decreased insignificantly by 11.5%, 26.4%, 11.4%, 37.9%, 0.02%, and 35.5%, respectively, at the end of the hemoperfusion treatment compared to the pre-treatment.. The administration of HA 330-based hemoperfusion in septic shock patients revealed improvements in SOFA scores, leukocyte count, and CRP and procalcitonin levels. However, there was no statistically significant change in concentrations of inflammatory cytokines and hemodynamic parameters during HA 330 treatment.

Topics: Adult; Continuous Renal Replacement Therapy; Critical Illness; Cytokines; HMGB Proteins; Humans; Interleukin-10; Interleukin-6; Interleukin-8; Procalcitonin; Prognosis; Sepsis; Shock, Septic; Tumor Necrosis Factor-alpha

Escherichia coli and Group B streptococci (GBS) are the main causes of neonatal early-onset sepsis (EOS). Despite antibiotic therapy, EOS is associated with high morbidity and mortality. Dual inhibition of complement C5 and the Toll-like receptor co-factor CD14 has in animal studies been a promising novel therapy for sepsis.. Whole blood was collected from the umbilical cord after caesarean section (n = 30). Blood was anti-coagulated with lepirudin. C5 inhibitor (eculizumab) and anti-CD14 was added 8 min prior to, or 15 and 30 min after adding E. coli or GBS. Total bacterial incubation time was 120 min (n = 16) and 240 min (n = 14). Cytokines and the terminal complement complex (TCC) were measured using multiplex technology and ELISA.. Dual inhibition significantly attenuated TCC formation by 25-79% when adding inhibitors with up to 30 min delay in both E. coli- and GBS-induced inflammation. TNF, IL-6 and IL-8 plasma concentration were significantly reduced by 28-87% in E. coli-induced inflammation when adding inhibitors with up to 30 min delay. The dual inhibition did not significantly reduce TNF, IL-6 and IL-8 plasma concentration in GBS-induced inflammation.. Dual inhibition of C5 and CD14 holds promise as a potential future treatment for severe neonatal EOS.. Neonatal sepsis can cause severe host inflammation with high morbidity and mortality, but there are still no effective adjunctive immunologic interventions available. Adding CD14 and complement C5 inhibitors up to 30 min after incubation of E. coli or Group B streptococci in a human umbilical cord blood model significantly reduced complement activation and cytokine release. Dual inhibition of C5 and CD14 is a potential future therapy to modulate systemic inflammation in severe cases of neonatal sepsis.

Topics: Animals; Cesarean Section; Complement C5; Cytokines; Escherichia coli; Female; Fetal Blood; Humans; Infant, Newborn; Inflammation; Interleukin-6; Interleukin-8; Lipopolysaccharide Receptors; Neonatal Sepsis; Pregnancy; Sepsis

Topics: Animals; Biomarkers; Dog Diseases; Dogs; Female; Interleukin-10; Interleukin-6; Interleukin-8; Pyometra; S100A12 Protein; Secretory Leukocyte Peptidase Inhibitor; Sepsis

There are no guidelines in China or worldwide that clearly recommend indicators for the early diagnosis of sepsis in the emergency department. Simple and unified joint diagnostic criteria are also scarce. We compare the Quick Sequential Organ Failure Assessment (qSOFA) score and inflammatory mediator concentrations in patients with normal infection, sepsis, and sepsis death.. This study used a prospective and consecutive manner, including 79 patients with sepsis in the Emergency Department of Shenzhen People's Hospital from December 2020 to June 2021, and 79 patients with common infections (non-sepsis) matched by age and sex during the same period. The sepsis patients were then divided into a sepsis survival group (n = 67) and a sepsis death group (n = 12) based on whether they survived within 28 days. The baseline characteristics, qSOFA scores, the concentrations of tumor necrosis factor-α(TNF-α), interleukin (IL)-6, IL-1b, IL-8, IL-10, procalcitonin (PCT), high-sensitivity C-reactive protein (HSCRP) and other indicators were collected in all subjects.. PCT and qSOFA were independent risk factors for predicting sepsis in the emergency department. The AUC value of PCT was the largest (0.819) among all diagnostic indicators of sepsis, with a cut-off value of 0.775 ng/ml and sensitivity and specificity of 0.785 and 0.709, respectively. The AUC of qSOFA combined PCT was the largest (0.842) in the combination of the 2 indicators, and the sensitivity and specificity were 0.722 and 0.848, respectively. IL-6 was an independent risk factor for predicting death within 28 days. IL-8 had the largest AUC value (0.826) among all indicators predicting sepsis death, with a cut-off value of 215 pg/ml and sensitivity and specificity of 0.667 and 0.895, respectively. Among the combination of two indicators, qSOFA combined with IL-8 had the largest AUC value (0.782) and sensitivity and specificity of 0.833 and 0.612, respectively.. QSOFA and PCT are independent risk factors for sepsis, and qSOFA combined with PCT may be an ideal combination for early diagnosis of sepsis in the emergency department. IL-6 is an independent risk factor for death within 28 days of sepsis, and qSOFA combined with IL-8 may be an ideal combination for early prediction of death within 28 days in sepsis patients in the emergency department.

Topics: Emergency Service, Hospital; Hospital Mortality; Humans; Interleukin-6; Interleukin-8; Organ Dysfunction Scores; Procalcitonin; Prognosis; Prospective Studies; Retrospective Studies; ROC Curve; Sepsis; Tumor Necrosis Factor-alpha

There is a need for research exploring the temporal trends of nonpulmonary organ dysfunction (NPOD) and biomarkers in order to identify unique predictive or prognostic phenotypes. We examined the associations between the number and trajectories of NPODs and plasma biomarkers of early and late inflammatory cascade activation, specifically plasma interleukin-1 receptor antagonist (IL-1ra) and interleukin-8 (IL-8), respectively, in the setting of acute respiratory failure (ARF).. Secondary analysis of the Randomized Evaluation for Sedation Titration for Respiratory Failure clinical trial and Biomarkers in Acute Lung Injury (BALI) ancillary study.. Multicenter.. Intubated pediatric patients with ARF.. NPODs were evaluated against plasma IL-1ra and IL-8 levels on individual days (1 to 4 d after intubation) and longitudinally across days.. Within the BALI cohort, 432 patients had at least one value for IL-1ra or IL-8 within days 0 through 5. 36.6% had a primary diagnosis of pneumonia, 18.5% had a primary diagnosis of sepsis and 8.1% died. Multivariable logistic regression models showed that increasing levels of both plasma IL-1ra and IL-8 were statistically significantly associated with increasing numbers of NPODs (IL-1ra: days 1-3; IL-8: days 1-4), independent of sepsis diagnosis, severity of oxygenation defect, age, and race/ethnicity. Longitudinal trajectory analysis identified four distinct NPOD trajectories and seven distinct plasma IL-1ra and IL-8 trajectories. Multivariable ordinal logistic regression revealed that specific IL-1ra and IL-8 trajectory groups were associated with greater NPOD trajectory group ( p = 0.004 and p < 0.0001, respectively), independent of severity of oxygenation defect, age, sepsis diagnosis, and race/ethnicity.. Both the inflammatory biomarkers and number of NPODs exhibit distinct trajectories over time with strong associations with one another. These biomarkers and their trajectory patterns may be useful in evaluating the severity of multiple organ dysfunction syndrome in critically ill children and identifying those phenotypes with time-sensitive, treatable traits.

Topics: Biomarkers; Child; Cytokines; Humans; Interleukin 1 Receptor Antagonist Protein; Interleukin-8; Respiratory Distress Syndrome; Respiratory Insufficiency; Sepsis

Sepsis is a life-threatening systemic organ dysfunction caused by the host's unregulated response to a widespread bacterial infection. Endothelial injury is a major pathophysiologic symptom of sepsis and is considered a critical factor in promoting the progression of disease severity. ELAV like RNA binding protein 1(ELAVL1) is a ubiquitously expressed RNA-binding protein that may play an important role during sepsis. Nonetheless, the molecular mechanisms of ELAVL1 on endothelial cell damage in sepsis have not been well defined. Here, we aimed to confirm the role of ELAVL1 in sepsis-induced endothelial cell damage using lipopolysaccharide (LPS)-induced zebrafish and endothelial cells (ECs) models. We found that zebrafish larvae treated with LPS exhibited systemic endothelial cell damage, mostly manifested as pericardial edema, curved tail, and impaired angiogenesis. LPS treatments also significantly induced the expression levels of inflammatory cytokines (interleukin-6 (IL-6), IL-8, and tumor necrosis factor (TNF)-α) in vivo. In vitro, we observed the increase of ELAVL1 cytoplasmic translocation with LPS treatment. Mechanistically, targeted disruption of the ELAVL1 gene decreased the expression of TNF-α, IL-6, and IL-8 during induction of sepsis and alleviated LPS-induced blood vessel injury in zebrafish. Taken together, our study indicates that ELAVL1 knockdown may alleviate sepsis-induced endothelial cells injury by suppressing cytokine storm. Our research suggests that inhibition of ELAVL1 could reduce the level of inflammatory cytokine production induced by LPS and protect against endothelial cell injury. ELAVL1 might be a potential therapeutic target to block endothelial cells injury associated with sepsis.

Topics: Animals; Cytokine Release Syndrome; Endothelial Cells; Interleukin-6; Interleukin-8; Lipopolysaccharides; Sepsis; Tumor Necrosis Factor-alpha; Zebrafish

Metrnl play an immunocytokine-like role in several diseases, which is also known as meteorin-like because it is homologous to the neurotrophic factor meteorin (Metrn). Although the expression and function of Metrnl, including neurotrophic, immunomodulatory, and insulin resistance functions in different tissues have been extensively studied, its role in sepsis has remained largely limited.. The present work analyzed the levels of Metrnl and cytokines in the circulation, such as tumor necrosis factor (TNF-α), interleukin (IL-1)β, IL-6, IL-8, together with IL-10 among septic adult patients. Clinical information was obtained from such patients, including sofa score, procalcitonin(PCT)count, and C-reactive count (CRP) within 24 h when entering the intensive care unit (ICU). We constructed a sepsis model in Metrnl-deficient or normal wild-type mice using cecal ligation and perforation to study its functions in bacterial burden, survival, cytokine/chemokine generation, peritoneal lavage fluid neutrophils, macrophage and lymphocyte recruitment, and Treg/Th17 immune cell balance after CLP-induced sepsis.. The expression of Metrnl was remarkably elevated in the early phase of sepsis clinically. Its serum content in patients dying of sepsis slightly decreased relative to that in survivors. Furthermore, the concentration of Metrnl in septic cases when entering the ICU independently predicted the 28-day mortality. For septic patients who had low serum Metrnl content (≤ 274.40 pg/mL), the death risk increased by 2.3 folds relative to those who had a high serum content. It is reported that Metrnl is probably insufficient among patients dying of sepsis. Additionally, the content of Metrnl in the serum of septic patients when entering the ICU is markedly and negatively related to the levels of TNF-α, IL-1β, IL-6, IL-8, IL-17, PCT, and Sofa score. Collectively, Metrnl could be a potential therapeutic target for sepsis. A low-lethality non-severe sepsis (NSS) model was constructed, which suggested that Metrnl insufficiency elevated the death rate and reduced bacterial clearance during sepsis. For Metrnl-deficient mice, impaired sepsis immunity defense might be related to decreased macrophage recruitment and Treg/Th17 lymphocyte imbalance. Recombinant Metrnl administered to Metrnl-deficient mice abolished the immunity defense impairment following NSS while protecting the high-lethality severe sepsis (SS) model in wild-type (WT) mice. In addition, Metrnl-induced sepsis prevention was intricately associated with the increased recruitment of peritoneal macrophages and modulation of the Treg/TH17 immune cell balance. Furthermore, CCL3 exposure in Metrnl-deficient mice reduced peritoneal bacterial loads while improving survival during sepsis partially by promoting the recruitment of peritoneal macrophages. Furthermore, Metrnl regulated the polarization of M1 macrophages through the ROS signaling pathway and promoted macrophage phagocytosis, thereby killing Escherichia coli.. The present proof-of-concept work suggests that Metrnl-mediated recruitment of macrophages significantly affects sepsis defense in the host and modulates the Treg/Th17 immune cell balance. Findings in this work shed more light on the development of host-directed treatments that can be used to manipulate host immunity to treat sepsis.

Topics: Animals; Cytokines; Interleukin-6; Interleukin-8; Interleukins; Macrophages; Mice; Sepsis; T-Lymphocytes, Regulatory; Th17 Cells; Tumor Necrosis Factor-alpha

Sepsis-associated encephalopathy (SAE) is frequently present at the acute and chronic phase of sepsis, which is characterized by delirium, coma, and cognitive dysfunction. Despite the increased morbidity and mortality of SAE, the pathogenesis of SAE remains unclear. This study aims to discover the potential biomarkers, so as to clear the pathogenesis potentially contributing to the development of SAE and provide new therapeutic strategies for the treatment of SAE.. The GSE135838 dataset was obtained from the Gene Expression Omnibus (GEO) database and utilized for analysis the differentially expressed genes (DEGs). The DEGs were analyzed by limma package of R language and the extracellular protein-differentially expressed genes (EP-DEGs) were screened by the Human Protein Atlas (HPA) and UniProt database. Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were carried out to analyze the function and pathway of EP-DEGs. STRING, Cytoscape, MCODE and Cytohubba were used to construct a protein-protein interaction (PPI) network and screen key EP-DEGs. Key EP-DEGs levels were detected in the cerebrospinal fluid (CSF) of SAE patients and non-sepsis patients with critical illness. ROC curve was used to evaluate the diagnostic of SAE.. We screened 82 EP-DEGs from DEGs. EP-DEGs were enriched in cytokine-cytokine receptor interaction, IL-17 signaling pathway and NOD-like receptor signaling pathway. We identified 2 key extracellular proteins IL-1B and IL-8. We clinically verified that IL-6 and IL-8 levels were increased in CSF of SAE patients and CSF IL-8 (AUC = 0.882, 95 % CI = 0.775-0.988) had a higher accuracy in the diagnosis of SAE than CSF IL-6 (AUC = 0.824, 95 % CI = 0.686-0.961). Furthermore, we found that the IL-8 levels in CSF might not associated with Glasgow Coma Scale (GCS) scores of SAE patients.. IL-8 may be the key extracellular cytokine in the pathogenesis of SAE. Bioinformatics methods were used to explore the biomarkers of SAE and validated the results in clinical samples. Our findings indicate that the IL-8 in CSF might be the potential diagnostic biomarker and therapeutic target in SAE.

Topics: Biomarkers; Computational Biology; Gene Expression Profiling; Humans; Interleukin-6; Interleukin-8; Sepsis; Sepsis-Associated Encephalopathy

Burn injuries are the most frequent injuries in the world, with a death rate of 2.3-3.6%. Children and people of working age constitute 85-90% of the burn cases. Burn injury results in metabolic problems, a generalized inflammatory response, inefficient energy use, and other physiological alternations that may cause organ and system dysfunction and sepsis. Sepsis is mostly caused by multiple organ failures and has unique characteristics in burn injuries, which make it the most dangerous complication of burn injuries. This study aimed to investigate the correlation between sepsis in burn patients and the level of interleukin 8 (IL-8) in their serum. In total, 60 patients with burn injuries were included in this study. Blood samples were obtained from 60 burn patients and 30 healthy individuals as controls. The BacT/Alert and Vitek2 systems were used to identify the bacteria and determine their susceptibility to these bacteria. Moreover, enzyme-linked immunosorbent assay (ELISA) was used to determine IL-8 serum levels. Based on the results, elevated levels of IL-8 were observed in the serum of burn patients, compared to healthy individuals. Concentration of IL-8 was significantly higher in patients with sepsis, compared to healthy individuals without sepsis.

Topics: Burns; Child; Enzyme-Linked Immunosorbent Assay; Humans; Interleukin-6; Interleukin-8; Sepsis

Although early diagnosis and management are critical for prognosis of pediatric sepsis, there are no specific diagnostic biomarkers for the hyperinflammatory state and organ dysfunction, important stages of sepsis.. We enrolled 129 children with infection into three groups: non-sepsis infection (33), Sepsis 1.0 (hyperinflammatory state, 67), and Sepsis 3.0 (organ dysfunction, 29). Another 32 children with no infections were included as controls. Serum C-reactive protein (CRP), procalcitonin (PCT), interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-17, tumor necrosis factor (TNF)-α, interferon (IFN)-α, and IFN-γ were assessed to diagnose the two stages, and their diagnostic capacities were evaluated using receiver operating characteristic (ROC) curves. We also examined whether combining biomarkers improved diagnostic efficiency.. Significantly higher CRP, PCT, and IL-6 levels were detected in the Sepsis 1.0 than the non-sepsis infection group (p < 0.001). The areas under the curve (AUCs) for diagnosing Sepsis 1.0 were 0.974 (CRP), 0.913 (PCT) and 0.919 (IL-6). A combination of any two biomarkers increased diagnostic sensitivity to ≥92.54% and specificity to 100.00%. Significantly higher PCT, IL-8, and IL-10 levels were found in the Sepsis 3.0 than the Sepsis 1.0 group (p ≤ 0.01), with AUCs for diagnosing Sepsis 3.0 0.807 (PCT), 0.711 (IL-8), and 0.860 (IL-10). Combining these three biomarkers increased diagnostic sensitivity to 96.55% and specificity to 94.03%.. In pediatric sepsis, combining any two of CRP, PCT, and IL-6 can accurately diagnose the hyperinflammatory state and increase diagnostic specificity. Early diagnosis of organ dysfunction requires a combination of PCT, IL-8, and IL-10.

Topics: Biomarkers; C-Reactive Protein; Child; Early Diagnosis; Humans; Interleukin-10; Interleukin-6; Interleukin-8; Multiple Organ Failure; Procalcitonin; ROC Curve; Sepsis; Tumor Necrosis Factor-alpha

Objective To investigate the role and mechanism of long noncoding RNA (lncRNA) LOC102640791 in sepsis inflammatory response. Methods The mice model of sepsis was established by intraperitoneal injection of lipopolysaccharide (LPS). The cell model of sepsis was established by treating of RAW264.7 macrophages with LPS. Mice or cells were randomly divided into the control group and the LPS group. The levels of lncRNA and miRNA in serum were detected by microarrays. The levels of LOC102640791 and miR-320-3p were tested by the real time quantitative PCR. The levels of TNF-α, IL-6, IL-8, IL-4 and IL-10 in serum and cell culture supernatant of RAW264.7 were detected by the ELISA. Luciferase reporter gene technology was used to verify the relationship between LOC102640791 and miR-320-3p. Results Compared with the control group, the LPS group had lower expression of LOC102640791 and higher expression of miR-320-3p. Compared with the LPS group, the LPS group with high expression of LOC102640791 and the LPS group with low expression of miR-320-3p had higher expression of pro-inflammatory factors (TNF-α, IL-6 and IL-8) and lower expression of anti-inflammatory factors (IL-4 and IL-10). Wild type LOC102640791 can inhibit the luciferase activity of miR-320-3p. Conclusion LOC102640791 alleviates sepsis inflammatory response by sponging miR-320-5p.

Topics: Animals; Inflammation; Interleukin-10; Interleukin-4; Interleukin-6; Interleukin-8; Lipopolysaccharides; Mice; MicroRNAs; RNA, Long Noncoding; Sepsis; Tumor Necrosis Factor-alpha

Multiple organ dysfunction syndrome (MODS) is a critical driver of sepsis morbidity and mortality in children. Early identification of those at risk of death and persistent organ dysfunctions is necessary to enrich patients for future trials of sepsis therapeutics. Here, we sought to integrate endothelial and PERSEVERE biomarkers to estimate the composite risk of death or organ dysfunctions on day 7 of septic shock.. We measured endothelial dysfunction markers from day 1 serum among those with existing PERSEVERE data. TreeNet® classification model was derived incorporating 22 clinical and biological variables to estimate risk. Based on relative variable importance, a simplified 6-biomarker model was developed thereafter.. Among 502 patients, 49 patients died before day 7 and 124 patients had persistence of MODS on day 7 of septic shock. Area under the receiver operator characteristic curve (AUROC) for the newly derived PERSEVEREnce model to predict death or day 7 MODS was 0.93 (0.91-0.95) with a summary AUROC of 0.80 (0.76-0.84) upon tenfold cross-validation. The simplified model, based on IL-8, HSP70, ICAM-1, Angpt2/Tie2, Angpt2/Angpt1, and Thrombomodulin, performed similarly. Interaction between variables-ICAM-1 with IL-8 and Thrombomodulin with Angpt2/Angpt1-contributed to the models' predictive capabilities. Model performance varied when estimating risk of individual organ dysfunctions with AUROCS ranging from 0.91 to 0.97 and 0.68 to 0.89 in training and test sets, respectively.. The newly derived PERSEVEREnce biomarker model reliably estimates risk of death or persistent organ dysfunctions on day 7 of septic shock. If validated, this tool can be used for prognostic enrichment in future pediatric trials of sepsis therapeutics.

Topics: Biomarkers; Child; Humans; Intercellular Adhesion Molecule-1; Interleukin-8; Multiple Organ Failure; Prognosis; Sepsis; Shock, Septic; Thrombomodulin

Our research attempted to explore the effect of miR-135a on lipopolysaccharide (LPS)-induced THP-1cells damage and its potential mechanism.. LPS (1 μg/mL) was selected to mimic the injury of sepsis in vitro. qRT-PCR was used to detect miR-135a expression. The association between miR-135a and Myomesin 1 (MYOM1) was speculated bythe predication website and confirmed by the dual-luciferase assay. MYOM1 expression was observed by qRT-PCR and western blotting assays. The biological properties of THP-1cells were analyzed by cell counting kit-8 and flow cytometry assays. The concentration of TNF-α, IL-6 and IL-8 in cell supernatant was calculated by enzyme-linked immunosorbent assay.. A marked augmentation of miR-135a was observed in LPS-induced THP-1 cells. Moreover, depletion of miR-135a alleviated the LPS-induced THP-1 cells injury from the perspective of improving cell viability and reducing cell apoptosis. Importantly, MYOM1, which was under expressed in LPS-induced THP-1 cells, was identified as a target of miR-135a and negatively regulated by miR-135a. Additionally, the mitigative impact of miR-135a inhibitor on THP-1cells damage triggered by LPS was suppressed by MYOM1 depletion.. Our study suggested that the protective effect of miR-135a inhibitor on LPS-induced THP-1 cells injury was realized by regulation of MYOM1, which might afford a pair of novel molecules for sepsis clinical diagnosis.

Topics: Apoptosis; Connectin; Humans; Interleukin-6; Interleukin-8; Lipopolysaccharides; MicroRNAs; Sepsis; Tumor Necrosis Factor-alpha

Early prognostic stratification of patients with sepsis is a difficult clinical challenge. Aim of this study was to evaluate novel molecules in association with clinical parameters as predictors of 90-days mortality in patients admitted with sepsis at Humanitas Research Hospital.. Plasma samples were collected from 178 patients, diagnosed based on Sepsis-3 criteria, at admission to the Emergency Department and after 5 days of hospitalization. Levels of pentraxin 3 (PTX3), soluble IL-1 type 2 receptor (sIL-1R2), and of a panel of pro- and anti-inflammatory cytokines were measured by ELISA. Cox proportional-hazard models were used to evaluate predictors of 90-days mortality.. Circulating levels of PTX3, sIL-1R2, IL-1β, IL-6, IL-8, IL-10, IL-18, IL-1ra, TNF-α increased significantly in sepsis patients on admission, with the highest levels measured in shock patients, and correlated with SOFA score (PTX3: r=0.44, p<0.0001; sIL-1R2: r=0.35, p<0.0001), as well as with 90-days mortality. After 5 days of hospitalization, PTX3 and cytokines, but not sIL-1R2 levels, decreased significantly, in parallel with a general improvement of clinical parameters. The combination of age, blood urea nitrogen, PTX3, IL-6 and IL-18, defined a prognostic index predicting 90-days mortality in Sepsis-3 patients and showing better apparent discrimination capacity than the SOFA score (AUC=0.863, 95% CI: 0.780-0.945. These data suggest that a prognostic index based on selected cytokines, PTX3 and clinical parameters, and hence easily adoptable in clinical practice, performs in predicting 90-days mortality better than SOFA. An independent validation is required.

Topics: Biomarkers; C-Reactive Protein; Cytokines; Humans; Infant, Newborn; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Interleukin-10; Interleukin-18; Interleukin-6; Interleukin-8; Prognosis; ROC Curve; Sepsis; Serum Amyloid P-Component; Tumor Necrosis Factor-alpha

In this retrospective study, we aimed to compare the laboratory and clinical results of cytokine hem-adsorption as an immunomodulation therapy in COVID-19 ICU patients with or without sepsis.. The levels of PCT, CRP, and ferritin were determined as indicators of infection/sepsis; the levels of in-terleukins (IL-6, IL-8 and IL-10, and TNF-α) were determined as indicators of cytokine storm were compared. APACHE score, SOFA score, and mortality rates were compared for the progression of the disease in 23 COVID-19 patients.. The therapy was generally successful in reducing the levels of IL-6, IL-8, IL-10, and TNF-α but the levels measured after the procedure did not differ among the patients with or without sepsis, suggesting that the presence of sepsis did not affect the efficacy and function of the cytokine hemadsorption procedure in COVID-19 patients. All parameters were reduced after the procedure except the levels of PCT and ferritin and mortality rates of patients diagnosed with sepsis. The level of PCT was significantly higher in these patients compared with the patients without sepsis while the ferritin and mortality did not show any significant difference between the two groups, suggesting that the cytokine hemadsorption may be safe in the treatment of critical COVID-19 patients.. As a result, the progression of sepsis in COVID-19 may be avoided with cytokine hemadsorption applied as an immunomodulator therapy. However, this therapy should be further explored and validated prior to its introduction to everyday clinical practice when the epidemic conditions end.

Topics: COVID-19; Cytokines; Ferritins; Hemadsorption; Humans; Immunologic Factors; Interleukin-10; Interleukin-6; Interleukin-8; Prognosis; Retrospective Studies; ROC Curve; Sepsis; Tumor Necrosis Factor-alpha

To determine the association of a combined ratio change of inflammatory biomarkers at 72 h after admission on sepsis severity and prognosis from pulmonary infections.. Data on adult patients diagnosed with sepsis, or septic shock were retrospectively analyzed. Patients were divided into two groups, according to their outcome of hospitalization. Blood specimens were obtained on admission (T. Our findings suggested that a combined ratio change of inflammatory biomarkers was an effective predictor for sepsis severity and prognosis.

Topics: Adult; Biomarkers; Humans; Intensive Care Units; Interleukin-10; Interleukin-6; Interleukin-8; Pneumonia; Prognosis; Retrospective Studies; ROC Curve; Sepsis

The association between lipoprotein levels and late-onset neonatal sepsis has shown controversial results. The aims are to assess lipid profile, cytokines, and Monocyte-to-HDL (M/H) ratio as diagnostic and prognostic markers for late-onset neonatal sepsis.. This prospective study included 49 septic neonates and 17 controls. Cholesterol (CT), Triglyceride (TG), Very-Low-Density (VLDLc), Low-Density (LDLc), and High-Density Lipoproteins (HDLc) were measured at admission (D0) and on days 3, 7 and 10 to evaluate septic shock outcomes. Cytokines and monocytes were evaluated by flow cytometry.. Septic newborns showed higher IL-6 and IL-8 at D0 and CT levels on D7 and on D10, which also presented higher TG, VLDLc and non-HDL cholesterol concentrations than controls. The septic shock group (n = 22) revealed a higher number of male subjects, CRP, IL-6, IL-8 and IL-10 levels, while lower TG, HDLc, monocyte numbers and M/H ratio at admission compared to the non-shock group (n = 27). M/H ratio and non-HDL cholesterol on D0 were risk factors for septic shock (OR = 0.70, 0.49‒0.99; OR = 0.96, 0.92‒0.99, respectively). Decreasing levels from D0 to D3 of CT (OR = 0.96, 0.93‒0.99), VLDLc (OR = 0.91, 0.85‒0.98), and non-HDL cholesterol (OR = 0.92, 0.87‒0.98) were also predictors of septic shock.. Lower M/H ratios and non-HDL cholesterol at admission and decreasing levels of cholesterol, VLDLc and non-HDL cholesterol during a hospital stay are associated with the development of septic shock in newborns with late-onset neonatal sepsis.

Topics: Cholesterol; Cholesterol, HDL; Cytokines; Female; Humans; Infant, Newborn; Interleukin-6; Interleukin-8; Lipoproteins; Male; Monocytes; Neonatal Sepsis; Prospective Studies; Sepsis; Shock, Septic; Triglycerides

Sepsis is a syndrome where the dysregulated host response to infection threatens the life of the patient. The isoform of the cholesteryl-ester transfer protein (CETPI) is synthesized in the small intestine, and it is present in human plasma. CETPI and peptides derived from its C-terminal sequence present the ability to bind and deactivate bacterial lipopolysaccharides (LPS). The present study establishes the relationship between the plasma levels of CETPI and disease severity of sepsis due to Gram-negative bacteria.. Plasma samples from healthy subjects and patients with positive blood culture for Gram-negative bacteria were collected at the Intensive Care Unit (ICU) of INCMNSZ (Mexico City). 47 healthy subjects, 50 patients with infection, and 55 patients with sepsis and septic shock, were enrolled in this study. CETPI plasma levels were measured by an enzyme-linked immunosorbent assay and its expression confirmed by Western Blot analysis. Plasma cytokines (IL-1β, TNFα, IL-6, IL-8, IL-12p70, IFNγ, and IL-10) were measured in both, healthy subjects, and patients, and directly correlated with their CETPI plasma levels and severity of clinical parameters. Sequential Organ Failure Assessment (SOFA) scores were evaluated at ICU admission and within 24 h of admission. Plasma LPS and CETPI levels were also measured and studied in patients  with liver dysfunction.. The level of CETPI in plasma was found to be higher in patients with positive blood culture for Gram-negative bacteria that in control subjects, showing a direct correlation with their SOFA values. Accordingly, septic shock patients showing a high CETPI plasma concentration, presented a negative correlation with cytokines IL-8, IL-1β, and IL-10. Also, in patients  with liver dysfunction, since higher CETPI levels correlated with a high plasma LPS concentration, LPS neutralization carried out by CETPI might be considered a physiological response that will have to be studied in detail.. Elevated levels of plasma CETPI were associated with disease severity and organ failure in patients  with Gram-negative bacteraemia, defining CETPI as a protein implicated in the systemic response to LPS.

Topics: Bacteremia; Cholesterol Ester Transfer Proteins; Cytokines; Esters; Humans; Interleukin-10; Interleukin-8; Lipopolysaccharides; Peptides; Protein Isoforms; Sepsis; Shock, Septic

Primary responses in sepsis-mediated inflammation are regulated by pro-inflammatory cytokines. Variations in the cytokine genes might modify their transcription or expression, plasma cytokines levels and response to sepsis. Activation protein-1 (AP-1) and NF-κB regulate cytokines gene expression in sepsis. A total of 90 severely septic and 91 non-infected patients were prospectively studied.

Topics: Aged; Biomarkers; Cell Count; Cells, Cultured; Disease Progression; Female; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Humans; Interleukin-8; Male; Middle Aged; Neutrophils; Prognosis; Prospective Studies; Sepsis; Spain; Tumor Necrosis Factor-alpha

BACKGROUND This retrospective, observational study from a single center aimed to evaluate the association between complement (C)3 and C4, lymphocytes markers CD4 and CD8, and the interleukins IL-1ß, IL-2R, IL-6, IL-10, and IL-8 in patients with sepsis-induced myocardial dysfunction (SIMD) and a reduced left ventricular ejection fraction (LVEF) of < 50%. MATERIAL AND METHODS Patients with sepsis from July 2017 to December 2020 were divided into a SIMD group (42 patients) and NO-SIMD group (214 patients). Diagnostic criteria of sepsis were based on SEPSIS 3.0 guidelines. SIMD was defined as LVEF.

Topics: Aged; Cardiomyopathies; Female; Humans; Interleukin-8; Male; Middle Aged; Retrospective Studies; Sepsis

Topics: Adolescent; Biomarkers; Child; Female; Fever; Humans; Infant; Inflammation; Interleukin-6; Interleukin-8; Male; Neoplasms; Neutropenia; Prospective Studies; Sepsis

We hypothesised that plasma concentrations of biomarkers of neutrophil activation and pro-inflammatory cytokines differ according to the phase of rapidly evolving sepsis. In an observational study, we measured heparin-binding protein (HBP), myeloperoxidase (MPO), IL-6 and IL-8 in 167 sepsis patients on intensive care unit admission. We prospectively used the emergence of the first sepsis-associated organ dysfunction (OD) as a surrogate for the sepsis phase. Fifty-five patients (of 167, 33%) developed the first OD > 1 h before, 74 (44%) within ± 1 h, and 38 (23%) > 1 h after intensive care unit admission. HBP and MPO were elevated at a median of 12 h before the first OD, remained high up to 24 h, and were not associated with sepsis phase. IL-6 and IL-8 rose and declined rapidly close to OD emergence. Elevation of neutrophil activation markers HBP and MPO was an early event in the evolution of sepsis, lasting beyond the subsidence of the pro-inflammatory cytokine reaction. Thus, as sepsis biomarkers, HBP and MPO were not as prone as IL-6 and IL-8 to the effect of sample timing.

Topics: Aged; Antimicrobial Cationic Peptides; Biomarkers; Blood Proteins; Critical Illness; Female; Humans; Intensive Care Units; Interleukin-6; Interleukin-8; Male; Middle Aged; Neutrophil Activation; Neutrophils; Peroxidase; Sepsis

To investigate the clinical value of expression level of interleukin-2 receptor (IL-2R) and interleukin-8 (IL-8) in the fever patients with hematological malignancies.. A total of 121 inpatients in the First Affiliated Hospital of Anhui Medical University from April 2018 to October 2019 were enrolled in this study. The patients were separated into infection group (61 cases) and non-infection group (60 cases). In the meantime, 40 healthy people without fever or infection in the hospital for physical examination were set as matched group. C-reactive protein (CRP), procalcitonin (PCT), and cytokines were detected in all the patients with fever after admission and infection control. While, blood samples were taken from healthy people during physical examination.. The expression levels of IL-2R in infection group were higher than those in the control group (P<0.001), and the level of serum IL-2R in infection group was also higher than that in the non-infection group (P<0.05). Based on Spearman analysis, in patients with malignant hematologic disease, serum IL-2R level was positively correlated with CRP (r=0.557, P<0.001) and IL-8 (r=0.479, P<0.001), and IL-8 level was positively correlated with CRP (r=0.318, P<0.001). Compared with the non-infection group, the area under the curve (AUC) for the level of CRP, PCT, and IL-2R of the infection group was 0.714 (95%CI: 0.623-0.806), 0.765 (95%CI: 0.680-0.851), and 0.761 (95%CI: 0.686-0.836), the sensitivity was 0.705, 0.852, and 0.705, and the specificity was 0.717, 0.70, and 0.60, respectively. While, AUC of CRP+PCT, CRP+IL-2R, PCT+IL-2R, and CRP+PCT+IL-2R was 0.789 (95%CI: 0.712-0.866), 0.702 (95%CI: 0.623-0.782), 0.757 (95%CI: 0.677-0.838), and 0.789 (95%CI: 0.712-0.866), the sensitivity was 0.738, 0.934, 0.705, and 0.738, and the specificity was 0.840, 0.470, 0.810, and 0.840, respectively.. CRP, PCT, IL-2R, and IL-8 are useful parameters for diagnosis of the infectious fever in patients with hematological malignancies, which provides the basis of initial diagnosis and rational use of antibioties for clinician.. 血清白介素-2受体、白介素-8表达水平对恶性血液病患者感染的临床价值.. 探讨恶性血液病发热患者白介素-2受体（IL-2R）及白介素-8（IL-8）表达水平的临床意义.. 选择2018年4月至2019年10月于安徽医科大学第一附属医院血液内科住院的121例恶性血液病发热患者，将患者分为感染组（61例）和非感染组（60例），同时选择无发热和感染的健康体检者为对照组（40例）。全部发热患者在入院后和感染控制后实时抽血进行C反应蛋白（CRP）、降钙素原（PCT）和细胞因子检测，健康体检者在体检时抽血检测.. 感染组血清中IL-2R水平高于对照组，有极其显著统计学差异（P<0.001），感染组血清IL-2R水平高于非感染组，有统计学差异（P<0.05）。基于Spearman分析，恶性血液病患者血清中IL-2R水平与CRP（r=0.557，P<0.001）和IL-8（r=0.479，P<0.001）呈正相关，IL-8水平与CRP呈明显正相关（r=0.318，P<0.001）。与非感染组相比，感染组CRP、PCT和IL-2R的ROC曲线下面积（AUC）分别为0.714（95%CI：0.623-0.806）、0.765（95%CI：0.680-0.851）和0.761（95%CI：0.686-0.836），灵敏度分别为0.705、0.852和0.705，特异度分别为0.717、0.70和0.60；CRP+PCT、CRP+IL-2R、PCT+IL-2R和CRP+PCT+IL-2R联合诊断的AUC分别为0.789（95%CI：0.712-0.866）、0.702（95%CI：0.623-0.782）、0.757（95%CI：0.677-0.838）和0.789（95%CI：0.712-0.866），灵敏度分别为0.738、0.934、0.705和0.738，特异度分别为0.840、0.470、0.810和0.840.. 联合检测CRP、PCT、IL-2R和IL-8有助于恶性血液病感染的诊断，为临床医师初期准确诊断及合理使用抗生素提供有力的依据.

Topics: Biomarkers; C-Reactive Protein; Calcitonin; Calcitonin Gene-Related Peptide; Hematologic Neoplasms; Humans; Interleukin-8; Protein Precursors; Receptors, Interleukin-2; Sepsis

Acute kidney injury (AKI) is the most common complication of sepsis. The current incidence of sepsis is high (0.3% of total population) worldwide, and septic AKI may cause death in patients. Long non‑coding (lnc)RNAs serve important roles in the pathogenesis of AKI. Therefore, the present study investigated the mechanism underlying lncRNA plasmacytoma variant translocation 1 (PVT1)‑mediated regulation of pyroptosis in septic AKI. Septic kidney injury was induced in mice using the caecal ligation and puncture method, and lipopolysaccharide (LPS)‑induced HK‑2 cell models were also established. Haematoxylin‑eosin staining was performed to assess pathological alterations of kidney tissues in the mice. The levels of IL‑1β, IL‑18 and lactate dehydrogenase were determined by conducting ELISAs. Reverse transcription‑quantitative PCR was used to detect the expression levels of PVT1 and microRNA (miR)‑20a‑5p. To assess pyroptosis, the protein expression levels of nucleotide‑binding oligomerization domain‑like receptor protein 3 (NLRP3), IL‑1β, IL‑18, apoptosis‑associated speck‑like protein containing a CARD and cleaved caspase‑1 were measured via western blotting. Flow cytometry was performed to assess the rate of cell pyroptosis. Dual luciferase reporter assays were used to assess the binding relationships of PVT1/miR‑20a‑5p and miR‑20a‑5p/NLRP3. PVT1 expression was significantly increased, whereas miR‑20a‑5p expression was significantly decreased in sepsis model mice and LPS‑induced HK‑2 cells compared with sham mice and control HK‑2 cells, respectively. PVT1 knockdown significantly suppressed cell pyroptosis and downregulated the expression of inflammatory factors in LPS‑induced HK‑2 cells. The results also indicated that PVT1 served as a sponge of miR‑20a‑5p, and miR‑20a‑5p directly targeted NLRP3. miR‑20a‑5p knockdown significantly promoted LPS‑induced cell pyroptosis. Moreover, PVT1 knockdown inhibited LPS‑induced cell pyroptosis by targeting the miR‑20a‑5p/NLRP3 signalling pathway. The results of the present study suggested that PVT1 modulated NLRP3‑mediated pyroptosis in septic AKI by targeting miR‑20a‑5p, which might suggest significant potential therapeutic targets for septic AKI.

Topics: Acute Kidney Injury; Animals; Caspase 1; Cecum; Cell Line; Gene Expression Regulation; Humans; Interleukin-1beta; Interleukin-8; Ligation; Mice; MicroRNAs; NLR Family, Pyrin Domain-Containing 3 Protein; Punctures; Pyroptosis; RNA, Long Noncoding; Sepsis

Emerging evidence has indicated that interleukin-8 (IL-8) gene-251A/T polymorphism may affect individual susceptibility to sepsis. However, the results of published studies are inconclusive. The aim of this meta-analysis was to elucidate the association between this polymorphism and the risk and mortality of sepsis.. Relevant publications were searched from PubMed, EmBase, and Web of Science databases up to January 31, 2021, with studies only in English. The reference lists of the retrieved studies were investigated as well. Pooled odds ratio (OR) with 95% confidence interval (CI) was calculated to figure out the relationship between IL-8-251 A/T polymorphisms and the risk and mortality of sepsis. All of the data were analyzed with Stata 16.0.. The results of this meta-analysis will be submitted to a peer-reviewed journal for publication.. This meta-analysis will summarize the relationship between IL-8-251 A/T polymorphism and the risk and mortality of sepsis.

Topics: Genetic Predisposition to Disease; Humans; Interleukin-8; Meta-Analysis as Topic; Odds Ratio; Polymorphism, Single Nucleotide; Randomized Controlled Trials as Topic; Research Design; Risk Factors; Sepsis; Systematic Reviews as Topic

A sufficient response of neutrophil granulocytes stimulated by interleukin (IL)-8 is vital during systemic inflammation, for example, in sepsis or severe trauma. Moreover, IL-8 is clinically used as biomarker of inflammatory processes. However, the effects of IL-8 on cellular key regulators of neutrophil properties such as the intracellular pH (pHi) in dependence of ion transport proteins and during inflammation remain to be elucidated. Therefore, we investigated in detail the fundamental changes in pHi, cellular shape, and chemotactic activity elicited by IL-8. Using flow cytometric methods, we determined that the IL-8-induced cellular activity was largely dependent on specific ion channels and transporters, such as the sodium-proton exchanger 1 (NHE1) and non-NHE1-dependent sodium flux. Exposing neutrophils in vitro to a proinflammatory micromilieu with N-formyl-Met-Leu-Phe, LPS, or IL-8 resulted in a diminished response regarding the increase in cellular size and pH. The detailed kinetics of the reduced reactivity of the neutrophil granulocytes could be illustrated in a near-real-time flow cytometric measurement. Last, the LPS-mediated impairment of the IL-8-induced response in neutrophils was confirmed in a translational, animal-free human whole blood model. Overall, we provide novel mechanistic insights for the interaction of IL-8 with neutrophil granulocytes and report in detail about its alteration during systemic inflammation.

Topics: Granulocytes; Humans; Inflammation; Interleukin-8; Neutrophils; Sepsis

Liver X receptors (LXRs) are nuclear receptors activated by oxidized lipids and were previously implicated in several metabolic development and inflammatory disorders. Although neutrophils express both LXR-α and LXR-β, the consequences of their activation, particularly during sepsis, remain unknown.. We used the model of cecal ligation and puncture (CLP) to investigate the role of LXR activation during sepsis.. In this study, we verified that LXR activation reduces neutrophil chemotactic and killing abilities in vitro. Mice treated with LXR agonists showed higher sepsis-induced mortality, which could be associated with reduced neutrophil infiltration at the infectious foci, increased bacteremia, systemic inflammatory response, and multiorgan failure. In contrast, septic mice treated with LXR antagonist showed increased number of neutrophils in the peritoneal cavity, reduced bacterial load, and multiorgan dysfunction. More important, neutrophils from septic patients showed increased ABCA1 messenger ribonucleic acid levels (a marker of LXR activation) and impaired chemotactic response toward CXCL8 compared with cells from healthy individuals.. Therefore, our findings suggest that LXR activation impairs neutrophil functions, which might contribute to poor sepsis outcome.

Topics: Adult; Animals; ATP Binding Cassette Transporter 1; Cecum; Disease Models, Animal; Female; Humans; Inflammation; Interleukin-8; Ligation; Liver X Receptors; Male; Mice; Mice, Inbred C57BL; Middle Aged; Multiple Organ Failure; Neutrophil Infiltration; Neutrophils; Punctures; Sepsis

Topics: Biomarkers; Humans; Interleukin-8; Prognosis; Prospective Studies; Sepsis

BACKGROUNDElevated levels of inflammatory cytokines have been associated with poor outcomes among COVID-19 patients. It is unknown, however, how these levels compare with those observed in critically ill patients with acute respiratory distress syndrome (ARDS) or sepsis due to other causes.METHODSWe used a Luminex assay to determine expression of 76 cytokines from plasma of hospitalized COVID-19 patients and banked plasma samples from ARDS and sepsis patients. Our analysis focused on detecting statistical differences in levels of 6 cytokines associated with cytokine storm (IL-1β, IL-1RA, IL-6, IL-8, IL-18, and TNF-α) between patients with moderate COVID-19, severe COVID-19, and ARDS or sepsis.RESULTSFifteen hospitalized COVID-19 patients, 9 of whom were critically ill, were compared with critically ill patients with ARDS (n = 12) or sepsis (n = 16). There were no statistically significant differences in baseline levels of IL-1β, IL-1RA, IL-6, IL-8, IL-18, and TNF-α between patients with COVID-19 and critically ill controls with ARDS or sepsis.CONCLUSIONLevels of inflammatory cytokines were not higher in severe COVID-19 patients than in moderate COVID-19 or critically ill patients with ARDS or sepsis in this small cohort. Broad use of immunosuppressive therapies in ARDS has failed in numerous Phase 3 studies; use of these therapies in unselected patients with COVID-19 may be unwarranted.FUNDINGFunding was received from NHLBI K23 HL125663 (AJR); The Bill and Melinda Gates Foundation OPP1113682 (AJR and CAB); Burroughs Wellcome Fund Investigators in the Pathogenesis of Infectious Diseases #1016687 NIH/NIAID U19AI057229-16; Stanford Maternal Child Health Research Institute; and Chan Zuckerberg Biohub (CAB).

Topics: Adult; Aged; Case-Control Studies; Coronavirus Infections; COVID-19; Cytokine Release Syndrome; Cytokines; Female; Humans; Interleukin 1 Receptor Antagonist Protein; Interleukin-18; Interleukin-1beta; Interleukin-6; Interleukin-8; Male; Middle Aged; Pandemics; Pneumonia, Viral; Respiratory Distress Syndrome; Sepsis; Severity of Illness Index; Tumor Necrosis Factor-alpha

Endothelial cells (ECs) are an active component of the immune system and interact directly with inflammatory cytokines. While ECs are known to be polarized cells, the potential role of apicobasal polarity in response to inflammatory mediators has been scarcely studied. Acute inflammation is vital in maintaining healthy tissue in response to infection; however, chronic inflammation can lead to the production of systemic inflammatory cytokines and deregulated leukocyte trafficking, even in the absence of a local infection. Elevated levels of cytokines in circulation underlie the pathogenesis of sepsis, the leading cause of intensive care death. Because ECs constitute a key barrier between circulation (luminal interface) and tissue (abluminal interface), we hypothesize that ECs respond differentially to inflammatory challenge originating in the tissue versus circulation as in local and systemic inflammation, respectively. To begin this investigation, we stimulated ECs abluminally and luminally with the inflammatory cytokine tumor necrosis factor alpha (TNF-α) to mimic a key feature of local and systemic inflammation, respectively, in a microvascular mimetic (μSiM-MVM). Polarized IL-8 secretion and polymorphonuclear neutrophil (PMN) transmigration were quantified to characterize the EC response to luminal versus abluminal TNF-α. We observed that ECs uniformly secrete IL-8 in response to abluminal TNF-α and is followed by PMN transmigration. The response to abluminal treatment was coupled with the formation of ICAM-1-rich membrane ruffles on the apical surface of ECs. In contrast, luminally stimulated ECs secreted five times more IL-8 into the luminal compartment than the abluminal compartment and sequestered PMNs on the apical EC surface. Our results identify clear differences in the response of ECs to TNF-α originating from the abluminal versus luminal side of a monolayer for the first time and may provide novel insight into future inflammatory disease intervention strategies.

Topics: Biomimetics; Cell Adhesion; Cell Communication; Cell Movement; Cytokines; Endothelial Cells; Human Umbilical Vein Endothelial Cells; Humans; Immune System; In Vitro Techniques; Inflammation; Inflammation Mediators; Intercellular Adhesion Molecule-1; Interleukin-8; Microcirculation; Microfluidics; Microscopy, Fluorescence; Neutrophils; Permeability; Sepsis; Tumor Necrosis Factor-alpha

Interleukin (IL)-8 has been reported to be associated with the progression of sepsis. Recent studies have explored the relationship between the IL-8 - 251 A/T polymorphism and sepsis risk. This study evaluated the association between the IL-8 - 251 A/T polymorphism and sepsis susceptibility in a Chinese Han population. We designed a case-control study with 254 sepsis cases and 322 controls. Genotyping was performed using the polymerase chain reaction-restriction fragment length polymorphism method. SPSS 20.0 software was used for all statistical analysis (SPSS Inc., Chicago, USA). This study showed that the IL-8 - 251 A/T polymorphism was associated with a decreased risk of sepsis. Stratified analyses found that this association held true in females, non-smokers, and older individuals (age > 60 years). The IL-8 - 251 A/T polymorphism was also related to the severity and 28-day mortality of sepsis. The IL-8 - 251 A/T polymorphism is associated with a decreased risk of sepsis.

Topics: Aged; Asian People; Case-Control Studies; Female; Genetic Predisposition to Disease; Genotype; Genotyping Techniques; Humans; Interleukin-8; Male; Middle Aged; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length; Polymorphism, Single Nucleotide; Risk Assessment; Sepsis; Survival Analysis

Enrichment strategies improve therapeutic targeting and trial efficiency, but enrichment factors for sepsis trials are lacking. We determined whether concentrations of soluble tumor necrosis factor receptor-1 (sTNFR1), interleukin-8 (IL8), and angiopoietin-2 (Ang2) could identify sepsis patients at higher mortality risk and serve as prognostic enrichment factors.. In a multicenter prospective cohort study of 400 critically ill septic patients, we derived and validated thresholds for each marker and expressed prognostic enrichment using risk differences (RD) of 30-day mortality as predictive values. We then used decision curve analysis to simulate the prognostic enrichment of each marker and compare different prognostic enrichment strategies.. An admission sTNFR1 concentration > 8861 pg/ml identified patients with increased mortality in both the derivation (RD 21.6%) and validation (RD 17.8%) populations. Among immunocompetent patients, an IL8 concentration > 94 pg/ml identified patients with increased mortality in both the derivation (RD 17.7%) and validation (RD 27.0%) populations. An Ang2 level > 9761 pg/ml identified patients at 21.3% and 12.3% increased risk of mortality in the derivation and validation populations, respectively. Using sTNFR1 or IL8 to select high-risk patients improved clinical trial power and efficiency compared to selecting patients with septic shock. Ang2 did not outperform septic shock as an enrichment factor.. Thresholds for sTNFR1 and IL8 consistently identified sepsis patients with higher mortality risk and may have utility for prognostic enrichment in sepsis trials.

Topics: Aged; Biomarkers; Cohort Studies; Female; Hospital Mortality; Humans; Interleukin-8; Male; Middle Aged; Prognosis; Prospective Studies; Receptors, Tumor Necrosis Factor, Type I; ROC Curve; Sepsis; Vesicular Transport Proteins

We aimed to demonstrate the potential of precision medicine to describe the inflammatory landscape present in children with suspected appendicitis. Our primary objective was to determine levels of seven inflammatory protein mediators previously associated with intra-abdominal inflammation (C-reactive protein-CRP, procalcitonin-PCT, interleukin-6 (IL), IL-8, IL-10, monocyte chemoattractant protein-1-MCP-1, and serum amyloid A-SAA) in a cohort of children with suspected appendicitis. Subsequently, using a multiplex proteomics approach, we examined an expansive array of novel candidate cytokine and chemokines within this population.. We performed a secondary analysis of targeted proteomics data from Alberta Sepsis Network studies. Plasma mediator levels, analyzed by Luminex multiplex assays, were evaluated in children aged 5-17 years with nonappendicitis abdominal pain (NAAP), acute appendicitis (AA), and nonappendicitis sepsis (NAS). We used multivariate regression analysis to evaluate the seven target proteins, followed by decision tree and heat mapping analyses for all proteins evaluated.. 185 children were included: 83 with NAAP, 79 AA, and 23 NAS. Plasma levels of IL-6, CRP, MCP-1, PCT, and SAA were significantly different in children with AA compared to those with NAAP (. Multiplex proteomic analyses described the inflammatory landscape of children presenting to the ED with suspected appendicitis. We have demonstrated the feasibility of this approach to identify potential novel candidate cytokines/chemokine patterns associated with a specific illness (appendicitis) amongst those with a broad ED presentation (abdominal pain). This approach can be modelled for future research initiatives in pediatric emergency medicine.

Topics: Adolescent; Appendicitis; Chemokine CCL2; Chemokines; Child; Child, Preschool; Cytokines; Humans; Interleukin-10; Interleukin-6; Interleukin-8; Precision Medicine; Prospective Studies; Proteomics; Sepsis; Serum Amyloid A Protein

Topics: Aged; APACHE; Cardiovascular Diseases; Cohort Studies; Critical Illness; Disseminated Intravascular Coagulation; Extracellular Traps; Female; Gastrointestinal Diseases; Humans; Intensive Care Units; Interleukin-8; Kidney Diseases; Male; Middle Aged; Mitogen-Activated Protein Kinases; Mortality; Multivariate Analysis; Nervous System Diseases; Neutrophils; Organ Dysfunction Scores; Prospective Studies; Reproducibility of Results; Respiratory Tract Diseases; Risk Assessment; Sepsis; Wounds and Injuries

Inflammation, reflected by high plasma interleukin-6 concentration, is associated with acute kidney injury (AKI) in septic patients. Neutrophil activation has pathophysiological significance in experimental septic AKI. We hypothesized that neutrophil activation is associated with AKI in critically ill sepsis patients.. We measured plasma (n = 182) and urine (n = 118) activin A (a rapidly released cytosolic neutrophil protein), interleukin-8 (a chemotactic factor for neutrophils), myeloperoxidase (a neutrophil biomarker released in tissues), and interleukin-6 on intensive care unit admission (plasma and urine) and 24 hours later (plasma) in sepsis patients manifesting their first organ dysfunction between 24 hours preceding admission and the second calendar day in intensive care unit. AKI was defined by the Kidney Disease: Improving Global Outcomes criteria.. Plasma admission interleukin-8 (240 [60-971] vs 50 [19-164] pg/mL, P < .001) and activin A (845 [554-1895] vs 469 [285-862] pg/mL, P < .001) were but myeloperoxidase (169 [111-300] vs 144 [88-215] ng/mL, P = .059) was not higher among patients with AKI compared with those without. Urine admission interleukin-8 (50.4 [19.8-145.3] vs 9.5 [2.7-28.7] ng/mL, P < .001) and myeloperoxidase (7.7 [1.5-12.6] vs 1.9 [0.4-6.9] ng/mL, P < .001) were but activin A (9.7 [1.4-42.6] vs 4.0 [0.0-33.0] ng/mL, P = .064) was not higher in AKI than non-AKI patients. Urine myeloperoxidase correlated with urine interleukin-8 (R = .627, P < .001) but not with plasma myeloperoxidase (R = .131, P = .158).. Interleukin-8 in plasma and urine was associated with septic AKI. Elevated plasma activin A indicates intravascular neutrophil activation in septic AKI. Concomitant plasma and urine myeloperoxidase measurements suggest neutrophil accumulation into injured kidneys.

Topics: Activins; Acute Kidney Injury; Aged; Female; Humans; Interleukin-8; Male; Middle Aged; Neutrophil Activation; Peroxidase; Sepsis

Sepsis is a condition caused by infection followed by unregulated inflammatory response which may lead to the organ dysfunction. During such condition, over-production of oxidants is one of the factors which contribute cellular toxicity and ultimately organ failure and mortality. Antioxidants having free radicals scavenging activity exert protective role in various diseases. This study has been designed to evaluate the levels of oxidative and antioxidative activity in sepsis patients and their correlation with the severity of the sepsis. A total of 100 sepsis patients and 50 healthy controls subjects were enrolled in this study from the period October 2016 to June 2017. The investigation included measurements of oxidative enzyme, myeloperoxidase (MPO), antioxidant enzymes including superoxide dismutase activity (SOD) and catalase activity (CAT) and cytokines (TNF-α, IL-8 and IFN-γ). Furthermore, the level of these activities was correlated with severity of sepsis. Augmented levels of oxidants were found in sepsis as demonstrated by DMPO nitrone adduct formation and plasma MPO level activity (1.37 ± 0.51 in sepsis vs 0.405 ± 0.16 in control subjects). Cytokines were also found to be increased in sepsis patients. However, plasma SOD and CAT activities were significantly attenuated (P < .001) in the sepsis patients compared with controls subjects. Moreover, inverse relation between antioxidant enzymes (SOD and CAT) and organ failure assessment (SOFA), physiological score (APACHE II), organ toxicity specific markers have been observed as demonstrated by Pearson's correlation coefficient. This study suggests that imbalance between oxidant and antioxidant plays key role in the severity of sepsis.

Topics: Adult; Antioxidants; Catalase; Cross-Sectional Studies; Female; Humans; Interferon-gamma; Interleukin-8; Male; Middle Aged; Oxidative Stress; Peroxidase; Reactive Oxygen Species; Sepsis; Superoxide Dismutase; Tumor Necrosis Factor-alpha

The microbial etiology and source of sepsis influence the inflammatory response. Therefore, the plasma levels of cytokines (IL-6, IL-8, and IL-10), chemokines (CCL2/MCP-1, MIP-1

Topics: Aged; Antimicrobial Cationic Peptides; Biomarkers; Blood Proteins; Carrier Proteins; Chemokine CCL2; Chemokine CCL4; Critical Care; Female; Humans; Hydrocortisone; Interleukin-10; Interleukin-6; Interleukin-8; Lipopolysaccharide Receptors; Male; Middle Aged; Sepsis

Translocation of bacteria across the intestinal barrier is important in the pathogenesis of systemic sepsis and multiple organ dysfunction syndromes. Inflammatory cytokines increase paracellular permeability that allows increased luminal bacteria to translocate across mucosal epithelium and further deteriorate the gut barrier. In order to reduce this risk, the prophylactic use of probiotics has been recently addressed. In this paper, we investigate the protective role toward tumour necrosis factor (TNF)-α induced non-pathogenic Escherichia coli translocation across Caco-2 monolayers of Lactobacillus strains. According to our experimental data, Lactobacillus plantarum L9 and Lactobacillus acidophilus LA have good capacities to adhere to Caco-2 cells. Addition of L. plantarum L9 and L. acidophilus LA to the enterocyte monolayer surface result in significant inhibition of E. coli adhesion and cell internalisation. However, L. plantarum L9 and L. acidophilus LA did not inhibit the growth of the non-pathogenic E. coli B5 after 24 h incubation. Exposure to TNF-α for 6 h caused a dramatic increase in E. coli B5 translocation across Caco-2 cells, which was uncoupled from increases in paracellular permeability. Pretreatment with L. plantarum L9 prevent TNF-α induced transcellular bacterial translocation and IL-8 production in Caco-2 cells. L. plantarum L9 also did not affect the integrity of the monolayers, as indicated by lactate dehydrogenase release, horseradish peroxidase permeability, and transepithelial electrical resistance. L. plantarum L9 showed the potential to protect enterocytes from an acute inflammatory response and therefore could be good potential prophylactic agents in counteracting bacterial translocation.

Topics: Bacterial Adhesion; Bacterial Translocation; Caco-2 Cells; Cell Line, Tumor; Escherichia coli; Humans; Inflammation; Interleukin-8; Intestinal Mucosa; Lactobacillus acidophilus; Lactobacillus plantarum; Multiple Organ Failure; Probiotics; Sepsis; Tumor Necrosis Factor-alpha

microRNAs (miRNAs) play an essential role in inflammation processes including sepsis. This study aimed to identify miRNAs as candidates for therapies that are involved in the innate immune response and to assess their potential functions in the activation of the endothelium. We stimulated THP-1 monocytes with 10 ng/ml LPS for 4 h and used the supernatant for the stimulation of human umbilical vein endothelial cells (HUVEC) or human pulmonary microvascular endothelial cells (HPMEC) for 16 h. miRNA array analysis (of 1,891 miRNAs) identified a 1.5-fold upregulation of miR-146a, miR-146b, and miR-155 in stimulated endothelial cells. HUVEC were transfected with miRNA inhibitors for miR-146a, miR-146b, and miR-155 to investigate the function of these miRNAs in endothelial inflammatory pathways. Inhibition of miR-146a resulted in a diminished release of interleukin (IL)-6 and IL-8 by respective 68% and 55% (P<0.001). Inhibition of miR-146b reduced the expression of IL-6 by 49% (P<0.001). Inhibition of miR-155 reduced the expression of IL-6 and IL-8 by respective 31% (P<0.001) and 14%. The inhibition of miR-146a, miR-146b, and miR-155 reduced the release of HSP10 by 50%, 35%, and 69% (P<0.05), respectively, but did not influence the expression of HSP27 or TXA2. In conclusion, miR-146a, miR-146b, and miR-155 are exerting anti-inflammatory properties by down-regulating IL-6 and IL-8, and influencing the expression of HSP10 in the activated endothelium. We provide evidence for the central role of selected miRNAs in sepsis and their use in the development of small interfering RNA therapeutics to target immune cells and sepsis pathways.

Topics: Cells, Cultured; Chaperonin 10; Culture Media, Conditioned; Humans; In Vitro Techniques; Interleukin-6; Interleukin-8; MicroRNAs; Sepsis

Immunoparalysis was observed in both patients with cancer and sepsis. In cancer patients, Cytotoxic T lymphocyte antigen-4 and programmed cell death protein 1/programmed death-ligand 1 axis are two key components of immunoparalysis. Several emerging therapies against these two axes gained significant clinical benefit. In severe sepsis patients, immunoparalysis was known as compensatory anti-inflammatory response syndrome and this has been suggested as an important cause of death in patients with sepsis. It would be interesting to see if immune status was different in severe sepsis patients with or without active cancer. The aim of this study was to assess the differences in immune profiles, and clinical outcomes between severe sepsis patients with or without cancer admitted to ICU.. A combined retrospective and prospective observational study from a cohort of adult sepsis patients admitted to three medical ICUs at Kaohsiung Chang Gung Memorial Hospital in Taiwan between August 2013 and June 2016.. Of the 2744 patients admitted to the ICU, 532 patients with sepsis were included. Patients were divided into those with or without active cancer according to their medical history. Of the 532 patients, 95 (17.9%) patients had active cancer, and 437 (82.1%) patients had no active cancer history. Patients with active cancer were younger (p = 0.001) and were less likely to have diabetes mellitus (p < 0.001), hypertension (p < 0.001), coronary artery disease (p = 0.004), chronic obstructive pulmonary disease (p = 0.002) or stroke (p = 0.002) compared to patients without active cancer. Patients with active cancer also exhibited higher baseline lactate levels (p = 0.038), and higher baseline plasma interleukin (IL)-10 levels (p = 0.040), higher trend of granulocyte colony-stimulating factor (G-CSF) (p = 0.004) compared to patients without active cancer. The 14-day, 28-day and 90-day mortality rates were higher for patients with active cancer than those without active cancer (P < 0.001 for all intervals).. Among patients admitted to the ICU with sepsis, those with underling active cancer had higher baseline levels of plasma IL-10, higher trend of G-CSF and higher mortality rate than those without active cancer.

Topics: Aged; Female; Hospitalization; Humans; Intensive Care Units; Interleukin-10; Interleukin-8; Male; Middle Aged; Neoplasms; Prognosis; ROC Curve; Sepsis; Treatment Outcome

The present study was designed to investigate the anti-sepsis effects of physcion 8-O-β-glucopyranoside (POG) isolated from Rumex japonicas and explore its possible pharmacological mechanisms. POG was extracted from R. japonicas by bioactivity-guided isolation with the anti-sepsis agents. Survival analysis in septic mouse induced by LPS and heat-killed Escherichia coli were used to evaluate the protective effect of POG (40 mg·kg

Topics: Animals; Anti-Inflammatory Agents; Drugs, Chinese Herbal; Emodin; Glucosides; Humans; Interleukin-1beta; Interleukin-6; Interleukin-8; Macrophages; Male; Mice; Mice, Inbred ICR; RAW 264.7 Cells; Rumex; Sepsis; Tumor Necrosis Factor-alpha

This study analyzes the sepsis healing therapeutic potential of carnosine against experimentally sepsis-induced male albino rats. Carnosine in 2 different doses, 25 mg/kg and 50 mg/kg, were administered for 30 consecutive days. At the end of the treatment, lipid peroxidation, catalase, superoxide dismutase, glutathione peroxidase and myeloperoxidase activities were measured. Lungs weight and total protein content were determined in the bronchoalveolar fluid (BALF). Cytokines such as macrophage inhibitory factor (MIF), interleukin-8 (IL-8) and tumour necrosis factor-alpha (TNF-α) were determined in the BALF. In addition, the histopathological analysis was also carried out to understand the effect of carnosine in the cellular architecture. Carnosine treatment significantly renormalized the lipid peroxidation and other antioxidant enzymes. IL-β, TNF-α, and MIF were found to be reduced after carnosine treatment. After carnosine treatment, the intensity of sepsis was significantly reduced evidenced by histopathological analysis. In western blot analysis, carnosine treatment causes the upregulation of IκBα together with the downregulation of the expressions of p65 and p-IKKα/β (Ser 180/Ser 181).

Topics: Acute Lung Injury; Animals; Antioxidants; Carnosine; Catalase; Disease Models, Animal; Glutathione; Glutathione Peroxidase; Interleukin-8; Lipid Peroxidation; Lung; Male; Malondialdehyde; Oxidative Stress; Peroxidase; Protective Agents; Rats; Rats, Wistar; Sepsis; Superoxide Dismutase; Tumor Necrosis Factor-alpha

Distinction between inflammation secondary to surgery, especially coronary artery bypass graft with cardiopulmonary bypass (CPB), and inflammation due to infection is difficult in surgical intensive care unit (ICU) patients. Development of biomarkers of infection could help clinicians in the early identification and thus treatment of sepsis in these patients. We compared the time course of the neutrophil CD64 index, a high affinity immunoglobulin FC γ receptor I whose expression is increased in bacterial infection, in 39 patients undergoing cardiac surgery with CPB and 11 patients admitted to the ICU with severe sepsis or septic shock. The CD64 index was significantly more elevated in septic patients than in patients who had CPB except at day 5. The CD64 index increased moderately on day 1 after cardiac surgery but the value remained lower than in septic patients. The duration for which the CD64 index was greater than 1.0 was longer in septic than in CPB patients. Receiver operating curves to differentiate CPB from sepsis on day 1 were not significantly different between C-reactive protein (CRP) concentrations and CD 64 index. Nevertheless, combination of low CD64 index with low CRP concentrations on day 1 ruled out sepsis except in three patients. There were no correlations between the CD64 index and cytokine levels (tumor necrosis factor [TNF]-α, interferon [IFN]γ, interleukin [IL]-6, IL-10, IL-8, IL-12) measured in subpopulations. In conclusion, CD64 index only in combination with CRP concentrations could be used to discriminate inflammation due to surgery from that due to infection in this particular population.

Topics: Aged; Biomarkers; C-Reactive Protein; Cardiopulmonary Bypass; Female; Humans; Intensive Care Units; Interleukin-10; Interleukin-12; Interleukin-6; Interleukin-8; Male; Middle Aged; Prospective Studies; Receptors, IgG; Sepsis; Shock, Septic; Tumor Necrosis Factor-alpha

Experimental studies suggest that calcium channel blockers can improve sepsis outcome. The aim of this study was to determine the association between prior use of calcium channel blockers and the outcome of patients admitted to the ICU with sepsis.. A prospective observational study.. The ICUs of two tertiary care hospitals in the Netherlands.. In total, 1,060 consecutive patients admitted with sepsis were analyzed, 18.6% of whom used calcium channel blockers.. None.. Considering large baseline differences between calcium channel blocker users and nonusers, a propensity score matched cohort was constructed to account for differential likelihoods of receiving calcium channel blockers. Fifteen plasma biomarkers providing insight in key host responses implicated in sepsis pathogenesis were measured during the first 4 days after admission. Severity of illness over the first 24 hours, sites of infection and causative pathogens were similar in both groups. Prior use of calcium channel blockers was associated with improved 30-day survival in the propensity-matched cohort (20.2% vs 32.9% in non-calcium channel blockers users; p = 0.009) and in multivariate analysis (odds ratio, 0.48; 95% CI, 0.31-0.74; p = 0.0007). Prior calcium channel blocker use was not associated with changes in the plasma levels of host biomarkers indicative of activation of the cytokine network, the vascular endothelium and the coagulation system, with the exception of antithrombin levels, which were less decreased in calcium channel blocker users.. Prior calcium channel blocker use is associated with reduced mortality in patients following ICU admission with sepsis.

Topics: Aged; Antithrombins; APACHE; Biomarkers; Calcium Channel Blockers; Critical Illness; Female; Humans; Intensive Care Units; Interleukin-6; Interleukin-8; Male; Middle Aged; Propensity Score; Prospective Studies; Protein C; Sepsis

Topics: Aged; Anti-Bacterial Agents; Biomarkers; Community-Acquired Infections; Diabetes Mellitus; Disease Management; Disseminated Intravascular Coagulation; Female; Fluid Therapy; Humans; Intensive Care Units; Interleukin-8; Male; Middle Aged; Prognosis; Prospective Studies; Respiratory Insufficiency; Sepsis; Staphylococcal Infections; Staphylococcus aureus; Survival Analysis; Tertiary Care Centers; Thailand

The present study investigates curcumin effect against sepsis-induced chronic lung injury (CLI) of male albino rats. Rats were grouped into four groups such rats undergoing a sham cecal ligature puncture (CLP), rats undergoing CLP, rats undergoing CLP and treated with saline and rats undergoing CLP and treated with curcumin (100 mg/kg bwt). After 45 days of treatment, bronchoalveolar fluid (BALF), blood and lung tissues were collected from the each animal. The total protein content, wet and dry (W/D) weight of lung tissues and some inflammatory cells in the BALF were measured. Histopathological analysis was carried out to investigate the alteration of the cellular architecture of lung tissues. Lipid peroxidation malondialdehyde (MDA), superoxide dismutase (SOD) and myeloperoxidase (MPO) levels were determined. Cytokines such as interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-a) and macrophage inhibitory factor (MIF) were measured in the BALF. Curcumin administration significantly reduced CLP-induced inflammation and pulmonary edema. Curcumin treatment is significantly reduced MPO activity, and inflammatory cell accumulation in the BALF and also protein level, MDA, SOD, and W/D ratio were significantly reduced in the lung tissues. Also, curcumin reduced the expression of IL-A, TNF-a and MIF levels in the lung tissues. Histopathological study revealed the significant reduction of CLP-induced CLI in the curcumin-treated male albino rats. Taking all these data together, it is concluded that curcumin can act as a suitable therapeutic agent against CLP-induced CLI of male albino rats.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Bronchoalveolar Lavage Fluid; Cecum; Curcumin; Interleukin-8; Intramolecular Oxidoreductases; Lipid Peroxidation; Lung; Lung Injury; Macrophage Migration-Inhibitory Factors; Male; Malondialdehyde; Peroxidase; Rats; Rats, Sprague-Dawley; Sepsis; Superoxide Dismutase; Tumor Necrosis Factor-alpha

Complement 5a (C5a) has been implicated in the pathogenesis of sepsis by inducing the functional impairment of neutrophils; however, the utility of C5a receptors (C5aRs; C5aR and C5L2) as biomarkers for the management of sepsis is uncertain. This study investigated the dynamic expression of C5aR and C5L2 on neutrophils and their effects on neutrophil function. We found that sepsis patients displayed low expression levels of C5aR and C5L2 on neutrophils compared to healthy and systemic inflammatory response syndrome (SIRS) subjects, and this expression pattern was correlated with disease severity. Additionally, the expression levels of C5aR and C5L2 were associated with the survival of sepsis patients. In vitro, the addition of C5a significantly reduced C5aR and C5L2 expression levels and IL-8 production in neutrophils from sepsis patients. Those findings suggest that the reduced expression of C5aRs was associated with the functional impairment of neutrophils and a poor prognosis for sepsis patients. Overall, these findings may help establish C5aRs expression levels as early markers to predict the severity of sepsis.

Topics: Adult; Aged; Biomarkers; Case-Control Studies; Complement C5a; Female; Gene Expression Regulation; Humans; Interleukin-8; Male; Middle Aged; Neutrophils; Primary Cell Culture; Prognosis; Receptor, Anaphylatoxin C5a; Receptors, Chemokine; Sepsis; Severity of Illness Index; Signal Transduction; Survival Analysis; Treatment Outcome

Interleukin-17A is a proinflammatory cytokine known to play a role in host defense and pathologic inflammation in murine models of lung injury. The relationship between interleukin-17A and inflammation in human lung injury is unknown. Our primary objective was to determine whether interleukin-17A levels are associated with alveolar measures of inflammation and injury in patients with acute respiratory distress syndrome. Our secondary objective was to test whether interleukin-17A levels are associated with acute respiratory distress syndrome-related outcomes.. Observational study.. Six North American medical centers.. We studied two groups of patients with acute respiratory distress syndrome: 1) patients previously enrolled in a placebo-controlled clinical trial of omega-3 fatty acids performed at five North American medical centers (n = 86, acute respiratory distress syndrome 1), and 2) patients with systemic inflammatory response syndrome admitted to an ICU who developed acute respiratory distress syndrome (n = 140, acute respiratory distress syndrome 2). In acute respiratory distress syndrome 1, we used paired serum and bronchoalveolar lavage fluid samples obtained within 48 hours of acute respiratory distress syndrome onset, whereas in acute respiratory distress syndrome 2, we used plasma obtained within the first 24 hours of ICU admission.. None.. We measured circulating interleukin-17A in acute respiratory distress syndrome 1 and acute respiratory distress syndrome 2. We also measured interleukin-17A, neutrophil counts, and total protein in bronchoalveolar lavage fluid from acute respiratory distress syndrome 1. We found that bronchoalveolar lavage interleukin-17A was strongly associated with higher bronchoalveolar lavage percent neutrophils (p < 0.001) and bronchoalveolar lavage total protein (p < 0.01) in acute respiratory distress syndrome1. In both acute respiratory distress syndrome 1 and acute respiratory distress syndrome 2, elevated interleukin-17A was associated with higher Sequential Organ Failure Assessment scores (p < 0.05).. Elevated circulating and alveolar levels of interleukin-17A are associated with increased percentage of alveolar neutrophils, alveolar permeability, and organ dysfunction in acute respiratory distress syndrome.

Topics: Acute Lung Injury; Aged; Bronchoalveolar Lavage Fluid; Cytokines; Female; Humans; Inflammation; Intensive Care Units; Interleukin-17; Interleukin-8; Leukocyte Count; Male; Middle Aged; Neutrophils; Organ Dysfunction Scores; Pulmonary Alveoli; Respiratory Distress Syndrome; Sepsis; Treatment Outcome

The purpose of the study is to evaluate the incidence, association with serum cytokine profile, and prognostic value of thrombocytopenia, in critically ill patients with severe sepsis/septic shock.. A cohort of 105 consecutive patients admitted in intensive care unit was included in our analysis. Serum levels of intercellular adhesion molecule, vascular cell adhesion molecule, interferon γ, interleukin 8, and soluble form of the urokinase-type plasminogen activator receptor (suPAR) were measured.. Thrombocytopenia was observed in 53% of patients at the time of admission. Platelet counts showed a statistically significant negative correlation with serum levels of intercellular adhesion molecule, suPAR, and interleukin 8 (P < .0001). In multivariate analysis, high Acute Physiological and Chronic Health Evaluation II score, high serum suPAR, and low platelet counts were associated with increased mortality, and receiver operating characteristic curve analysis was used to determine the best cutoff value for mortality prediction. Each variable with a value above or below the predefined cutoff levels were given 1 point. Patients were categorized in risk groups based on total point score. High-risk (2-3), intermediate-risk (1), and low-risk (0 points) groups consisted of 43%, 22%, and 35% and 28-day mortality was observed in 69%, 26%, and 3% of the patients in each group, respectively.. Thrombocytopenia is associated with poor prognosis and a distinct serum cytokine profile.

Topics: Adult; Aged; Biomarkers; Critical Care; Critical Illness; Cytokines; Female; Greece; Hospital Mortality; Humans; Incidence; Interleukin-8; Male; Middle Aged; Prognosis; Prospective Studies; Receptors, Urokinase Plasminogen Activator; ROC Curve; Sepsis; Thrombocytopenia

Cirrhosis represents a state of functional immune paresis with increased infection risk.. To investigate polymorphonuclear (PMN) leukocyte and monocyte function in ambulatory cirrhotics, and their potential relation with cirrhosis etiology or patient outcome.. Consecutive ambulatory cirrhotics without current or recent (<1 month) infection or acute decompensation were prospectively enrolled in 2013 and followed for a median time of 20 months until death, transplant or end of 2014. Oxidative burst and phagocytosis of circulating PMNs and monocytes were investigated at baseline and after in vitro Escherichia coli stimulation. Seventeen healthy blood donors served as controls. Baseline clinical and laboratory data as well as follow-up data on the development of cirrhosis complications, including acute-on-chronic liver failure (ACLF), and bacterial infections were collected.. Sixty patients were included (70 % male, median age 63 years, 52 % with alcoholic cirrhosis). Compared to controls, cirrhotics showed increased resting and stimulated burst as well as reduced phagocytosis of PMNs, and increased stimulated monocyte burst (p < 0.05 for all). Alcoholic etiology was not related to PMN or monocyte dysfunction (p > 0.05 for all). In Cox regression analysis, increased stimulated monocyte and PMN burst were independent predictors of sepsis, severe sepsis and ACLF occurrence. Also, increased stimulated monocyte burst was associated with worse transplant-free survival (p < 0.05 for all).. Stimulated PMN and monocyte oxidative burst are increased in ambulatory cirrhotics without acute decompensation. In turn, these changes are associated to sepsis and ACLF occurrence.

Topics: Acute-On-Chronic Liver Failure; Aged; Ambulatory Care; Bacterial Infections; Case-Control Studies; Cytokines; Disease Progression; Escherichia coli; Female; Humans; Interleukin-6; Interleukin-8; Liver Cirrhosis; Liver Cirrhosis, Alcoholic; Male; Middle Aged; Monocytes; Neutrophils; Phagocytosis; Prognosis; Prospective Studies; Respiratory Burst; Sepsis; Sweden; Tumor Necrosis Factor-alpha

A key step in neutrophil-mediated tissue damage is the migration of activated neutrophils across the vascular endothelium. Previously, we identified protein kinase C δ as a critical regulator of neutrophil migration in sepsis but did not identify specific steps in migration. In this study, we used our novel biomimetic microfluidic assay to delineate systematically the mechanism by which protein kinase C δ regulates individual steps in human neutrophil-endothelial interaction during inflammation. The biomimetic microfluidic assay includes a network of vascular channels, produced from in vivo images connected to a tissue compartment through a porous barrier. HUVECs cultured in vascular channels formed a complete lumen under physiologic shear flow. HUVECs were pretreated with TNF-α ± a protein kinase C δ inhibitor, and the tissue compartment was filled with a chemoattractant (fMLP or IL-8). Under physiologic shear flow, the role of protein kinase C δ on spatial and temporal neutrophil adherence/migration was quantified. Protein kinase C δ inhibition significantly reduced neutrophil adhesion in response to fMLP and IL-8 only under low shear rate and near bifurcations. Protein kinase C δ inhibition also decreased adherence to nonactivated HUVECs in response to fMLP or IL-8. Protein kinase C δ inhibition reduced neutrophil migration into the tissue compartment in response to fMLP and to a lesser degree, to IL-8. Antibody-coated microparticles demonstrated that protein kinase C δ inhibition down-regulated E-selectin and ICAM-1 but not VCAM-1 expression. With the use of a physiologically relevant in vitro model system, we demonstrate that protein kinase C δ plays an important role in the regulation of neutrophil adherence/migration during inflammation and identifies key steps regulated by protein kinase C δ in neutrophil-endothelial interactions.

Topics: Animals; Cell Adhesion; Chemotaxis, Leukocyte; Disease Models, Animal; E-Selectin; Endothelium, Vascular; Human Umbilical Vein Endothelial Cells; Humans; Intercellular Adhesion Molecule-1; Interleukin-8; Lung; Male; Microfluidic Analytical Techniques; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Peptide Fragments; Protein Kinase C-delta; Protein Kinase Inhibitors; Rats; Rats, Sprague-Dawley; Recombinant Fusion Proteins; Rheology; Sepsis; Tumor Necrosis Factor-alpha

Immunocompromised patients who develop sepsis while neutropenic are at high risk for morbidity and mortality; however, it is unknown if neutropenic sepsis is associated with distinct clinical and biological characteristics.. We conducted a prospective cohort study of patients admitted to the medical intensive care unit of an academic medical center with severe sepsis. Patients were followed for the development of acute respiratory distress syndrome (ARDS), acute kidney injury (AKI), and mortality. Plasma proteins, representing the host inflammatory response, anti-inflammatory response, and endothelial leak were measured in 30 % of subjects. Clinical characteristics and plasma protein concentrations of patients with neutropenia at enrollment were compared to patients without neutropenia.. Of 797 subjects enrolled, 103 (13 %) were neutropenic at ICU admission. The neutropenic subjects were more often in shock, admitted from the hospital ward, had higher APACHE III scores, and more likely bacteremic. Neutropenia was an independent risk factor for AKI (RR 1.28; 95 % CI 1.04, 1.57; p = 0.03), but not ARDS (RR 0.90; 95 % CI 0.70, 1.17; p = 0.42) or 30-day mortality (RR 1.05; 95 % CI 0.85, 1.31; p = 0.65). Neutropenic subjects had higher plasma interleukin (IL)-6 (457 vs. 249 pg/ml; p = 0.03), IL-8 (581 vs. 94 pg/ml; p <0.001), and granulocyte colony-stimulating factor (G-CSF) (3624 vs. 99 pg/ml; p <0.001). Angiopoietin-2 and IL-1 receptor antagonist concentrations did not differ between groups.. Neutropenic sepsis is associated with a higher AKI risk and concentrations of inflammatory mediators IL-6, IL-8, and G-CSF relative to non-neutropenic patients. These differences may have implications for future therapies targeting neutropenic sepsis.

Topics: Acute Kidney Injury; Adult; Aged; Angiopoietin-2; APACHE; Biomarkers; Chi-Square Distribution; Cohort Studies; Critical Illness; Female; Granulocyte Colony-Stimulating Factor; Humans; Intensive Care Units; Interleukin-6; Interleukin-8; Interleukins; Male; Middle Aged; Neutropenia; Pennsylvania; Prospective Studies; Receptors, Interleukin-1; Respiratory Distress Syndrome; Sepsis

Diabetes is associated with chronic inflammation and activation of the vascular endothelium and the coagulation system, which in a more acute manner are also observed in sepsis. Insulin and metformin exert immune modulatory effects. In this study, we aimed to determine the association of diabetes and preadmission insulin and metformin use with sepsis outcome and host response.. We evaluated 1104 patients with sepsis, admitted to the intensive care unit and stratified according to the presence or absence of diabetes mellitus. The host response was examined by a targeted approach (by measuring 15 plasma biomarkers reflective of pathways implicated in sepsis pathogenesis) and an unbiased approach (by analyzing whole genome expression profiles in blood leukocytes).. Diabetes mellitus was not associated with differences in sepsis presentation or mortality up to 90 days after admission. Plasma biomarker measurements revealed signs of systemic inflammation, and strong endothelial and coagulation activation in patients with sepsis, none of which were altered in those with diabetes. Patients with and without diabetes mellitus, who had sepsis demonstrated similar transcriptional alterations, comprising 74 % of the expressed gene content and involving over-expression of genes associated with pro-inflammatory, anti-inflammatory, Toll-like receptor and metabolic signaling pathways and under-expression of genes associated with T cell signaling pathways. Amongst patients with diabetes mellitus and sepsis, preadmission treatment with insulin or metformin was not associated with an altered sepsis outcome or host response.. Neither diabetes mellitus nor preadmission insulin or metformin use are associated with altered disease presentation, outcome or host response in patients with sepsis requiring intensive care.

Topics: Aged; Biomarkers; Chemokine CX3CL1; Critical Illness; Diabetes Mellitus; E-Selectin; Female; Humans; Hyperglycemia; Inflammation; Insulin; Intensive Care Units; Intercellular Adhesion Molecule-1; Interferon-gamma; Interleukin-10; Interleukin-1beta; Interleukin-6; Interleukin-8; Male; Metformin; Middle Aged; Prospective Studies; Sepsis; Statistics, Nonparametric; Survival Analysis; Treatment Outcome; Tumor Necrosis Factor-alpha

In spite of advances in neonatal care and the new generation of antibiotics, neonatal sepsis is still a major cause of morbidity and mortality. Early diagnosis of neonatal sepsis is difficult because clinical signs are non-specific. Thus, new biomarkers are still needed for diagnosis. Gelsolin is an actin-binding plasma protein. Furthermore, extracellular gelsolin binds lipopolysaccharide and lipoteichoic acid, which are major virulence factors of Gram-negative and Gram-positive bacteria. The result of this binding is the inhibition of gelsolin's F-actin depolymerizing activity. Thus, gelsolin inhibits the release of IL-8 from human neutrophils subjected to lipoteichoic acid, lipopolysaccharide and heat-inactivated bacteria treatment. Our hypothesis is that pGSN levels decrease in neonatal infants with sepsis and this decrease might be used as a reliable biological marker. Forty patients who were diagnosed with severe sepsis at a neonatal intensive care unit were enrolled in the sepsis group. Twenty patients who were followed for prematurity were enrolled in the control group. The pGSN level at the time of diagnosis in the sepsis group was 33.98±11.44μg/ml, which was significantly lower than that of control group (60.05±11.3μg/ml, P<0.001) and after treatment (53.38±31.26μg/ml, P=0.003). Area under ROC curve was 0.96 (p: 0.0001, 95% CI; 0.90-0.99). Sensitivity was 90.32 (95% CI; 74.2-97.8), specificity was 95 (95% CI; 75.1-99.2). Plasma gelsolin significantly decreased in septic patient and recovery of decreased gelsolin levels correlated with clinical improvement. Thus, plasma gelsolin may be a usable marker for severe sepsis.

Topics: Actins; Area Under Curve; Biomarkers; Female; Gelsolin; Humans; Infant, Newborn; Interleukin-8; Lipopolysaccharides; Male; Morbidity; Neonatal Sepsis; Neutrophils; Prospective Studies; ROC Curve; Sensitivity and Specificity; Sepsis; Teichoic Acids

A new 23S ribosomal RNA genes-targeted in situ hybridization (ISH) probe to detect global bacterial genomic DNA (59 species from 35 genera; referred to as the GB probe) phagocytized in leukocytes was recently developed. This method provided early and direct evidence of bacterial infection with high sensitivity and specificity in spontaneous bacterial peritonitis ascites. However, the utility of this method in febrile neutropenia (FN) is unknown.. We prospectively evaluated the utility of the ISH approach using the GB probe and previously reported probes in patients with neutropenia and fever undergoing chemotherapy at our institution between June 2011 and July 2013. Blood samples for culture analysis and ISH tests were collected simultaneously at the onset of fever; the latter were performed repeatedly.. Fifty febrile episodes were evaluated. In 24 episodes of fever of unknown origin and 15 episodes of local infection (all negative for blood cultures), ISH tests identified causal bacteria in 21% and 13% of cases, respectively, at the onset of fever. In seven sepsis cases (all positive for blood culture), positive ISH test results at fever onset were achieved in 71%; for two patients with neutrophil counts of 0/μl and 171/μl, respectively, negative results were obtained.. This new ISH approach could prove useful for early detection of bacteria in patients with neutropenia and blood culture-negative, with fever of unknown etiology after chemotherapy. Using this method in combination with blood culture, even in cases with extremely low neutrophil counts, might contribute to better management of FN.

Topics: Adult; Aged; Antineoplastic Agents; Bacteria; Bacterial Infections; Biomarkers; Blood Culture; Calcitonin; Chemotherapy-Induced Febrile Neutropenia; DNA, Bacterial; Female; Genes, rRNA; Humans; In Situ Hybridization; Interleukin-6; Interleukin-8; Leukocyte Count; Male; Middle Aged; Prospective Studies; RNA, Bacterial; RNA, Ribosomal, 23S; Sensitivity and Specificity; Sepsis; Young Adult

Sepsis patients with cardiac dysfunction have significantly higher mortality. Although several pathways are associated with myocardial damage in sepsis, the precise cause(s) remains unclear and treatment options are limited. This study was designed to develop a new model to investigate the early events of cardiac damage during sepsis progression.. Francisella tularensis subspecies novicida (Ft.n) is a Gram-negative intracellular pathogen causing severe sepsis syndrome in mice. BALB/c mice (N=12) were sham treated or infected with Ft.n through the intranasal route. Serial electrocardiograms were recorded at multiple time points until 96 hours. Hearts were then harvested for histology and gene expression studies. Similar to septic patients, we illustrate both cardiac electrical and structural phenotypes in our murine Ft.n infection model, including prominent R' wave formation, prolonged QRS intervals, and significant left ventricular dysfunction. Notably, in infected animals, we detected numerous microlesions in the myocardium, previously observed following nosocomial Streptococcus infection and in sepsis patients. We show that Ft.n-mediated microlesions are attributed to cardiomyocyte apoptosis, increased immune cell infiltration, and expression of inflammatory mediators (tumor necrosis factor, interleukin [IL]-1β, IL-8, and superoxide dismutase 2). Finally, we identify increased expression of microRNA-155 and rapid degradation of heat shock factor 1 following cardiac Ft.n infection as a primary cause of myocardial inflammation and apoptosis.. We have developed and characterized an Ft.n infection model to understand the pathogenesis of cardiac dysregulation in sepsis. Our findings illustrate novel in vivo phenotypes underlying cardiac dysfunction during Ft.n infection with significant translational impact on our understanding of sepsis pathophysiology.

Topics: Animals; Apoptosis; Cytokines; Disease Models, Animal; Electrocardiography; Heart; Heat Shock Transcription Factors; Interleukin-1beta; Interleukin-8; Mice; MicroRNAs; Myocardium; Myocytes, Cardiac; Sepsis; Superoxide Dismutase; Tularemia; Tumor Necrosis Factor-alpha

To assess the clinical relevance of IL8 gene polymorphisms in patients with sepsis and its association with systemic IL-8 levels.. PCR and DNA sequencing were used to examine the polymorphism of IL8 in 152 patients with sepsis and in 199 healthy volunteers in China. The distribution frequencies of the genotype and allele were compared among different groups. The serum IL-8 was measured by ELISA and analyzed in relation to polymorphisms of IL8.. The homozygote TT genotype and T allele of rs4073 (genotype: p=0.01, allele: p=0.002), the homozygote CC genotype and C allele (genotype: p=0.03, allele: p=0.003) of rs2227306, homozygote AA genotype and A allele of re1126647 (genotype: p=0.01, allele: p=0.002) were associated with susceptibility to sepsis in males. Serum IL-8 levels were significantly increased in patients with sepsis but showed no correlation with IL8 rs4073, rs2227306 and rs1126647 polymorphisms.. The male population carrying the homozygote TT genotype and T allele of rs4073, the homozygote CC genotype and C allele of rs2227306 and homozygote AA genotype and A allele of rs1126647 are more susceptible to sepsis, suggesting there is a protective effect in females carrying these genotypes and alleles respectively. There was no association between rs4073, rs2227306 and rs1126647 polymorphisms and serum levels of IL-8 in patients with sepsis.

Topics: Adult; Aged; Alleles; China; Female; Heterozygote; Homozygote; Humans; Interleukin-8; Male; Middle Aged; Polymorphism, Genetic; Sepsis; Sex Factors

Aging-related changes in platelet and monocyte interactions may contribute to adverse outcomes in sepsis but remain relatively unexamined. We hypothesized that differential platelet-monocyte aggregate (PMA) formation in older septic patients alters inflammatory responses and mortality.. We prospectively studied 113 septic adults admitted to the intensive care unit with severe sepsis or septic shock. Patients were dichotomized a priori into one of two groups: older (age ≥ 65 years, n = 28) and younger (age < 65 years, n = 85). PMA levels were measured in whole blood via flow cytometry within 24 hours of admission. Plasma levels of IL-6 and IL-8, proinflammatory cytokines produced by monocytes upon PMA formation, were determined by commercial assays. Patients were followed for the primary outcome of 28-day, all-cause mortality.. Elevated PMA levels were associated with an increased risk of mortality in older septic patients (hazard ratio for mortality 5.64, 95% confidence interval 0.64-49.61). This association remained after adjusting for potential confounding variables in multivariate regression. Receiver operating curve analyses demonstrated that PMA levels greater than or equal to 8.43% best predicted 28-day mortality in older septic patients (area under the receiver operating curve 0.82). Plasma IL-6 and IL-8 levels were also significantly higher in older nonsurvivors. In younger patients, neither PMA levels nor plasma monokines were significantly associated with mortality.. Increased PMA formation, and associated proinflammatory monokine synthesis, predicts mortality in older septic patients. Although larger studies are needed, our findings suggest that heightened PMA formation in older septic patients may contribute to injurious inflammatory responses and an increased risk of mortality.

Topics: Aged; Biomarkers; Blood Platelets; Cell Aggregation; Female; Flow Cytometry; Humans; Intensive Care Units; Interleukin-6; Interleukin-8; Male; Monocytes; Predictive Value of Tests; Prospective Studies; ROC Curve; Sensitivity and Specificity; Sepsis; Shock, Septic

The innate immune response molecules and their use as a predictor of mortality in cancer patients with severe sepsis and septic shock are poorly investigated.. To analyze the value of interleukin (IL)-1ß, IL-6, IL-8, IL-10, IL-12, tumor necrosis factor α (TNF-α), soluble triggering receptor expressed on myeloid cells 1 (sTREM-1), and high-mobility group box 1 (HMGB-1) as predictors of mortality in cancer patients with severe sepsis and septic shock compared with septic patients without malignancies.. Prospective, observational cohort study.. Tertiary level adult intensive care unit (ICU).. Seventy-five patients with severe sepsis or septic shock, 40 with cancer and 35 without.. Laboratory data were collected at ICU admission, 24 and 48 hours after. Plasma concentrations of HMGB-1 and sTREM-1 were measured by enzyme-linked immunosorbent assay, whereas cytokines were measured by cytometric bead array.. Intensive care unit mortality in cancer and noncancer patients was 40% and 28.6% (P = .29), and 28-day mortality was 45% and 34.3% (P = .34). Proinflammatory cytokines IL-1ß, IL-6, IL-8, IL-12, and TNF-α showed significantly higher values in the cancer group. Interleukin-10 at 48 hours (P = .01), sTREM-1 in all measurements (P < .01) and HMGB-1 at 24 hours (P < .01) showed significantly lower values in the cancer group. In addition, for the cancer group, sTREM-1 at 24 hours (P = .02) and 48 hours (P = .01) showed higher levels in nonsurvivors patients. The area under the receiver operating characteristic curve for predicting ICU mortality for sTREM-1 was 0.73 (95% confidence interval, 0.57-0.89; P = .01). Multivariate logistic analysis showed that the days spent in mechanical ventilation and levels of sTREM-1 and IL-1ß at 48 hours were independent predictors of ICU mortality; corticosteroids requirement and levels of sTREM-1 and TNF-α at 24 hours were independent predictors of 28-day mortality.. Patients with cancer have different immune profile in sepsis when compared with patients without cancer, as demonstrated for levels of cytokines, sTREM-1 and HMGB-1. sTREM-1 and days spent in mechanical ventilation proved to be good predictors of ICU and 28-day mortality in cancer patients.

Topics: Aged; Aged, 80 and over; Biomarkers; Case-Control Studies; Cohort Studies; Cytokines; Enzyme-Linked Immunosorbent Assay; Female; HMGB1 Protein; Humans; Intensive Care Units; Interleukin-10; Interleukin-6; Interleukin-8; Male; Membrane Glycoproteins; Middle Aged; Neoplasms; Prognosis; Prospective Studies; Receptors, Immunologic; Respiration, Artificial; ROC Curve; Sepsis; Shock, Septic; Triggering Receptor Expressed on Myeloid Cells-1; Tumor Necrosis Factor-alpha

Sepsis-related mortality has been found increased in RAG-1 knockout mice. However, in patients admitted to medical intensive care units, it is unknown whether severe lymphocyte depletion at admission is associated with increased interleukin (IL)-7 and IL-15 levels in circulation, and increased mortality. We prospectively enrolled 92 patients who were admitted to medical intensive care units for severe sepsis or septic shock. At admission, 24 patients (26.1%) had severe lymphopenia, defined as lymphocyte counts of less than 0.5 × 10(3)/μL. Severe lymphopenia was associated with significantly higher plasma levels of tumor necrosis factor α, IL-6, IL-8, and IL-10 and was also independently associated with 28-day mortality (adjusted hazard ratio, 3.532; 95% confidence interval, 1.482-8.416; P = 0.004). The levels of plasma IL-15, but not IL-7, were increased modestly in patients with severe lymphopenia compared with those without (median, 12.2 vs. 6.4 pg/mL; P = 0.005). The elevated plasma IL-15 levels were contrarily associated with significantly decreased B-cell lymphoma 2 mRNA expression in peripheral blood mononuclear cells. In conclusion, severe lymphopenia was associated with increased mortality in patients with severe sepsis. We found that patients with sepsis with severe lymphopenia had down-regulated B-cell lymphoma 2 mRNA expression in peripheral blood mononuclear cells, despite increased plasma IL-15 concentrations. Whether IL-7 and IL-15 are insufficient in patients with severe lymphopenia during severe sepsis warrants further investigations.

Topics: Aged; Aged, 80 and over; Animals; Female; Genes, RAG-1; Humans; Interleukin-10; Interleukin-15; Interleukin-6; Interleukin-7; Interleukin-8; Lymphopenia; Male; Mice; Mice, Knockout; Middle Aged; Prospective Studies; Sepsis

There is a strong interest in finding adequate biomarkers to aid in the diagnosis and prognosis of influenza A (H1N1)pdm09 virus infection. In this study, serum levels of inflammatory cytokines and laboratory markers were evaluated to assess their usefulness as biomarkers of influenza A (H1N1)pdm09 and their association with fatal cases. Serum samples of consecutive patients with a clinical presentation suggestive of influenza A (H1N1)pdm09 and progression to sepsis were evaluated. Serum inflammatory cytokines and routine laboratory tests were performed and correlated with positivity for influenza A (H1N1)pdm09 influenza by real time reverse transcription polymerase chain reaction and the results of three clinical severity scores (Sequential Organ Failure Assessment [SOFA], CURB-65, and Acute Physiology and Chronic Health Evaluation II [APACHE II]). High SOFA scores and some of its individual components, but not CURB-65 or APACHE II scores, correlate with fatal cases regardless of etiology. Total and unconjugated bilirubin, Ca(++), Cl(-), prothrombin times, and partial thromboplastin times discriminate influenza A (H1N1)pdm09 from other causes of community-acquired pneumonia. High levels of IL-8, IL-10, and IL-17 were increased in influenza A (H1N1)pdm09 patients when compared with controls (p<0.05). IL-6 levels were significantly elevated in influenza A (H1N1)pdm09 patients and non-(H1N1)pdm09 patients when compared with controls (p<0.05). TGF-β serum levels discern between healthy controls, influenza A (H1N1)pdm09 patients, and patients with other causes of community-acquired pneumonia. TGF-β levels were negatively correlated with SOFA on admission in influenza A (H1N1)pdm09 patients. TGF-β levels are a useful tool for differentiating influenza A (H1N1)pdm09 from other causes of pneumonia progressing to sepsis.

Topics: Adult; Bilirubin; Biomarkers; Community-Acquired Infections; Female; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Interleukin-10; Interleukin-17; Interleukin-6; Interleukin-8; Male; Partial Thromboplastin Time; Pneumonia; Prothrombin Time; Reverse Transcriptase Polymerase Chain Reaction; Sepsis; Severity of Illness Index; Transforming Growth Factor beta

This study aimed to explore the effect and mechanisms of rhein on sepsis-induced acute kidney injury by injecting lipopolysaccharide (LPS) and cecal ligation and puncture (CLP) in vivo, and on LPS-induced HK-2 cells in vitro. For histopathological analysis, rhein effectively attenuated the severity of renal injury. Rhein could significantly decrease concentration of BUN and SCr and level of TNF-α and IL-1β in two different mouse models of experimental sepsis. Moreover, rhein could markedly attenuate circulating leukocyte infiltration and enhance phagocytic activity of macrophages partly impaired at 12 h after CLP. Rhein could enhance cell viability and suppresse the release of MCP-1 and IL-8 in LPS-stimulated HK-2 cells Furthermore, rhein down regulated the expression of phosphorylated NF-κB p65, IκBα and IKKβ stimulated by LPS both in vivo and in vitro. All these results suggest that rhein has protective effects on endotoxin-induced kidney injury. The underlying mechanism of rhein on anti-endotoxin kidney injury may be closely related with its anti-inflammatory and immunomodulatory properties by decreasing NF-κB activation through restraining the expression and phosphorylation of the relevant proteins in NF-κB signal pathway, hindering transcription of NF-κB p65.These evidence suggest that rhein has a potential application to treat endotoxemia-associated acute kidney injury.

Topics: Acute Kidney Injury; Animals; Anthraquinones; Blood Urea Nitrogen; Cell Line; Creatine; Disease Models, Animal; I-kappa B Kinase; I-kappa B Proteins; Immunohistochemistry; Interleukin-1beta; Interleukin-8; Kidney; Lipopolysaccharides; Macrophages; Mice; Mice, Inbred BALB C; NF-kappa B; NF-KappaB Inhibitor alpha; Phosphorylation; Sepsis; Signal Transduction; Transcription Factor RelA; Transcription, Genetic; Tumor Necrosis Factor-alpha

Promising results have been reported with blood purification as adjuvant treatment; however, the immunological mechanisms remain unclear. We have been developing a new blood purification system for regulating excessive immune reactions in severe sepsis and septic shock using a granulocyte adsorbing column (Adacolumn [Ada]), and a cytokine-adsorbing hemofilter (AN69ST hemofilter [AN69]). Fresh porcine blood was circulated for 6 h in five experimental groups including Ada and AN69 to assess the effects of leukocyte adsorption, phagocytic activity and adhesiveness of granulocytes. In the present study, we found that Ada mainly adsorbed granulocytes and monocytes, but not lymphocytes. The phagocytic activity level of granulocytes decreased, and adhesiveness increased, but the number of CD11b-positive cells markedly decreased in the current system. Elevated cytokine levels (IL-1β, IL-8 and IL-10) at the outlet of Ada were significantly lower than at the outlet of AN69 due to cytokine adsorption. Further studies are needed to better understand cellular interactions.

Topics: Adsorption; Animals; Disease Models, Animal; Hemodiafiltration; Immunity, Cellular; Interleukin-10; Interleukin-8; Leukocyte Count; Pilot Projects; Sepsis; Shock, Septic; Swine

To explore the significance of interleukin-6 (IL-6) and IL-8 in the diagnosis of neonatal sepsis.. This was a prospective study conducted between August 2014 and February 2015. A total of 140 neonates who were suspected infectious were enrolled and classified into a sepsis group (n=49) and a local infection group (n=91). Sixty-one neonates who were non-infectious served as the control group. Serum levels of IL-6 and IL-8 were measured before treatment and 3 days after treatment. The value of serum IL-6 and IL-8 for the diagnosis of neonatal sepsis was assessed by receiver operating characteristic (ROC) curve analysis.. Before treatment, serum levels of IL-6 and IL-8 in the sepsis group were higher than those in the local infection and control groups (P<0.05), and the local infection group had higher serum levels of IL-6 and IL-8 than the control group (P<0.05). After three days of treatment, the serum IL-6 level in the sepsis group remained higher than that in the local infection and control groups (P<0.05), and the local infection group had higher serum level of IL-6 than the control group (P<0.05). There was no significant difference in the serum IL-8 level among the three groups. According to the ROC curve, when the cut-off value of serum IL-6 was 32 pg/mL, the sensitivity, specificity and accuracy of serum IL-6 for the diagnosis of neonatal sepsis were 87.8%, 79.6% and 81.6% respectively; when the cut-off value of serum IL-8 was 54 pg/mL, the sensitivity, specificity and accuracy of serum IL-6 for the diagnosis of neonatal sepsis were 77.6%, 63.8% and 67.2% respectively. With the combination of serum IL-6 and IL-8 levels, the sensitivity, specificity and accuracy for the diagnosis of neonatal sepsis were 71.4%, 86.2% and 82.6% respectively.. IL-6 and IL-8 participate in the inflammatory response and the serum levels of both vary with the severity of infection. The diagnostic value of IL-6 for neonatal sepsis is higher than IL-8. The combined detection of serum levels IL-6 and IL-8 may increase the accuracy of diagnosis of neonatal sepsis.

Topics: C-Reactive Protein; Female; Humans; Infant, Newborn; Interleukin-6; Interleukin-8; Male; ROC Curve; Sepsis

The knowledge of systemic inflammation and local cytokine expression in porcine endocarditis models is limited, though it could provide valuable information about the pathogenesis and comparability to human endocarditis. Analyses of bacteriology and hematology were performed on blood samples from pigs with non-bacterial thrombotic endocarditis (NBTE, n = 11), Staphylococcus aureus infective endocarditis (IE, n = 2), animals with S. aureus sepsis without endocarditis (n = 2) and controls (n = 2). Furthermore, immunohistochemistry was used to examine the local expression of IL-1β and IL-8. Bacterial blood cultures were continuously positive in IE pigs from inoculation to euthanasia, and negative in all other pigs at all times. The total white blood cell counts and total neutrophil counts were massively elevated in pigs with IE. Local IL-1β and IL-8 expression in IE pigs were moderate to high, and high, respectively. In addition, slight local expression of IL-1β and IL-8 was present in some NBTE pigs. In the IE model, both the systemic inflammatory response and the high local expression of IL-8 were comparable to the human disease. Furthermore, the results indicate IL-1β and IL-8 as important contributors in the endocarditis pathogenesis.

Topics: Animals; Disease Models, Animal; Endocarditis, Bacterial; Endocarditis, Non-Infective; Female; Humans; Immunohistochemistry; Interleukin-1beta; Interleukin-8; Leukocyte Count; Myocardium; Sepsis; Staphylococcal Infections; Sus scrofa; Systemic Inflammatory Response Syndrome

The purpose of the study is to evaluate the prevalence and clinical significance of hypolipidemia and the relationship to cytokine concentrations and outcomes in septic patients.. A prospective study was undertaken including 50 patients with severe sepsis due to community-acquired infections. Serum concentrations of total cholesterol, triglyceride, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein as well as tumor necrosis factor α (TNF-α), interleukin (IL) 6, IL-8, IL-10, and transforming growth factor (TGF) β1 were determined on admission and days 3 and 10 during hospitalization.. Of the 50 patients enrolled, 28 survived, whereas 22 died during their hospital stay. Sepsis survivors had significantly higher HDL-C concentrations than nonsurvivors, whereas all patients with HDL-C values greater than 25 mg/dL survived. Baseline levels of TGF-β1 were significantly higher in survivors. High-density lipoprotein levels correlated inversely with TNF-α, IL-6, and IL-10 concentrations and positively with baseline TGF-β1 levels. Independent risk factors of mortality were IL-10 levels on day 3, whereas HDL-C concentration on admission was related to survival.. Low cholesterol and lipoprotein concentrations are detected in septic patients, especially in individuals with poor outcome. High-density lipoprotein cholesterol concentration seems to be an early independent predictive marker of survival in severe sepsis.

Topics: Aged; Biomarkers; Cholesterol; Community-Acquired Infections; Cytokines; Female; Hospital Mortality; Humans; Interleukin-10; Interleukin-6; Interleukin-8; Lipids; Lipoproteins, HDL; Male; Middle Aged; Prospective Studies; Sepsis; Transforming Growth Factor beta; Triglycerides; Tumor Necrosis Factor-alpha

Early prediction of postoperative sepsis remains an enormous clinical challenge. Association of TNF-α-308 G/A polymorphism with sepsis remains controversial. We, therefore, investigated this polymorphism with serum levels of cytokines TNF-α, IL-6, and IL-8 in relation to development of sepsis following major gastrointestinal surgery.. Two hundred and thirty-nine patients undergoing major gastrointestinal surgery were enrolled. Polymorphism was studied through the analysis of restriction fragments of Nco1-digested DNA with the polymerase chain reaction. All patients were followed for 1 month following surgery for evidence of sepsis. Levels of serum cytokines TNF-α, IL-6, and IL-8 were measured preoperatively and postoperatively by enzyme-linked immunosorbent assay (ELISA).. Forty-seven (19.66 %) patients developed postoperative sepsis. Patients with postoperative sepsis were significantly (p = 0.002) more likely to possess AA homozygous genotype with higher capacity to produce cytokines TNF-α (p < 0.0001), IL-6 (p < 0.0001), and IL-8 (p < 0.0001) as compared to other genotypes. When compared with patients carrying at least one G allele, the AA genotype was associated with a significantly higher probability (odds ratio (OR) = 4.17; p = 0.003; 95 % confidence interval (CI) = 1.5-11.48) of developing sepsis. Compared with the GG genotype, AA was associated with a significantly higher probability (OR = 5.18; p = 0.0008; 95 % CI = 1.82-14.76) of sepsis development.. TNF-α-308 G/A polymorphism is significantly associated with the development of postoperative sepsis and with increased expression of cytokines TNF-α, IL-6, and IL-8.

Topics: Adolescent; Adult; Biomarkers; Digestive System Surgical Procedures; Enzyme-Linked Immunosorbent Assay; Female; Follow-Up Studies; Genetic Markers; Genetic Predisposition to Disease; Genotype; Humans; Interleukin-6; Interleukin-8; Male; Middle Aged; Odds Ratio; Polymorphism, Single Nucleotide; Postoperative Complications; Postoperative Period; Preoperative Period; Risk Factors; Sepsis; Tumor Necrosis Factor-alpha; Young Adult

To observe the effects of blood purification in the treatment of burn sepsis, in order to provide evidence for its application.. Twenty-seven patients with burn sepsis admitted to our burn ward from June 2012 to December 2013, conforming to the study criteria, were divided into conventional treatment group (CT, n = 15) and blood purification group (BP, n = 12) according to the random number table. After the diagnosis of sepsis was confirmed, patients in group CT received CT, while patients in group BP received both CT and continuous veno-venous hemodiafiltration for 48 hours. At the time of diagnosis of sepsis (before treatment) and post treatment hour (PTH) 24 and 48, levels of blood lactate and PaO2 were analyzed with blood gas analyzer, and the oxygenation index (OI) was calculated; blood sodium, blood glucose, blood urea nitrogen (BUN), creatinine, white blood cell count (WBC), procalcitonin (PCT) were determined; acute physiology and chronic health evaluation (APACHE) II score was estimated basing on the body temperature, respiratory rate, mean arterial pressure, PaO2, and blood pH values. The levels of TNF-α, IL-8, and IL-6 in serum were determined by ELISA. Data were processed with Fisher's exact test, t test, analysis of variance for repeated measurement, LSD- t test, and LSD test.. (1) The levels of blood lactate of patients in group BP were significantly lower than those of group CT at PTH 24 and 48 (with t values respectively 1.62 and 2.44, P values below 0.05). Compared with that detected before treatment, the level of blood lactate in group BP was significantly decreased at PTH 48 (P < 0.05). The OI values of patients in group BP at PTH 24 and 48 [(247 ± 30), (288 ± 41) mmHg, 1 mmHg = 0.133 kPa] were significantly higher than those of group CT [(211 ± 32), (212 ± 30) mmHg, with t values respectively 3.02 and 5.63, P values below 0.01]. Compared with that detected before treatment, the OI values of patients in group BP at PTH 24 and 48 were significantly higher (P values below 0.01). (2) Compared with those of group CT at PTH 24 and 48, the levels of blood sodium, BUN, and creatinine were significantly lower (with t values from 1.74 to 6.75, P < 0.05 or P < 0.01), while the level of blood glucose was approximately the same (with t values respectively -0.92, -0.38, P values above 0.05) in group BP. Compared with those detected before treatment, the levels of blood sodium, BUN, and creatinine of group BP at PTH 24 and 48 were significantly lower (P < 0.05 or P < 0.01). (3) The levels of WBC and PCT of patients in group BP at PTH 24 and 48 were significantly lower than those of group CT (with t values from 2.11 to 6.63, P < 0.05 or P < 0.01). Compared with those detected before treatment, the levels of WBC and PCT of patients in group BP at PTH 24 and 48 were significantly lower (P < 0.05 or P < 0.01). (4) The APACHE II scores of patients in group BP at PTH 24 and 48 [(18.7 ± 2.6) and (16.7 ± 3.0) scores] were significantly lower than those of group CT [(23.1 ± 1.6) and (25.5 ± 1.6) scores, with t values respectively 5.44 and 9.87, P values below 0.01]. Compared with those calculated before treatment, the APACHE II scores of patients in group CT were significantly increased (P < 0.05 or P < 0.01), while those in group BP were decreased at PTH 24 and 48 (P < 0.05 or P < 0.01). (5) The levels of TNF-α, IL-6, and IL-8 in serum of patients in group BP at PTH 24 and 48 were significantly lower than those of group CT (with t values from 6.12 to 19.78, P values below 0.01). Compared with those detected before treatment, the levels of TNF-α, IL-6, and IL-8 in serum of group BP at PTH 24 and 48 were significantly decreased (with P values below 0.01).. BP+CT is effective in improving organ function, correcting the disorder of internal environment, and controlling inflammation. Therefore, BP is an important method in the treatment of burn sepsis.

Topics: Aged; Animals; Blood Gas Analysis; Burns; Humans; Interleukin-6; Interleukin-8; Sepsis; Serum; Tumor Necrosis Factor-alpha

Once a patient is in septic shock, survival rates drop by 7.6% for every hour of delay in antibiotic therapy. Biomarkers based on the molecular mechanism of sepsis are important for timely diagnosis and triage. Here, we study the potential roles of a panel of cellular and viral miRNAs as sepsis biomarkers. We performed genome-wide microRNA (miRNA) expression profiling in leukocytes from septic patients and nonseptic controls, combined with quantitative RT-PCR in plasmas from two cohorts of septic patients, two cohorts of nonseptic surgical patients and healthy volunteers. Enzyme-linked immunosorbent assay, miRNA transfection and chromatin immunoprecipitation were used to study the effects of Kaposi sarcoma herpes virus (KSHV) miRNAs on interleukin's secretion. Differences related to sepsis etiology were noted for plasma levels of 10 cellular and 2 KSHV miRNAs (miR-K-10b and miR-K-12-12*) between septic and nonseptic patients. All the sepsis groups had high KSHV miRNAs levels compared with controls; Afro-American patients had higher levels of KSHV-miR-K12-12* than non-Afro-American patients. Both KSHV miRNAs were increased on postoperative day 1, but returned to baseline on day 7; they acted as direct agonists of Toll-like receptor 8 (TLR8), which might explain the increased secretion of the IL-6 and IL-10. Cellular and KSHV miRNAs are differentially expressed in sepsis and early postsurgical patients and may be exploited for diagnostic and therapeutic purposes. Increased miR-K-10b and miR-K12-12* are functionally involved in sepsis as agonists of TLR8, forming a positive feedback that may lead to cytokine dysregulation.

Topics: Aged; APACHE; Black or African American; Case-Control Studies; Feedback, Physiological; Female; Gene Expression Profiling; Gene Expression Regulation; Herpesvirus 8, Human; Humans; Interleukin-6; Interleukin-8; Leukocytes, Mononuclear; Male; MicroRNAs; Middle Aged; Sarcoma, Kaposi; Sepsis; Signal Transduction; Survival Analysis; Toll-Like Receptor 8; Wounds and Injuries

Bacterial sepsis induced immunsuppression via antigen hyporesponsibility increases the risk of nosokomial infections and mortality. Pattern recognition receptors (PRR) might have a central role in the pathophysiology of hyporesponsibility.. In this study we evaluated in a human E. coli sepsis cohort, the role of PRR including TLR's and Trem-1. Expression of Trem-1, TLR2, TLR4, CD14 and HLA-DR on blood monozytes and neutrophils were examined using flow cytometry from 22 patients with E. coli sepsis and 6 healthy controls. LPS and LTA stimulated TNF alpha, IL-10, IL-8 and IL-6 production was studied in a 24 h whole blood assay. Free cytokine serum concentration of TNF alpha, PCT and IP-10 were evaluated.. We found a significant higher expression of Trem-1 and TLR-2 on monocytes and neutrophils in patients compared to healthy volunteers. TLR2 expression (p < 0.05) was higher and HLA-DR lower (p < 0.05) on monocytes of patients with severe sepsis compared to patients with simple sepsis. Trem-1 expression was tendentially higher (p = 0,07) on monocytes and lower on neutrophils of patients with severe sepsis. Trem-1 expression on neutrophils was associated with the IL-10 (LPS: r = 0,61, p < 0.02) and TNF-α inducibility (LPS: r = 0,78, p < 0,002). In addition Trem-1 expression on neutrophils shows a negative correlation to the serum levels of TNF alpha (r = -0,63; p < 0,005), IP-10 (r = -0,5; p < 0,035) and procalcitonin (r = -0,59; p < 0,007).. Patients with E. coli sepsis are characterized by an association of Trem-1 expression on blood neutrophils with cytokine inducibility. The TREM-1 pathway on neutrophils might play a role in producing an adequate inflammatory and bactericidal response in bacterial sepsis.. The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/4441869398748313.

Topics: Aged; Case-Control Studies; Cytokines; Escherichia coli Infections; Female; Flow Cytometry; HLA-DR Antigens; Humans; Immune Tolerance; Interleukin-10; Interleukin-6; Interleukin-8; Lipopolysaccharide Receptors; Male; Membrane Glycoproteins; Monocytes; Neutrophils; Prospective Studies; Receptors, Immunologic; Sepsis; Toll-Like Receptor 2; Triggering Receptor Expressed on Myeloid Cells-1; Tumor Necrosis Factor-alpha; Up-Regulation

Our hypothesis is that specific proinflammatory and anti-inflammatory urinary cytokines are useful in the diagnostic evaluation of risk for sepsis in term neonates. We conducted a pilot, prospective hospital-based longitudinal observational study to test the urine of term neonates with a 13 biomarker panel of cytokines.. Infants were divided into 2 groups: The control group (n = 15) consisted of infants admitted to newborn nursery, and the test group (n = 15) consisted of infants admitted to the neonatal intensive care unit for presumed sepsis. Bagged urine samples were collected from 30 term neonates for testing our hypothesis.. Urinary interleukin (IL)-8 (P = .004*), inducible protein (IP)-10 (P = .007*), and monocyte chemoattractant protein (MCP)-1 (P = .02) were significantly increased in the test group compared with the control group.. Urinary IL-8, IP-10, and MCP-1 are proinflammatory cytokines that are increased in the neonate during an infectious inflammatory process. These may be useful predictors as an adjunct to the current protocols to recognize neonatal sepsis.

Topics: Biomarkers; Chemokine CCL2; Chemokine CXCL10; Cytokines; Female; Humans; Infant, Newborn; Intensive Care Units, Neonatal; Interleukin-8; Longitudinal Studies; Male; Pilot Projects; Prospective Studies; Sepsis

Complement and the TLR family constitute two important branches of innate immunity. We previously showed attenuating effects on inflammation and thromogenicity by inhibiting the TLR coreceptor CD14 in porcine sepsis. In the present study, we explored the effect of the C5 and leukotriene B4 inhibitor Ornithodoros moubata complement inhibitor (OmCI; also known as coversin) alone and combined with anti-CD14 on the early inflammatory, hemostatic, and hemodynamic responses in porcine Escherichia coli-induced sepsis. Pigs were randomly allocated to negative controls (n = 6), positive controls (n = 8), intervention with OmCI (n = 8), or with OmCI and anti-CD14 (n = 8). OmCI ablated C5 activation and formation of the terminal complement complex and significantly decreased leukotriene B4 levels in septic pigs. Granulocyte tissue factor expression, formation of thrombin-antithrombin complexes (p < 0.001), and formation of TNF-α and IL-6 (p < 0.05) were efficiently inhibited by OmCI alone and abolished or strongly attenuated by the combination of OmCI and anti-CD14 (p < 0.001 for all). Additionally, the combined therapy attenuated the formation of plasminogen activator inhibitor-1 (p < 0.05), IL-1β, and IL-8, increased the formation of IL-10, and abolished the expression of wCD11R3 (CD11b) and the fall in neutrophil cell count (p < 0.001 for all). Finally, OmCI combined with anti-CD14 delayed increases in heart rate by 60 min (p < 0.05) and mean pulmonary artery pressure by 30 min (p < 0.01). Ex vivo studies confirmed the additional effect of combining anti-CD14 with OmCI. In conclusion, upstream inhibition of the key innate immunity molecules, C5 and CD14, is a potential broad-acting treatment regimen in sepsis as it efficiently attenuated inflammation and thrombogenicity and delayed hemodynamic changes.

Topics: Animals; Antithrombin III; Arterial Pressure; Arthropod Proteins; Carrier Proteins; CD11b Antigen; Complement C5; Escherichia coli; Escherichia coli Infections; Granulocyte-Macrophage Colony-Stimulating Factor; Heart Rate; Hemodynamics; Immunity, Innate; Inflammation; Interleukin-10; Interleukin-1beta; Interleukin-6; Interleukin-8; Leukocyte Count; Leukotriene B4; Lipopolysaccharide Receptors; Neutrophils; Peptide Hydrolases; Plasminogen Activator Inhibitor 1; Sepsis; Sus scrofa; Tumor Necrosis Factor-alpha

Staphylococci are a major contribution for neonatal sepsis, which is the main risk factor for bronchopulmonary dysplasia. This study investigated the expression of pro-inflammatory mediators in endothelial and respiratory cells from newborns exposed to staphylococci.. Human vascular endothelial cells and small airway epithelial cells were incubated with neonatal blood isolates of Staphylococcus epidermidis (n = 14) and Staphylococcus aureus (n = 14). The extracellular release of IL-8, IL-10, sICAM-1, ICAM-1 mRNA and the expression of membrane bound ICAM-1 were assessed by ELISA, RT-PCR and immunofluorescence microscopy.. Staphylococcus epidermidis induced higher levels of IL-8 (mean 38.5 ng/mL) and ICAM-1 mRNA (mean ratio 1.037) in the small airway epithelial cells than S. aureus (IL-8 mean 22.2 ng/mL, p < 0.01 and ICAM-1 mRNA mean ratio 0.715, p < 0.01). In the endothelial cells, ICAM-1 remained more integrated in the cell membranes after exposure to S. epidermidis compared with S. aureus, which induced disintegration and release of soluble ICAM-1 into the supernatants.. Staphylococcus epidermidis induced a higher chemoattractive response than S. aureus. A persistent transmigration of granulocytes into the lung tissue in neonatal S. epidermidis sepsis might contribute to the development of bronchopulmonary dysplasia.

Topics: Biomarkers; Cells, Cultured; Endothelial Cells; Enzyme-Linked Immunosorbent Assay; Fluorescent Antibody Technique; Humans; Infant, Newborn; Intercellular Adhesion Molecule-1; Interleukin-10; Interleukin-8; Real-Time Polymerase Chain Reaction; Respiratory Mucosa; Sepsis; Staphylococcal Infections; Staphylococcus aureus; Staphylococcus epidermidis

Cytokines (IL-6, IL-8 and TNF-α), sCD163, and C-reactive protein were serially measured in an attempt to identify a set of tests which can reliably confirm or refute the diagnosis of neonatal sepsis at an early stage.. One hundred neonates suspected to have sepsis on clinical grounds and who met the inclusion criteria were enrolled for the study. Based on the positive or negative blood culture reports they were classified as infected (n=50) and non-infected (n=50) neonates respectively. Fifty healthy neonates without any signs of sepsis were also included in the study as control group. The initial blood sample was taken on day 0 (at the time of sepsis evaluation) and two further samples were taken on days 1 and 2 for monitoring the clinical progress and response to treatment. In the control group the cord blood and 48 hours venous sample was collected. Plasma CRP (ng/ml), IL-6 (pg/ml), IL-8 (pg/ml), TNF-α (ng/ml) and sCD163 (ng/ml) were determined by double antibody method Enzyme Linked Immunosorbent Assay in all the three blood samples.. The cut of levels for CRP at >19,689 ng/ml had a sensitivity of 68%, specificity of 92%, for IL-6 at >95.32 pg/ml had a sensitivity of 54%, specificity of 96%, for IL-8 at >70.86 pg/ml had a sensitivity of 78%, specificity of 70%, for sCD163 at >896.78 ng/ml had a sensitivity of 100%, specificity of 88% for the diagnosis of infection before antibiotics. TNF-α levels of >12.6 ng/ml showed 100% sensitivity and 72% specificity for the diagnosis of inflammation.. The most powerful predictor to differentiate between the non-infected and infected neonates before antibiotics was sCD163. The most powerful indicator for evaluation of prognosis is IL-6. sCD163 can be used alone to screen for sepsis in neonates before the results of blood culture are received.

Topics: Antigens, CD; Antigens, Differentiation, Myelomonocytic; Biomarkers; C-Reactive Protein; Case-Control Studies; Early Diagnosis; Enzyme-Linked Immunosorbent Assay; Female; Humans; Infant, Newborn; Interleukin-6; Interleukin-8; Male; Receptors, Cell Surface; Sensitivity and Specificity; Sepsis; Tumor Necrosis Factor-alpha

The aim of the present study was to develop and investigate nanoporous activated carbon materials for their ability to adsorb inflammatory cytokines directly from blood, for a range of therapeutic applications, including: systemic inflammatory response syndrome (SIRS) related to sepsis, cardio-pulmonary by-pass surgery, or ischemic reperfusion injury. Building on the previously established relationship between the porous structure of beaded polymer-derived activated carbon and its capacity to adsorb inflammatory molecules, we have developed and characterized monolithic porous carbon columns produced from the same polymer precursor matrix as carbon microbeads. The monolithic columns developed were assessed for their ability to adsorb inflammatory molecules from blood in a circulating system. Preliminary findings demonstrated good removal of the inflammatory cytokines IL-8 (100% removal), IL-6 (80% removal), and TNF (51% removal) from blood. The efficiency of cleansing is dependent on the size of the adsorbed molecule and the porous structure of the monolith, highlighting their potential for use as a hemoadsorption device.

Topics: Adsorption; Carbon; Cytokines; Extracorporeal Circulation; Humans; Interleukin-6; Interleukin-8; Microspheres; Porosity; Sepsis; Tumor Necrosis Factor-alpha

We previously created a risk prediction model for severe sepsis not clinically apparent during the first 24 hours of hospitalization in children with high-risk febrile neutropenia (HRFN), which identified 3 variables, age ≥ 12 years, serum C-reactive protein (CRP) ≥ 90 mg/L and interleukin-8 ≥ 300 pg/mL, evaluated at the time of admission and at 24 hours of hospitalization. The combination of these 3 variables identified a risk for severe sepsis ranging from 8% to 73% with a relative risk of 3.15 (95% confidence interval: 1.1-9.06). The aim of this study was to validate prospectively our risk prediction model for severe sepsis in a new cohort of children with cancer and HRFN.. Predictors of severe sepsis identified in our previous model (age, CRP and interleukin-8) were evaluated at admission and at 24 hours of hospitalization in a new cohort of children with HRFN between April 2009 and July 2011. Diagnosis of severe sepsis, not clinically apparent during the first 24 hours of hospitalization, was made after discharge by a blind evaluator.. A total of 447 HRFN episodes were studied, of which 76 (17%) had a diagnosis of severe sepsis. The combination of age ≥ 12 years, CRP ≥ 90 mg/L and interleukin-8 ≥ 300 pg/mL at admission and/or at 24 hours in the new cohort identified a risk for severe sepsis ranging from 7% to 46% with an RR of 6.7 (95% CI: 2.3-19.5).. We validated a risk prediction model for severe sepsis applicable to children with HRFN episodes within the first 24 hours of admission. We propose to incorporate this model in the initial patient assessment to offer a more selective management for children at risk for severe sepsis.

Topics: Adolescent; C-Reactive Protein; Chemotherapy-Induced Febrile Neutropenia; Child; Child, Preschool; Female; Humans; Interleukin-8; Male; Models, Statistical; Neoplasms; Risk; Sepsis

Evidence suggests that adjunctive treatment with intravenous immunoglobulin preparations enriched with IgA and IgM reduce mortality in sepsis. The mode of action of polyvalent immunoglobulin is complex, including neutralization of toxins and modulation of complement activation and cytokine formation toward an anti-inflammatory profile. In this study we explored the effect of Pentaglobin, containing IgG, IgA and IgM, on the initial inflammatory reaction as well as on hemodynamics, using a well characterized and standardized porcine model of sepsis. Anesthetized and mechanically ventilated pigs, mean weight 14.9 kg, were allocated into two groups of 8 animals, receiving either Pentaglobin or saline, before sepsis was induced by intravenous Escherichia coli infusion. Five negative controls received saline only. All animals were observed for 4 h under extensive invasive monitoring. Pentaglobin significantly (p < 0.05) attenuated IL-1β formation by 38% at the end of the experiment, and markedly increased (p < 0.05) the formation of IL-10 at 60 min. TNF-α, IL-6, IL-8 and expression of the cell surface marker wCD11R3 were lower in the Pentaglobin group, but the differences were not significant. The serum concentration of LPS was three times higher in the Pentaglobin group (p < 0.005), indicating binding of LPS to Pentaglobin. Complementary in vitro experiments showed a higher binding affinity for IgM and IgA to LPS than for IgG. LPS-induced formation of IL-6 was significantly (p < 0.05) attenuated by Pentaglobin in an in vitro whole blood model. In conclusion, Pentaglobin decreased the key inflammasome IL-1β molecule in an E. coli-model of pigs sepsis.

Topics: Animals; Antigen-Antibody Complex; Biomarkers; Escherichia coli; Escherichia coli Infections; Hemodynamics; Immunoglobulin A; Immunoglobulin M; Immunoglobulins, Intravenous; Inflammation; Interleukin-10; Interleukin-1beta; Interleukin-6; Interleukin-8; Lipopolysaccharides; Protein Binding; Sepsis; Swine; Tumor Necrosis Factor-alpha

Acute hyperglycemia is considered as a pro-inflammatory state and is related to an adverse outcome in critically ill adults. Neonates are susceptible to infections and systemic inflammatory response syndrome induced by pro-inflammatory cytokines. This study focuses on the interaction between neonatal glucose homeostasis and the pro-inflammatory cytokine production in term and preterm infants in-vitro.. We analyzed the pro-inflammatory cytokine production in whole cord blood of term infants (n = 10), preterm infants > 32 weeks (n=16) and preterm infants ≤32 weeks of gestational age (n = 13) and in adult controls (n=14) using an in-vitro sepsis-model. Whole blood was pre-incubated with different concentrations of glucose (0-1000 mg/dl) and insulin (0-62.5 IE/l) and stimulated with lipopolysaccharide. The intracytoplasmatic TNF-α, IL-6, and IL-8 response was measured by flow cytometry.. In-vitro hyperglycemia induced a dose-dependent increase of IL-8 in all age groups while TNF-α was demonstrated to be stimulated by glucose in cord blood samples of preterm infants ≤32 weeks of gestational age and term infants. In contrast, insulin showed no significant effects on pro-inflammatory cytokine production in-vitro.. Acute hyperglycemia may induce pro-inflammatory cytokine responses in neonatal whole blood in-vitro. These data provide a basis for further in-vitro signal transduction studies and in-vivo investigations about the significance of neonatal glucose homeostasis and its impact on long-term outcome of this susceptible patient cohort.

Topics: Cytokines; Fetal Blood; Gestational Age; Glucose; Humans; Hyperglycemia; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Insulin; Interleukin-6; Interleukin-8; Lipopolysaccharides; Models, Biological; Sepsis; Tumor Necrosis Factor-alpha

To examine the association among interleukin-6, interleukin-8, tumor necrosis factor-α, interleukin-10, and interleukin-1β and white matter injury in very-low-birth-weight infants with clinical sepsis and to help predict infants at risk for development of white matter injury.. A prospective cohort study was carried out.. Neonatal intensive care unit.. Very low birth weight infants with clinical early-onset sepsis. Exclusion criteria were death before 14 days, major malformations, and congenital infections.. Ultrasound brain scans were carried out on the third day and weekly until the sixth week of life or discharge and confirmed by a magnetic resonance image performed in the first year. Plasma was assayed for interleukin-6, interleukin-8, tumor necrosis factor-α, interleukin-10, and interleukin-1β in the same sample collected for sepsis work-up. Mann-Whitney, chi-square, t tests, multiple regression, and receiver operating characteristic analysis were applied.. From July 2005 to October 2007 we studied 84 very-low-birth-weight infants, 27 (32%) with white matter injury, and 57 (68%) control subjects (with no white matter injury). Proven early-onset sepsis and necrotizing enterocolitis were high risk for white matter injury after adjustment for gestational age and birth weight (relative risk, 3.04; 1.93-4.80 and relative risk, 2.2; 1.31-3.74, respectively). Interleukin-6, interleukin-8, and tumor necrosis factor-α levels were higher in infants with white matter injury than in control subjects (p < .0001). Interleukin-1β and interleukin-10 were similar. The areas under the curve for interleukin-6, interleukin-8, and tumor necrosis factor-α were 0.96 (0.92-0.99), 0.97 (0.94-1.0), and 0.93 (0.86-0.99), respectively. Interleukin-8 ≥100 pg/mL was the best predictor of white matter injury; the sensitivity and specificity were 96% and 83%, respectively, and negative predictive value was 98%.. Very-low-birth-weight infants with proven early-onset sepsis, necrotizing enterocolitis, and high plasma levels of interleukin-6, interleukin-8, and tumor necrosis factor-α are at high risk for white matter injury.

Topics: Brain Injuries; Cytokines; Female; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Infant, Very Low Birth Weight; Interleukin-10; Interleukin-1beta; Interleukin-6; Interleukin-8; Leukoencephalopathies; Male; Prospective Studies; Risk Factors; Sepsis; Tumor Necrosis Factor-alpha; Ultrasonography

Candida is one of the leading causes of sepsis, and an effective host immune response to Candida critically depends on the cytokines IL-1β and IL-18, which need caspase-1 cleavage to become bioactive. Caspase-12 has been suggested to inhibit caspase-1 activation and has been implicated as a susceptibility factor for bacterial sepsis. In populations of African descent, CASPASE-12 is either functional or non-functional. Here, we have assessed the frequencies of both CASPASE-12 alleles in an African-American Candida sepsis patients cohort compared to uninfected patients with similar predisposing factors. African-American Candida sepsis patients (n = 93) and non-infected African-American patients (n = 88) were genotyped for the CASPASE-12 genotype. Serum cytokine concentrations of IL-6, IL-8, and IFNγ were measured in the serum of infected patients. Statistical comparisons were performed in order to assess the effect of the CASPASE-12 genotype on susceptibility to candidemia and on serum cytokine concentrations. Our findings demonstrate that CASPASE-12 does not influence the susceptibility to Candida sepsis, nor has any effect on the serum cytokine concentrations in Candida sepsis patients during the course of infection. Although the functional CASPASE-12 allele has been suggested to increase susceptibility to bacterial sepsis, this could not be confirmed in our larger cohort of fungal sepsis patients.

Topics: Black or African American; Candida; Candidemia; Caspase 12; Disease Susceptibility; Female; Genetic Variation; Genotype; Humans; Interferon-gamma; Interleukin-6; Interleukin-8; Male; Middle Aged; Sepsis

The aims of this study were to investigate the usefulness of serum C-reactive protein, procalcitonin, tumor necrosis factor alpha, interleukin-6, and interleukin-8 as postmortem markers of sepsis and to compare C-reactive protein and procalcitonin values in serum, vitreous humor, and cerebrospinal fluid in a series of sepsis cases and control subjects, in order to determine whether these measurements may be employed for the postmortem diagnosis of sepsis. Two study groups were formed, a sepsis group (eight subjects coming from the intensive care unit of two university hospitals, with a clinical diagnosis of sepsis in vivo) and control group (ten autopsy cases admitted to two university medicolegal centers, deceased from natural and unnatural causes, without elements to presume an underlying sepsis as the cause of death). Serum C-reactive protein and procalcitonin concentrations were significantly different between sepsis cases and control cases, whereas serum tumor necrosis factor alpha, interleukin-6, and interleukin-8 values were not significantly different between the two groups, suggesting that measurement of interleukin-6, interleukin-8, and tumor necrosis factor alpha is non-optimal for postmortem discrimination of cases with sepsis. In the sepsis group, vitreous procalcitonin was detectable in seven out of eight cases. In the control group, vitreous procalcitonin was clearly detectable only in one case, which also showed an increase of all markers in serum and for which the cause of death was myocardial infarction associated with multi-organic failure. According to the results of this study, the determination of vitreous procalcitonin may be an alternative to the serum procalcitonin for the postmortem diagnosis of sepsis.

Topics: Adolescent; Adult; Aged; Biomarkers; C-Reactive Protein; Calcitonin; Calcitonin Gene-Related Peptide; Case-Control Studies; Child; Child, Preschool; Female; Forensic Pathology; Humans; Interleukin-6; Interleukin-8; Male; Middle Aged; Protein Precursors; Sepsis; Tumor Necrosis Factor-alpha; Vitreous Body; Young Adult

Mortality of sepsis is still high. Crucial for therapeutic response are the early start of treatment as well as the choice of antibiotics or antibiotic combinations. β-lactam antibiotics with bactericidal mode of action are often recommended in guidelines. But this antibiotic class can trigger the immune system to a maximum by releasing cell wall components or exotoxins. This may lead to a worsening of the patient's clinical situation. In contrast, antibiotics with bacteriostatic action often inhibit bacterial protein synthesis with decrease of production of virulence factors and minimize release of cell wall components. The purpose of this review is to summarise the significance of some bacteriostatic antibiotics and to discuss whether a combination of bactericidal and bacteriostatic agents may improve the course of the illness.

Topics: Animals; Anti-Bacterial Agents; Bacteria; Bacterial Infections; beta-Lactams; Cell Wall; Critical Care; Cross Infection; Drug Therapy, Combination; Exotoxins; Guideline Adherence; Humans; Immunization; Interleukin-8; Sepsis; Staphylococcal Infections; Staphylococcus aureus; Virulence Factors

Early diagnosis of sepsis in children with febrile neutropenia and cancer still remains a challenge for modern medicine because of lack of specific laboratory markers and clinical signs especially at the beginning of the infection. The objective of this study was to evaluate the ability of interleukin-6 and interleukin-8 to predict bacteremia and sepsis during the first 2 days in oncohematologic patients with febrile neutropenia.. A total of 61 febrile neutropenic episodes in 37 children were studied. Serum samples were collected on day 1 and day 2 from the onset of fever and analyzed using an automated random access analyzer.. Neutropenic children with febrile episodes were classified into the following 2 groups: (1) fever of unknown origin group--patients with a negative blood culture--and (2) bacteremia/sepsis group--patients with a positive blood culture or clinical sepsis. High negative predictive values were found on day 1 for interleukin-6 and interleukin-8 (89% and 82%, respectively) for exclusion of bacteremia/sepsis.. These interleukins could be used as a screening tool for the rejection of sepsis or bacteremia on the first day of fever in neutropenic children with cancer.

Topics: Adolescent; Bacteremia; Biomarkers; Child; Child, Preschool; Diagnosis, Differential; Female; Fever; Humans; Infant; Interleukin-6; Interleukin-8; Male; Neoplasms; Neutropenia; Sepsis

The present study aimed to investigate the effect of curcumin on sepsis-induced acute lung injury (ALI) in rats, and explore its possible mechanisms. Male Sprague-Dawley rats were randomly divided into the following five experimental groups (n = 20 per group): animals undergoing a sham cecal ligature puncture (CLP) (sham group); animals undergoing CLP (control group); or animals undergoing CLP and treated with vehicle (vehicle group), curcumin at 50 mg/kg (low-dose curcumin [L-Cur] group), or curcumin at 200 mg/kg (high-dose curcumin [H-Cur] group).At 6, 12, 24 h after CLP, blood, bronchoalveolar lavage fluid (BALF) and lung tissue were collected. The lung wet/dry weight (W/D) ratio, protein level, and the number of inflammatory cells in the BALF were determined. Optical microscopy was performed to examine the pathologic changes in lungs. Myeloperoxidase (MPO) activity, malondialdehyde (MDA) content, as well as superoxidase dismutase (SOD) activity were measured in lung tissues. The expression of inflammatory cytokines, tumor necrosis factor-alpha (TNF-α), interluekin-8 (IL-8), and macrophage migration inhibitory factor (MIF) were determined in the BALF. Survival rates were recorded at 72 h in the five groups in another experiment. Treatment with curcumin significantly attenuated the CLP-induced pulmonary edema and inflammation, as it significantly decreased lung W/D ratio, protein concentration, and the accumulation of the inflammatory cells in the BALF, as well as pulmonary MPO activity. This was supported by the histopathologic examination, which revealed marked attenuation of CLP-induced ALI in curcumin treated rats. In addition, curcumin significantly increased SOD activity with significant decrease in MDA content in the lung. Also, curcumin caused down-regulation of the inflammatory cytokines TNF-α, IL-8, and MIF levels in the lung. Importantly, curcumin improved the survival rate of rats by 40%-50% with CLP-induced ALI. Taken together, these results demonstrate the protective effects of curcumin against the CLP-induced ALI. This effect can be attributed to curcumin ability to counteract the inflammatory cells infiltration and, hence, ROS generation and regulate cytokine effects.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents, Non-Steroidal; Bronchoalveolar Lavage Fluid; Curcumin; Dose-Response Relationship, Drug; Interleukin-8; Lung; Macrophage Migration-Inhibitory Factors; Male; Malondialdehyde; Models, Animal; Oxidative Stress; Peroxidase; Rats; Rats, Sprague-Dawley; Sepsis; Superoxide Dismutase; Tumor Necrosis Factor-alpha

The aim of the present study was to describe the variation in adiponectin and resistin levels, 2 adipokines with opposing effects on metabolism, in mechanically ventilated patients with sepsis and their relationships to disease severity and cytokine levels.. An observational prospective study was conducted in a secondary/tertiary unit. Forty-one mechanically ventilated patients diagnosed as having sepsis were included in the study. The Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores were estimated. Adiponectin, resistin, and cytokines were measured upon sepsis diagnosis and every 3 to 4 days thereafter until day 30. Adiponectin and resistin were also measured in 40 controls.. The patients had higher adiponectin (10.9 ± 6.1 μg/mL vs 6.0 ± 2.9 μg/mL, P < .001) and resistin (24.7 ng/mL vs 3.8 ng/mL, P < .001) levels compared with the controls. Adiponectin increased and resistin decreased significantly over time in the entire cohort. Resistin correlated with Acute Physiology and Chronic Health Evaluation II, Sequential Organ Failure Assessment, interleukin (IL)-6, IL-8, and IL-10 and was significantly higher in severe sepsis/septic shock compared with sepsis. No correlations between adiponectin and clinical scores were noted.. Adiponectin and resistin change reciprocally during the course of sepsis. Resistin relates to the severity of sepsis and the degree of inflammatory response. Adiponectin and resistin may play a critical role in the metabolic adaptations observed in sepsis.

Topics: Adiponectin; Adult; APACHE; Critical Illness; Cytokines; Female; Health Status Indicators; Humans; Interleukin-10; Interleukin-6; Interleukin-8; Male; Middle Aged; Organ Dysfunction Scores; Prospective Studies; Resistin; Sepsis; Time Factors

Biomarkers, such as C-reactive protein [CRP] and procalcitonin [PCT], are insufficiently sensitive or specific to stratify patients with sepsis. We investigate the prognostic value of pancreatic stone protein/regenerating protein (PSP/reg) concentration in patients with severe infections.. PSP/reg, CRP, PCT, tumor necrosis factor-alpha (TNF-α), interleukin 1 beta (IL1-β), IL-6 and IL-8 were prospectively measured in cohort of patients ≥ 18 years of age with severe sepsis or septic shock within 24 hours of admission in a medico-surgical intensive care unit (ICU) of a community and referral university hospital, and the ability to predict in-hospital mortality was determined.. We evaluated 107 patients, 33 with severe sepsis and 74 with septic shock, with in-hospital mortality rates of 6% (2/33) and 25% (17/74), respectively. Plasma concentrations of PSP/reg (343.5 vs. 73.5 ng/ml, P < 0.001), PCT (39.3 vs. 12.0 ng/ml, P < 0.001), IL-8 (682 vs. 184 ng/ml, P < 0.001) and IL-6 (1955 vs. 544 pg/ml, P < 0.01) were significantly higher in patients with septic shock than with severe sepsis. Of note, median PSP/reg was 13.0 ng/ml (IQR: 4.8) in 20 severely burned patients without infection. The area under the ROC curve for PSP/reg (0.65 [95% CI: 0.51 to 0.80]) was higher than for CRP (0.44 [0.29 to 0.60]), PCT 0.46 [0.29 to 0.61]), IL-8 (0.61 [0.43 to 0.77]) or IL-6 (0.59 [0.44 to 0.75]) in predicting in-hospital mortality. In patients with septic shock, PSP/reg was the only biomarker associated with in-hospital mortality (P = 0.049). Risk of mortality increased continuously for each ascending quartile of PSP/reg.. Measurement of PSP/reg concentration within 24 hours of ICU admission may predict in-hospital mortality in patients with septic shock, identifying patients who may benefit most from tailored ICU management.

Topics: Biomarkers; C-Reactive Protein; Calcitonin; Calcitonin Gene-Related Peptide; Female; Health Status Indicators; Hospital Mortality; Humans; Intensive Care Units; Interleukin-1beta; Interleukin-6; Interleukin-8; Lithostathine; Male; Middle Aged; Pancreatitis; Predictive Value of Tests; Prospective Studies; Protein Precursors; Sepsis; Shock, Septic; Tumor Necrosis Factor-alpha

To evaluate and compare the gene expression of interleukin(IL)-1β, IL-8, and interferon-γ during the first 72 hours after birth in healthy foals and during the first 72 hours after hospitalization in sick neonatal foals and investigate correlations of clinicopathologic variables with cytokine expressions in healthy and sick neonatal foals.. 33 foals < 7 days old (10 healthy foals, 7 foals with sepsis, 6 foals with peripartum asphyxia syndrome, and 12 foals with other diseases [2 with failure of passive transfer of immunity only were not further evaluated]).. A blood sample (15 mL) was collected from each foal immediately after birth or hospital admission (0 hours) and at 24 and 72 hours later. Clinicopathologic variables were evaluated, and cytokine gene expression in WBCs was measured with an absolute quantitative real-time reverse transcriptase PCR assay.. At all time points, gene expression of interferon-γ was low in all groups. No time-dependent changes in cytokine expressions were detected in healthy or sick foals. Foals with sepsis had significantly higher IL-1β gene expression than did healthy foals, foals with peripartum asphyxia syndrome, or foals with other diseases. At 0 hours, IL-1β expression was correlated with plasma fibrinogen concentration in healthy foals and with the neutrophil-to-lymphocyte ratio in foals with sepsis; IL-8 expression was correlated with monocyte count in foals with sepsis and with arterial pH, plasma fibrinogen concentration, and plasma lactate concentration in foals with peripartum asphyxia syndrome.. Data have suggested that evaluation of IL-1β expression in sick neonatal foals could help identify those with sepsis.

Topics: Animals; Animals, Newborn; Asphyxia; Fibrinogen; Horse Diseases; Horses; Interferon-gamma; Interleukin-1beta; Interleukin-8; Lactic Acid; Real-Time Polymerase Chain Reaction; RNA; Sepsis; Statistics, Nonparametric

To determine whether the carbon monoxide (CO)-releasing molecules (CORM)-liberated CO suppress inflammatory responses in the small intestine of septic mice.. The C57BL/6 mice (male, n = 36; weight 20 ± 2 g) were assigned to four groups in three respective experiments. Sepsis in mice was induced by cecal ligation and puncture (CLP) (24 h). Tricarbonyldichlororuthenium (II) dimer (CORM-2) (8 mg/kg, i.v.) was administrated immediately after induction of CLP. The levels of inflammatory cytokines [interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α)] in tissue homogenates were measured with enzyme-linked immunosorbent assay. The levels of malondialdehyde (MDA) in the tissues were determined. The levels of nitric oxide (NO) in tissue homogenate were measured and the expression levels of intercellular adhesion molecule 1 (ICAM-1) and inducible nitric oxide synthase (iNOS) in the small intestine were also assessed. NO and IL-8 levels in the supernatants were determined after the human adenocarcinoma cell line Caco-2 was stimulated by lipopolysaccharide (LPS) (10 g/mL) for 4 h in vitro.. At 24 h after CLP, histological analysis showed that the ileum and jejunum from CLP mice induced severe edema and sloughing of the villous tips, as well as infiltration of inflammatory cells into the mucosa. Semi-quantitative analysis of histological samples of ileum and jejunum showed that granulocyte infiltration in the septic mice was significantly increased compared to that in the sham group. Administration of CORM-2 significantly decreased granulocyte infiltration. At 24 h after CLP, the tissue MDA levels in the mid-ileum and mid-jejunum significantly increased compared to the sham animals (103.68 ± 23.88 nmol/mL vs 39.66 ± 8.23 nmol/mL, 89.66 ± 9.98 nmol/mL vs 32.32 ± 7.43 nmol/mL, P < 0.01). In vitro administration of CORM-2, tissue MDA levels were significantly decreased (50.65 ± 11.46 nmol/mL, 59.32 ± 6.62 nmol/mL, P < 0.05). Meanwhile, the tissue IL-1β and TNF-α levels in the mid-ileum significantly increased compared to the sham animals (6.66 ± 1.09 pg/mL vs 1.67 ± 0.45 pg/mL, 19.34 ± 3.99 pg/mL vs 3.98 ± 0.87 pg/mL, P < 0.01). In vitro administration of CORM-2, tissue IL-1β and TNF-α levels were significantly decreased (3.87 ± 1.08 pg/mL, 10.45 ± 2.48 pg/mL, P < 0.05). The levels of NO in mid-ileum and mid-jejunum tissue homogenate were also decreased (14.69 ± 2.45 nmol/mL vs 24.36 ± 2.97 nmol/mL, 18.47 ± 2.47 nmol/mL vs 27.33 ± 3.87 nmol/mL, P < 0.05). The expression of iNOS and ICAM-1 in the mid-ileum of septic mice at 24 h after CLP induction significantly increased compared to the sham animals. In vitro administration of CORM-2, expression of iNOS and ICAM-1 were significantly decreased. In parallel, the levels of NO and IL-8 in the supernatants of Caco-2 stimulated by LPS was markedly decreased in CORM-2-treated Caco-2 cells (2.22 ± 0.12 nmol/mL vs 6.25 ± 1.69 nmol/mL, 24.97 ± 3.01 pg/mL vs 49.45 ± 5.11 pg/mL, P < 0.05).. CORM-released CO attenuates the inflammatory cytokine production (IL-1β and TNF-α), and suppress the oxidative stress in the small intestine during sepsis by interfering with protein expression of ICAM-1 and iNOS.

Topics: Animals; Caco-2 Cells; Carbon Monoxide; Disease Models, Animal; Enteritis; Humans; Ileitis; Inflammation Mediators; Intercellular Adhesion Molecule-1; Interleukin-1beta; Interleukin-8; Intestine, Small; Jejunal Diseases; Male; Malondialdehyde; Mice; Mice, Inbred C57BL; Nitric Oxide; Nitric Oxide Synthase Type II; Organometallic Compounds; Peroxidase; Sepsis; Time Factors; Tumor Necrosis Factor-alpha

Toll-like receptor 2 (TLR2) signaling plays a critical role in orchestrating the innate immune response and the development of sepsis and subsequent organ dysfunction after trauma. The objectives of this prospective study were to identify haplotype tag single-nucleotide polymorphisms (htSNPs) within the entire TLR2 gene and to investigate their clinical relevance in patients with major trauma. A total of 410 patients with major trauma were prospectively recruited. The htSNPs of the TLR2 gene was determined using HapMap database and linkage disequilibrium analysis. The htSNPs were genotyped using polymerase chain reaction-restriction fragment length polymorphism method. The whole peripheral blood samples obtained immediately after admission were stimulated with bacterial lipoprotein and then determined for production of tumor necrosis factor-α, interleukin 8, and interleukin 10. Sepsis morbidity rate and multiple organ dysfunction (MOD) scores were accessed. Three SNPs (rs1898830, rs3804099, and rs7656411) were identified as htSNPs for the TLR2 gene. All of them were shown to be high-frequency SNPs in this study cohort. Two of them (rs1898830 and rs3804099) and the haplotype ATT were significantly associated with cytokine production by peripheral blood leukocytes in response to bacterial lipoprotein stimulation. Only rs3804099, however, was significantly associated with higher sepsis morbidity rate and MOD scores in patients with major trauma. In addition, the patients with the haplotype ATT had lower sepsis morbidity rate than those without the haplotype ATT. Therefore, three SNPs might act as htSNPs for the entire TLR2 gene in the Chinese population. The rs3804099 and the haplotype ATT might be used as relevant risk estimates for the development of sepsis and MOD in patients with major trauma.

Topics: Asian People; Genotype; Haplotypes; Humans; Interleukin-10; Interleukin-8; Multiple Organ Failure; Polymorphism, Restriction Fragment Length; Polymorphism, Single Nucleotide; Prospective Studies; Sepsis; Toll-Like Receptor 2; Tumor Necrosis Factor-alpha; Wounds and Injuries

It is well known that signaling in neutrophils through both the complement component 5a (C5a) and C5a receptor (C5aR) and the toll-like receptor 4 (TLR4) pathways plays an essential role in innate defense. Neutrophil dysfunction, as seen during sepsis in severe mastitis during the periparturient period, is correlated with elevated concentrations of anaphylatoxin C5a. The aim of the current study was to elucidate the effect of C5a on TLR4 signaling in bovine neutrophils. Neutrophils were incubated with a high (but physiological) dose of purified C5a, and mRNA was extracted from neutrophils at different time points postincubation (PI). The incubation with C5a resulted in a biphasic C5aR expression profile, a phenomenon that might be explained by internalization (at 10 min PI) with subsequent reconstitution (starting at 40 min PI) of this receptor. The expression of TLR4, as well as its coreceptor, CD14, showed a similar biphasic change as observed with C5aR. In addition, changes in the mRNA expression levels of several genes belonging to the TLR4 pathway, such as TICAM-1, IKKα, and MAP3K7 were noted. The maximal expression of TLR4, CD14, and C5aR mRNA at 80 min PI was accompanied by a peak in IL8 mRNA, indicating that C5a is able to induce IL-8 production in neutrophils in vitro without the need of a costimulatory factor such as lipopolysaccharide. Moreover, a relatively constant expression of RELA was accompanied by increased expression of ATF3, an endogenous inhibitor of nuclear factor-κB mediated transcription, implying that C5a regulates TLR4 signaling and IL-8 synthesis independently. A significant time-dependent correlation was found between C5aR and TLR4, with the majority of the selected TLR4-dependent genes showing a significant correlation with C5aR at 80 min PI, when C5aR and TLR4 mRNA expression reached its maximum, suggesting crosstalk between both receptors. Taken together, this study showed that C5a is able to (1) alter the expression of genes belonging to the TLR4 pathway and (2) induce IL8 gene expression in bovine neutrophils. In addition, indications for cross-talk between complement activation and TLR4 signaling were found in the present study.

Topics: Animals; Cattle; Cattle Diseases; Complement C5a; Gene Expression; Immunity, Innate; Interleukin-8; Lipopolysaccharide Receptors; Neutrophils; Receptor, Anaphylatoxin C5a; RNA, Messenger; Sepsis; Signal Transduction; Toll-Like Receptor 4

A major goal for the clinical research in sepsis is mapping the various mediators driving the systemic manifestations of infection. Identifying relevant mediators responsible for the physiological alterations during sepsis may offer diagnostic and therapeutic opportunities. We aimed to explore the novel approach of simultaneously measuring several biomolecules using the multiplex technique and to study its relevance in diagnosing and monitoring septic patients. In 30 patients fulfilling American College of Chest Physicians and the Society of Critical Care Medicine sepsis criteria, we simultaneously measured 17 cytokines during the first 7 days after admission. We analysed the results with respect to the presence of septic shock and survival. Five patients died during the study. We found a significant positive correlation between the monocyte chemotactic protein (MCP)-1, macrophage inflammatory protein (MIP)-1β and interleukin (IL)-8 levels in the first 3 days and Sepsis-related Organ Failure Assessment score on day 1. Most cytokines showed no significant difference between patients with mild or severe sepsis. The initial levels of MIP-1β and granulocyte macrophage colony-stimulating factor were lower in patients with septic shock than in patients without shock. IL-8 and MCP-1 early after admission were higher in the non-survivors (p < 0.05). In the multivariate logistical regression, the initial levels of IL-8 were the most predictive for fatal outcome. Moreover, IL-1β, IL-6, IL-8, IL-12, interferon-γ, granulocyte colony-stimulating factor and tumour necrosis factor-α exhibited persistent increases in non-survivors. The simultaneous evaluation of multiple cytokines in sepsis may identify complex cytokine patterns that reflect the systemic response associated with shock and mortality.

Topics: Adult; Aged; Aged, 80 and over; Calcitonin; Chemokine CCL2; Cytokines; Female; Humans; Interleukin-8; Male; Middle Aged; Protein Precursors; Sepsis; Severity of Illness Index

Alarmin high mobility group box 1 (HMGB1) is essential for correct DNA folding and transcription. It can be released from damaged cells or secreted by stimulated cells. HMGB1 has been detected in serum or plasma as a late marker of sepsis, but its suitability as a marker of sepsis has been disputed.. One-week-old germ-free piglets were orally infected/colonized with enteric bacterial pathogens (Salmonella Typhimurium or Escherichia coli O55) or with probiotic bacteria (E. coli Nissle 1917) for 24 h. The transcriptions of HMGB1, interleukin (IL)-8, tumor necrosis factor (TNF)-α, and IL-10 (quantitative reverse transcription and polymerase chain reaction), their protein levels (ELISA), and clinical state of the piglets (somnolence, anorexia, diarrhea, tachycardia, tachypnea, and tremor) were estimated.. The piglets infected with enteric pathogens suffered from infections. HMGB1 was transcribed in the terminal ileum constitutively, regardless of any bacterial presence. In contrast, the transcription of cytokines was upregulated by virulent bacteria. HMGB1, IL-8, and TNF-α levels in the ileum were increased by both enteric pathogens, while IL-10 levels increased in E. coli O55-infected piglets only. HMGB1 significantly increased in the plasma of piglets infected with virulent E. coli only, but cytokine levels were in most cases increased by both virulent bacteria. HMGB1 and cytokine levels in ileum lavages and plasma of piglets colonized with probiotic E. coli remained comparable to those of the non-stimulated germ-free piglets.. The local and systemic expression of HMGB1, its relationship to the inflammatory cytokines, and clinical findings showed HMGB1 as a suitable marker of severity of sepsis in the gnotobiotic piglet infection model.

Topics: Animals; Animals, Newborn; Bacterial Infections; Biomarkers; Diarrhea; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Escherichia coli; Germ-Free Life; HMGB1 Protein; Ileum; Inflammation; Interleukin-10; Interleukin-8; Reverse Transcriptase Polymerase Chain Reaction; Salmonella typhimurium; Sepsis; Severity of Illness Index; Swine; Tachycardia; Tremor; Tumor Necrosis Factor-alpha

To investigate the effects of Tongfu granules and its constituents on barrier function of small intestine in rats with sepsis.. The male rats were divided into model group, Tongfu granules group, Rhubarb group and Magnoliae cortex group by random digits table, normal rats as control group. Intraperitoneal injection of lipopolysaccharide (LPS, 6 mg/kg) was used to reproduce sepsis model. After establishment of model, rats in Tongfu granules group were given Tongfu granules 28 g×kg(-1)×d(-1) by gavage, and Rhubarb group and Magnoliae cortex group rats were given Rhubarb or Magnoliae cortex 5 g×kg(-1)×d(-1) by gavage, while the model group was given normal saline in same quantity, once a day. Blood samples of rats were collected at 24, 48, 72 hours for measuring tumor necrosis factor-α (TNF-α) and interleukin-8 (IL-8) with enzyme linked immunosorbent assay (ELISA). The pathological changes in intestinal mucosa were observed, and the pathological scores was estimated at 72 hours.. The levels of TNF-α and IL-8 were significantly higher in model group than those in control group at different time points. The serum levels of TNF-α and IL-8 were significantly lower in treatment groups than those in model group, and the level of TNF-α (ng/L) in Tongfu granules group was significantly lower than that in Rhubarb and Magnoliae cortex groups at different time points (24 hours: 44.64±1.48 vs. 47.18±1.83 and 46.96±2.23, 48 hours: 51.38±1.36 vs. 57.17±2.23 and 59.41±2.01, 72 hours: 55.54±2.58 vs. 64.34±1.02 and 65.96±3.45, all P<0.05), and IL-8 (ng/L) level at 72 hours was significantly lower than that in Magnoliae cortex group (65.53±4.52 vs. 69.14±2.82,P<0.05). The scores of the lesions were significantly higher in model group than that in control group (3.90±0.17 vs. 0). The scores of Rhubarb group, Magnoliae cortex group and Tongfu granules group were 3.15±0.28, 3.18±0.08, and 2.95±0.15, respectively, which were lower than those of the model group (all P<0.01), and the Tongfu granules group descended obviously than other groups. In control group, the intercellular tight junctions were normal, and the morphology of microvilli and mitochondria was also normal. In model group, the microvilli of intestinal mucosa of the small intestine were absent or disintegrated. The intercellular tight junctions were seen to be blurred in Rhubarb and Magnoliae cortex groups, and they were close to normal state in Tongfu granules group. Their integrity was better preserved compared with that of the model group.. Injury of barrier function of the small intestine was found in septic rat. It was found that traditional Chinese medicine Tongfu granules, Rhubarb and Magnoliae cortex could protect the barrier function of the small intestine by decreasing the TNF-α and IL-8 levels in septic rats. Above-mentioned effects of Tongfu granules were better than Rhubarb and Magnoliae cortex.

Topics: Animals; Drugs, Chinese Herbal; Interleukin-8; Intestinal Mucosa; Intestine, Small; Male; Phytotherapy; Rats; Rats, Sprague-Dawley; Sepsis; Tumor Necrosis Factor-alpha

Development of organ dysfunction associated with sepsis is due in part to oxidative damage to mitochondria. Melatonin regulates the sleep-wake cycle and also has potent antioxidant activity. The aim of this study was to determine the effects of melatonin and other structurally related compounds on mitochondrial function, endogenous glutathione (GSH), and control of cytokine expression under conditions mimicking sepsis.. Human endothelial cells were treated with lipopolysaccharide (LPS) plus peptidoglycan G (PepG) to simulate sepsis, in the presence of melatonin, 6-hydroxymelatonin, tryptamine, or indole-3-carboxylic acid. Nuclear factor κB (NFκB) activation, interleukin (IL)-6 and IL-8, total glutathione, mitochondrial membrane potential, and metabolic activity were measured.. LPS and PepG treatment resulted in elevated IL-6 and IL-8 levels preceded by activation of NFκB (all P<0.0001). Treatment with all four compounds resulted in lower IL-6 and IL-8 levels, and lower NFκB activation (P<0.0001). Loss of mitochondrial membrane potential and endogenous glutathione was seen when cells were exposed to LPS/PepG, but these were maintained in cells co-treated with melatonin, tryptamine, or 6-hydroxymelatonin (P<0.05), but not indole-3-carboxylic acid. Metabolic activity decreased after exposure to LPS/PepG and was maintained by melatonin and 6-hydroxymelatonin at the highest concentrations only.. We have shown that in addition to melatonin, other structurally related indoleamine compounds have effects on NFκB activation and cytokine expression, GSH, mitochondrial membrane potential, and metabolic activity in endothelial cells cultured under conditions mimicking sepsis. Further work is needed to determine whether these compounds represent therapeutic approaches for disrupting the oxidative stress-inflammatory response signalling pathway in sepsis.

Topics: Antioxidants; Cells, Cultured; Endothelium, Vascular; Glutathione; Humans; Inflammation; Interleukin-6; Interleukin-8; Melatonin; Membrane Potential, Mitochondrial; Mitochondria; NF-kappa B; Oxidative Stress; Sepsis; Signal Transduction

A high mortality occurs in dogs with idiopathic immune-mediated haemolytic anaemia (IMHA) during the first 2 weeks after the diagnosis. The aim of this study was to investigate the inflammatory response and coagulation abnormalities in dogs with IMHA in relation to the prognosis and to establish the contribution of whole blood tissue factor (TF) and IL-8 gene expressions. Gene expressions in dogs with IMHA were compared to healthy dogs, dogs with DIC, dogs with sepsis, and in two groups of dogs that underwent intensive care treatment but had no evidence for either DIC or sepsis. The whole blood TF and IL-8 expressions were up regulated in all non-IMHA groups. Similarly, the TF expression in IMHA dogs was high, but the intravascular IL-8 expression was not increased. The dogs with IMHA had a pronounced inflammatory response that included a high WBC, left shift and monocytosis in comparison to the other disease groups. Coagulation factor activities in IMHA dogs were decreased fitting consumptive coagulopathy and the acute phase proteins FVIII and fibrinogen were increased. The platelet parameters suggested platelet activation and high platelet turnover in IMHA dogs. The model that best explained mortality contained monocytosis, increased activated partial thromboplastin time and elevated creatinine. Whole blood TF gene expression is up regulated and may contribute to consumptive coagulopathy in dogs with IMHA. Increased TF expression by activated platelets is an alternative explanation and should be investigated.

Topics: Anemia, Hemolytic, Autoimmune; Animals; Blood Coagulation; Disseminated Intravascular Coagulation; Dog Diseases; Dogs; Female; Inflammation; Interleukin-8; Male; Prognosis; Real-Time Polymerase Chain Reaction; Sepsis; Thromboplastin

Sepsis leads to a complex systemic response of cytokines (both pro- and anti-inflammatory) and more recently recognized adipokine mediators. Endothelial nitric oxide (NO) may be a key component in regulating this response, but the pharmacologic manipulation of endothelial NO via L-arginine supplementation or inhibitors has provided inconsistent clinical data related to outcomes. These failures are related to the metabolism of L-arginine in the liver, toxicity of L-arginine, and asymmetric dimethylarginine inhibition, all of which may explain the "arginine paradox." L-citrulline (CIT) offers a potentially valuable means of supplementing arginine and therefore impacting favorably NO availability. The goal of this study was to determine whether CIT supplementation altered the systemic response of mediators and cytokines in a rat model of sepsis with varying degrees of severity.. Sepsis was induced with 2 models of cecal ligation and puncture (CLP) of varying severity in Wistar rats. CIT supplementation was provided to half the animals as 8% CIT-supplemented feed for 3 weeks. Baseline mediator levels were assessed in the Wistar rats followed by comparison of the following groups at days 0, 1, and 3: sham-operated; CLP 8-mm (localized); and CLP 12-mm (extensive). The following analyses were performed in the groups: interleukin-6 (IL-6), IL-8, IL-10, resistin, and adiponectin levels (enzyme-linked immunosorbent assay performed in duplicate). L-arginine and CIT were measured with high-performance liquid chromatography combined with mass spectrometry.. Ninety-eight Wistar rats were evaluated, and survival was similar in both sepsis models with and without CIT. Serum IL-6 levels were lower in the CIT/CLP 8-mm group compared to the standard rat chow (STD)/CLP 8-mm group (41 vs 117 pg/mL; P = .011) on postoperative day 3. Serum IL-8 and IL-10 responses were similar across all groups. Serum resistin levels were lower in the CIT/CLP 12-mm group compared to the STD/CLP 12-mm group in the more severe sepsis model on day 3 (19 vs 38 ng/mL; P < .0001). The levels of serum L-arginine were greater in the CIT-supplemented animals compared to STD rodent diet animals before surgical insult (86.3 vs 294.0 μM; P = .004). Adiponectin was not affected by CIT supplementation.. CIT may decrease the proinflammatory mediator response (IL-6 and resistin) without impairing the secretion of anti-inflammatory mediators (IL-10 and adiponectin) and thereby provide a safe means of immunomodulation that preserves the anti-inflammatory mediator response.

Topics: Animals; Arginine; Citrulline; Disease Models, Animal; Endothelial Cells; Immunologic Factors; Inflammation Mediators; Interleukin-10; Interleukin-6; Interleukin-8; Nitric Oxide; Rats; Rats, Wistar; Sepsis

Sepsis is a severe infection-induced systemic inflammatory syndrome. Inhibition of downstream inflammatory mediators of sepsis, e.g., TNF-alpha, has failed in clinical trials. The aim of this study was to investigate the effects of inhibiting CD14, a key upstream innate immunity molecule, on the early inflammatory and hemostatic responses in a pig model of gram-negative sepsis. The study comprised two arms, whole live Escherichia coli bacteria and E. coli lipopolysaccharide (LPS) (n=25 and n=9 animals, respectively). The animals were allocated into treatment (anti-CD14) and control (IgG isotype or saline) groups. Inflammatory, hemostatic, physiological, and microbiological parameters were measured. The proinflammatory cytokines TNF-alpha, IL-1beta, IL-6, and IL-8, but not the anti-inflammatory cytokine IL-10, were efficiently inhibited by anti-CD14. Furthermore, anti-CD14 preserved the leukocyte count and significantly reduced granulocyte enzyme matrix metalloproteinase-9 release and expression of the granulocyte membrane activation molecule wCD11R3 (pig CD11b). The hemostatic markers thrombin-antithrombin III complexes and plasminogen activator inhibitor-1 were significantly attenuated. Anti-CD14 did not affect LPS or E. coli DNA levels. This study documents that CD14 inhibition efficiently attenuates the proinflammatory cytokine response and granulocyte activation and reverses the procoagulant state but does not interfere with LPS levels or bacterial counts in E. coli-induced sepsis.-Thorgersen, E. B., Hellerud, B. C., Nielsen, E. W., Barratt-Due, A., Fure, H., Lindstad, J. K., Pharo, A., Fosse, E., Tønnessen, T. I., Johansen, H. T., Castellheim, A., Mollnes, T. E. CD14 inhibition efficiently attenuates early inflammatory and hemostatic responses in Escherichia coli sepsis in pigs.

Topics: Animals; Antibodies, Monoclonal; Escherichia coli; Female; Flow Cytometry; Interleukin-1beta; Interleukin-6; Interleukin-8; Lipopolysaccharide Receptors; Lipopolysaccharides; Male; Sepsis; Swine; Tumor Necrosis Factor-alpha

To improve survival from septic acute lung injury (ALI), extracorporeal life support (ECLS) is one of the ultimate solutions. We evaluated biochemical and pathological characteristics of recovery phase of septic ALI treated in acute phase by inhaled nitric oxide (NO) and surfactant with ECLS and hypothesized that this combination should exert better lung protective effects than that with conventional mechanical ventilation (CMV).. ALI was induced by i.v. endotoxin and 4-6h CMV in young piglets (9-14kg) followed by treatment protocol for 24h in 4 modalities (n=5): VENT, CMV only; VNOS, VENT plus inhaled NO (10ppm) and surfactant (50mg/kg); ECMO, a veno-venous by-pass as extracorporeal membrane oxygenation; ENOS, ECMO plus inhaled NO and surfactant. After treatment they were weaned and maintained for recovery until day 7, and their lungs were processed for assessment of injury and reparation.. Plasma interleukin-8 levels in ENOS were lower than ECMO. On day 7 mRNA expression of inducible NO synthase and nitrite/nitrate levels in BALF were higher in VENT than in ECMO, interleukin-8 mRNA expression and lung apoptosis were lower in ENOS than in ECMO; disaturated phosphatidylcholine and mRNA expression of hepatocyte growth factor were higher, interleukin-8 content, NO synthase mRNA expression and malondialdehyde in lung tissue were lower, and morphologically lung injury and apoptosis were milder, in ENOS than in VENT.. ECLS combined with inhaled NO and surfactant alleviated septic injury and facilitated reparation in the lung recovery in contrast to CMV or ECMO alone.

Topics: Acute Lung Injury; Animals; Apoptosis; Bronchoalveolar Lavage Fluid; Combined Modality Therapy; Disease Models, Animal; Extracorporeal Membrane Oxygenation; Gene Expression Regulation; Interleukin-8; Male; Malondialdehyde; Nitric Oxide; Nitric Oxide Synthase Type II; Pulmonary Surfactants; Respiration, Artificial; RNA, Messenger; Sepsis; Swine

Sivelestat sodium hydrate is a selective inhibitor of neutrophil elastase, which is effective in acute lung injury associated with systemic inflammatory response syndrome. However, the effectiveness of sivelestat in sepsis has not been fully examined. In the present study, the effect of sivelestat on severe sepsis in a rat cecal ligation and puncture (CLP) model was investigated. Adult male Sprague-Dawley rats underwent CLP and were randomly divided into two groups: sivelestat-treated group and saline-treated controls. The serum concentrations of several inflammatory mediators were measured. Hematoxylin-eosin staining, and immunohistochemical staining for high-mobility group box chromosomal protein 1 (HMGB1), IL-8, and CD68 were performed on the lungs to assess pathological changes found 12 h after the CLP procedure. Treatment with sivelestat significantly improved the survival rate of the post-CLP septic animals (P = 0.030). Sivelestat also induced a significant reduction in serum IL-1beta (P = 0.038) and IL-10 (P = 0.008) levels in these CLP rats. Serum HMGB1 levels had no significant difference between the sivelestat-treated and the control group. The lungs from sivelestat-treated rats exhibited less severe pathological changes and decreased the numbers of HMGB1, IL-8, and CD68-positive cells (P < 0.001). Sivelestat significantly improved survival rate of rats with clinically relevant sepsis, possibly by attenuating sepsis-induced systemic inflammatory response and lung injury. This may explain the implicated health benefits of sivelestat in reducing morbidity and mortality from sepsis.

Topics: Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Cecum; Disease Models, Animal; Glycine; HMGB1 Protein; Inflammation; Interleukin-8; Ligation; Lung; Male; Proteinase Inhibitory Proteins, Secretory; Rats; Rats, Sprague-Dawley; Sepsis; Sulfonamides; Survival Analysis

High-mobility group box protein 1 (HMGB1) is a nuclear protein that may be released actively from monocytes and macrophages or passively from necrotic or damaged cells. Several experimental data suggest that burn injury is accompanied by elevated plasma HMGB, but there are only few data available about its changes in burned patients. The aim of this study was to follow the time course and the prognostic value of plasma HMGB1 and cytokine changes in patients with severe burn injury affecting more than 10% of body surface area (n = 26). Blood samples were taken on admission and on the following 5 days. Plasma HMGB1 concentration was measured by the enzyme-linked immunosorbent assay method, whereas IL-6, IL-8, and IL-10 were assayed by the cytometric bead array kit. The HMGB1 and IL-10 concentrations were elevated on admission and gradually decreased thereafter. Significant differences were observed between survivors and nonsurvivors in HMGB1 (P < 0.01) and IL-10 (P < 0.001) concentrations on admission with higher levels in nonsurvivors. IL-6 and IL-8 started to increase markedly from day 2. Positive correlation (r = 0.669, P < 0.01) was found between burned body surface and HMGB1 on admission. Receiver operating characteristic analysis of data on admission showed that at a level of 16 ng/mL, HMGB1 indicated lethality, with 75.0% sensitivity and 85.7% specificity. Using the cutoff level of 14 pg/mL, IL-10 predicted intensive care unit mortality, with 85.7% sensitivity and 84.2% specificity. Very early HMGB1 and IL-10 release may have an important impact on the immune function of patients after burn trauma.

Topics: Adult; Aged; Burns; Cytokines; Female; HMGB1 Protein; Humans; Interleukin-10; Interleukin-6; Interleukin-8; Interleukins; Male; Middle Aged; Prognosis; Sepsis; Severity of Illness Index

Mammalian cells synthesize morphine and the respective biosynthetic pathway has been elucidated. Human neutrophils release this alkaloid into the media after exposure to morphine precursors. However, the exact role of endogenous morphine in inflammatory processes remains unclear. We postulate that morphine is released during infection and can be determined in the serum of patients with severe infection such as sepsis.. The presence and subcellular immunolocalization of endogenous morphine was investigated by ELISA, mass spectrometry analysis and laser confocal microscopy. Neutrophils were activated with Interleukin-8 (IL-8) or lipopolysaccharide (LPS). Morphine secretion was determined by a morphine-specific ELISA. mu opioid receptor expression was assessed with flow cytometry. Serum morphine concentrations of septic patients were determined with a morphine-specific ELISA and morphine identity was confirmed in human neutrophils and serum of septic patients by mass spectrometry analysis. The effects of the concentration of morphine found in serum of septic patients on LPS-induced release of IL-8 by human neutrophils were tested.. We confirmed the presence of morphine in human neutrophil extracts and showed its colocalisation with lactoferrin within the secondary granules of neutrophils. Morphine secretion was quantified in the supernatant of activated human polymorphonuclear neutrophils in the presence and absence of Ca(2+). LPS and IL-8 were able to induce a significant release of morphine only in presence of Ca(2+). LPS treatment increased mu opioid receptor expression on neutrophils. Low concentration of morphine (8 nM) significantly inhibited the release of IL-8 from neutrophils when coincubated with LPS. This effect was reversed by naloxone. Patients with sepsis, severe sepsis and septic shock had significant higher circulating morphine levels compared to patients with systemic inflammatory response syndrome and healthy controls. Mass spectrometry analysis showed that endogenous morphine from serum of patient with sepsis was identical to poppy-derived morphine.. Our results indicate that morphine concentrations are increased significantly in the serum of patients with systemic infection and that morphine is, at least in part, secreted from neutrophils during sepsis. Morphine concentrations equivalent to those found in the serum of septic patients significantly inhibited LPS-induced IL-8 secretion in neutrophils.

Topics: Blotting, Western; Electrophoresis, Polyacrylamide Gel; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Humans; Immunohistochemistry; Interleukin-8; Lipopolysaccharides; Lymphocyte Activation; Microscopy, Confocal; Morphine; Neutrophils; Receptors, Opioid, mu; Sepsis; Tandem Mass Spectrometry

This pilot study in parenteral nutrition-dependent infants with short bowel syndrome (SBS) evaluated the impact of feeding route and intestinal permeability on bloodstream infection (BSI), small bowel bacterial overgrowth (SBBO), and systemic immune responses, as well as fecal calprotectin as a biomarker for SBBO.. Ten infants (ages 4.2-15.4 months) with SBS caused by necrotizing enterocolitis were evaluated. Nutritional assessment, breath hydrogen testing, intestinal permeability, fecal calprotectin, serum flagellin- and lipopolysaccharide-specific antibody titers, and proinflammatory cytokine concentrations (tumor necrosis factor-alpha [TNF-alpha], interleukin-1 beta, -6, and -8) were performed at baseline and at 60 and 120 days. Healthy, age-matched control subjects (n = 5) were recruited.. BSI incidence was high (80%), and SBBO was common (50%). SBBO increased the odds for BSI (>7-fold; P = .009). Calprotectin levels were higher in children with SBS and SBBO versus those without SBBO and healthy control subjects (P < .05). Serum TNF-alpha, was elevated at baseline versus controls. Serum TNF-alpha and interleukin-1 beta, -6, and -8 levels diminished with increased enteral nutrition. Anti-flagellin and anti-lipopolysaccharide immunoglobulin G levels in children with SBS were lower versus control subjects and rose over time.. In children with SBS, SBBO increases the risk for BSI, and systemic proinflammatory response decreases with increasing enteral feeding and weaning parenteral nutrition.

Topics: Enteral Nutrition; Enterocolitis, Necrotizing; Feces; Female; Flagellin; Humans; Incidence; Infant; Interleukin-1beta; Interleukin-6; Interleukin-8; Intestine, Small; Leukocyte L1 Antigen Complex; Male; Pilot Projects; Sepsis; Short Bowel Syndrome; Tumor Necrosis Factor-alpha

Acute respiratory distress syndrome (ARDS) is characterized by overwhelming lung inflammation. This study explored the inflammatory mediators in bronchoalveolar lavage fluid (BALF) for prognostic relevance in patients with infection-induced ARDS. Thirty-nine patients with infection-induced ARDS (28 pneumonia and 11 extrapulmonary sepsis) and two patients with cardiogenic lung edema as the control were included. The expression profiles of inflammatory mediators in BALF were compared between ARDS and cardiogenic lung edema. A group of inflammatory mediators that showed higher expression in ARDS was analyzed for their relationships with clinical features and outcome. We found that 17 patients who died had higher levels of interleukin (IL)-6 (P = 0.012), IL-8 (P = 0.001) and monocyte chemoattractant protein-1 (P = 0.036) in BALF compared with those who survived. Furthermore, there was an inverse relationship between the BALF levels of IL-6 (P = 0.026), IL-8 (P = 0.008) and macrophage inflammatory protein (MIP)-1 alpha (P = 0.048) and the changes of lung compliance between days 1 and 4, whereas the BALF levels of IL-8 (P = 0.033) and MIP-1 alpha (P = 0.029) were positively correlated with the changes of sequential organ failure assessment scores between days 1 and 4. In multivariate logistic regression analysis, only IL-8 (P = 0.013) and lung injury score (LIS) (P = 0.017) independently predicted the mortality, and IL-8 (P = 0.002) was most likely predictive of mortality in analysis of area under the receiver operating characteristic curve. In conclusion, we show the expression profiles of inflammatory mediators in BALF of infection-induced ARDS. Among the mediators, IL-8 is the most significant predictor for mortality, and several mediators are correlated with clinical severity. However, potential selection bias due to limited control subjects and lack of serum inflammatory mediator data suggest a necessity of further studies to confirm our findings.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Bronchoalveolar Lavage Fluid; Chemokine CCL2; Chemokine CCL3; Female; Humans; Inflammation Mediators; Interleukin-6; Interleukin-8; Lung Compliance; Male; Middle Aged; Pneumonia; Prognosis; Prospective Studies; Respiratory Distress Syndrome; Sepsis; Young Adult

Sepsis is a generalized inflammatory disease, caused by the hyperinflammatory response of the host, rather than by invading organisms. Endothelial cells play a crucial role in the pathogenesis of sepsis. In this study, we investigated the effects of interleukin-8 (IL-8), a known neutrophil chemoattractant, on lipopolysaccharide (LPS) -induced reactive oxygen species (ROS) production by endothelial cells, and its significance in the pathogenesis of LPS-mediated sepsis. The results revealed that IL-8 directly induced ROS production in human umbilical vein endothelial cells (HUVECs), and also mediated LPS-induced ROS production by HUVECs. Stimulation of HUVECs by LPS strongly enhanced tissue factor expression, a hallmark of severe sepsis, which was suppressed by IL-8 knockdown. We further discovered that NADPH oxidase (Nox) 1 expression in LPS-stimulated HUVECs was markedly repressed by IL-8 knockdown, and Nox1 knockdown reduced tissue factor expression, suggesting that the LPS/IL-8 signalling in endothelial cells was predominantly mediated by Nox1. In conclusion, LPS stimulation of endothelial cells causes activation of the IL-8-Nox1 axis, enhances the production of ROS, and ultimately contributes to the progression of severe sepsis.

Topics: Cell Line; Endothelium, Vascular; Enzyme Activation; Humans; Interleukin-8; Lipopolysaccharides; NADPH Oxidases; Reactive Oxygen Species; RNA, Small Interfering; Sepsis; Signal Transduction; Thromboplastin

Excessive complement-activated product complement 5a (C5a) has been implicated in the pathogenesis of sepsis development. Herein, we employed in vitro and in vivo models of sepsis to investigate the functional relationship between overtly produced C5a and IL-8. Our data revealed that C5a could strongly amplify IL-8 expression from human whole blood cells induced by LPS and other types of TLR agonists. ERK1/2 and p38, but not JNK, were mainly participated in signaling pathways for IL-8 production. In the whole blood stimulated by Escherichiacoli, C5a levels were quickly elevated and blockage of C5a significantly decreased E. coli-elicited IL-8 production. In the mouse model of sepsis induced by cecal ligation and puncture (CLP), the markedly increased keratinocyte-derived cytokine (KC) could be strongly suppressed by blockage of C5a. These data suggest that excessive C5a functions as a critical inflammatory mediator to enhance IL-8 production mainly through MAPK signaling pathways.

Topics: Animals; Antibodies, Monoclonal; Ascitic Fluid; Blood; Blood Cells; Chemokine CXCL1; Complement C5a; Disease Models, Animal; Escherichia coli K12; Gene Expression; Granulocytes; Humans; Interleukin-8; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinases; Monocytes; Phosphorylation; Sepsis; Signal Transduction; Toll-Like Receptors

Different isoforms of nitric oxide synthases (NOS) and determinants of oxidative/nitrosative stress play important roles in the pathophysiology of pulmonary dysfunction induced by acute lung injury (ALI) and sepsis. However, the time changes of these pathogenic factors are largely undetermined.. Twenty-four chronically instrumented sheep were subjected to inhalation of 48 breaths of cotton smoke and instillation of live Pseudomonas aeruginosa into both lungs and were euthanized at 4, 8, 12, 18, and 24 hours post-injury. Additional sheep received sham injury and were euthanized after 24 hrs (control). All animals were mechanically ventilated and fluid resuscitated. Lung tissue was obtained at the respective time points for the measurement of neuronal, endothelial, and inducible NOS (nNOS, eNOS, iNOS) mRNA and their protein expression, calcium-dependent and -independent NOS activity, 3-nitrotyrosine (3-NT), and poly(ADP-ribose) (PAR) protein expression.. The injury induced severe pulmonary dysfunction as indicated by a progressive decline in oxygenation index and concomitant increase in pulmonary shunt fraction. These changes were associated with an early and transient increase in eNOS and an early and profound increase in iNOS expression, while expression of nNOS remained unchanged. Both 3-NT, a marker of protein nitration, and PAR, an indicator of DNA damage, increased early but only transiently.. Identification of the time course of the described pathogenetic factors provides important additional information on the pulmonary response to ALI and sepsis in the ovine model. This information may be crucial for future studies, especially when considering the timing of novel treatment strategies including selective inhibition of NOS isoforms, modulation of peroxynitrite, and PARP.

Topics: Acute Lung Injury; Animals; Disease Models, Animal; Interleukin-8; Lung; Nitrates; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Nitrites; Poly Adenosine Diphosphate Ribose; Reverse Transcriptase Polymerase Chain Reaction; Sepsis; Sheep; Time Factors; Tyrosine

Sepsis and septic shock are frequently encountered in the intensive care unit. Despite the evolution of intensive care medicine during the last decades, septic shock is still associated with high mortality and complications of sepsis such as cholestasis, liver dysfunction, and massive intravascular volume deficit. Little is known about the whole pattern of changes at the transcriptional level during the development of acute sepsis. Here we present a detailed molecular biological analysis of the events in the liver during the first day of acute bacterial infection in a clinically relevant model of porcine peritoneal sepsis. Before and 21 h after induction of sepsis by autologous fecal inoculum, liver samples were taken for microarray analysis. There were two groups of animals (7 control and 8 sepsis), two of each group where used in microarray, the remaining were used for confirmation of selected genes by real-time polymerase chain reaction. Pathway analysis revealed that in acute sepsis, gene expression was significantly changed in processes related to apoptosis, inflammation, and oxidant/redox balance. Although after 21 h these animals are expected to die within the next 3 to 4 h from massive complications, functional induction of apoptosis could not be confirmed. Computer analysis identified three key regulator genes (IL8, CCL2, and CXCL2) among the first genes to be upregulated specifically in the sepsis group, and these can directly or indirectly control the bulk of the sepsis response. Induction of inflammatory mediators by sepsis was supported by the detection of corresponding cytokines (interleukin 6 and interleukin 8) in the blood.

Topics: Animals; Chemokine CCL2; Chemokine CXCL2; Fluid Therapy; Interleukin-8; Liver; Oligonucleotide Array Sequence Analysis; Peritonitis; Resuscitation; Sepsis; Swine

Obese patients display an exaggerated morbidity during sepsis. Since consumption of a western-style diet (WD) is a major factor for obesity in the United States, the purpose of the present study was to examine the influence of chronic WD consumption on hepatic inflammation in mice made septic via cecal ligation and puncture (CLP). Feeding mice diets high in fat has been shown to enhance evidence of TLR signaling and this pathway also mediates the hepatic response to invading bacteria. Therefore, we hypothesized that the combined effects of sepsis and feeding WD on TRL-4 signaling would exacerbate hepatic inflammation. Male C57BL/6 mice were fed purified control diet (CD) or WD that was enriched in butter fat (34.4% of calories) for 3 weeks prior to CLP. Intravital microscopy was used to evaluate leukocyte adhesion in the hepatic microcirculation. To demonstrate the direct effect of saturated fatty acid on hepatocytes, C3A human hepatocytes were cultured in medium containing 100 μM palmitic acid (PA). Quantitative real-time PCR was used to assess mRNA expression of tumor necrosis factor-alpha (TNF-α, monocyte chemotactic protein-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1), toll-like receptor-4 (TLR-4) and interleukin-8 (IL-8).. Feeding WD increased firm adhesion of leukocytes in the sinusoids and terminal hepatic venules by 8-fold six hours after CLP; the increase in platelet adhesion was similar to the response observed with leukocytes. Adhesion was accompanied by enhanced expression of TNF-α, MCP-1 and ICAM-1. Messenger RNA expression of TLR-4 was also exacerbated in the WD+CLP group. Exposure of C3A cells to PA up-regulated IL-8 and TLR-4 expression. In addition, PA stimulated the static adhesion of U937 monocytes to C3A cells, a phenomenon blocked by inclusion of an anti-TLR-4/MD2 antibody in the culture medium.. These findings indicate a link between obesity-enhanced susceptibility to sepsis and consumption of a western-style diet.

Topics: Animals; Cecum; Chemokine CCL2; Diet; Disease Models, Animal; Fatty Acids; Hepatitis; Humans; Inflammation; Intercellular Adhesion Molecule-1; Interleukin-8; Ligation; Liver; Male; Mice; Mice, Inbred C57BL; Sepsis; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha

Serum soluble triggering receptor expressed on myeloid cells-1 (sTREM-1), a detector of acute inflammatory response to microbial products and a good marker for diagnosing sepsis and pneumonia, has not yet been described as a predictor for infection or a prognostic factor in patients with acute respiratory distress syndrome (ARDS).. This prospective observational cohort study enrolled 63 ventilated adult patients with ARDS; 50 as septic and 13 as non-septic, and followed them for 28 days in intensive care units at a university hospital in Taiwan. Serial serum sTREM-1 levels and cytokines, such as interleukin (IL)-1, IL-8, and tumor necrosis factor-α, on days 1, 3, 5, 7 and 14 were measured by an enzyme-linked immunosorbent assay. The association between biomarkers and clinical infectious diagnosis/outcome in ARDS was explored.. Serum sTREM-1 and cytokine levels could not differentiate septic from non-septic ARDS. Serum log sTREM-1 and inflammatory cytokine levels were correlated positively (r = 0.325 for IL-1β; r = 0.247 for IL-8; r = 0.480 for tumor necrosis factor-α). As prognostic factors, higher serum sTREM-1 level on day 1 and increasing levels over time, especially in the first 5 days, were independent predictors of mortality on day 28, using a multivariate Cox regression model. Serum sTREM-1 levels remained stable or even increased in the non-surviving patients, but decreased in the survivors.. Serum sTREM-1 level might not be a reliable marker for infection in ARDS patients. However, as an inflammatory marker, initial serum sTREM-1 level and its trend over time, especially in the first 5 days, could be predictive of short-term mortality. A progressive decline in serum sTREM-1 levels during follow-up indicates a favorable outcome, whereas persistently elevated sTREM-1 indicates a poor prognosis and should lead to a re-evaluation of therapy.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Biomarkers; Enzyme-Linked Immunosorbent Assay; Female; Hospitals, University; Humans; Intensive Care Units; Interleukin-1; Interleukin-8; Male; Membrane Glycoproteins; Middle Aged; Pneumonia, Bacterial; Proportional Hazards Models; Prospective Studies; Receptors, Immunologic; Respiratory Distress Syndrome; Sepsis; Taiwan; Time Factors; Triggering Receptor Expressed on Myeloid Cells-1; Tumor Necrosis Factor-alpha

To explore the characteristics of immune imbalance in patients with multiple organ dysfunction syndrome (MODS) induced by severe intra-abdominal infection and its relationship with changing of TCM sthenia-asthenia syndrome.. Forty-six patients with MODS induced by severe intra-abdominal infection and treated with etiological and syndrome differentiation of integrative medicine were observed in succession. Patients' peripheral blood levels of interleukin-6/interleukin-10 ratio (IL-6/IL-10), human leukocyte antigen DR site (HLA-DR), helper T lymphocyte1/2 ratio (Th1/Th2), and the regulatory T lymphocyte (Treg) were measured on the 1st, 3rd and 7th day of the research respectively. And the distribution laws of TCM syndrome types, sthenia (S), asthenia (A), and mingled sthenia/asthenia (M), in patients were observed as well.. IL-6/IL-10 ratio at all the testing time points showed insignificant difference in patients of types S and M, while in those of type A, it was more lowered on the 7th day than that on the 1st day. HLA-DR lowered to <30% on the 7th day in all patients of type A and showed significant difference to that on the 1st day (P <0.05), while HLA-DR <30% was not found in all patients of types S and M. Th1/Th2 ratio in patients of types S and A was insignificant different at the foremost 3 days, but lowered significantly on the 7th day, while in patients of type M, it was unchanged in all the 7 days of observation. Treg level was unchanged in the foremost 3 days in patients of types S and M, while in those of type A, it raised on the 3rd day, but no raising was found in the subsequent 4 days. Comparisons of various indexes detected at corresponding time points respectively among patients with various syndrome types showed that, for levels of IL-6/IL-8, HLA-DR, and Th1/Th2, the sequence was S>M>A; and for Treg, it was A>M>S.. In the pathological process of MODS induced by severe intra-abdominal infection, the index IL-6/IL-10, reflecting the balance of the pro-/anti-inflammatory cytokines and the indexes HLA-DR, Th1/Th2 and Treg reflecting the immune function, all can exactly reflect the TCM asthenia-sthenia syndrome types. The sequence in patients of various syndrome types for levels of IL-6/IL-10, HLA-DR and Th1/Th2, is S> M>A, but for Treg it is the inverse, as A>M>S.

Topics: Adolescent; Adult; Aged; Diagnosis, Differential; HLA-DR Antigens; Humans; Interleukin-6; Interleukin-8; Medicine, Chinese Traditional; Middle Aged; Multiple Organ Failure; Peritonitis; Sepsis; T-Lymphocytes, Regulatory; Th1 Cells; Th2 Cells; Yang Deficiency; Young Adult

To evaluate the long pentraxin PTX3 in patients with severe leptospirosis and to compare the results with the widely used short pentraxin C-reactive protein and the pro-inflammatory cytokines IL-6 and IL-8.. This observational cohort study was carried out in Semarang, Indonesia, where leptospirosis is endemic and mortality is high. Consecutive patients with severe leptospirosis were sampled on admission and during follow-up.. A total number of 52 patients entered the study, the mortality was 27%. Severe leptospirosis patient yielded elevated plasma PTX3 levels. PTX3 correlated with IL-8 and to a lesser extent with CRP and IL-6 levels. High levels of PTX3, IL-6 and IL-8 were associated with mortality (OR 5.6, 95%CI: 1.2-26; OR 3.2, 95%CI: 1.2-8.1; OR 6.5, 95%CI: 1.5-28). Moreover, PTX3 levels were associated with disease severity (OR 9.5; 95%CI: 2.9-45). This association was unique, since none of the other markers showed this relation. C-reactive protein was not able to differentiate the severe from the severest cases.. The long pentraxin PTX3 is elevated in patients with severe leptospirosis and is associated with fatal disease and disease severity. PTX3 may be used as a marker to monitor disease severity in severe leptospirosis or predict outcome.

Topics: Adult; Biomarkers; C-Reactive Protein; Female; Humans; Indonesia; Interleukin-6; Interleukin-8; Leptospirosis; Male; Middle Aged; Odds Ratio; Predictive Value of Tests; Prognosis; ROC Curve; Sepsis; Serum Amyloid P-Component; Severity of Illness Index; Shock, Septic

To study the effects of high mobile group box-1 protein (HMGB1) and lipopolysaccharide (LPS) singly or in combination on release of cytokines from human liver carcinoma cell line (HepG2).. HepG2 cells were cultured, and purified HMGB1 protein was prepared by chromatography on Ni(2+)-NTA Sepharose column under natural conditions with recombinant expression plasmid pET14b-HMGB1. Different concentrations of HMGB1 (0, 0.01, 0.1, 1, 10 mg/L) and LPS (0, 0.1, 1, 10, 100 mg/L) were added into the cultured cells for 24 hours, respectively. Then the supernatant were collected to detect the levels of granulocyte/macrophage colony stimulating factor (GM-CSF), interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), and interleukin-1 beta (IL-1 beta), IL-2, IL-4, IL-6, IL-8, IL-10, and IL-12 by using LiquiChip system. Lastly, HepG2 cells were co-stimulated with 10 mg/L LPS and 1 mg/L HMGB1 for 24 hours. The supernatant were collected to determine the levels of above ten of cytokines .. The expression and release of IL-6 and IL-8 increased from HepG2 cells after being stimulated by LPS in a dose-dependent manner, but there were no changes in other eight kinds of cytokines (P<0.05 or P<0.01). Low concentration of HMGB1 could up-regulate the expression of IL-6 and IL-8 in HepG2 cells (both P<0.01). But the extent of induction decreased with higher concentration of HMGB1. Similar to LPS, there was no effect of HMGB1 on the expression of other eight kinds of cytokines from cultured HepG2 cells. Furthermore, high concentration of HMGB1 could obviously inhibit the upregulation of IL-6 and IL-8 by high concentration of LPS when the HepG2 cells were co-stimulated with LPS and HMGB1 (both P<0.01).. HepG2 cells could only express and release a few kinds of cytokines when the cells were stimulated with pro-inflammatory agents, such as LPS or HMGB1. Two kinds of cytokines, IL-6 and IL-8 could be up-regulated by LPS and low concentration of HMGB1, and HMGB1 acted as an inhibitor of LPS to down-regulate the expression and release of IL-6 and IL-8 from HepG2 cells.

Topics: Cytokines; Hep G2 Cells; HMGB1 Protein; Humans; Interleukin-6; Interleukin-8; Lipopolysaccharides; Sepsis; Tumor Necrosis Factor-alpha

Some studies showed increased levels ofproinflammatory cytokines like IL-6, IL-8 and TNF-alpha in the blood samples of pregnant women with PROM (Premature rupture of membranes) and their neonates. The aim of this study was to find a relationship between increased level of IL-8 and PROM, a cost benefit method for early diagnosis and reduction of hospitalization period of neonatal sepsis. This case control study was conducted in Obstetrics and Gynecology Department of Al-Zahra Hospital at Tabriz University of Medical Sciences, Iran from 10th April 2001 to 20th June 2003. We studied 50 LBW (Low birth weight) neonates born from mothers with PROM as the case group and fifty LBW neonates born from mothers without PROM as our control group Neonates born from pregnant women with PROM underwent sepsis workup and blood samples from their umbilical cord were sent for blood culture and IL-8 level measurement. Mean levels of IL-8 in study and control groups were 128.12 and 39.2 pg mL(-1), respectively. We had no positive blood culture and no bacteria could be isolated. Significantly elevated values (p<0.0003) were showed in cases with PROM compared to cases without PROM (medians 67.5 pg mL(-1) vs. 29.5 pg mL(-1), respectively). This study showed a strong relationship between IL-8 elevation and PROM. Increased levels of IL-8 can be used as indicator for early diagnosis of neonatal sepsis.

Topics: Case-Control Studies; Extraembryonic Membranes; Female; Fetal Blood; Fetal Membranes, Premature Rupture; Gestational Age; Humans; Infant, Low Birth Weight; Infant, Newborn; Interleukin-8; Male; Pregnancy; Sepsis

Neutrophils (polymorphonuclear leukocytes [PMNs]) are critical to the immune response, including clearance of infectious pathogens. Sepsis is associated with impaired PMN function, including chemotaxis. PMNs express peroxisome proliferator-activated receptor-gamma (PPAR-gamma), a ligand-activated nuclear transcription factor involved in immune and inflammatory regulation. The role of PPAR-gamma in PMN responses, however, is not well characterized. We report that freshly isolated human PMNs constitutively express PPAR-gamma, which is up-regulated by the sepsis-induced cytokines TNF-alpha and IL-4. PMN chemotactic responses to formylmethionyl-leucyl-phenylalanine (fMLP) and IL-8 were dose-dependently inhibited by treatment with the PPAR-gamma ligands troglitazone and 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) and by transfection of PMN-like HL-60 cells with a constitutively active PPAR-gamma construct. Inhibition of chemotaxis by PPAR-gamma ligands correlated with decreases in extracellular signal-regulated kinase-1 and -2 activation, actin polymerization, and adherence to a fibrinogen substrate. Furthermore, PMN expression of PPAR-gamma was increased in sepsis patients and mice with either of 2 models of sepsis. Finally, treatment with the PPAR-gamma antagonist GW9662 significantly reversed the inhibition of PMN chemotaxis and increased peritoneal PMN recruitment in murine sepsis. This study indicates that PPAR-gamma activation is involved in PMN chemotactic responses in vitro and may play a role in the migration of these cells in vivo.

Topics: Actins; Anilides; Animals; Antineoplastic Agents; Cell Adhesion; Chemotaxis; Chromans; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Fibrinogen; HL-60 Cells; Humans; Inflammation; Interleukin-4; Interleukin-8; Male; Mice; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; N-Formylmethionine Leucyl-Phenylalanine; PPAR gamma; Prostaglandin D2; Sepsis; Thiazolidinediones; Troglitazone; Tumor Necrosis Factor-alpha; Up-Regulation

The ScpC protease of Streptococcus pyogenes degrades interleukin-8 (IL-8), a chemokine that mediates neutrophil transmigration and activation. The ability to degrade IL-8 differs dramatically among clinical isolates of S. pyogenes. Bacteria expressing ScpC overcome immune clearance by preventing the recruitment of neutrophils in soft tissue infection of mice. To study the role of ScpC in streptococcal sepsis, we generated an ScpC mutant that did not degrade IL-8 and thus failed to prevent the recruitment of immune cells as well as to cause disease after soft tissue infection. In a murine model of sepsis, challenge with the ScpC mutant resulted in more severe systemic disease with higher bacteremia levels and mortality than did challenge with the wild-type strain. As expected, the blood level of KC, the murine IL-8 homologue, increased in mice infected with the ScpC mutant. However, the elevated KC levels did not influence neutrophil numbers in blood, as it did in soft tissue, indicating that additional factors contributed to neutrophil transmigration in blood. In addition, the absence of ScpC increased tumor necrosis factor, IL-6, and C5a levels in blood, which contributed to disease severity. Thus, the ScpC mutant triggers high neutrophil infiltration but not lethal outcome after soft tissue infection, whereas intravenous infection leads to highly aggressive systemic disease.

Topics: Animals; Bacterial Proteins; Blood; Cell Line; Complement C5a; Humans; Interleukin-6; Interleukin-8; Mice; Mutation, Missense; Peptide Hydrolases; Sepsis; Skin; Soft Tissue Infections; Streptococcal Infections; Streptococcus pyogenes; Survival Analysis; Tumor Necrosis Factor-alpha; Virulence Factors

Intraamniotic infections negatively affect the mortality and morbidity in parturients and newborns. The prognosis of the disease is associated with a timely diagnosis of these conditions. One of approaches to providing timely information on the risk of the initiation of intra-amniotic infection and early-onset neonatal sepsis is the examination of cytokine levels.. The purpose of the work was to evaluate the importance of the cytokines, IL-6, IL-8, and TNF-alpha, and the adhesive molecule, sICAM-1, as risk factors for early-onset neonatal sepsis and intra-amniotic infections.. In a group of 152 women we sampled the blood from the umbilical cord vein immediately after delivery for the determination of the cytokines IL-6, IL-8 and TNF-alpha, and the adhesive molecule, sICAM-1, in newborns.. The sensitivity and specificity results are as follows, respectively: IL-6, 0.800 and 0.972; TNF-alpha, 0.364 and 0.943; IL-8, 0.875 and 0.965; and sICAM-1, 0.833 and 0.952.. For screening purposes, it is suitable to determine levels of IL-8, IL-6, and sICAM-1. For the screening examination, one of the cytokines mentioned is sufficient, i.e., IL-8 or IL-6, or the level of the adhesive molecule, sICAM-1. It is unnecessary to combine these markers.

Topics: Adult; Amniotic Fluid; Bayes Theorem; Biomarkers; Cesarean Section; Cytokines; Delivery, Obstetric; Female; Fetal Blood; Humans; Infant, Newborn; Intercellular Adhesion Molecule-1; Interleukin-6; Interleukin-8; Male; Maternal Age; Neonatal Screening; Pregnancy; Probability; Risk; Sepsis; Tumor Necrosis Factor-alpha

In this study we tested how a combination of early and late paraclinic markers could predict early onset neonatal sepsis (EONS).. The first 24 hours after the suspicion of EONS, we measured interleukine (IL)-6, IL-8, IL-10, IL-18, tumor necrosis factor-alpha (TNF-alpha), interferon gamma (INF-gamma), procalcitonin (PCT) and C-reactive protein (CRP) at 8-hour intervals on 123 neonates clinically suspected for EONS. The neonates were divided into two groups. The sepsis group: 1A with blood culture verified bacteraemia and 1B strongly suspected sepsis (29 patients). The no sepsis group: 2A treated with antibiotics (37 patients) and 2B not treated with antibiotics (57 patients).. Combined evaluation of each of the early markers with PCT > 25 ng/ml for prediction of EONS at time 0, gave the following sensitivities and specificities: IL-6 > 250 pg/ml: 71% and 88%; IL-8 > 900 pg/ml: 50% and 88%; IL-10 > 40 pg/ml: 43% and 87%; and immature/total (I/T) ratio > 0.35: 59% and 88%. The results of IL-18, TNF-alpha and IFN-gamma did not predict EONS.. IL-6 combined with PCT values is a fair way to evaluate EONS at the time of suspicion of infection. The "old" early marker, I/T ratio, is almost as efficient as IL-6. By combining an early and a late marker it may be possible to reduce the diagnostic "non-conclusive" period of paraclinic values.

Topics: Anti-Bacterial Agents; Bacteremia; Biomarkers; C-Reactive Protein; Calcitonin; Calcitonin Gene-Related Peptide; Cytokines; Escherichia coli Infections; Female; Humans; Infant, Newborn; Inflammation Mediators; Interferon-gamma; Interleukin-10; Interleukin-18; Interleukin-6; Interleukin-8; Leukocyte Count; Male; Neutrophils; Protein Precursors; Retrospective Studies; Sensitivity and Specificity; Sepsis; Staphylococcal Infections; Streptococcal Infections; Streptococcus agalactiae; Tumor Necrosis Factor-alpha

Neonatal sepsis (NS) continues to be one of the most significant causes of neonatal morbidity and mortality. Early identification of Neonatal sepsis is a major diagnostic problem because of the nonspecific clinical signs and limitations of the current diagnostic procedures. Neutrophil CD64 expression has been proposed as a diagnostic test for evaluation of infection and sepsis. We compared the diagnostic utility of neutrophil CD64 expression with IL-6, IL-8, TNFalpha and CRP assays. Peripheral blood samples were taken from 25 neonates classified into two groups; proven NS (n = 15), clinical NS (n = 10) and healthy newborns (n = 10). CD64 expression was analysed by flowcytometry, while serum level of interleukins (IL-6, IL-8), and TNFalpha was determined by ELISA. Expression of CD64 was significantly enhanced in the groups with proven sepsis and clinical NS as compared to the controls (P < 0.05). Similary, TNFalpha, IL-6, IL-8 and CRP levels were significantly elevated in the groups with sepsis and clinical NS as compared to the controls (P < 0.05). Our data indicate that, in addition to serum levels of interleukins (IL-6, IL-8), and TNFalpha, expression of CD64 on neutrophils by flowcytometry could be useful as an indicator of NS due to its early appearance, sensitivity and specificity (96%). In conclusion, neutrophil expression of CD64 is a useful diagnostic tool for early detection of neonatal sepsis. The assay is rapid, easy and reliable.

Topics: Biomarkers; C-Reactive Protein; Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; Humans; Infant, Newborn; Interleukin-6; Interleukin-8; Male; Neutrophils; Receptors, IgG; Reproducibility of Results; Sensitivity and Specificity; Sepsis; Tumor Necrosis Factor-alpha

The purpose of this study was to determine cord blood cytokine levels and their relationship with morbidity and mortality in neonates with prolonged, premature rupture of membranes (PPROM). Forty two premature neonates of 29-35 weeks gestational age with PPROM exceeding 24 hours were considered as the PPROM group and simultaneously, 41 premature neonates without PPROM were considered as the control group. All the neonates were admitted to the Neonatology Unit for further evaluation of subsequent complications such as early neonatal sepsis, pneumonia, intraventicular haemorrhage (IVH), respiratory distress syndrome (RDS), necrotizing enterocolitis (NEC) and chronic lung disease (CLD). Cord blood and mothers' blood samples were obtained during delivery in both groups and tested for IL-6, IL-8 and TNF-alpha levels. Twenty one percent of patients with PPROM had histological chorioamnionitis. The risk for developing early neonatal sepsis increased significantly in neonates whose mothers had histological chorioamnionitis (p < 0.05). There was a statistically significant relationship between PPROM and risk of developing NEC (p < 0.05); no significant increase was seen as regards early neonatal sepsis, IVH, RDS, pneumonia, or BPD. The mean IL-8 levels in cord blood and mothers' serum were significantly higher in the PPROM group (p < 0.001, p< 0.005). In addition, IL-6 levels found in mothers' serum were significantly higher than those found in the control group (p < 0.01). However, levels in cord blood were similar (p > 0.05). TNF-alpha levels were similar in both groups (p > 0.05). Neonates who developed NEC had higher IL-8 levels in their cord blood when compared to those without NEC (p < 0.05). In conclusion, the presence of PPROM increases the risk of chorioamnionitis. In addition, PPROM increases the risk of NEC, and patients who developed NEC had significantly higher cord blood IL-8 values. We may conclude that patients with PPROM and higher IL-8 levels in cord blood might be considered as at possible risk of NEC.

Topics: Adult; Chorioamnionitis; Cytokines; Enterocolitis, Necrotizing; Female; Fetal Blood; Fetal Membranes, Premature Rupture; Humans; Infant, Newborn; Infant, Premature; Interleukin-6; Interleukin-8; Neonatology; Pregnancy; Risk; Sepsis

Patients with chemotherapy-related neutropenia and fever are usually hospitalized and treated on empirical intravenous broad-spectrum antibiotic regimens. Early diagnosis of sepsis in children with febrile neutropenia remains difficult due to non-specific clinical and laboratory signs of infection. We aimed to analyze whether IL-6 and IL-8 could define a group of patients at low risk of septicemia.. A prospective study was performed to assess the potential value of IL-6, IL-8 and C-reactive protein serum levels to predict severe bacterial infection or bacteremia in febrile neutropenic children with cancer during chemotherapy. Statistical test used: Friedman test, Wilcoxon-Test, Kruskal-Wallis H test, Mann-Whitney U-Test and Receiver Operating Characteristics.. The analysis of cytokine levels measured at the onset of fever indicated that IL-6 and IL-8 are useful to define a possible group of patients with low risk of sepsis. In predicting bacteremia or severe bacterial infection, IL-6 was the best predictor with the optimum IL-6 cut-off level of 42 pg/ml showing a high sensitivity (90%) and specificity (85%).. These findings may have clinical implications for risk-based antimicrobial treatment strategies.

Topics: Adolescent; Adult; Anti-Bacterial Agents; C-Reactive Protein; Ceftazidime; Child; Child, Preschool; Female; Fever; Germany; Humans; Infant; Interleukin-6; Interleukin-8; Male; Neoplasms; Neutropenia; Prospective Studies; Risk Factors; Sepsis

Severe sepsis is not clinically apparent during the first 24 hours of hospitalization in most children with cancer and febrile neutropenia (FN), delaying targeted interventions that could impact mortality. The aim of this study was to prospectively evaluate biomarkers obtained within 24 hours of hospitalization as predictors of severe sepsis before it becomes clinically evident.. Children with cancer, admitted with FN at high risk for an invasive bacterial infection in 6 public hospitals in Santiago, Chile, were monitored throughout their clinical course for occurrence of severe sepsis. Clinical, demographic and 6 biomarkers [eg, blood urea nitrogen, serum glucose, lactic dehydrogenase, serum C-reactive protein (CRP), interleukin (IL)-8, and procalcitonin] were obtained at the time of admission and after 24 hours. Biomarkers independently associated with severe sepsis diagnosed after the first 24 hours of hospitalization were identified by logistic regression analysis.. A total of 601 high risk FN episodes were enrolled between June 2004 and October 2006; 151 (25%) developed severe sepsis of which 116 (77%) were not clinically apparent during the first 24 hours of hospitalization. Risk factors for severe sepsis were age > or =12 years [odds ratio (OR): 3.85; 95% confidence interval (CI): 2.41-6.15], admission CRP > or =90 mg/L (OR: 2.03; 95% CI: 1.32-3.14), admission IL-8 > or =200 pg/mL (OR: 2.39; 95% CI: 1.51-3.78), 24-hour CRP > or =100 mg/L (OR: 3.06; 95% CI: 1.94-4.85), and 24-hour IL-8 > or =300 pg/mL (OR: 3.13; 95% CI 1.92-5.08).. Age > or =12 years and admission or 24-hour values of CRP > or =90/100 mg/L and IL-8 > or =200/300 pg/mL are predictors of sepsis not clinically apparent during the first 24 hours of hospitalization.

Topics: Adolescent; Age Factors; Biomarkers; Blood Glucose; Blood Urea Nitrogen; C-Reactive Protein; Calcitonin; Calcitonin Gene-Related Peptide; Child; Child, Preschool; Chile; Female; Fever of Unknown Origin; Hospitalization; Humans; Interleukin-8; L-Lactate Dehydrogenase; Logistic Models; Male; Neoplasms; Neutropenia; Prospective Studies; Protein Precursors; Sepsis

Interleukin-8 (IL-8, also known as neutrophil-activating peptide 1, NAP1 and CXCL8, CXC chemokine ligand 8) is recognized as a potent effector of neutrophil functions. IL-8 is a major response factor following NfkB activation by cytokines or lipopolysaccharide and several different cell types T lymphocytes, monocytes, epithelial and endothelial cells secrete this polypeptide. IL-8 is not to be determined at significant concentrations in plasma due to its receptor binding but may play a major role in tissues. The prediction of sepsis is a major and current field of research in the treatment of surgical patients. The aim of this study was to compare the determination of IL-8 in whole blood cell lysates (whole blood IL-8) and in plasma for the prediction of sepsis in postoperative intensive care.. Whole blood IL-8, IL-8 in plasma, and CRP were measured in the daily routine monitoring of 84 patients in a surgical intensive care unit. Sepsis was defined by the criteria of the Society of Critical Care Medicine (SCCM). For comparison the APACHE II score (APACHE=Acute Physiology and Chronic Health Evaluation) was calculated. The diagnostic value of the three tests was compared by receiver operating characteristic (ROC) curves.. Whole blood IL-8 showed higher areas under the curve (AUC) than IL-8 in plasma and CRP. The ROC curves for the APACHE II scores gave similar results.. Sepsis is a complex disease and is induced by systemic infection of patients suffering from systemic inflammatory response syndromes (SIRS). Therefore, the identification of infection or the host response to infection is of crucial importance. The prediction of an individual marker or interleukin or its binding to surface proteins is not necessarily indicative for sepsis. In cases with unequivocally identified bacterial infections, the current results suggest that whole blood IL-8 may have a similar diagnostic accuracy as plasma levels. Of note, this technique needs less blood and is not being affected by hemolysis.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; C-Reactive Protein; Child; Female; Humans; Interleukin-8; Male; Middle Aged; Plasma; Postoperative Complications; ROC Curve; Sepsis

The aim of this study was to test the hypothesis that elevated lipopolysaccharide binding protein (LBP) serum concentration is a useful marker in the early diagnosis of invasive bacterial infection in children. We measured LBP in serum and cerebrospinal fluid (CSF) of children with proven invasive infection caused by Haemophilus influenzae, Streptococcus pneumoniae and Neisseria meningitidis.. Samples were collected from 39 children (aged 2 months to 17 years) with bacterial sepsis (n = 19) or meningitis (n = 20). Bacterial infection was diagnosed when a blood or CSF culture was positive and clinical signs of invasive infection were present. The control group consisted of serum (n = 60) and CSF (n = 19) samples from children with neurologic disease, juvenile idiopathic arthritis or viral infection. In 10 patients with bacterial infection, follow-up samples (24 and 48 hours) were available. LBP values were measured by an immunochemiluminescence analyzer (IMMULITE; DPC Biermann, Bad Nauheim, Germany) and compared with tumor necrosis factor-alpha and interleukin-8 concentrations.. The median LBP serum concentrations in patients with bacterial infection were markedly elevated compared with the control groups (45.0 [33.1-55.2] versus 8.3 [6.8-10.1] microg/mL [median and 5-95% confidence interval]; P < 0.0001). Follow-up serum values of LBP were persistently elevated despite adequate antibiotic treatment, whereas tumor necrosis factor-alpha and interleukin-8 concentrations decreased. In contrast, LBP concentrations in the CSF were below the detection limit of 0.5 microg/mL in 67% of patients with bacterial meningitis (median <0.5 microg/mL), whereas tumor necrosis factor-alpha and interleukin-8 levels were highly elevated.. LBP serum concentration is elevated in serum of children with invasive bacterial infection and could be a promising diagnostic marker.

Topics: Acute-Phase Proteins; Adolescent; Biomarkers; Carrier Proteins; Cerebrospinal Fluid; Child; Child, Preschool; Haemophilus Infections; Haemophilus influenzae; Humans; Immunoassay; Infant; Interleukin-8; Luminescent Measurements; Membrane Glycoproteins; Meningitis, Bacterial; Meningococcal Infections; Neisseria meningitidis; Pneumococcal Infections; Sepsis; Serum; Streptococcus pneumoniae; Time Factors; Tumor Necrosis Factor-alpha

The aim of this study was to assess the prognostic value of tumor necrosis factor (TNF) alpha, interleukin (IL)-8, IL-4, and IL-10 in combat casualties. Fifty-six casualties with severe trauma (blast and explosive) who developed sepsis and 20 casualties with the same severity of trauma without sepsis were enrolled in this study. Fifty-five casualties developed multiple organ dysfunction syndrome; 36 died. Blood was drawn on the first day of trauma. Concentrations of IL-8, TNF-alpha, IL-4, and IL-10 were determined in plasma using enzyme-linked immunosorbent assays. Mean values of IL-8 were 230-fold, IL-10 were 42-fold, and TNF-alpha were 17-fold higher in trauma and sepsis group (p < 0.01). Mean values of IL-8 were 60-fold, TNF-alpha were 43.5-fold, and IL-10 were 70-fold higher in the multiple organ dysfunction syndrome group (p < 0.01). Mean values of IL-8 were 2.3-fold and IL-10 were 1.4-fold higher in nonsurvivors and TNF-alpha were 2.2-fold higher in survivors (p < 0.01). IL-4 had no significance as a predictor of severity and outcome.

Topics: Adolescent; Adult; Aged; Biomarkers; Blast Injuries; Child; Cytokines; Enzyme-Linked Immunosorbent Assay; Follow-Up Studies; Humans; Interleukin-10; Interleukin-8; Male; Middle Aged; Prognosis; Retrospective Studies; Sepsis; Trauma Severity Indices; Tumor Necrosis Factor-alpha; Warfare

Neonatal sepsis is a disease of infants who are less than 1 month of age. These infants are clinically ill, and their blood culture are positive for bacteria. The reported incidence of neonatal sepsis for all infants is 1 to 10 per 1000 live births. The mortality rate is 4.2-26%. The clinical signs are not specific and diagnosis of neonatal sepsis is one of the most difficult tasks in clinical medicine. The aim of this work was determination of CD11b sensitivity and specificity for early detection of neonatal sepsis. We studied 65 neonates with gestational age of 27 to 38 weeks who were suspected for sepsis within the 28 days of life. Whole blood was obtained from neonates to determine CD11b expression on peripheral blood neutrophils by flow cytometry. C-Reactive protein (CRP) was measured qualitatively. Neonates were divided into two groups. Classification was based on the result of the blood culture. In the sepsis group all of the neonates (n=8) showed positive blood culture and clinical symptoms. In the suspected group (n=57) the neonates showed clinical signs but blood cultures were negative. Sensitivity and specificity of CD11b were 75%, 100% respectively. Also positive and negative predictive values of CD11b were 100% and 86% respectively. Results of present study and previous studies showed that measurement of neutrophil surface markers can be useful for diagnosis of infection in the early phases. Also, the quantitative measurement of CRP in addition to CD11b further enhances the ability to diagnose infections and improves sensitivity and negative predictive value by 100%.

Topics: C-Reactive Protein; CD11b Antigen; CD18 Antigens; Early Diagnosis; Humans; Infant; Infant, Newborn; Interleukin-8; Leukocyte Count; Neutrophils; Sensitivity and Specificity; Sepsis

To determine serum IL-1beta, IL-6, IL-8, and TNF-alpha levels in neonatal sepsis at the time of diagnosis and after therapy, and to show the meaningful on the follow up.. This prospective study was performed on newborns who were hospitalized for neonatal sepsis and who were classified as culture-proven sepsis (n=12), as culture-negative sepsis (n=21), and as healthy newborns (n=17).. At the time of diagnosis, serum IL-1beta, IL-6, IL-8, and TNF-alpha levels of culture-proven sepsis were significantly higher than those of the control groups (P<.05). At the time of diagnosis, IL-1beta, IL-6, IL-8, and TNF-alpha levels of culture-proven sepsis and culture-negative sepsis were significantly higher than levels at the seventh day after antibiotic treatment.. Serum IL-1beta, IL-6, IL-8, and TNF-alpha are mediators of inflammation and can be used at the diagnosis and at the evaluation of the therapeutic efficiency in neonatal sepsis.

Topics: Anti-Bacterial Agents; Anti-Infective Agents; Chemotaxis; Female; Gene Expression Regulation; Humans; Infant, Newborn; Inflammation; Interleukin-1beta; Interleukin-6; Interleukin-8; Male; Prospective Studies; Sepsis; Tumor Necrosis Factor-alpha

Tissue factor (TF) is a transmembrane glycoprotein that binds its zymogen cofactor, Factor VIIa (FVIIa) on the cell surface. Together (TF/FVIIa) they activate Factor X (FX) and Factor IX (FIX) and start the extrinsic pathway of blood coagulation. As such, the TF/FVIIa complex plays an important role in normal physiology as well as in thrombotic diseases such as unstable angina (UA), disseminated intravascular coagulation (DIC), and deep vein thrombosis (DVT). In addition to its function as an initiator of coagulation, TF/FVIIa plays an important role in inflammation. Expression of TF on the cell surface and its appearance as a soluble molecule are characteristic features of acute and chronic inflammation in conditions such as sepsis and atherosclerosis. Here we demonstrate that BCX-3607, a small molecule potent inhibitor of TF/FVIIa, reduces thrombus weight in an animal model of DVT. BCX-3607 also decreases the level of interleukin-6 (IL-6) in a LPS-stimulated mouse model of endotoxemia. Additionally, in vitro studies indicate that BCX-3607 blocks the generation of TF/FVIIa-induced IL-8 mRNA in human keratinocytes and reduces the TF/FVIIa-mediated generation of IL-6 and IL-8 in human umbilical vein endothelial cells (HUVEC). Therefore, BCX-3607 might block the TF/FVIIa-mediated coagulation and inflammation associated with pathological conditions.

Topics: Animals; Anti-Inflammatory Agents; Atherosclerosis; Blotting, Northern; Cells, Cultured; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelium, Vascular; Endotoxemia; Factor VIIa; Fibrinolytic Agents; Humans; Inflammation; Interleukin-6; Interleukin-8; Keratinocytes; Lipopolysaccharides; Male; Mice; Models, Biological; Models, Chemical; Prothrombin Time; Pyridines; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sepsis; Thromboplastin; Time Factors

To define the significance of soluble triggering receptor expressed on myeloid cells 1 (sTREM-1) in the septic cascade by comparing its kinetics to those of other proinflammatory mediators and of interleukin (IL) 10.. Prospective study in a tertiary unit.. Blood was sampled from 90 patients with septic syndrome due to ventilator-associated pneumonia for 7 days after the appearance of symptoms. Concentrations of tumor necrosis factor (TNF) alpha, IL-6, IL-8, IL-10, and sTREM-1 were determined by enzyme-linked immunosorbent assay.. Serum levels of TNFalpha, IL-6, IL-10, and sTREM-1 were higher in nonsurvivors than in survivors; similar differences were not found for IL-8. Positive correlations were found between the ratios IL-10/TNFalpha and sTREM-1/TNFalpha, between IL-10/IL-6 and sTREM-1/IL-6, and between IL-10/IL-8 and sTREM-1/IL-8. Median values of IL-10/TNFalpha upon presentation of sepsis, severe sepsis, and septic shock were 3.21, 2.16, and 2.86, respectively (NS). Respective values for sTREM-1/TNFalpha were 21.28, 7.33, and 27.78 (p=0.047 between sepsis and severe sepsis, p=0.003 between severe sepsis and septic shock).. sTREM-1 follows the kinetics of IL-10 and should therefore be considered an anti-inflammatory mediator in sepsis. Decreased ratios of sTREM-1/TNFalpha might determine transition from sepsis to severe sepsis and from severe sepsis to septic shock.

Topics: Aged; Cytokines; Disease Progression; Enzyme-Linked Immunosorbent Assay; Female; Humans; Inflammation Mediators; Interleukin-10; Interleukin-6; Interleukin-8; Male; Membrane Glycoproteins; Middle Aged; Myeloid Cells; Prospective Studies; Receptors, Immunologic; Sepsis; Statistics, Nonparametric; Triggering Receptor Expressed on Myeloid Cells-1; Tumor Necrosis Factor-alpha

Interindividual differences of endothelial cells in response to endotoxins might contribute to the diversity in clinical outcome among septic patients. The present study was conducted to test the hypothesis that endothelial cells (EC) with high and low proinflammatory potential exist and to dissect the molecular basis underlying this phenomenon. Thirty human umbilical vein endothelial cell (HUVEC) lines were stimulated for 24 h with lipopolysaccharide (LPS) and screened for interleukin (IL)-8 production. Based on IL-8 production five low and five high producers, tentatively called types I and II responders, respectively, were selected for genome-wide gene expression profiling. From the 74 genes that were modulated by LPS in all type II responders, 33 genes were not influenced in type I responders. Among the 41 genes that were increased in both responders, 17 were expressed significantly stronger in type II responders. Apart from IL-8, significant differences in the expression of proinflammatory related genes between types I and II responders were found for adhesion molecules [intercellular adhesion molecule (ICAM-1), E-selectin)], chemokines [monocyte chemoattractant protein (MCP-1), granulocyte chemotactic protein (GCP-2)], cytokines (IL-6) and the transcription factor CCAAT/enhancer binding protein-delta (C/EBP-delta). Type I responders also displayed a low response towards tumour necrosis factor (TNF)-alpha. In general, maximal activation of nuclear factor (NF)-kappaB was achieved in type I responders at higher concentrations of LPS compared to type II responders. In the present study we demonstrate that LPS-mediated gene expression differs quantitatively and qualitatively in types I and II responders. Our results suggest a pivotal role for common transcription factors as a low inflammatory response was also observed after TNF-alpha stimulation. Further studies are required to elucidate the relevance of these findings in terms of clinical outcome in septic patients.

Topics: Cells, Cultured; Chemokines; Electrophoretic Mobility Shift Assay; Endothelial Cells; Endothelium, Vascular; Gene Expression Profiling; Gene Expression Regulation; Humans; Inflammation Mediators; Interleukin-8; Lipopolysaccharides; Reverse Transcriptase Polymerase Chain Reaction; Sepsis; Transcription Factors; Tumor Necrosis Factor-alpha

Interleukin-6 (IL-6), interleukin-8 (IL-8), and procalcitonin (PCT) are important parameters in the diagnosis of sepsis and for differentiating between viral and bacterial infection in children. We compared the value of IL-6, IL-8, and PCT with C-reactive protein (CRP) in the diagnosis and treatment of late-onset sepsis among infants admitted to the neonatal intensive care unit (group I) and febrile infants admitted to general hospitals from home (group II). Group I was divided into subgroups Ia, positive blood culture (all Gram-positive cocci); Ib, negative blood culture; and Ic, controls. Group II was divided into subgroups IIa, systemic enterovirus infection, and IIb, no enterovirus infection. Enterovirus was identified by real-time (RT) polymerase chain reaction (PCR) and/or by culture in blood and cerebrospinal fluid (CSF). The positive predictive values of IL-6, IL-8, and PCT (78%, 72%, and 83%, respectively) were better than that of CRP (63%) in the diagnosis of neonatal sepsis. After 48 h of antibiotic treatment, IL-6 and IL-8 levels significantly decreased and PCT stabilized in clinically recovered patients, suggesting that these markers may be useful in distinguishing patients in which antibiotic treatment may be discontinued. Among infants of subgroup IIa, 80%-90% had normal values of IL-6, IL-8, and PCT, whereas CRP was increased in 40%. In conclusion, IL-6, IL-8, and PCT are better parameters than CRP in the diagnosis and follow-up of neonatal sepsis due to coagulase-negative staphylococci (CoNS) and in the exclusion of bacterial infection among those with enteroviral infection among febrile infants presenting from home.

Topics: C-Reactive Protein; Calcitonin; Calcitonin Gene-Related Peptide; Female; Humans; Infant; Infant, Newborn; Intensive Care Units, Neonatal; Interleukin-6; Interleukin-8; Male; Protein Precursors; Sepsis

In sepsis, Gram-positive and Gram-negative bacteria provoke similar inflammatory processes. Whereas lipopolysaccharides (LPSs) are acknowledged as the principal immunostimulatory components of Gram-negative bacteria, the effect of the Gram-positive cell wall component lipoteichoic acid (LTA) is less well characterized. In the present study, we investigated the effect of highly purified LTA from Staphylococcus aureus on cytokine generation by isolated human neutrophils.. Isolated human neutrophils from healthy volunteers.. Incubation of neutrophils with purified LTA from S. aureus in the absence or presence of interleukin (IL)-10, anti-CD14, or anti-Toll-like-receptor antibodies.. Measurement of tumor necrosis factor (TNF)-alpha, IL-1beta, and IL-8 by enzyme-linked immunosorbent assay. Analysis of IL-8 mRNA by reverse transcriptase polymerase chain reaction.. The LTA challenge provoked a dramatic release of cytokines, with an early appearance of TNF-alpha and IL-1beta and a delayed liberation of IL-8. The first phase of IL-8 production was induced directly by LTA, whereas the second phase was endogenously mediated by TNF-alpha, as it was largely abrogated by neutralizing anti-TNF-alpha antibodies. In contrast, IL1-beta was not involved in LTA-induced IL-8 generation. Interestingly, the late phase of IL-8 generation could also be attenuated by exogenous IL-10, probably as a consequence of its downregulatory effects on TNF-alpha generation. When investigating the mechanism of LTA-induced cellular activation, activity-neutralizing antibodies demonstrated that CD14 was involved in LTA-mediated neutrophil cytokine generation. Using antibodies that neutralize the activity of Toll-like receptor 2 (TLR2) or 4 (TLR4), we also show that CD14-dependent, LTA-induced neutrophil activation did not proceed via TLR2- or TLR4-mediated pathways. In conclusion, LTA is a potent activator of human neutrophil cytokine generation, with the synthesis of the chemokine IL-8 being largely dependent on TNF-alpha generation in an autocrine fashion. This LTA-induced effect was inhibited by IL-10, dependent on CD14, and independent of TLR 2 or 4.

Topics: Analysis of Variance; Cells, Cultured; Cytokines; Humans; Interleukin-10; Interleukin-8; Lipopolysaccharide Receptors; Lipopolysaccharides; Neutrophils; Sepsis; Staphylococcal Infections; Staphylococcus aureus; Teichoic Acids; Toll-Like Receptors; Tumor Necrosis Factor-alpha

Sepsis is a common and often fatal disease. Because sepsis can be caused by many different organisms, biomarkers that can aid in diagnosing sepsis and monitoring treatment efficacy are highly warranted. New sepsis markers may provide additional information to complement the currently used markers.. We used a combination of in-house and commercially available multiplex immunoassays based on Luminex xMAP technology to assay biomarkers of potential interest in EDTA-plasma samples.. A 3-plex assay for soluble urokinase plasminogen activator receptor (suPAR), soluble triggering receptor expressed on myeloid cells-1 (sTREM-1), and macrophage migration inhibiting factor (MIF) was developed and validated in-house. This 3-plex assay was added to a commercially available interleukin-1beta (IL-1beta), IL-6, IL-8, granulocyte/macrophage colony-stimulating factor, and tumor necrosis factor-alpha human cytokine panel. No cross-reactivity was observed when the assays were combined. Correlation between values obtained with the 8-plex, the 5-cytokine panel, the 3 in-house 1-plex assays, and a suPAR ELISA ranged from 0.86 to 0.99. Mean within- and between-run CVs were 8.0% and 11%, respectively. Recoveries of suPAR, sTREM-1, and MIF calibrators were 108%, 88%, and 51%, respectively. In plasma collected from 10 patients with bacterial sepsis confirmed by blood culture, the assay detected significantly increased concentrations of all 8 analytes compared with healthy controls.. A commercially available xMAP panel can be expanded with markers of interest. The combined multiplex assay can measure the 8 analytes with high reproducibility. The xMAP technology is an appealing tool for assaying conventional cytokines in combination with new markers.

Topics: Biomarkers; Chemotactic Factors; Cross Reactions; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Immunoassay; Interleukin-1; Interleukin-6; Interleukin-8; Macrophages; Membrane Glycoproteins; Receptors, Cell Surface; Receptors, Immunologic; Receptors, Urokinase Plasminogen Activator; Sepsis; Triggering Receptor Expressed on Myeloid Cells-1; Tumor Necrosis Factor-alpha

In the present study, we examined whether the performance of hemoperfusion with an immobilized polymyxin B fiber column (DHP-PMX) reduces circulating interleukin-8 concentration in patients with sepsis. Fifteen patients with sepsis satisfying the following criteria were enrolled in the study: (i) signs of systemic inflammatory response syndrome caused by infection; and (ii) mean arterial blood pressure > or =60 mm Hg (irrespective of the use of catecholamines). A thermodilution catheter was inserted prior to DHP-PMX for appropriate intravenous infusion, and the DHP-PMX was carried out twice at 24 h intervals (for 3 h each time). Circulating interleukin-8 concentration was measured seven times. The sequential organ failure assessment (SOFA) score was calculated twice. Circulating interleukin-8 concentration was 55 +/- 15.7 pg/mL before DHP-PMX, while it was 101 +/- 58.8 pg/mL immediately after the first session of treatment. It was 24 +/- 9.0 pg/mL before the second session of DHP-PMX, and it was 28 +/- 8.0 pg/mL immediately after the second session. The IL-8 level was 17 +/- 4.3 pg/mL at 48 h afterward, and 18 +/- 4.3 pg/mL at 72 h afterward, showing a significant decrease from 48 h onwards, compared with before treatment (P < 0.05). The SOFA score was 9 +/- 1.5 and the APACHE II score was 19 +/- 2.0 before DHP-PMX, while the SOFA score was 7.0 +/- 0.9 at 72 h afterward, showing a significant decrease compared with before treatment (P < 0.05). The present findings indicate that DHP-PMX indirectly reduces circulating interleukin-8 concentration and improves SOFA score.

Topics: Adult; Aged; Anti-Bacterial Agents; Female; Hemoperfusion; Humans; Interleukin-8; Male; Membranes, Artificial; Middle Aged; Polymyxin B; Prospective Studies; Respiration, Artificial; Sepsis

1. In recent studies, the vascular adventitia has been established as an important source of inducible nitric oxide synthase (iNOS) and subsequent nitric oxide (NO) production, even more powerful than the media in response to certain inflammatory factors, such as lipopolysaccharide (LPS). The adventitia has an independent L-arginine (L-Arg)/NOS/NO pathway and is involved in the regulation of vascular function. In the present study, we explored the changes in and the pathophysiological significance of the L-Arg/NOS/NO pathway in the adventitia of rats with sepsis. 2. Sepsis was induced by caecal ligation and puncture in order to observe changes in L-Arg transport, NOS gene expression and activity and NO generation in the vascular adventitia to determine the mechanism of activation of the L-Arg/NOS/NO pathway. 3. Severe sepsis resulted in severe disturbance of haemodynamic features, with decreased mean arterial blood pressure, brachycardia and inhibited cardiac function (decreased left ventricular +/-dP/dt(max)). Left ventricular end-diastolic pressure was elevated threefold (P < 0.01) under anaesthesia. Rats with sepsis showed severe glucopenia and lacticaemia. Plasma levels of the inflammatory factors macrophage chemoattractant protein-1 and interleukin-8 were increased five- and 29-fold, respectively (P < 0.01). 4. In the adventitia of the thoracic and abdominal aortas, the L-Arg/NO pathway was similarly characterized: the uptake of [(3)H]-L-Arg was Na(+) independent, with the peak occurring at approximately 40 min incubation. Total NOS activity was largely calcium independent (> 90%). The V(max) of L-Arg transport in the sepsis group was increased by 83.5% (P < 0.01), but the K(m) value was not significantly different compared with controls. 5. The mRNA levels of cationic amino acid transporter (CAT)-1 and CAT-2B in the sepsis group were increased by 86 and 62%, respectively (both P < 0.01). Inducible NOS activity was increased 2.8-fold compared with controls (P < 0.01) and iNOS mRNA levels were elevated approximately sixfold (P < 0.01). The NO levels in the plasma and incubation media (incubation for 40 min) in the sepsis group were increased by 144 and 273%, respectively (both P < 0.01). 6. The Arg/NOS/NO pathway was activated in the vascular adventitia of rats with sepsis shock. The L-Arg/NOS/NO pathway in the aortic adventitia may play an important role in the pathogenesis of sepsis and septic shock.

Topics: Animals; Aorta, Thoracic; Arginine; Blood Pressure; Blood Vessels; Cationic Amino Acid Transporter 1; Cationic Amino Acid Transporter 2; Chemokine CCL2; Connective Tissue; Heart Rate; Interleukin-8; Kinetics; Male; Nitric Oxide; Nitric Oxide Synthase Type II; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Sepsis; Shock, Septic; Up-Regulation; Ventricular Function, Left

The aim of the present study was to investigate which biomarker/s reliably assess severity and mortality early in the sepsis process. In 47 critically-ill patients within the 24h of septic onset, Interleukins (IL)-8, -1beta, -6, -10, and -12p70, tumor necrosis factor-alpha (TNF-alpha), procalcitonin (PCT) and C-reactive protein (CRP) were measured in serum. Additionally, CD64 expression was measured in neutrophils. In early sepsis, neutrophil CD64 expression and IL-8 levels are the only biomarkers that increased with sepsis severity, differentiating disease stages: sepsis, severe sepsis and septic shock (p<0.001). The biomarkers that best evaluate the severity of sepsis (via APACHE II) were CD64, IL-8 and IL-6 (p<0.01), and the severity of organ failure (via SOFA) were CD64 and IL-8 (p<0.01). CD64 expression and IL-8 levels were associated with mortality within 28-days (OR=1.3, p=0.01 for CD64 and OR=1.26, p=0.024 for IL-8 by logistic regression analysis) and ROC curve analysis showed high sensitivity and specificity for predicting sepsis stages and the 28 day mortality. We conclude that there is an early increase of neutrophil CD64 expression and IL-8 levels during sepsis. Based on this single measurement it is possible to reliably assess the stage, detect the severity and predict the 28-day mortality of sepsis.

Topics: Adult; Aged; APACHE; Case-Control Studies; Female; Humans; Interleukin-8; Male; Middle Aged; Neutrophils; Receptors, IgG; Sepsis

Endotoxin is known to be a primary initiator of sepsis and septic shock. Migration of immunocompetent cells due to chemotactic attraction plays a central role in the initiation of the immune response. Two major groups of chemokines can be distinguished: C-x-C chemokines like Interleukin-8 attract mainly neutrophils, C-C chemokines (e.g. RANTES) attract monocytes and T-cells. The aim of this study was to get further insight into chemokine profiles after a single endotoxin bolus in man.. We investigated the effect of systemically administered endotoxin (4ng/kg BW i.v.) in 8 healthy volunteers. Clinical data (heart rate, mean arterial pressure, temperature), serum levels of IL-8, and RANTES, as well as white blood cell count were obtained before and hourly for five hours after endotoxin administration.. Heart rate and MAP showed significant changes (p<0.05) after 2-3 hours. All volunteers presented with low-grade fever after 2 hours. WBC was elevated 43% and 63% after 4 and 5 hours, respectively. Both chemokines were significantly different from baseline two hours after endotoxin challenge: While IL-8 was significantly increased RANTES serum levels were diminished.. From our data we conclude that this endotoxin model was effective to mimic the clinical appearance of sepsis. Chemokines like IL-8 and RANTES are integrated in the early immune response to endotoxin challenge in man.

Topics: Adult; Blood Pressure; Chemokine CCL5; Endotoxins; Female; Heart Rate; Humans; Interleukin-8; Leukocyte Count; Male; Sepsis

In order to define the significance of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) upon progression from sepsis or severe sepsis to septic shock a prospective study was designed with 90 enrolled patients with septic syndrome due to ventilator-associated pneumonia. Blood was sampled on seven consecutive days upon initiation of symptoms and concentrations of tumour necrosis factor-alpha (TNFalpha), interleukin-6 (IL-6), IL-8 and sTREM-1 were estimated in serum by an enzymeimmunoassay. No differences in concentrations of TNFalpha, IL-6 and IL-8 were found between patients with sepsis, severe sepsis and septic shock on the first day of presentation of symptoms. Patients presenting with septic shock had concentrations of sTREM-1 significantly higher than both patients with sepsis and severe sepsis on the first day; no difference was found between patients with sepsis and severe sepsis. A positive correlation was detected between sTREM-1 and the white blood cell count. Serum levels of sTREM-1 were significantly lower in patients where VAP resolved compared to those where VAP did not resolve; similar findings were noted between patients who eventually survived and those who died. IL-6 followed the kinetics of sTREM-1 in correlation to patients's prognosis; levels of TNFalpha and IL-8 were unrelated to prognosis. It is concluded that sTREM-1 is particularly increased upon evolution from sepsis or severe sepsis to septic shock. Its sustained increase is an indication of poor outcome. The underlined pathophysiological role of sTREM-1 for the transition from sepsis or severe sepsis to septic shock might constitute a novel target for immunomodulatory therapy.

Topics: Aged; Disease Progression; Female; Humans; Interleukin-6; Interleukin-8; Male; Membrane Glycoproteins; Middle Aged; Pneumonia; Prospective Studies; Receptors, Immunologic; Sepsis; Shock, Septic; Triggering Receptor Expressed on Myeloid Cells-1; Tumor Necrosis Factor-alpha

Despite recent identification of specific pattern recognition receptors (PRR) for distinct microbial structures, data indicating their relevance in human infectious diseases are limited. We determined the expression levels of the Toll-like receptor (TLR)2 and TLR4 by flow cytometry on granulocytes and monocytes of healthy neonates compared with healthy adults. The basal expression of TLR2 was only slightly lower in neonatal phagocytes, whereas no differences could be detected for TLR4. Analyzing neonates with sepsis, we found an impressive up-regulation of TLR2 on blood phagocytes already at initial presentation of symptoms. Comparison with C-reactive protein, IL-8, and IL-6 suggested that TLR2 expression on monocytes is comparably valuable as an early sepsis marker. TLR2 was differentially regulated during neonatal sepsis, showing a constant up-regulation on monocytes but only a transient increase on granulocytes. Surprisingly, TLR4 showed no remarkable changes. Our results revealed a mild deficiency of TLR2 expression in newborns and demonstrated a differential expression of TLR2 but not TLR4 in the course of neonatal sepsis, which could reflect specific inflammatory responses to distinct pathogens. The definition of TLR expression patterns might open a new field of therapeutic targets for neonatal sepsis.

Topics: C-Reactive Protein; Female; Flow Cytometry; Granulocytes; Humans; Infant, Newborn; Inflammation; Interleukin-6; Interleukin-8; Leukocytes; Male; Monocytes; Sepsis; Time Factors; Toll-Like Receptor 2; Toll-Like Receptor 4; Toll-Like Receptors; Up-Regulation

Sepsis causes more than with 215,000 deaths per year in the United States alone. Death can be caused by multiple system organ failure, with the lung, in the form of the acute respiratory distress syndrome (ARDS), often being the first organ to fail. We developed a chronic porcine model of septic shock and ARDS and hypothesized that blocking the proteases neutrophil elastase (NE) and matrix metalloproteinases (MMP-2 and MMP-9) with the modified tetracycline, COL-3, would significantly improve morbidity in this model. Pigs were anesthetized and instrumented for hemodynamic monitoring and were then randomized to one of three groups: control (n = 3), laparotomy only; superior mesenteric artery occlusion (SMA) + fecal blood clot (FC; n = 7), with intraperitoneal placement of a FC; and SMA + FC + COL (n = 5), ingestion of COL-3 12 h before injury. Animals emerged from anesthesia and were monitored and treated with fluids and antibiotics in an animal intensive care unit continuously for 48 h. Serum and bronchoalveolar lavage fluid (BALF) were sampled and bacterial cultures, MMP-2, MMP-9, NE, and multiple cytokine concentrations were measured. Pigs were reanesthetized and placed on a ventilator when significant lung impairment occurred (PaO2/FiO2 < 250). At necropsy, lung water and histology were assessed. All animals in the SMA + FC group developed septic shock evidenced by a significant fall in arterial blood pressure that was not responsive to fluids. Lung injury typical of ARDS (i.e., a fall in lung compliance and PaO2/FiO2 ratio and a significant increase in lung water) developed in this group. Additionally, there was a significant increase in plasma IL-1 and IL-6 and in BALF IL-6, IL-8, IL-10, NE, and protein concentration in the SMA + FC group. COL-3 treatment prevented septic shock and ARDS and significantly decreased cytokine levels in plasma and BALF. COL-3 treatment also significantly reduced NE activity (P < 0.05) and reduced MMP-2 and MMP-9 activity in BALF by 64% and 34%, respectively, compared with the SMA + FC group. We conclude that prophylactic COL-3 prevented the development of ARDS and unexpectedly also prevented septic shock in a chronic insidious onset animal model of sepsis-induced ARDS. The mechanism of this protection is unclear, as COL-3 inhibited numerous inflammatory mediators. Nevertheless, COL-3 significantly reduced the morbidity in a clinically applicable animal model, demonstrating the possibility that COL-3 may be useful in reduc

Topics: Animals; Bronchoalveolar Lavage Fluid; Cytokines; Disease Models, Animal; Female; Inflammation; Interleukin-1; Interleukin-10; Interleukin-6; Interleukin-8; Leukocyte Elastase; Lung; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mesenteric Artery, Superior; Models, Chemical; Oxygen; Peptide Hydrolases; Pulmonary Edema; Respiratory Distress Syndrome; Sepsis; Swine; Tetracycline; Tetracyclines; Time Factors

The immunostimulatory activity of viridans streptococcal strains isolated from neutropenic patients with severe sepsis (n=9) or uncomplicated bacteraemia (n=10) was compared. Peripheral blood mononuclear cells from healthy individuals were stimulated with heat-killed bacteria or culture supernatants, and cytokine production assessed. All strains were potent inducers of IL1beta, IL8, and TNFalpha production. Heat-killed bacteria induced consistently higher IL1beta and TNFalpha production than did the cell-free bacterial supernatants (P<0.01). The strains did not induce any proliferative response, nor any significant TNFbeta or IFNgamma production. No difference in cytokine-inducing capacity could be detected between the cohorts of severe and nonsevere isolates. Comparison of strains causing severe and nonsevere episodes in the same patient (n=2) revealed a significantly higher induction of IL1beta by the severe episodes associated isolates as compared to the nonsevere (P<0.04). The study underscores the importance of the host-pathogen interplay in determining the level of inflammation, and hence the severity of disease.

Topics: Bacteremia; Cells, Cultured; Cytokines; Humans; Inflammation; Interleukin-1; Interleukin-8; Leukocytes, Mononuclear; Neutropenia; Sepsis; Tumor Necrosis Factor-alpha; Viridans Streptococci

This study was performed to evaluate the impact of pro- and anti-inflammatory molecules and human leukocyte antigen DR (HLA-DR) expression as markers of immune status for the final outcome of septic patients. The study included 30 patients with severe sepsis due to community-acquired infections. Concentrations of tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), IL-8, IL-10, and transforming growth factor beta1 (TGF-beta1) in serum, as well as monocyte HLA-DR expression, were determined on admission and on days 3, 10, 13, and 17 during hospitalization. Of the 30 patients enrolled, 13 survived, while 17 died during their hospital stay. All patients had significantly lower HLA-DR expression and higher pro- and anti-inflammatory cytokine levels than healthy individuals. HLA-DR expression was significantly decreased in nonsurvivors at almost all time points. In nonsurvivors, higher levels in serum of TNF-alpha on days 13 and 17; IL-6 levels on day 3; and IL-10 on days 3, 10, and 13 were found. Baseline levels of TGF-beta1 were significantly higher in survivors. Independent risk factors of mortality were IL-10 levels on days 3 and 10, while monocyte HLA-DR expression on admission was a good predictor for survival. Several pro- and anti-inflammatory cytokines are oversynthesized during severe infections, especially in patients with a poor outcome. Monocyte HLA-DR expression is an early and constant predictive marker for survival in severe sepsis, while serum IL-10 levels on days 3 and 10 have negative prognostic value for the final outcome.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Community-Acquired Infections; Cytokines; Female; HLA-DR Antigens; Humans; Interleukin-10; Interleukin-6; Interleukin-8; Male; Middle Aged; Monocytes; Prognosis; Sepsis; Transforming Growth Factor beta; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

This study was undertaken to clarify the effects of propofol on endotoxin-induced acute lung injury. Rabbits were randomly assigned to one of four groups. Each group received intravenous infusion of saline only, saline and Escherichia coli endotoxin, propofol (1 mg/kg bolus, then 5 mg/kg/hr) and endotoxin, or propofol (4 mg/kg bolus, then 20 mg/kg/hr) and endotoxin respectively. Infusion of saline or propofol was started 0.5 hr before the infusion of saline or endotoxin, and continued for 6 hr thereafter. The lungs of rabbits were ventilated with 40% oxygen. Mean blood pressure, heart rate, arterial oxygen tension (PaO2), and peripheral blood leukocyte and platelet count were recorded. The wet/dry (W/D) weight ratio of lung and lung injury score were measured, and analysis of bronchoalveolar lavage fluid (BALF) was done. Endotoxin decreased PaO2, and peripheral blood leukocyte and platelet count. And it increased W/D ratio of lung, lung injury score and leukocyte count, percentage of PMN cells, concentration of albumin, thromboxane B2 and IL-8 in BALF. Propofol attenuated all these changes except the leukocyte count in peripheral blood. In conclusion, propofol attenuated endotoxin-induced acute lung injury in rabbits mainly by inhibiting neutrophil and IL-8 responses, which may play a central role in sepsis-related lung injury.

Topics: Acute Disease; Albumins; Anesthetics, Intravenous; Animals; Blood Platelets; Blood Pressure; Bronchoalveolar Lavage Fluid; Endotoxins; Escherichia coli; Free Radical Scavengers; Interleukin-8; Leukocytes; Lung; Lung Injury; Male; Organ Size; Oxygen; Propofol; Rabbits; Sepsis; Sodium Chloride; Thromboxane B2; Time Factors

Cytokines have been considered as important participants in the post-burn pathophysiological process. The aim of this study was to investigate the course of a proinflammatory cytokine interleukin-8 (IL-8) and an anti-inflammatory cytokine IL-10 in burned patients and whether there was a correlation between mortality and serum levels of these cytokines. Thirty-six acutely burned patients, admitted to Ankara Numune hospital burn unit, entered into the study. A series of serum samples were collected, and serum levels of IL-8 and IL-10 were determined using enzyme-linked immunosorbent assay kit. According to definition utilised, 21 patients developed septic shock and nine of them died. There was no mortality among the 17 non-septic patients. In all 36 patients, there was an increase in serum IL-8 levels, and a peak level was detected shortly after burn injury. The peak IL-8 value of the non-survivors was greater when compared with that of the others. On admission, a significant difference in serum IL-8 values was found between survivors and those who died. In all patients, a peak level of IL-10 was detected between 5 and 9 days of injury. In non-septic survivors, this peak level was less when compared with that of the others. After this peak level, in all patients, serum IL-10 levels showed a decrease, but in non-survivors, a second peak level was detected. A greater understanding of the pathology of the burn sepsis allows rationale use and assessment of current therapies. The results obtained in this study provide useful information on the formulation approaches to this task. Also, IL-8 and IL-10 are prognostic factors in burn sepsis.

Topics: Adult; Burns; Enzyme-Linked Immunosorbent Assay; Female; Humans; Interleukin-10; Interleukin-8; Male; Middle Aged; Prognosis; Sepsis

Pre-B cell colony-enhancing factor (PBEF) is a highly conserved 52-kDa protein, originally identified as a growth factor for early stage B cells. We show here that PBEF is also upregulated in neutrophils by IL-1beta and functions as a novel inhibitor of apoptosis in response to a variety of inflammatory stimuli. Induction of PBEF occurs 5-10 hours after LPS exposure. Prevention of PBEF translation with an antisense oligonucleotide completely abrogates the inhibitory effects of LPS, IL-1, GM-CSF, IL-8, and TNF-alpha on neutrophil apoptosis. Immunoreactive PBEF is detectable in culture supernatants from LPS-stimulated neutrophils, and a recombinant PBEF fusion protein inhibits neutrophil apoptosis. PBEF is also expressed in neutrophils from critically ill patients with sepsis in whom rates of apoptosis are profoundly delayed. Expression occurs at higher levels than those seen in experimental inflammation, and a PBEF antisense oligonucleotide significantly restores the normal kinetics of apoptosis in septic polymorphonuclear neutrophils. Inhibition of apoptosis by PBEF is associated with reduced activity of caspases-8 and -3, but not caspase-9. These data identify PBEF as a novel inflammatory cytokine that plays a requisite role in the delayed neutrophil apoptosis of clinical and experimental sepsis.

Topics: Animals; Apoptosis; Caspases; Cells, Cultured; CHO Cells; Cricetinae; Cricetulus; Culture Media; Cytokines; Gene Expression Regulation; Granulocyte-Macrophage Colony-Stimulating Factor; HL-60 Cells; Humans; Interleukin-1; Interleukin-8; Kinetics; Lipopolysaccharides; Monocytes; Neutrophils; Nicotinamide Phosphoribosyltransferase; Oligonucleotides, Antisense; Recombinant Fusion Proteins; Sepsis; Time Factors; Tumor Necrosis Factor-alpha

The reduced responsiveness of monocytes or granulocytes toward endotoxin (endotoxin tolerance) during sepsis may depend on Toll-like receptors (TLR). The expression of TLR-2 and TLR-4 was measured on neutrophils (PMN) and monocytes from patients with sepsis (n = 21) or healthy controls (n = 12). Leukocytes (1 x 10/mL) were incubated at 37 degrees C with or without a TLR-4 (LPS 1 microg/mL) or a TLR-2 ligand (MALP-2 2 nM). Surface expression of TLR-2 and TLR-4 at 0, 4, and 16 h was determined in FACS after staining with specific antibodies. The release of IL-8 and TNF-alpha was measured by ELISA. Freshly isolated PMN from patients with sepsis exhibited significantly (P < 0.05) higher mean fluorescence for TLR-2 (78.0 +/- 18.6) and TLR-4 (11.4 +/- 2.3) than controls (12.8 +/- 2.2 and 2.3 +/- 0.4). Similarly, monocytes from patients exhibited higher TLR-2 and TLR-4 expression (300.8 +/- 40.6 and 92.7 +/- 12.1) than cells from controls (149.5 +/- 27.1 and 52.2 +/- 7.6). In patients with sepsis, expression of TLR-2 and TLR-4 on PMN increased during 16 h of incubation (106.2 +/- 22.1 and 34.5 +/- 5.3), whereas it remained unchanged in controls (19.3 +/- 6.1 and 5.4 +/- 1.9). Incubation with LPS or MALP-2 had no effect on TLR-4 or TLR-2 expression in cells from either controls or patients. Despite increased TLR expression in cells from patients with sepsis, the endotoxin-induced release of TNF-alpha and IL-8 was indistinguishable from that in controls. Therefore, the endotoxin tolerance seen in patients with sepsis does not depend solely on TLR-2 or TLR-4 expression, and other mechanisms must be involved.

Topics: Adult; Aged; Cell Separation; Cytokines; Endotoxins; Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; Humans; Interleukin-8; Leukocytes; Leukocytes, Mononuclear; Ligands; Male; Membrane Glycoproteins; Middle Aged; Monocytes; Neutrophils; Receptors, Cell Surface; Sepsis; Time Factors; Toll-Like Receptor 2; Toll-Like Receptor 4; Toll-Like Receptors; Tumor Necrosis Factor-alpha

This study was conducted on thirty-seven neonates and healthy neonates (sixteen full term and fourteen preterm). The study aimed at revealing the role played by the NK cells in neonatal sepsis and evaluating the sensitivity of NK cell number and cytotoxicity as diagnostic markers in infants with suspected early neonatal sepsis compared with the circulating cytokine IL-8 and CRP levels. All samples of peripheral blood lymphocytes were subjected to determination of CD16 and CD56 positive cells using flow cytometry and NK cytotoxicity using the standard 4h 51Cr release assay. Sera were separated to measure IL-8 using ELISA. Determination of CRP, using turbdimetric assay, as well as blood cultures were done for patient's group only. Out of the 37 cases of suspected early neonatal sepsis, 16 were given final diagnosis of sepsis. Seven infants (43.8%) in the sepsis group had culture-proven diagnosis, one of which had meningitis. The median CRP value was significantly higher in sepsis group (88 mg/L; range: 17-159 mg/L) compared with that in non-septic group (15.4 mg/L; range: 7.6-23.2 mg/L, p < 0.001) only 12-60 h after admission. On the other hand, newborns in the sepsis group had significantly higher serum levels of IL-8 (median 310 pg/mL; range: 37-583 pg/ml) at study entry than that in the non septic group (median 63 pg/mL; range: 32-94 pg/ml, P < 0.001). On admission, the NK activity, rather than the number of CD16 and CD56 positive cells was much affected where NK cytotoxicity was significantly lower in sepsis group (3.4 +/- 2.1%, range 0.9-7%) than that of the nonseptic group (18.3 +/- 6.7%: range 10.7- 25.3%, p < 0.01) and healthy neonates (23.8 +/- 4.7%: range 12.2-32.3%, p < 0.001). We may conclude that defective NK cell activity rather than NK cell number plays an important role in susceptibility to early onset neonatal sepsis. Evaluation of NK cytotoxicity as a marker in early diagnosis of neonatal sepsis reveals that the sensitivity, specificity and predictive values of reduced NK cytotoxicity (10% killing) was higher than both of CRP and IL-8, either individually or in combination. Additionally, reduced NK cytotoxicity showed high correlation with the severity and outcome of neonatal sepsis. Our data raise the possibility that the addition of NK cell activity to the standard work-up of critically ill patients with suspected sepsis could increase diagnostic certainty and generate an improved patient management.

Topics: Bacteremia; Biomarkers; C-Reactive Protein; CD56 Antigen; Cytotoxicity Tests, Immunologic; Cytotoxicity, Immunologic; Female; Flow Cytometry; Gestational Age; Humans; Infant, Newborn; Infant, Premature; Interleukin-8; Killer Cells, Natural; Leukocyte Count; Male; Neutropenia; Predictive Value of Tests; Receptors, IgG; Sensitivity and Specificity; Sepsis

Ubiquitin is suggested to play a key role in essential intracellular functions, such as heat shock response, protein breakdown, and regulation of immune responses. Ubiquitin has also been detected in the extracellular space, but the function and biologic significance is unclear. We describe a new function of extracellular ubiquitin and show that extracellular ubiquitin specifically inhibits ex vivo secretion of tumor necrosis factor-alpha (TNF-alpha) and TNF-alpha mRNA expression from peripheral blood mononuclear cells (PBMNCs) in response to endotoxin in a dose-dependent manner. In contrast, the TNF-alpha response to zymosan or Staphylococcus aureus as well as the interleukin-6 (IL-6) and IL-8 responses to endotoxin were unaffected by ubiquitin. Measurement of serum ubiquitin levels showed a significant 5- to 7-fold increase in sepsis and trauma patients, to the level required for inhibition of the PBMNC TNF-alpha response to endotoxin by ubiquitin. Elevated ubiquitin levels in serum were significantly correlated with a reduced TNF-alpha production. Antibodies to ubiquitin were able to (1) significantly increase (2- to 5-fold) the TNF-alpha response to endotoxin in whole blood from trauma and sepsis patients, (2) completely neutralize the inhibitory effect of trauma patients' serum on healthy donors' TNF-alpha production, and (3) partially neutralize the inhibitory effect of sepsis patients' serum on healthy donors' TNF-alpha production. Ubiquitin-depleted serum from trauma patients lost the inhibitory activity for TNF-alpha production, whereas extracted endogenous ubiquitin exerts the inhibitory activity. The results demonstrate that extracellular ubiquitin acts as a cytokinelike protein with anti-inflammatory properties and indicate that extracellular ubiquitin is involved in the regulation of immunodepression in critical illness.

Topics: Adult; Animals; Cattle; Cells, Cultured; Critical Illness; Depression, Chemical; Endotoxins; Female; Gene Expression Regulation; Humans; Interleukin-6; Interleukin-8; Leukocytes, Mononuclear; Lipopolysaccharides; Male; Multiple Trauma; RNA, Messenger; Sepsis; Shock, Septic; Tumor Necrosis Factor-alpha; Ubiquitin; Wounds, Nonpenetrating

Endotoxin not only activates the Toll-mediated signaling pathway within endothelial cells that leads to neutrophil migration but also causes the polymerization of microtubules. The potential role of this polymerization event, however, is unknown.. Human umbilical vein endothelial cells stimulated with endotoxin were pretreated with or without the microtubule depolymerizing agent colchicine. Toll-mediated signaling events and protein production were in turn investigated by Western blot, gel shift, and enzyme-linked immunosorbent assay. Finally, neutrophil adhesion was assayed fluorometrically under the various conditions.. Endotoxin led to activation of the various Toll-mediated pathways, production of intercellular adhesion molecule-1 and interleukin-8, and subsequent neutrophil adhesion. Pretreatment with colchicine led to selective inhibition of anti-dual phosphorylated extracellular signal-regulated kinase-1/2, anti-dual phosphorylated c-jun N-terminal kinase, and adaptor protein-1; selective enhancement of p38; and no effect on nuclear factor-kappaB. This selective modulation of intracellular signaling resulted in attenuated intercellular adhesion molecule-1, interleukin-8 and prostaglandin E2 production, but enhanced cyclooxygenase-2 expression. As a result, microtubule disruption led to a significant reduction in neutrophil adhesion.. Microtubule formation is essential to optimal endotoxin-induced intracellular signaling through anti-dual phosphorylated extracellular signal-regulated kinase-1/2, anti-dual phosphorylated c-jun N-terminal kinase, and adaptor protein-1. Failure of these signaling events is associated with a marked reduction in the formation of a proadhesive phenotype that may prove to be beneficial in modulating neutrophil recruitment during sepsis.

Topics: Adaptor Protein Complex 1; Blotting, Western; Cells, Cultured; Colchicine; Cyclooxygenase 2; Dinoprostone; Drosophila Proteins; Electrophoretic Mobility Shift Assay; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Escherichia coli; Humans; Intercellular Adhesion Molecule-1; Interleukin-8; Isoenzymes; JNK Mitogen-Activated Protein Kinases; Lipopolysaccharides; Membrane Glycoproteins; Membrane Proteins; Microtubules; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; Neutrophil Activation; Neutrophil Infiltration; NF-kappa B; Polymers; Prostaglandin-Endoperoxide Synthases; Receptors, Cell Surface; Sepsis; Signal Transduction; Toll-Like Receptors; Umbilical Veins

Flagellin is a recently identified bacterial product that elicits immune response via toll-like receptor 5. Here, we demonstrate that flagellin is an extraordinarily potent proinflammatory stimulus in the lung during sepsis. In vitro, flagellin triggers the production of interleukin (IL)-8 by human lung epithelial (A549) cells, with 50% of the maximal response obtained at a concentration of 2 x 10(-14) M. Flagellin also induces the expression of ICAM-1 in vitro. Intravenous administration of flagellin to mice elicited a severe acute lung inflammation that was significantly more pronounced than following lipopolysaccharide (LPS) administration. Flagellin induced a local release of proinflammatory cytokines, the accumulation of inflammatory cells, and the development of pulmonary hyperpermeability. These effects were associated with the nuclear translocation of the transcription NF-kappaB in the lung. Flagellin remained active in inducing pulmonary inflammation at doses as low as 10 ng/mouse. In the plasma of patients with sepsis, flagellin levels amounted to 7.1 +/- 0.1 ng/mL. Plasma flagellin levels showed a significant positive correlation with the lung injury score, with the alveolar-arterial oxygen difference as well as with the duration of the sepsis. Flagellin emerges as a potent trigger of acute respiratory complications in gram-negative bacterial sepsis.

Topics: Active Transport, Cell Nucleus; Animals; Cells, Cultured; Chemokine CCL4; Chemokine CXCL2; Chemokines; Dose-Response Relationship, Drug; Flagellin; Gram-Negative Bacteria; Humans; Inflammation; Interleukin-1; Interleukin-8; Lipopolysaccharides; Lung; Macrophage Inflammatory Proteins; Male; Mice; Mice, Inbred BALB C; Monokines; Neutrophils; NF-kappa B; Nitric Oxide; Salmonella; Sepsis; Time Factors; Tumor Cells, Cultured

To investigate whether the serum levels of interleukin-1beta, 6, 8, tumour necrosis factor-alpha and the soluble receptor of IL-2 are useful in the diagnosis of neonatal sepsis, and whether their diagnostic power is increased when in combination with classical markers such as C-reactive protein and white blood cell count.. Blood samples were collected at admission from 40 neonates with suspected infection. Patients were included in different groups according to the bacteriological and laboratory results: Group I consisted of 20 newborns with positive blood cultures and other biological tests suggestive of infection. Group II included 20 neonates with negative blood cultures and biological tests not suggestive of infection. The control group included 20 healthy neonates with no clinical or biological data of infection.. Mean values of C-reactive protein were significantly higher in Group I. No differences were found between the groups for white blood cell count, with the exception of the presence of leucocytosis in Group II. Levels of interleukin-1beta, 6, 8, tumour necrosis factor-alpha, soluble receptor of interleukin-2, and C-reactive protein were significantly higher in infected neonates than in the control groups. Detection sensitivity and specificity were 80 and 92% for C-reactive protein, 60 and 87% for interleukin-1beta, 61 and 80% for interleukin-6, 62 and 96% for interleukin-8, 54 and 92% for tumour necrosis factor-alpha and 63 and 94% for soluble receptor of interleukin-2. The discriminant analysis showed that the best combination for sepsis diagnosis was C-reactive protein + interleukin-8 + soluble receptor of interleukin-2, with a sensitivity of 85% and a specificity of 97.1%.. Our study suggests that no individual test can on its own identify infected neonates, and that although the combination of C-reactive protein, interleukin-8 and the soluble receptor of interleukin-2 exhibits a high specificity, its sensitivity is limited.

Topics: Antineoplastic Agents; C-Reactive Protein; Female; Humans; Infant, Newborn; Interleukin-1; Interleukin-6; Interleukin-8; Leukocyte Count; Male; Receptors, Interleukin-2; Reproducibility of Results; Sensitivity and Specificity; Sepsis; Tumor Necrosis Factor-alpha

Blockade of tissue factor before lethal sepsis prevents acute lung injury and renal failure in baboons, indicating that activation of coagulation by tissue factor is an early event in the pathogenesis of acute lung injury and organ dysfunction. We hypothesized that blockade of tissue factor would also attenuate these injuries in established sepsis by prevention of further fibrin deposition and inflammation. Twelve male baboons received heat-killed Escherichia coli intravenously followed 12 hours later by live E. coli infusion. Six animals were treated 2 hours after the live bacteria with site-inactivated Factor VIIa, a competitive tissue factor inhibitor, and six animals were vehicle-treated sepsis control subjects. Animals were ventilated and monitored for 48 hours. Physiologic and hematologic parameters were measured every 6 hours, and pathologic evaluation was performed after 48 hours. Animals treated with site inactivated Factor VIIa had less severe lung injury, with preserved gas exchange, better lung compliance and histology scores, and decreased lung wet/dry weight. In treated animals, urine output was higher, metabolic acidosis was attenuated, and renal tubular architecture was protected. Coagulopathy was attenuated, and plasma interleukin-6, interleukin-8, and soluble tumor necrosis factor receptor-1 levels were significantly lower in the treated animals. These results show that blockade of coagulation attenuates acute lung and renal injury in established Gram-negative sepsis accompanied by antiinflammatory effects of therapy.

Topics: Acute Kidney Injury; Animals; Antigens, CD; Cytokines; Disease Models, Animal; Drug Monitoring; Escherichia coli Infections; Factor VIIa; Hemodynamics; Inflammation; Interleukin-6; Interleukin-8; Lung Compliance; Male; Papio; Pulmonary Gas Exchange; Receptors, Tumor Necrosis Factor; Receptors, Tumor Necrosis Factor, Type I; Respiratory Distress Syndrome; Sepsis; Severity of Illness Index; Thromboplastin

Forty patients with severe sepsis or septic shock recently received C1 inhibitor. In the present study we studied the effect of C1 inhibitor therapy on circulating elastase-alpha(1)-antitrypsin complex (EA) and lactoferrin (LF) levels in these patients to gain further insight about agonists involved in the activation of neutrophils in human sepsis. Elevated levels of EA and LF were found in 65 and 85% of the septic patients, respectively. Patients with elevated EA levels had higher organ dysfunction scores, higher levels of cytokines, and higher levels of complement activation products than patients with normal EA levels. C1 inhibitor therapy reduced EA as well as complement activation and IL-8 release in the patients with elevated EA on admission. We conclude that neutrophil activation in human sepsis correlates with the severity of organ dysfunction and involves complement and interleukin-8 as agonists. The effect of C1 inhibitor therapy on neutrophils may provide an explanation for the beneficial, although mild, effects of this treatment on organ dysfunction in sepsis.

Topics: Adult; Aged; alpha 1-Antitrypsin; Biomarkers; Complement Activation; Complement C1 Inactivator Proteins; Complement C1 Inhibitor Protein; Cytokines; Female; Humans; Interleukin-8; Lactoferrin; Leukocyte Elastase; Male; Middle Aged; Multiple Organ Failure; Neutrophils; Sepsis; Serpins; Shock, Septic

Toll-like receptors (TLR) play a pivotal role in the innate immune response, and the expression levels of these receptors may reflect the sensitivity of immune cells to infections. The binding of lipopolysaccharide (LPS) to TLR-4 triggers human monocytes to produce cytokines, which play a dominant role in the inflammatory response, as can be observed during sepsis and after polytrauma. Here, we evaluated TLR-4 expression of isolated monocytes in the presence of tumor necrosis factor (TNF)-alpha, interleukin (IL) 6, IL-8, and IL-10, and we investigated cellular activation of this treatment. TNF-alpha significantly down-regulated TLR-4 mRNA expression after 6 h (100% vs. 38.5% +/- 4%; P < 0.05). This down-regulation was followed by a dose- and time-dependent diminished expression of TLR-4 surface protein (100% vs. 8.0% +/- 5%; P < 0.01). Forty-eight hours after TNF-alpha treatment, a reduced nuclear factor (NF)-kappaB translocation and a diminished IL-6 secretion after LPS stimulation were found (100% vs. 42.0% +/- 23%; P < 0.05). In contrast, IL-6 incubation upregulated TLR-4 cell surface protein (100% vs. 165.8% +/- 24%; P < 0.05) and increased the ability to activate NF-kappaB and AP-1 after LPS stimulation. Stimulation with IL-8 or IL-10 had no significant effects. We conclude that not only LPS but also TNF-alpha and IL-6 have the potency to regulate the immune response via TLR-4. Down-regulation of TLR-4 by TNF-alpha is associated with LPS hyporeactivity for NF-kappaB formation, whereas upregulation of TLR-4 via IL-6 can increase the responsiveness of mononuclear phagocytes.

Topics: Biological Transport; Cell Nucleus; Cells, Cultured; Cytokines; DNA; DNA, Complementary; Dose-Response Relationship, Drug; Down-Regulation; Flow Cytometry; Humans; Inflammation; Interleukin-10; Interleukin-6; Interleukin-8; Leukocytes, Mononuclear; Lipopolysaccharides; Membrane Glycoproteins; Monocytes; NF-kappa B; Phagocytes; Protein Binding; Receptors, Cell Surface; Reverse Transcriptase Polymerase Chain Reaction; RNA; RNA, Messenger; Sepsis; Time Factors; Toll-Like Receptor 4; Toll-Like Receptors; Tumor Necrosis Factor-alpha

Some mediators of inflammation are associated with sepsis, involving nervous system. Proinflammatory cytokines, TNF-alpha, IL-6, and IL-8, and procalcitonin (PCT), proinflammatory protein, were investigated in patients with neurologic complications in sepsis. TNF-alpha, IL-6, IL-8, and PCT were prospectively investigated in 62 patients with neurologic complications in sepsis. TNF-alpha and IL-6 were studied both in serum as in the CSF, IL-8 and PCT were studied only in serum. TNF-alpha, IL-6, and IL-8 were studied by ELISA (R & D Systems), and the PCT by immunoluminometric assay (BRAHMS). Mean value of TNF-alpha in serum was 578+/-214 pg/ml, and in CSF was 458+/-167 pg/ml (p<0.01). Mean value of IL-6 in serum was 749+/-213 pg/ml, and in CSF was 617.5+/-182 pg/ml (p<0.01). Mean value of IL-8 in serum was 332+/-196 pg/ml (p<0.01). Mean value of PCT in serum was 80+/-16 ng/ml (p<0.01). The investigated parameters do not permit the identifying of cases with neurologic complications. The increased correlation coefficient between cytokines in serum and in CSF suggests the damage of the blood-brain barrier. The raise of PCT in serum, induced by TNF-alpha and IL-6, is an argument of the severity of sepsis.

Topics: Aged; Calcitonin; Calcitonin Gene-Related Peptide; Female; Humans; Interleukin-6; Interleukin-8; Male; Nervous System Diseases; Protein Precursors; Sepsis; Tumor Necrosis Factor-alpha

To analyze the effect of cytokines generated in sepsis and endotoxemia (tumor necrosis factor [TNF]-alpha and interleukins [IL]-1beta, -6, and -8) on activation of human platelets and to study the effect of cytokines on platelet activation in the presence of alpha-thrombin, a potent inducer of coagulation and platelet activation generated in sepsis and endotoxemia.. flow cytometric study of platelet activation induced by cytokines and/or thrombin in the whole blood and platelet-rich plasma (PRP) of healthy volunteers.. Research laboratory in a Canadian hospital.. Nine healthy volunteers recruited from laboratory staff.. Venous blood samples were obtained into acid-citrate-dextrose anticoagulant. Whole blood and PRP were diluted with appropriate buffer optimized for analyzing platelet activation by flow cytometry. TNF-alpha, IL-1beta, IL-6, and IL-8 were added to blood or PRP in concentrations ranging from 1 to 100 ng/mL and incubated for 15 mins at 37 degrees C in the presence or absence of a submaximal concentration of human alpha-thrombin (0.025 units/mL). Samples were stained with fluorescent antibodies against markers of platelet activation (P-selectin [CD62], lysosomal protein [CD63], and fibrinogen and von Willebrand factor receptors [CD41 and CD42b, respectively]) and analyzed by flow cytometry. The data obtained show that none of these cytokines trigger activation of resting platelets in whole blood or PRP and do not modulate the effect of thrombin on platelet activation as measured by quantitation of CD62, CD63, and CD42b markers on the platelet surface.. Cytokines TNF-alpha, IL-1beta, IL-6, and IL-8, which are extensively produced in sepsis and endotoxemia, do not trigger activation of resting human platelets directly or indirectly by mediating processes in white or red blood cells. The cytokines did not affect thrombin-induced platelet activation.

Topics: Cytokines; Endotoxemia; Flow Cytometry; Humans; In Vitro Techniques; Interleukin-1; Interleukin-6; Interleukin-8; Platelet Activation; Sepsis; Statistics, Nonparametric; Tumor Necrosis Factor-alpha

Staphylococcus aureus alpha-toxin is a pore-forming bacterial exotoxin that has been implicated as a significant virulence factor in human staphylococcal diseases. In primary cultures of rat pneumocyte type II cells and the human A549 alveolar epithelial cell line, purified alpha-toxin provoked rapid-onset phosphatidylinositol (PtdIns) hydrolysis as well as liberation of nitric oxide and the prostanoids PGE(2), PGI(2), and thromboxane A(2). In addition, sustained upregulation of proinflammatory interleukin (IL)-8 mRNA expression and protein secretion occurred. "Priming" with low-dose IL-1beta markedly enhanced the IL-8 response to alpha-toxin, which was then accompanied by IL-6 appearance. The cytokine response was blocked by the intracellular Ca(2+)-chelating reagent 1,2-bis(2-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid, the protein kinase C inhibitor bis-indolyl maleimide I, as well as two independent inhibitors of nuclear factor-kappaB activation, pyrrolidine dithiocarbamate and caffeic acid phenethyl ester. We conclude that alveolar epithelial cells are highly reactive target cells of staphylococcal alpha-toxin. alpha-Toxin pore-associated transmembrane Ca(2+) flux and PtdIns hydrolysis-related signaling with downstream activation of protein kinase C and nuclear translocation of nuclear factor-kappaB are suggested to represent important underlying mechanisms. Such reactivity of the alveolar epithelial cells may be relevant for pathogenic sequelae in staphylococcal lung disease.

Topics: Animals; Bacterial Toxins; Cell Line; Epithelial Cells; Granulocyte-Macrophage Colony-Stimulating Factor; Hemolysin Proteins; Inflammation Mediators; Inositol Phosphates; Interleukin-6; Interleukin-8; Male; Pneumonia; Pulmonary Alveoli; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sepsis; Signal Transduction; Staphylococcus aureus

Neonatal bacterial sepsis is often characterized by a fulminant clinical course and highly elevated plasma levels of proinflammatory cytokines. To evaluate in vitro activation of the neonatal immune system by specific infectious stimuli, cord blood cells from healthy neonates were examined for expression of tumor necrosis factor-alpha (TNF-alpha), IL-1beta, IL-6, and IL-8 in response to Streptococcus agalactiae (GBS), lipopolysaccharide (LPS), and lipoteichoic acid (LTA). Cytokine-expression was compared in mononuclear cells from cord and adult peripheral blood. TNF-alpha and IL-6 levels in the supernatant of cord blood cell cultures were significantly higher after stimulation with heat-killed GBS (10(7)/mL) than with LPS (2 microg/mL) or LTA (2 microg/mL) (TNF-alpha: 2215 versus 267.5 versus 40 pg/mL, p = 0.001; IL-6: 9667 versus 4909 versus 919 pg/mL, p = 0.006). mRNA expression of TNF-alpha, IL-1beta, IL-6, and IL-8 was equally pronounced after stimulation with either GBS, LPS, or LTA in cord or adult blood cells at various times. A MAb directed against the monocyte receptor molecule CD14 did not inhibit the release of cytokines in cord blood mononuclear cells after stimulation with GBS. In summary, activation of cord blood cells by infectious stimuli is comparable to the adult immune response in terms of expression of proinflammatory cytokines. GBS in particular proves to be a potent activator of the neonatal immune system when compared with LPS and LTA. CD14 seems not to be a crucial molecule for activation of cord blood cells by GBS.

Topics: Adult; Age Factors; Antibodies, Monoclonal; Fetal Blood; Gene Expression; Humans; In Vitro Techniques; Infant, Newborn; Interferon-gamma; Interleukin-1; Interleukin-6; Interleukin-8; Leukocytes, Mononuclear; Lipopolysaccharide Receptors; Lipopolysaccharides; RNA, Messenger; Sepsis; Streptococcal Infections; Streptococcus agalactiae; Tumor Necrosis Factor-alpha

There is growing evidence that sepsis-related complications in neonates are crucially mediated by the action of proinflammatory cytokines. It has previously been demonstrated that elevated IL-6 and IL-8 levels can predict brain damage and chronic lung disease in preterm infants. However, it is the current view that neonates have a reduced capability to produce proinflammatory cytokines. To clarify this issue, we analyzed the inflammatory response in term and preterm infants directly at the single cell level by flow cytometry. Endotoxin challenge was performed under defined conditions on monocytes obtained from 50 healthy adults and 119 neonates, which consist of 45 term infants, 63 preterm infants (26.1-36.7 wk of gestational age), and 11 preterm infants with proven infection (24.6-29.9 wk). Our results challenge the existing view of an immature inflammatory response by demonstrating that term infants and preterm infants display a higher percentage of IL-6- and IL-8-positive cells than adults. After preincubation with dexamethasone the number of cytokine-positive cells decreased in all groups, but the number of IL-8-positive cells remained higher in term and preterm infants >32 wk compared with adults. These observations demonstrate not only a well-developed but also an enhanced inflammatory response in term and preterm infants. Under consideration of several detrimental effects of IL-6 and IL-8, our data may have major implications on the pathophysiology of inflammatory-triggered neonatal diseases.

Topics: Adrenal Cortex Hormones; Adult; Cells, Cultured; Dexamethasone; Female; Flow Cytometry; Glucocorticoids; Humans; Infant, Newborn; Infant, Premature; Interleukin-6; Interleukin-8; Male; Monocytes; Sepsis

Topics: Animals; Interleukin-1; Interleukin-8; Janus Kinase 1; Protein-Tyrosine Kinases; Sepsis; Signal Transduction; Tumor Necrosis Factor-alpha

Extracorporeal circulation, such as cardiopulmonary bypass and hemodialysis, has been associated with an activation of the immune system. Continuous veno venous hemodiafiltration (CVVHD) is used in critically ill septic patients. During CVVHD, cytokines are excreted in ultrafiltrate. When the membranes, used in CVVHD, are incubated with leukocytes in vitro a slight production of cytokines is observed. Due to the underlying disease it is difficult to investigate the effect of CVVHD in septic patients. We therefore studied the separate effect of CVVHD on the chemotaxis of granulocytes, the proliferation of lymphocytes and the release of IL-8 and IL-10 in healthy pigs compared to an endotoxin and a control group.. Thirty-one pigs were anesthetized and mechanically ventilated. CVVHD was performed in 10 pigs. Eleven pigs received an infusion of Escherichia coli endotoxin 30 microg/kg, and 10 pigs served as a control group. The chemotaxis of granulocytes was measured in an assay chamber, and the cytokines IL-8 and IL-10 with an enzyme-linked immunosorbent assay. The adhesion molecules CD18 and CD62 on lymphocytes were measured using monoclonal antibodies, and the lymphocyte proliferation was measured without stimulation and in response to mitogens.. CVVHD was accompanied by lymphocytopenia and increased spontaneous lymphoproliferative response, but no change in adhesion molecules on lymphocytes or cytokine levels in plasma, and no decrease in the chemotaxis of granulocytes. Following endotoxin we observed a pronounced lymphocytopenia and an increased secretion of IL-8 and IL-10, a decrease in the expression of CD18 on lymphocytes and in the stimulated lymphocyte proliferation and in the chemotaxis of granulocytes.. CVVHD does not, in contrast to endotoxin-induced sepsis, influence chemotaxis of granulocytes, the production of IL-8 and IL-10 or the proliferation of lymphocytes.

Topics: Animals; CD18 Antigens; Chemotaxis, Leukocyte; Endotoxins; Granulocytes; Hemodiafiltration; Interleukin-10; Interleukin-8; Lymphocyte Activation; Male; Sepsis; Swine

To assess neutrophil CD11b and circulating interleukin 8 (IL-8) as markers of early-onset infection in neonates.. The study comprised 39 neonates, with a gestational age of 29 to 41 weeks, suspected of infection within 48 hours of life. Neutrophil surface expression of CD11b was quantified with flow cytometry and plasma IL-8 with an enzyme-linked immunosorbent assay. Both data were available from 35 of 39 neonates. Serum C-reactive protein was determined at initial evaluation and, later, on the basis of the clinical picture. Neonates were allocated retrospectively into 2 groups. In the sepsis group (N = 22), 4 had culture-proven sepsis, and 14 had an antenatal risk factor for infection. In the possible-infection group (N = 13), each neonate had a noninfective disorder, but co-occurring infection remained a possibility. Twelve healthy term infants served as controls.. CD11b expression and IL-8 levels both increased in order of sepsis > possible infection > healthy. Sensitivity and specificity by the CD11b test for sepsis were equal, at 1.00, and those by the IL-8 test 0.91 and 1.00, respectively; 6 (17.1%) of the 35 neonates had CD11b and IL-8 below cutoff levels.. Measuring neutrophil CD11b expression and circulating IL-8 provides a means to identify early-onset neonatal sepsis. The findings may be helpful in planning strategies to safely reduce the use of antimicrobials in neonates.

Topics: Biomarkers; CD11 Antigens; Humans; Infant, Newborn; Interleukin-8; Neutrophils; Predictive Value of Tests; Prospective Studies; Sensitivity and Specificity; Sepsis; Time Factors

Monitoring of peritoneal cytokine concentrations of tumor necrosis factor (TNF)-alpha was recommended for early detection of severe postoperative complications. In the present study the clinical application of cytokine monitoring was examined in the treatment course of severe peritonitis.. Nineteen patients with secondary peritonitis were followed up during 75 abdominal lavages. Serum and peritoneal interleukin (IL)-6, IL-8, and IL-10 and TNF-alpha were measured before the surgical intervention, after 1 hour, 3 hours, 6 hours, and 24 hours. Additionally, cardiorespiratory parameters, osmolarity, C-reactive protein, and total leucocyte count were recorded.. Serum and peritoneal cytokine concentrations did not correlate to each other as well as to the observed cardiorespiratory parameters. Peritoneal cytokine concentrations were 10- to 1000-fold higher to serum concentrations and showed an intermittent wash out. There were no differences in determined cytokine concentrations between survivors and nonsurvivors.. Once elevated, peritoneal cytokine measurements offer no new diagnostic or prognostic tool in abdominal lavage peritonitis treatment.

Topics: Ascitic Fluid; Biomarkers; Blood Pressure; C-Reactive Protein; Cytokines; Female; Humans; Interleukin-10; Interleukin-6; Interleukin-8; Leukocyte Count; Male; Oxygen; Peritoneal Lavage; Peritonitis; Postoperative Complications; Sepsis; Survival Rate; Tumor Necrosis Factor-alpha; Vasoconstrictor Agents

To study whether early-onset neonatal sepsis is associated with a prenatal immune response with elevated umbilical plasma levels of inflammatory mediators, and to study whether mediator levels may be helpful in identifying infected neonates.. Nested case-control study.. Cord blood was sampled from 7,073 consecutively delivered neonates. After review of the medical records, neonates suspected to suffer from infection were classified as infected (n = 52) or noninfected but sick controls (n = 33). We also included a group of healthy controls (n = 99). Umbilical plasma levels of tumour necrosis factor-alpha (TNFalpha), interleukin (IL)-1beta, IL-6, IL-8, soluble TNF receptors (p55 and p75), IL-1 receptor antagonist (IL-1RA) and C-reactive protein were measured by immunoassays.. Infected neonates had higher levels of TNFalpha, IL-1beta, IL-6, IL-8, p55, p75 and IL-1RA than healthy controls (all p < 0.01). Among preterm infants (GA <37 weeks), those with infection (n = 11) had higher levels of IL-1beta, IL-6, IL-8, p55 and p75 than noninfected sick controls (n = 13) (all p < 0.05), but among term infants, the infected did not differ from the noninfected sick controls. Receiver operator characteristic plots showed that IL-1beta, IL-6 and IL-8 identified preterm infected neonates accurately.. Early-onset neonatal sepsis is associated with a prenatal immune response with increased TNFalpha, IL-1beta, IL-6, IL-8, p55, p75 and IL-1RA levels in umbilical plasma. Among neonates who present symptoms suggestive of infection, cytokine levels may be helpful in identifying preterm, but not term infected individuals.

Topics: C-Reactive Protein; Case-Control Studies; Female; Fetal Blood; Gestational Age; Humans; Infant, Newborn; Inflammation Mediators; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Interleukin-6; Interleukin-8; Male; Receptors, Tumor Necrosis Factor; ROC Curve; Sensitivity and Specificity; Sepsis; Sialoglycoproteins; Tumor Necrosis Factor-alpha

To assess the diagnostic value of procalcitonin (PCT), interleukin (IL)-6, IL-8, and standard measurements in identifying critically ill patients with sepsis, we performed prospective measurements in 78 consecutive patients admitted with acute systemic inflammatory response syndrome (SIRS) and suspected infection. We estimated the relevance of the different parameters by using multivariable regression modeling, likelihood-ratio tests, and area under the receiver operating characteristic curves (AUC). The final diagnosis was SIRS in 18 patients, sepsis in 14, severe sepsis in 21, and septic shock in 25. PCT yielded the highest discriminative value, with an AUC of 0.92 (CI, 0.85 to 1.0), followed by IL-6 (0.75; CI, 0.63 to 0.87), and IL-8 (0.71; CI, 0.59 to 0.83; p < 0.001). At a cutoff of 1.1 ng/ml, PCT yielded a sensitivity of 97% and a specificity of 78% to differentiate patients with SIRS from those with sepsis-related conditions. Median PCT concentrations on admission (ng/ ml, range) were 0.6 (0 to 5.3) for SIRS; 3.5 (0.4 to 6.7) for sepsis; 6.2 (2.2 to 85) for severe sepsis; and 21.3 (1.2 to 654) for septic shock (p < 0.001). The addition of PCT to a model based solely on standard indicators improved the predictive power of detecting sepsis (likelihood ratio test; p = 0.001) and increased the AUC value for the routine value-based model from 0.77 (CI, 0.64 to 0.89) to 0.94 (CI, 0.89 to 0.99; p = 0.002). In contrast, no additive effect was seen for IL-6 (p = 0.56) or IL-8 (p = 0.14). Elevated PCT concentrations appear to be a promising indicator of sepsis in newly admitted, critically ill patients capable of complementing clinical signs and routine laboratory parameters suggestive of severe infection.

Topics: Adult; Area Under Curve; Biomarkers; Calcitonin; Calcitonin Gene-Related Peptide; Critical Care; Diagnosis, Differential; Female; Humans; Interleukin-6; Interleukin-8; Male; Predictive Value of Tests; Prospective Studies; Protein Precursors; Regression Analysis; Sensitivity and Specificity; Sepsis

Cytokine plasma levels are suggested to be sensitive indicators of neonatal sepsis, but conventional assays are time consuming. This study aimed at evaluating the significance of cord blood levels of interleukin (IL)-6 and IL-8 determined by a fully automated random access assay within 90 min of admission to predict systemic bacterial infection.. Cord blood levels of IL-6 and IL-8 were determined in 71 mature and 100 premature infants by a chemiluminescence assay (Immulite). Patients were divided into four groups according to a clinical and laboratory scoring system. Group A: documented early-onset infection; group B: infection possible; group C: infection unlikely, and group D: healthy newborns.. Median IL-6 levels in the subgroup of premature newborns were as follows: group A, 1,920 pg/ml (5-95% confidence interval 308-4,660 pg/ml); group B, 50 (15-102) pg/ml; group C, 21 (12-71) pg/ml, and group D, 8 (6-11) pg/ml. For IL-8, median levels for groups A-D were 289 (226-514) pg/ml, 87 (40-107) pg/ml, 44 (33-98) pg/ml and 21 (16-25) pg/ml, respectively. The difference between group A and the other groups was highly significant (IL-6 p < 0.0001, IL-8 p < 0.001). At a cut-off of 80 pg/ml, the sensitivity of IL-6 for the diagnosis of sepsis was 96% (specificity 95%). For IL-8 (cut-off 90 pg/ml), the sensitivity was 87% (specificity 94%).. In premature infants, the diagnosis of an early-onset infection can be established or ruled out with a high level of confidence by measuring IL-6 or IL-8 levels from cord blood using a random access chemiluminescence assay.

Topics: Apgar Score; C-Reactive Protein; Female; Fetal Blood; Fetal Membranes, Premature Rupture; Gestational Age; Humans; Infant, Newborn; Infant, Premature; Interleukin-6; Interleukin-8; Male; Pregnancy; Sensitivity and Specificity; Sepsis

We studied 174 patients with SIRS criteria, 45 with sepsis, eight with severe sepsis and 13 with septic shock. Serum TNF-alpha, IL-6, IL-8 and IL-10 levels were raised in SIRS patients, even in those cases in which an infection could not be documented, and more intensely in severe sepsis and in patients who died (11%). The slope of the regression line between IL-10 and TNF-alpha was sharper in patients with severe sepsis and in those who died; an imbalance between pro- and anti-inflammatory cytokines may be related to poor prognosis. Increased IL-6 and IL-10, decreased muscle mass, raised BUN and low body temperature were all independently related to prognosis.

Topics: Age Factors; Aged; Body Temperature; Cytokines; Female; Humans; Inflammation; Interleukin-10; Interleukin-6; Interleukin-8; Kinetics; Male; Middle Aged; Muscles; Prognosis; Sepsis; Shock, Septic; Treatment Outcome; Tumor Necrosis Factor-alpha

To evaluate the diagnostic value of peripheral circulatory reactive hyperemia and serum levels of interleukin-6 (IL-6), IL-8, and tumor necrosis factor-alpha (TNF-alpha) in early-onset neonatal sepsis.. Reactive hyperemia in the dorsal hand and serum levels of IL-6, IL-8, and TNF-alpha were studied in newborn infants (n = 32; gestational age 39 +/- 3 weeks) who had been admitted to the neonatal unit because of suspected sepsis <48 hours after birth. On admission, reactive hyperemia after a standardized arterial occlusion was measured with laser Doppler technique, and blood samples were taken for cytokine analyses. On the basis of predetermined criteria, the infants subsequently were classified as septic (n = 12) or not (n = 20).. The degree of reactive hyperemia was higher in the group with sepsis (median + 170% perfusion increase) than in that without (+37%). On admission, serum levels of IL-6, IL-8, and TNF-alpha all were higher in septic (median values: 1620, 331, and 22 pg/mL, respectively) than in nonseptic neonates (median values: 42, 63, and 13 pg/mL, respectively). In the group with sepsis, the degree of reactive hyperemia correlated to log IL-6 (r = 0.80) and log IL-8 values (r = 0.71).. Newborn infants with septicemia have increased reactive hyperemia and elevated cytokine levels very early in their disease. Reactive hyperemia in skin can be analyzed at the bedside and noninvasively and therefore may serve as an additional diagnostic tool in neonatal sepsis.

Topics: Biomarkers; Gestational Age; Hand; Humans; Hyperemia; Infant, Newborn; Interleukin-6; Interleukin-8; Laser-Doppler Flowmetry; Regional Blood Flow; Sensitivity and Specificity; Sepsis; Skin; Tumor Necrosis Factor-alpha

The objective of this study is to determine the plasma concentrations and diagnostic accuracy of interleukin-6 (IL-6) and interleukin-8 (IL-8) in newborn infection. One hundred and one newborn infants with clinical signs of infection during their primary hospitalization were investigated with the minimum of a blood culture, C-reactive protein (CRP), full blood examination (FBE), and cytokine concentrations (IL-6 and IL-8). Infection in infants was classified without knowledge of cytokine levels into four groups-definite (n = 11), probable (n = 12), uncertain (n = 52), and nil (n = 26). The median concentrations of IL-6 and IL-8 were significantly higher in the definitely infected group compared with the other three groups (p <0.05). At the cut-off concentration of highest accuracy, IL-6 (>175 pg/mL) and IL-8 (>28 pg/mL) had similar sensitivities (80 and 82%, respectively) and specificities (91 and 81%, respectively). Cut-off concentrations could be identified with improved sensitivities (90% for IL-6 and 100% for IL-8) that maintained specificity >50%. However, the confidence intervals were wide for all sensitivities and specificities. IL-6 and IL-8 had little diagnostic accuracy in infants with probable infection. IL-6 and IL-8 concentrations increase early in newborn infants with definite infection.

Topics: C-Reactive Protein; Female; Humans; Infant, Newborn; Interleukin-6; Interleukin-8; Male; ROC Curve; Sensitivity and Specificity; Sepsis

To investigate whether cord blood levels of C-reactive protein, interleukin-1beta, interleukin-6, interleukin-8, tumour necrosis factor-alpha and the soluble receptor of interleukin-2, are useful markers in the diagnosis of early neonatal sepsis.. Umbilical cord blood samples were obtained at birth from 261 neonates, but 5 of these newborns were excluded from the study. Group I included 10 newborns that developed early neonatal sepsis with a positive blood culture; Group II included 11 newborns with non-infectious perinatal diseases; Group III, which served as the control group, included 10 randomly selected patients, matched for gestational age, among the 235 healthy newborn babies.. There were no differences among the three study groups in levels of C-reactive protein. interleukin-1beta, tumour necrosis factor-alpha and the soluble receptor of interleukin-2. Interleukin-6 was significantly elevated in Group I (360.4+/-157.8 pg/ml) and Group II (158.8+/-122.3 pg/ml), when compared with Group III (8.6+/-3.12 pg/ml) (p < 0.01), whereas interleukin-8 was significantly elevated in Group I (389.3+/-115.9 pg/ml) compared with Groups II (30.2+/-5.1 pg/ml) (p < 0.05) and III (33.9+/-8.6 pg/ml) (p < 0.05). A cut-off of 100.8 pg/ml for interleukin-6 obtained by the ROC (receiver operating characteristic) method gave a sensitivity of 50% and a specificity of 87%, and a cut-off of 111.7 pg/ml for interleukin-8 showed a sensitivity of 78% and a specificity of 91%.. While cord blood levels of interleukin-6 appear to be related to pathological conditions in the perinatal period (infectious and non-infectious), interleukin-8 seems to be a good predictor of early bacterial neonatal infection.

Topics: Age Factors; Biomarkers; Female; Fetal Blood; Humans; Infant, Newborn; Interleukin-6; Interleukin-8; Male; Receptors, Interleukin-2; Sepsis

The levels of the proinflammatory cytokines interleukin 6 (IL-6) and IL-8, and the anti-inflammatory cytokines IL-10 and IL-13 were studied in child patients with sepsis. The changes of the cytokine inhibitors soluble IL-6 receptor and soluble p75 TNF-alpha receptor were also investigated in the patients' sera. An increase of pro- and anti-inflammatory cytokine levels was demonstrated at the time of diagnosis. Pharmacotherapy was accompanied by a decrease of the elevated concentrations of both cytokines and their inhibitors. The time pattern of changes in cytokine and cytokine inhibitor serum concentrations along with the time course of acute phase indices, including procalcitonin and C-reactive protein, allows for an evaluation of the system inflammatory response and may support diagnostic and prognosis methods.

Topics: Anti-Inflammatory Agents; Antigens, CD; C-Reactive Protein; Calcitonin; Calcitonin Gene-Related Peptide; Cytokines; Female; Humans; Infant; Infant, Newborn; Inflammation Mediators; Interleukin-10; Interleukin-13; Interleukin-6; Interleukin-8; Male; Prognosis; Protein Precursors; Receptors, Interleukin-6; Receptors, Tumor Necrosis Factor; Receptors, Tumor Necrosis Factor, Type II; Sepsis

To investigate the prevention and treatment effects of early and short -- term use of antibiotics with broad spectrum on postburn severe infection in severely burned patients.. Thirty -- five burn patients with TBSA from 50% to 95% were enrolled in the study. The patients were divided into early prevention [20 cases, antibiotics were used started from 6 postburn hours (PBH)] and delayed prevention (15 cases, antibiotics were applied after 48 PBH) groups. Plasma levels of LPS, TNFa and IL -- 8 were dynamically monitored with the concomitant observation of clinical signs of postburn sepsis.. After major burns, the plasma levels of LPS, TNFalpha and IL -- 8 increased evidently and reached the peak values on 3 similar 5 postburn days (PBD). But the levels of all above factors in the early group were obviously lower than those in the delayed group (P < 0.05 similar 0.01). The incidencies of sepsis and internal organ complications within 2 postburn weeks were much lower in the early group than those in the delayed group (P < 0.05). The subeschar bacterial quantification on 4 similar 7 PBD was evidently lower in the early group than that in the delayed group (P < 0.01).. Early and short -- term use of antibiotics with broad spectrum in severely burned patients could effectively prevent postburn severe infection and lower down the incidence of internal organ complications.

Topics: Adolescent; Adult; Anti-Bacterial Agents; Bacteria; Burns; Humans; Interleukin-8; Lipopolysaccharides; Middle Aged; Sepsis; Time Factors; Tumor Necrosis Factor-alpha

To explore the effects of extensive excision of massive invasive infected burn wound on the REE of burn patients with sepsis.. REEs and plasma levels of IL -- 6, IL -- 8, TNFalpha and LPS were determined before and after surgical interventions and when patients', condition improved in 8 burned cases with sepsis.. All the 8 patients survived after treatment. The REE level in patients after operation was significantly lower than those before the operation (P < 0.01). REE in patients whose condition improved decreased obviously when compared to that after operation (P < 0.01). The plasma levels of IL -- 6, IL -- 8, TNFalpha and LPS decreased markedly after the operation when compared to those before operation (P < 0.05). and there were lower levels of these factors when the patients', condition improved (P < 0.001). Furthermore, there were closely positive correlations between REE and plasma IL -- 6, IL -- 8, TNFalpha and LPS (P < 0.01).. Over -- releasing of some inflammatory mediators could be corrected by means of extensive excision of massive invasively infected burn wound. This might be beneficial to the control or the amelioration of the hypermetabolism in burn patients with sepsis.

Topics: Adolescent; Adult; Basal Metabolism; Burns; Child; Female; Humans; Interleukin-6; Interleukin-8; Lipopolysaccharides; Male; Middle Aged; Sepsis; Time Factors; Tumor Necrosis Factor-alpha

Despite the fact that gram-positive infections constitute around 50% of all cases leading to septic shock, little is yet known about the mechanisms involved. This study was carried out to find out more about the effects of cell wall components peptidoglycan (PepG) and lipoteichoic acid (LTA) of the gram-positive bacterium Streptococcus pyogenes in the pig. Specific pathogen-free pigs (20 kg bodyweight) were pretreated with metyrapone (a cortisol-synthesis inhibitor) and then were given 2-h infusions of 160 microg/kg of PepG (n = 5), 160 microg/kg LTA (n=5), or a combination of both (LTA + PepG, 160 microg/kg each, n = 5). Four hours after start of the infusions, the PepG, LTA, and LTA + PepG groups showed decreases in mean arterial pressure (change of -11%, -25%, and -47% from baseline, respectively), dynamic lung compliance (-18%, -24%, and -38%), arterial oxygen tension (-10%, -16%, and -37%), changes in blood leukocyte numbers (+11%, -27%, and -67%), and increases in pulmonary vascular resistance index (+7%, +106%, and +307% from baseline) and metabolic acidosis (base excess values decreased with 1.8, 2.3 and 8.1 units). The differences between the PepG and LTA + PepG groups were statistically significant (P < 0.05, Kruskal-Wallis tests), but not between LTA and LTA + PepG groups. However, no changes in systemic nitric oxide (NO) production could be detected, which is much in contrast to studies on lower order animals. Moreover, comparison of the results obtained using this model with those obtained in a model of endotoxin-induced septic shock showed distinct difference in the mechanisms by which gram-positive and gram-negative bacterial components exert their actions. For example, a marked fall in systemic blood pressure and dynamic lung compliance is seen in both models, but in the present gram-positive sepsis model, much less interleukin-8 and tumor necrosis factor-alpha are produced. In conclusion, this study showed that PepG and LTA act synergistically to cause respiratory failure and septic shock in the pig. The infusion of the combination of PepG and LTA in the pig could serve as a new, well-controlled model for studies of gram-positive sepsis.

Topics: Animals; Drug Synergism; Endothelin-1; Endotoxins; Female; Hydrocortisone; Interleukin-8; Leukocyte Count; Lipopolysaccharides; Lung Compliance; Male; Metyrapone; Nitric Oxide; Oxygen; Peptidoglycan; Pulmonary Circulation; Sepsis; Shock, Septic; Specific Pathogen-Free Organisms; Streptococcus pyogenes; Swine; Teichoic Acids; Tumor Necrosis Factor-alpha; Vascular Resistance

CD14, a pattern recognition receptor found on myeloid cells, is a critical component of the innate immune system that mediates local and systemic host responses to Gram-negative and Gram-positive bacterial products. Previous studies in normal animals have tested the effect of CD14 blockade on the systemic response to i.v. LPS. The goals of the study were to determine whether CD14 blockade protected against the deleterious systemic response associated with Escherichia coli pneumonia and to determine whether this strategy affected the pulmonary response to tissue infection. Rabbits were pretreated with either anti-CD14 mAb or isotype control mAb at 2.5 mg/kg. E. coli (1 x 109 CFU) was inoculated into the lungs, and the animals were observed for either 4 or 24 h. The blockade of CD14 improved the mean arterial blood pressure (p = 0.001) and decreased the i.v. fluid requirements (p = 0.01). Although this therapy protected the vascular compartment, rabbits treated with anti-CD14 mAb had increased bacterial burdens in the bronchoalveolar lavage fluid recovered from the instilled lung (p = 0.005) and widened alveolar-arterial oxygen difference. Blockade of CD14 prevents the deleterious systemic responses that occur in sepsis; however, other measures are necessary to control bacterial proliferation at the primary site of infection.

Topics: Animals; Antibodies, Monoclonal; Blood Pressure; Bronchoalveolar Lavage Fluid; Chemokine CCL2; Chemotactic Factors; Escherichia coli Infections; Growth Substances; Inflammation; Interleukin-8; Lipopolysaccharide Receptors; Lung; Pneumonia, Bacterial; Pulmonary Gas Exchange; Rabbits; Sepsis; Tumor Necrosis Factor-alpha

Cytokine mediators and leukocyte-endothelial cell adhesion molecules are critical and interdependent components of the acute inflammatory response in sepsis. We hypothesized that the administration of monoclonal antibodies to intercellular adhesion molecule-1 (CD54) or E- and L-selectin (CD62E/L) would decrease serum levels of the proinflammatory cytokines interleukin-1beta (IL-1), IL-6, and IL-8 and tumor necrosis factor receptor (TNFR-1) in baboons during sepsis. Adult male baboons received infusions of 1 x 10(9) colony forming units (CFU)/kg heat-killed Escherichia coli (E. coli) followed 12 h later by live E. coli (1 x 10(10) CFU/kg). At the time of live bacterial infusion, six septic animals were treated with a monoclonal antibody to CD54 and six with an antibody to CD62E and L (1 mg/kg). Eight untreated septic animals served as controls. Sequentially drawn serum samples were assayed for IL-1, IL-6, IL-8, and TNFR-1 using enzyme-linked immunoassay (ELISA). Data were compared using Mann-Whitney U tests and Chi-square analyses. Median survival was decreased in both treatment groups compared to controls (P < 0.05). Peak IL-1 level was higher than controls in septic animals treated with anti-CD54 but not anti-CD62E/L (P < 0.05, P = NS, respectively). Elevations in IL-6, IL-8, and TNFR-1 were increased and prolonged in both antibody treated groups compared to controls (P < 0.05). These results provide the first in vivo evidence that leukocyte-endothelial adhesion molecules CD54 and CD62E/L regulate cytokine production in sepsis.

Topics: Animals; Antibodies, Monoclonal; Antigens, CD; Cytokines; E-Selectin; Escherichia coli; Escherichia coli Infections; Inflammation Mediators; Intercellular Adhesion Molecule-1; Interleukin-1; Interleukin-6; Interleukin-8; L-Selectin; Male; Papio; Receptors, Tumor Necrosis Factor; Receptors, Tumor Necrosis Factor, Type I; Sepsis

In order to understand the role of an anti-inflammatory cytokine interleukin 10 (IL-10) in the pathophysiology of burn injury, IL-10 levels in serial serum samples of 22 burned patients were analyzed. The total body surface areas (TBSA) of the burn injury ranged from 30 to 90%. Among these 22 patients, 14 recovered and the other eight, who were septic, expired. A significant difference in serum IL-10 values on admission (5-20 h postburn) was found (P<0.05) between patients who survived or died from burn injury as analyzed by the Student's t test. In addition, a significant difference in serum IL-10 on admission was also found (P<0.05) between patients with TBSA of greater or less than 50%. An initial peak serum IL-10 response was detected within 2.5 days postburn. Significant differences in the peak serum IL-10 levels were not found between patients with TBSA of greater or less than 50% and patients who survived or expired from burn injury. Afterwards, serum IL-10 remained low in the survivors, while an increase in serum IL-10 could be detected in the non-survivors with proven sepsis. Levels of circulating IL-6 in these non-surviving patients showed a tendency to increase starting from about 1-2 weeks postburn which coincided temporally with the detection of infections. However, marked increases in circulating IL-10 levels were observed just before death in four of the eight non-survivors. The serum samples of these four patients were collected at 31 h (404.8 pg/ml), 2 h (773.9 pg/ml), 5 days (150.7 pg/ml) and 12 h (177.1 pg/ml) before the expiration of these patients, respectively. IL-10 levels of 28.6, 27. 5 and 13.5 pg/ml were detected in sera of three of the remaining four non-survivors that were collected at 2.5 h, 36 h and 30 h before the expiration of these patients, respectively. There was one non-surviving patient who suffered an 80% burn (patient D4 in Table 1 and Fig. 4) and his IL-10 level at 20 days postburn was 13.4 pg/ml. The serum sample of this patient was collected 22 days before death and he was not suffering from sepsis at this stage. In conclusion, an initial increase in serum levels of IL-10 was detected postburn. A marked increase in serum levels of IL-10 was detected in four of the eight septic patients just before their death. It was considered that a lack and/or a delay in the increase of circulating IL-10 may play a significant role in the pathophysiology of sepsis in burned patients.

Topics: Adolescent; Adult; Aged; Body Surface Area; Burns; Enzyme-Linked Immunosorbent Assay; Female; Follow-Up Studies; Humans; Interleukin-10; Interleukin-6; Interleukin-8; Male; Middle Aged; Patient Admission; Sepsis; Statistics as Topic; Survival Rate; Tumor Necrosis Factor-alpha

In experimental trauma-hemorrhage and sepsis, a sexual dimorphism of cell-mediated immune functions has been described, which has been related to higher susceptibility to and mortality from sepsis in males. Therefore, in the present study, sex differences with regard to cytokine release of endotoxin stimulated whole blood and its relation to the development of severe posttraumatic sepsis were investigated in blunt trauma patients with multiple injuries.. Eighty-four patients (25 female; 59 male) sustaining blunt injuries with an Injury Severity Score > 16 were enrolled in the study. Whole blood and serum were obtained during a 14-day period of hospitalization. The capacity of peripheral blood mononuclear cells to produce cytokines (tumor necrosis factor-alpha, interleukin [IL]-6, IL-8) was tested by using a whole blood assay. Serum samples were assayed for anti-inflammatory cytokines (IL-4, IL-10, and transforming growth factor beta1) and sex hormones (testosterone, estradiol, progesterone). Patients were monitored daily for sepsis criteria according to the ACCP/ SCCM consensus conference 1992.. Within the entire patient population, sex differences in posttraumatic cytokine release were not detectable. Male trauma patients developing severe sepsis (n = 16) presented with a significantly increased cytokine producing capacity in the early posttraumatic period (< or = 24 hours after admission to the emergency room) when compared with males with an uncomplicated recovery. In females, differences between the subgroups of patients with (n = 7) and without development of severe sepsis were not detectable. There were no differences in systemic levels of anti-inflammatory cytokines within the early posttraumatic period between the subgroups of male and female patients with and without development of severe sepsis. In females, differences in sex hormone levels were not detectable, whereas in males, development of severe sepsis later was found to coincide with significantly decreased testosterone and increased estradiol serum levels.. The present study demonstrates a sex-specific regulation of leukocyte function in patients with multiple injuries within the early posttraumatic period. In male patients with multiple injuries, increased cytokine-producing capacities may correspond to enhanced inflammatory responses, which increase susceptibility to sepsis, whereas in female patients, other regulatory mechanisms may be involved.

Topics: Adult; Blood; Cytokines; Endotoxins; Estradiol; Female; Hemorrhage; Humans; Interleukin-10; Interleukin-4; Interleukin-6; Interleukin-8; Leukocytes, Mononuclear; Male; Middle Aged; Multiple Trauma; Progesterone; Prospective Studies; Sepsis; Severity of Illness Index; Sex Characteristics; Testosterone; Time Factors; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Wounds, Nonpenetrating

To determine whether the group B streptococcal (GBS) polysaccharide exotoxin CM101, which induces a complement-activated cytokine-driven inflammatory response, is present in body fluids of infants with GBS disease.. With a sandwich enzyme-linked immunosorbent assay, CM101 was measured in plasma, urine, and cerebrospinal fluid from newborn infants who were evaluated for possible infection and from older infants with culture-confirmed GBS disease.. Urine from 11 newborn infants with culture-confirmed early-onset disease contained large amounts of CM101 (1.0 to 5.5 mg/48 h). Plasma concentrations were 62.6 +/- 10.5 microg/mL in these infants and were 69.0 +/- 21.2 microg/mL in 4 older infants with late-onset disease. Plasma CM101 concentrations did not correlate with indexes of illness severity, leukocyte counts, or interleukin-6 or interleukin-8 plasma concentrations. CM101 was present in cerebrospinal fluid of 5 infants with meningitis (8.4 +/- 1.6 microg/mL). CM101 was not found in control samples. CM101 isolated from urine had molecular weight and sugar composition similar to those obtained from GBS culture media, and they both elicited a comparable pathophysiologic response when infused intravenously in lambs.. CM101 is present in infants with GBS disease, and it appears to be the same as CM101 obtained from GBS culture media.

Topics: Animals; Bacterial Toxins; Body Fluids; Enzyme-Linked Immunosorbent Assay; Humans; Infant; Infant, Newborn; Interleukin-6; Interleukin-8; Leukocyte Count; Polysaccharides, Bacterial; Sepsis; Sheep; Streptococcal Infections; Streptococcus agalactiae

IL-18 levels in the blood of 13 sepsis patients were assessed. The IL-18 values were significantly correlated with their Acute Physiology and Chronic Health Evaluation (APACHE) II scores, and they were a good reflection of the severity of the disease. There was also a strong correlation between the IL-18 values and the patients' inflammatory cytokine levels. The results suggested strong involvement of IL-18 in the pathogenesis of sepsis.

Topics: APACHE; Burns; Female; Humans; Interleukin-18; Interleukin-6; Interleukin-8; Male; Sepsis; Time Factors; Tumor Necrosis Factor-alpha

To compare the prognostic significance of bactericidal/permeability-increasing protein (BPI), group II phospholipase A2 (PLA2-II), C-reactive protein (CRP), tumour necrosis factor-alpha (TNF), interleukin-8 (IL-8) and interferon-gamma (IFN) in terms of predicting severity of sepsis and outcome.. A prospective study.. Medical intensive care unit (ICU) of a university hospital.. Thirty-four patients with severe sepsis requiring ICU treatment.. The levels of BPI, PLA2-II, CRP, TNF, IL-8 and IFN were measured in these 34 patients. High levels of BPI were associated particularly with Gram-negative sepsis. BPI and BPI/neutrophil ratios correlated positively with PLA2-II, CRP, TNF and IL-8 and negatively with blood pressure. At 24 h, BPI/neutrophil ratios, IL-8 and Simplified Acute Physiology Scores II (SAPS II) scores were higher in non-survivors than in survivors. No such associations were noted in the levels of CRP, PLA2-II, TNF or IFN. The areas under the curve (AUC(ROC)s) of SAPS II scores and IL-8 were higher than AUC(ROC) of BPI/neutrophil ratio.. The BPI and BPI/neutrophil ratios may serve as adjunctive tools to illustrate the severity of sepsis. However, their predictive power for sepsis-related death was not comparable to that of SAPS II scores and IL-8.

Topics: Adult; Aged; Aged, 80 and over; Analysis of Variance; Antimicrobial Cationic Peptides; Area Under Curve; Blood Proteins; C-Reactive Protein; Enzyme-Linked Immunosorbent Assay; Female; Humans; Intensive Care Units; Interferon-gamma; Interleukin-8; Male; Membrane Proteins; Middle Aged; Phospholipases A; Phospholipases A2; Predictive Value of Tests; Prognosis; Prospective Studies; ROC Curve; Sensitivity and Specificity; Sepsis; Severity of Illness Index; Tumor Necrosis Factor-alpha

To investigate the clinical characteristics of invasive burn wound infection with sepsis in patients with major burns and to summarize the successful experiences in the treatment of such patients.. Eight patients with major burns, complicated by invasive burn would infection and sepsis were consecutively admitted to our hospital from September 1997 to October 1998. Among them, 6 patients developed multiple organ dysfunction syndrome (MODS) and 2 developed septic shock. The plasma concentrations of IL-6, IL-8, TNF alpha and lypopolysaccharide (LPS) were assayed before and after surgical intervention, as well as when the patient's vital signs became stable.. The patients' conditions usually deteriorated abruptly when extensive invasive burn wound infection emerged. While multi-microbial infection was usually found, Pseudomonas aeruginosa was the predominant bacteria isolated from the subeschar tissue. The plasma concentrations of IL-6, IL-8, TNF alpha and LPS before surgical intervention were significantly higher than those after surgical intervention (P < 0.05). The lowest levels of the inflammatory mediators were observed when the patients' conditions became stable, and the values were significantly lower than those before surgical intervention (P < 0.001).. Since the main cause of burn wound sepsis is the presence of a large area of infected burn wound, they should be excised and covered as early as possible. LPS and pro-inflammatory mediators play an important role in the pathogenesis of burn sepsis. Although favorable results should be attributed to comprehensive treatment, we believe that early, aggressive and thorough surgical excision of infected burn wounds, followed by sound and complete coverage of the area, play a crucial role.

Topics: Adolescent; Adult; Burns; Child; Escherichia coli; Female; Humans; Interleukin-6; Interleukin-8; Lipopolysaccharides; Male; Middle Aged; Pseudomonas aeruginosa; Sepsis; Skin Transplantation; Staphylococcus aureus; Tumor Necrosis Factor-alpha; Wound Infection

Neutrophils (polymorphonuclear neutrophils; PMN) and a redundant system of chemotactic cytokines (chemokines) have been implicated in the pathogenesis of the acute respiratory distress syndrome in patients with sepsis. PMN express two cell surface receptors for the CXC chemokines, CXCR1 and CXCR2. We investigated the expression and function of these receptors in patients with severe sepsis. Compared with normal donors, CXCR2 surface expression was down-regulated by 50% on PMN from septic patients (p < 0.005), while CXCR1 expression persisted. In vitro migratory responses to the CXCR1 ligand, IL-8, were similar in PMN from septic patients and normal donors. By contrast, the migratory response to the CXCR2 ligands, epithelial cell-derived neutrophil activator (ENA-78) and the growth-related oncogene proteins, was markedly suppressed in PMN from septic patients (p < 0.05). Ab specific for CXCR1 blocked in vitro migration of PMN from septic patients to IL-8 (p < 0.05), but not to FMLP. Thus, functionally significant down-regulation of CXCR2 occurs on PMN in septic patients. We conclude that in a complex milieu of multiple CXC chemokines, CXCR1 functions as the single dominant CXC chemokine receptor in patients with sepsis. These observations offer a potential strategy for attenuating adverse inflammation in sepsis while preserving host defenses mediated by bacteria-derived peptides such as FMLP.

Topics: Antibodies, Blocking; Antigens, CD; Cell Movement; Chemokine CXCL1; Chemokine CXCL5; Chemokines, CXC; Chemotactic Factors; Flow Cytometry; Growth Substances; Humans; Intercellular Signaling Peptides and Proteins; Interleukin-8; Neutrophils; Prospective Studies; Receptors, Chemokine; Receptors, Interleukin; Receptors, Interleukin-8A; Receptors, Interleukin-8B; Sepsis

The priming mechanism of macrophages to secrete cytokines in acute pancreatitis is important for remote organ failure following septic complication. The effects of novel carboxamide derivative, IS-741, on neutrophil chemoattractant production by bronchoalveolar macrophages were studied in rats with cerulein-induced pancreatitis complicated by sepsis.. Pancreatitis was induced by four intramuscular injections of cerulein (50 microg/kg at 1-hour intervals). Pancreatitis rats were injected intraperitoneally with 10 mg/kg of lipopolysaccharide (LPS) 6 h following the first cerulein injection as a septic challenge. Pancreatitis rats received a continuous intravenous injection of IS-741 (3 mg/kg/h) 30 min before the septic challenge.. Intense mononuclear cell infiltration and lung hemorrhage occurred in untreated pancreatitis rats complicated with sepsis, but hemorrhage was not seen in septic pancreatitis rats receiving a continuous intravenous injection of IS-741 shortly before sepsis induction. The IS-741-treated rats had lower serum concentrations of cytokine-induced neutrophil chemoattractant (CINC), as well as fewer the pulmonary neutrophils and infiltrates immunoreactive for CINC or Mac-1 (CD11b/CD18).. The novel carboxamide derivative IS-741 reduced CINC production by bronchoalveolar macrophages and effectively prevented pancreatitis-associated lung injury following the septic challenge.

Topics: Animals; CD18 Antigens; Ceruletide; Chemotaxis; Disease Models, Animal; Enzyme Inhibitors; Injections, Intravenous; Interleukin-8; Macrophage-1 Antigen; Macrophages, Alveolar; Male; Neutrophil Infiltration; Pancreatitis; Pyridines; Rats; Rats, Wistar; Sepsis

The cytokine production in endotoxin stimulated blood of patients immediately after polytrauma with high risk for developing sepsis or multi organ failure was analysed. Forty patients sustaining traumatic injury with >/=317 pts according to the Injury Severity Score (ISS), 10 of whom developed severe sepsis (ACCP/SCCM conference 1992) were included in the study. Levels of interleukin 8 (IL-8), IL-6 and tumour necrosis factor (TNF) were measured by ELISA in endotoxin-stimulated whole blood and IL-10 and IL-6 in serum. The allotype for the bi-allelic Nco I restriction length polymorphism in the TNF locus was determined for each patient.Two to four hours after polytrauma endotoxin-stimulated synthesis of TNF and IL-6 was found to be reduced in whole blood from patients compared to healthy donors, whereas no such differences were found for IL-8 synthesis. At this time, however, the patients who developed sepsis at a later stage (day 4-6) showed significantly (P<0.05) enhanced IL-8 synthesis in endotoxin stimulated whole blood in comparison to healthy donors. The IL-6 and TNF production of their blood was significantly enhanced compared to patients with uncomplicated recovery. Ninety per cent of the patients developing sepsis were of the TNFB2/TNFB2 allotype, whereas this was the case for only 30% of the non-septic group. Assessment of endotoxin-stimulated cytokine synthesis may provide a prognostic indicator for patients at high risk for developing a sepsis syndrome.

Topics: Adolescent; Adult; Biomarkers; Blood Cells; Cytokines; Female; Gene Frequency; Humans; Immunoglobulin Allotypes; Interleukin-10; Interleukin-6; Interleukin-8; Lipopolysaccharides; Male; Middle Aged; Polymorphism, Genetic; Polymorphism, Restriction Fragment Length; Sepsis; Time Factors; Tumor Necrosis Factor-alpha; Wounds and Injuries

The monocyte/macrophage (Mphi is central in the regulation of the immune response in states of trauma and sepsis. Because monocyte subsets, characterized by expression of the Fc-receptor (FcR), were shown to play distinct immunologic roles in trauma, it was the objective of this study to assess insights into the functional role of FcR positive (FcR+) and negative (FcR-) subclasses in surgical sepsis. In a prospective study, peripheral blood Mphi from 20 septic patients and 10 healthy volunteers were evaluated on consecutive days after the onset of sepsis. FcR+/- subsets were separated by rosetting with antibody-coated human erythrocytes. Receptor expression and synthesis of proinflammatory cytokines were used to evaluate the functional role of these cells. We demonstrated a significant monocytosis (350%; p<.01) and suppression of human lymphocyte antigen (HLA-DR) expression (35%; p<.05). Synthesis of Interleukin-1beta (IL-1beta; e.g., Day 1: 230+/-30 pg/mL) and Interleukin-6 (IL-6; e.g., Day 1: 1920+/-350 U/mL) were significantly higher (p<.05) in FcR+ subsets than in controls (IL-1beta: 100+/-5 pg/mL; IL-6: 353+/-75 U/mL). Tumor necrosis factor-alpha (TNF-alpha) was elevated in FcR+ monocytes but did not reach a significant value. Interleukin-8 (IL-8) synthesis showed only on Day 1 and in controls significant differences in FcR+ and FcR- cells (Day1: FcR-: 19.6+/-4.1 nM; FcR+: 9+/-4.3 nM). Sepsis results in a significant shift toward FcR+ monocytes. This cell population is characterized by high proinflammatory cytokine synthesis. The extent of this shift seems to identify a group of high risk septic patients that might benefit from immunomodulatory therapy.

Topics: Adult; Aged; Female; HLA-DR Antigens; Humans; Inflammation; Interleukin-1; Interleukin-6; Interleukin-8; Male; Middle Aged; Monocytes; Predictive Value of Tests; Receptors, Fc; Sepsis; Tumor Necrosis Factor-alpha

Studies in experimental animals have suggested that platelet-activating factor (PAF) is a mediator of sepsis-associated acute renal failure (ARF). In the present study we have evaluated whether an increased concentration of PAF within circulation or urine of septic patients correlated with the worsening of renal function.. The concentration of PAF and selected cytokines (TNF, IL-1, IL-6, IL-8) was evaluated in blood and urine of 12 patients with septic shock and ARF for 4 consecutive days.. The data obtained indicate that blood and urinary concentrations of PAF and of IL-1, IL-6 and IL-8 were significantly higher in septic patients than in controls subjects and in patients with chronic renal failure. The concentration of TNF was significantly increased only in urine. A significantly positive correlation was found among blood concentration of PAF and heart rate (r = 0.4193, P < 0.017), serum creatinine (r = 0.3671, P < 0.038), serum IL-6 (r = 0.5475, P < 0.005) and urine excretion of IL-8 (r = 0.3984, P < 0.044), whereas a negative correlation was present with the number of circulating platelets (r = -0.4285, P < 0.018). Moreover, a positive correlation among the concentration of PAF in urine and the serum concentration of IL-6 (r = 0.5654, P < 0.006) and urine excretion of IL-6 (r = 0.6589, P < 0.0008) and IL-8 (r = 0.6371, P < 0.0004) were found.. These results demonstrate in humans during ARF associated with septic shock the production of PAF, a mediator that has been previously implicated in the pathogenesis of experimental endotoxin-induced shock and renal injury. The observation that blood and urinary concentrations of PAF correlated with some of the clinical and laboratory parameters related to the severity of ARF and sepsis suggests that PAF may contribute to the development of renal injury in septic patients.

Topics: Acute Kidney Injury; Aged; Aged, 80 and over; Animals; Female; Humans; Interleukin-1; Interleukin-6; Interleukin-8; Male; Middle Aged; Platelet Activating Factor; Sepsis; Tumor Necrosis Factor-alpha

Cell adhesion molecule expression (CAM) and IL-8 release in lung microvascular endothelium facilitate neutrophil accumulation in the lung. This study investigated the effects of lipoteichoic acid (LTA), a cell wall component of Gram-positive bacteria, alone and with LPS or TNF-alpha, on CAM expression and IL-8 release in human lung microvascular endothelial cells (HLMVEC). The concentration-dependent effects of Staphylococcus aureus (S. aureus) LTA (0.3-30 microg/ml) on ICAM-1 and E-selectin expression and IL-8 release were bell shaped. Streptococcus pyogenes (S. pyogenes) LTA had no effect on CAM expression, but caused a concentration-dependent increase in IL-8 release. S. aureus and S. pyogenes LTA (30 microg/ml) abolished LPS-induced CAM expression, and S. aureus LTA reduced LPS-induced IL-8 release. In contrast, the effects of S. aureus LTA with TNF-alpha on CAM expression and IL-8 release were additive. Inhibitory effects of LTA were not due to decreased HLMVEC viability, as assessed by ethidium homodimer-1 uptake. Changes in neutrophil adhesion to HLMVEC paralleled changes in CAM expression. Using RT-PCR to assess mRNA levels, S. aureus LTA (3 microg/ml) caused a protein synthesis-dependent reduction (75%) in LPS-induced IL-8 mRNA and decreased the IL-8 mRNA half-life from >6 h with LPS to approximately 2 h. These results suggest that mechanisms exist to prevent excessive endothelial cell activation in the presence of high concentrations of bacterial products. However, inhibition of HLMVEC CAM expression and IL-8 release ultimately may contribute to decreased neutrophil accumulation, persistence of bacteria in the lung, and increased severity of infection.

Topics: Cell Adhesion Molecules; Drug Interactions; E-Selectin; Endothelium, Vascular; Half-Life; Humans; Intercellular Adhesion Molecule-1; Interleukin-8; Lipopolysaccharides; Lung; Lung Diseases; Microcirculation; Neutrophil Infiltration; RNA Stability; RNA, Messenger; Sepsis; Streptococcus; Streptococcus pyogenes; Teichoic Acids; Tumor Necrosis Factor-alpha

The standard therapy for patients with fever and chemotherapy-related neutropenia is hospitalization and infusion of broad-spectrum antibiotics. Early discharge of a defined group of patients at low risk for septicaemia would be of great advantage for these patients. In this study plasma interleukin-8 (IL-8) and interleukin-6 (IL-6) levels measured at start of fever (n = 72) could define a low-risk group of febrile patients with neutropenia due to chemotherapy. For this purpose we collected and analysed data on 72 fever episodes from 53 patients with chemotherapy-related neutropenia, aged between 1 and 66 years. Of the 72 episodes, 18 were classified as bacteraemia and/or clinical sepsis (sepsis group). The IL-6 and IL-8 plasma concentration were significantly increased in patients with chemotherapy-related neutropenia and fever due to bacteraemia versus fever of non-bacterial origin (P = 0.043 and P = 0.022 respectively). Logistic regression analysis, with sepsis as the outcome variable, revealed significant effects of age combined with either IL-6 or IL-8. Sepsis occurrence was lowest for patients <16 years and highest in patients between 16 and 50 years, and was higher in patients with increased IL-6 (P = 0.032) or IL-8 (P = 0.049). No significant effect of leucocyte count, C-reactive protein, sex or underlying malignancy at presentation was detected. The plasma IL-6 and IL-8 levels were fairly strongly correlated (Pearson r = 0.62). Using a cut-off value with 100% sensitivity, both IL-8 and IL-6 could define a low-risk group of neutropenic patients of 28% (CI 15-40%) at the start of the febrile period. Intervention studies are warranted to confirm this result and to investigate whether an early discharge based on IL-8 or IL-6 measurement is safe, increases the quality of life, and results in cost savings.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; C-Reactive Protein; Child; Child, Preschool; Fever; Humans; Infant; Interleukin-6; Interleukin-8; Leukocyte Count; Middle Aged; Neoplasms; Neutropenia; Risk Factors; Sensitivity and Specificity; Sepsis

Sepsis occurs following the presence of bacteria in the circulation and is associated with fever, hyperthermia, and hypotension. Hypophosphatemia develops in the early stages of sepsis. High levels of inflammatory cytokines also characterize early sepsis.. The aim of the present study was to correlate hypophosphatemia with cytokines and cytokine receptor levels during early sepsis. We aimed to reestablish the results obtained from patients in an in vivo experimental model, in order to understand the mechanism of hypophosphatemia induction in early sepsis.. Ninety-nine patients were enrolled in this study and their clinical condition was classified as the presence of infection, sepsis, and bacterial growth in blood cultures. Phosphate levels and cytokine levels were recorded. In order to determine whether hypophosphatemia is correlated to the increased inflammatory cytokines, we injected normal mice with recombinant cytokines and studied their effect on phosphate levels.. Our results revealed that 80% of the septic patients had hypophosphatemia associated with very high levels of tumor necrosis factor (TNF)alpha and interleukin (IL)-6 and of soluble IL receptor (sIL)-2R and IL-6R, especially in those patients with positive blood cultures. Injection of IL-6, TNFalpha and IL-1beta in mice markedly decreased the phosphate serum levels.. Significant associations were demonstrated between high levels of inflammatory cytokines and their receptors and between serum phosphate levels, especially in patients with positive blood culture. Our results point to a correlation between the high inflammatory cytokines levels and hypophosphatemia during early sepsis. Cytokine levels and hypophosphatemia may be included in sepsis evaluation and prognosis. Anticytokine strategies might, therefore, reverse hypophosphatemia and other parameters of sepsis.

Topics: Cytokines; Humans; Hypophosphatemia; Incidence; Infections; Interleukin-2; Interleukin-6; Interleukin-8; Prevalence; Receptors, Cytokine; Sepsis; Tumor Necrosis Factor-alpha

The objective of this study was to evaluate the role of inducible nitric oxide synthase (iNOS) and proinflammatory cytokines in alveolar macrophages (AMs) in the pathogenesis of ARDS following sepsis.. ICU in a university hospital.. Prospective exploratory, open-labeled study was carried out.. A total of 24 patients were investigated: 8 patients diagnosed as having ARDS following sepsis (ARDS group); 8 patients under general anesthesia in the operating room whose lung functions were normal (control group); and 8 patients who were intubated and artificially ventilated for 1 week in the ICU whose lung functions were not deteriorated without fulfilling the ARDS criteria and whose general state fulfilled the sepsis criteria (long-term ventilation group, or LTV group).. The expression of iNOS, interleukin-1beta (IL-1beta), interleukin-6 (IL-6), and interleukin-8 (IL-8) in AMs obtained from BAL fluid (BALF) was determined by the immunofluorescent technique. We observed the significant expression of iNOS, IL-6, and IL-8 only in the ARDS group. Meanwhile, NOx (the sum of NO2- + NO3-) was elevated in the BALF supernatant, and IL-6 and IL-8 levels in both the BALF supernatant and the serum were also elevated in the ARDS group. No significant expressions were detected in the control and the LTV group.. The result that iNOS was detected only in ARDS patients following sepsis suggests that iNOS together with proinflammatory cytokines produced by AMs might play a pivotal role in the pathogenesis of acute lung injury and be useful for monitoring disorders in the lung in such conditions.

Topics: Adult; Aged; Bronchoalveolar Lavage Fluid; Female; Fluorescent Antibody Technique; Humans; Inflammation Mediators; Interleukin-1; Interleukin-6; Interleukin-8; Interleukins; Macrophages, Alveolar; Male; Middle Aged; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Prospective Studies; Proteins; Pulmonary Edema; Sepsis

The objective of this study was to determine the effects of recombinant human granulocyte colony-stimulating factor (rhG-CSF) administration in septic patients with neutropenia.. Twenty consecutive septic patients were administered rhG-CSF subcutaneously (2 microg x kg(-1) x d(-1)) for 5 days (group G). They were compared with 14 septic patients treated earlier without rhG-CSF (group N). All patients in both groups met the criteria of total leukocyte count (TLC) less than 5,000/mm3 and C-reactive protein (CRP) more than 10 mg/dL. Changes in TLC, absolute neutrophil count (ANC), CRP, respiratory index (RI), Acute Physiology and Chronic Health Evaluation (APACHE) II score, and Goris's Multiple Organ Failure (MOF) index were evaluated. In addition, nucleated cell count (NCC), differentiation in bone marrow aspiration, neutrophil phagocytic and bactericidal activity, serum concentrations of interleukin-6 (IL-6) and IL-8 as inflammatory markers, and plasma concentration of leukocyte elastase (LE) as an indicator of the tissue injury were evaluated in group G.. In group G, TLC, ANC, NCC, and neutrophil functions increased significantly, whereas CRP, IL-6, and IL-8 decreased reciprocally. There was no deterioration of LE and RI. Consequently, the APACHE II score and MOF index improved. In group N, however, CRP showed no change concomitant with the APACHE II score and MOF index.. Administration of rhG-CSF attenuates inflammatory responses without inducing tissue injury in septic patients with neutropenia.

Topics: Adjuvants, Immunologic; Adolescent; Adult; Aged; APACHE; Biomarkers; C-Reactive Protein; Female; Granulocyte Colony-Stimulating Factor; Humans; Interleukin-1; Interleukin-6; Interleukin-8; Lenograstim; Leukocyte Count; Leukocyte Elastase; Male; Middle Aged; Multiple Organ Failure; Neutropenia; Recombinant Proteins; Sepsis; Tumor Necrosis Factor-alpha

Sepsis is associated with enhanced cytokine production. Here, we examined the in vitro removal of plasma cytokines during continuous plasmafiltration coupled with sorbent adsorption.. Proinflammatory (tumour necrosis factor-alpha, interleukins-1, -8) and anti-inflammatory (interleukin 1 receptor antagonist, soluble tumour necrosis factor receptor type I and II) cytokines in whole blood spiked with Escherichia coli endotoxin were determined during 2-h recirculation in the ultrafiltrate (condition A), plasma filtrate (condition B), before and after different sorbents (of the Amberlite-, Amberchrome- Ambersorb -type and charcoal). We studied the maximal adsorbing capacity, the 1% leakage test for cytokines and C3a des Arg and the adsorption of complement-dependent leukocyte chemiluminescence. Plasma proteins eluted from the resins were examined by sodium dodecyl sulphate polyacrylamide gel electrophoresis and immunoblotting with an anti-human alpha2-macroglobulin.. In condition B, we observed a 40- and 121-fold % increase (vs condition A) in the removed mass and clearance of tumour necrosis factor-alpha. For all other cytokines, the removed mass and the clearance increased from 2.3- up to 6-fold. The Amberchrome but not the Amberlite or Ambersorb resins could remove the highest amount of cytokines and could reduce complement-dependent chemiluminescence. Two protein bands of approximately 400,000 D and 200,000 D were eluted only from Amberchrome resins and immunoprecipitated by anti-human alpha2-macroglobulin and anti-human C3c antibodies, respectively.. These studies suggest an efficient removal of cytokines in continuous plasmafiltration with sorbent adsorption. The binding of alpha2-macroglobulin, a carrier of cytokines in plasma, might be a additional mechanism in the removal of cytokines from plasma.

Topics: Adsorption; Blood Coagulation Factors; Blood Proteins; Complement System Proteins; Cytokines; Hemofiltration; Humans; In Vitro Techniques; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Interleukin-8; Luminescent Measurements; Neutrophils; Plasma; Sepsis; Sialoglycoproteins; Tumor Necrosis Factor-alpha; Ultrafiltration

The activation of complement and the release of TNF-alpha, IL-6 and IL-8 are important pathogenic factors behind organ dysfunction in sepsis. The aim of this study was to determine whether infusion of anti-TNF antibodies alters complement activation and plasma concentrations of pro-inflammatory cytokines at high doses of Escherichia coli. Six baboons received intravenously 2 x 10(9) live E. coli bacteria per kg body weight (group 1), in addition five received pretreatment with 1 mg per kg body weight anti-TNF antibodies (group 2), and seven received 5 x 10(8) live E. coli bacteria per kg body weight (group 3). Two hours after the start of infusion of the bacteria, plasma concentrations of C3 activation products, C5a and the terminal SC5b-9 complement complex were increased in groups 1 and 2 (P < 0.05), but there was no significant difference between the groups. At 2 h the levels of TNF-alpha, IL-6 and IL-8 were lower in group 2 compared with group 1 (P<0.05). In group 2 compared with group 1 the TNF-alpha concentrations were, however, higher at 4, 8 and 24 h. The explanation for this phenomenon is probably that TNF-alpha binds to the anti-TNF antibody complex and is released slowly after it has been bound. The study showed that infusion of anti-TNF antibodies reduced the concentrations of TNF-alpha, IL-6 and IL-8, without any detectable influence on complement activation.

Topics: Animals; Antibodies, Monoclonal; Complement Activation; Complement C3; Complement C5a; Disease Models, Animal; Escherichia coli Infections; Immunoglobulins, Intravenous; Interleukin-6; Interleukin-8; Papio; Sepsis; Tumor Necrosis Factor-alpha

The aim of the present study was to investigate the relationship between the levels of pro-inflammatory [interleukin 6 (IL-6), IL-8, tumour necrosis factor alpha (TNF-alpha)], anti-inflammatory cytokines [IL-10, soluble TNF receptor type I (TNFsrI), TNFsrII], and the production of nitric oxide (NO) during a 1-week period in 23 patients with severe sepsis. The highest levels of pro-inflammatory cytokines and nitrate, the stable metabolite of NO, were found during the first day after inclusion and gradually declined thereafter. Detectable levels of IL-10, TNFsrI and TNFsrII were present in all patients at study entry but did not significantly change during the study period [analysis of variance (MANOVA); P > 0.05]. Serum nitrate levels correlated significantly with both pro-inflammatory cytokines (IL-6, IL-8, TNF-alpha) as well as anti-inflammatory cytokines (IL-10, TNFsrI, TNFsrII). Serum nitrate levels over time were higher in patients with positive blood cultures (n = 4) (MANOVA; P < 0.005), as compared to patients without proven bacteraemia. These data support the concept of an acute phase of sepsis that is characterized by an excess of pro-inflammatory cytokines, while anti-inflammatory cytokines are predominantly present during the secondary phase. The present findings indicate that pro-inflammatory cytokines are related to the induction of excessive NO production during the first phase of sepsis and that reduction of NO production occurs during the secondary phase. This may suggest that anti-inflammatory cytokines are able to diminish the production of NO in patients with severe sepsis.

Topics: Antigens, CD; Female; Humans; Inflammation; Interleukin-10; Interleukin-6; Interleukin-8; Interleukins; Male; Middle Aged; Nitrates; Nitric Oxide; Receptors, Tumor Necrosis Factor; Receptors, Tumor Necrosis Factor, Type I; Receptors, Tumor Necrosis Factor, Type II; Sepsis; Tumor Necrosis Factor-alpha

To look for relationships between the classification of sepsis and plasma cytokine concentrations.. Prospective, consecutive entry study of patients meeting severe sepsis criteria and having bacteriologically documented infections.. University hospital, surgical intensive care unit.. Fifty consecutive patients developing severe sepsis or septic shock between December 1991 and December 1993.. Concentrations of tumor necrosis factor, interleukin (IL)-6, IL-8, and leukemia inhibitory factor were measured by immunoradiometric assay in the plasma of patients as soon as they developed severe sepsis or septic shock. Septic shock patients were divided into three groups in a blinded fashion (i.e., without knowing the results of the concentrations of cytokines), according to the presence of sustained hyperlactacidemia and to the rapidity of the onset of sepsis. Peak concentrations of all cytokines were statistically different between severe sepsis and septic shock patients. This finding was almost exclusively due to the data from patients with rapid onset of septic shock, who demonstrated very high but transient cytokine concentrations. Septic shock patients may thus have different profiles in the time course of their cytokine concentrations. The transient, high peak concentrations of cytokines were also related to transient leukopenia. Among the cytokines measured, IL-8 appeared to be the one that correlated best with lactacidemia, the presence of disseminated intravascular coagulation, severe hypoxemia, the Acute Physiology and Chronic Health Evaluation II score, and mortality rate.. According to the profiles of the cytokines, septic shock patients do not represent a homogeneous population. These profiles should be described in order to distinguish between patients, and the profiles may be useful to identify those patients susceptible to new therapies.

Topics: Acidosis, Lactic; Adult; Aged; Aged, 80 and over; APACHE; Female; Growth Inhibitors; Humans; Interleukin-6; Interleukin-8; Leukemia Inhibitory Factor; Lymphokines; Male; Middle Aged; Prospective Studies; Sepsis; Single-Blind Method; Time Factors; Tumor Necrosis Factor-alpha

To determine the effect of the quinolone antibiotic ciprofloxacin, on interleukin-6, interleukin-8, and nitrite production by human endothelial cells.. Controlled cell culture experiments examining the immunomodulatory effects of an antibiotic.. University research laboratory attached to a large teaching hospital.. A human endothelial cell line.. Cells were incubated with tumor necrosis factor-alpha and interleukin-1beta in the presence of a range of ciprofloxacin concentrations. Interleukin-6, interleukin-8, and nitrite concentrations were measured in culture supernatants after 24 hrs using enzyme immunoassay. Ciprofloxacin decreased interleukin-6 accumulation (p = .001). Interleukin-8 was decreased at lower ciprofloxacin concentrations (p = .017) but was increased at 100 microg/mL (p = .0039). Ciprofloxacin had no effect on nitrite accumulation (p = .38).. Ciprofloxacin differentially modulates interleukin-6 and interleukin-8 expression. The response to infection is coordinated by a cascade of cytokines and other mediators. The widespread use of ciprofloxacin in patients with severe infections is likely to result in alterations in local concentrations of cytokines. Selective control of cytokine concentrations by antibacterial agents will clearly have important therapeutic implications and may be a future research consideration in antibiotic drug design.

Topics: Anti-Infective Agents; Cell Line; Ciprofloxacin; Drug Evaluation, Preclinical; Endothelium, Vascular; Humans; Interleukin-6; Interleukin-8; Lung Neoplasms; Nitrites; Sepsis; Tumor Cells, Cultured

The balance between proinflammatory cytokines and their inhibitors has rarely been investigated in pleural effusions of nonmalignant or noninfectious origin. To evaluate the impact of a lung and/or intrathoracic infection in such a circumstance, we compared the levels of proinflammatory cytokines (interleukin-8 [IL-8]); tumor necrosis factor-alpha (TNF-alpha); the cytokine antagonists and inhibitors (IL-1 receptor antagonist [IL-1ra]) and soluble TNF receptors Types I and II (sTNFRI, sTNFRII); and antiinflammatory cytokines (transforming growth factor-beta [TGF-beta]) in pleural effusion and plasma from septic (n = 15) and nonseptic (n = 9) patients. In addition, we analyzed the levels of IL-6 and its soluble receptor (sIL-6R). Bronchoalveolar lavage fluids (BALFs) were also studied in a few septic patients. High and nonsignificantly different levels of cytokines and inhibitors were detected in both groups of patients. The levels of IL-6 and sTNFRI and sTNFRII in pleural effusion were higher than in plasma, whereas the levels of IL-1ra and sIL-6R were higher in plasma. The levels of sIL-6R influenced the bioactivity of IL-6. There was no correlation between the levels of cytokines in plasma and in pleural effusion. In contrast, a significant correlation was observed for the soluble receptors sIL-6R (r = 0.67, p < 0.001), sTNFRI (r = 0.76, p < 0.001) and sTNFRII (r = 0.66, p = 0.001). Furthermore, a high correlation was found between the levels of both forms of sTNFRs in plasma (r = 0.95, p < 0.001) and in pleural effusion (r = 0.79, p < 0.001). In addition, a correlation was observed between the levels of TGF-beta in pleural effusion and in BALF. The highest levels of some markers in plasma and of others in pleura argue in favor of both a systemic and a compartmentalized response, independently of the presence of infection. Because cytokines can be trapped by the surrounding cells in their environment, measurable levels of cytokines in biologic fluids represent the "tip of the iceberg," which is not the case for soluble receptors. The correlations of these latter markers between plasma and pleura strongly suggest that exchanges between both compartments can occur in both directions.

Topics: Adult; Aged; Aged, 80 and over; Biological Assay; Cytokines; Enzyme-Linked Immunosorbent Assay; Female; Humans; Inflammation Mediators; Interleukin-1; Interleukin-6; Interleukin-8; Male; Middle Aged; Pleural Effusion; Receptors, Cytokine; Receptors, Interleukin-1; Receptors, Interleukin-6; Receptors, Tumor Necrosis Factor; Sepsis; Solubility; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

We measured the plasma levels of anti-inflammatory cytokines, including interleukin 1 receptor antagonist (IL-1ra), IL-4 and IL-10; inflammatory cytokines, including IL-2, IL-6, IL-8 and tumor necrosis factor receptor I and II (TNFR I and TNFR II); and endotoxin in 11 patients with septic shock associated with gram-negative bacteria and 12 patients with sepsis not associated with shock. The plasma levels of IL-1ra and IL-10 were elevated in the septic shock group compared with the sepsis group. TNFR I and TNFR II levels tend to be higher in the septic shock group. The plasma level of TRNF-alpha was significantly correlated with levels of IL-1ra, IL-4, IL-10, TNFR I, and TNFR II. The elevated levels of the anti-inflammatory cytokines, TNFR I, and TNFR II, appeared to reflect an attempt to suppress the shock syndrome.

Topics: Adult; Aged; Antigens, CD; Cytokines; Enzyme-Linked Immunosorbent Assay; Female; Humans; Interleukin 1 Receptor Antagonist Protein; Interleukin-10; Interleukin-2; Interleukin-4; Interleukin-6; Interleukin-8; Male; Middle Aged; Receptors, Tumor Necrosis Factor; Receptors, Tumor Necrosis Factor, Type I; Receptors, Tumor Necrosis Factor, Type II; Sepsis; Shock, Septic; Sialoglycoproteins

To better understand the role of granulocyte colony-stimulating factor (G-CSF) after the inflammatory response.. Serum G-CSF concentrations were measured serially in 19 trauma and 15 sepsis patients. Changes in G-CSF concentration were compared with those in the neutrophil ratio, phagocytic and bactericidal activities, and other cytokines.. G-CSF concentrations in trauma patients were elevated on day 1, but quickly decreased within 7 days. G-CSF reached its maximum 3 hours after injury, parallel with peaks of interleukin-6 (IL-6) and IL-8, but not of tumor necrosis factor-alpha (TNF-alpha). In sepsis patients, G-CSF as well as TNF-alpha, IL-6, and IL-8 concentrations were markedly elevated at diagnosis and remained high during the course of the illness. These levels decreased significantly in the 11 survivors. Up to 3 days after the trauma, nonsegmented neutrophil ratios were higher than those thereafter. Neutrophil phagocytic and bactericidal activities remained normal during the course of disease in both conditions.. These results suggest that G-CSF plays an important role in the maturation and maintenance of function of neutrophils during the inflammatory response to trauma and sepsis.

Topics: Adolescent; Adult; Aged; Female; Granulocyte Colony-Stimulating Factor; Humans; Inflammation; Interleukin-6; Interleukin-8; Leukocyte Count; Male; Middle Aged; Multiple Trauma; Neutrophils; Sepsis; Survival Analysis; Time Factors; Tumor Necrosis Factor-alpha

We studied paired bronchoalveolar lavage (BAL) in patients with sepsis-associated acute respiratory distress syndrome (ARDS). Patients were evaluated at one institution and underwent bronchoscopy with BAL within 48 h of the onset of ARDS. Patients were restudied with bronchoscopy and BAL after 4 d of treatment. Fifty-eight patients were initially studied, with 44 patients having follow-up bronchoscopy after 4 d. The overall 30-d survival for the ARDS group was 60%. In the initial lavage, there was no difference in the neutrophils between the survivors and nonsurvivors (survivors: 59 [0-98]%; Median [Range]; nonsurvivors: 55 [0-92]%). The follow-up lavage demonstrated a significant drop in the neutrophils for the survivors (36 [4-89]%, p < 0.002) which was not seen for the nonsurvivors (70 [26-95]%). Initial IL-8 concentrations in the BAL fluid were not significantly different between the two groups. In the follow-up lavage, there was a significant fall for the IL-8 concentrations for the survivors but not the nonsurvivors. We conclude that neutrophil influx in ARDS may rapidly resolve within a week of the onset of ARDS. The resolution of neutrophils was associated with a good prognosis.

Topics: Acute Disease; Adult; Aged; Bronchoalveolar Lavage Fluid; Bronchoscopy; Female; Humans; Interleukin-8; Lung; Male; Middle Aged; Prognosis; Respiratory Distress Syndrome; Sepsis; Survival Rate

To test the hypothesis that significantly higher concentrations of interleukin-8 (IL-8) are found in the pulmonary edema fluid and plasma of patients with a septic vs. a nonseptic etiology of acute respiratory distress syndrome (ARDS).. Prospective measurement of IL-8 concentrations in previously collected edema fluid and plasma.. Adult intensive care units at a university medical center.. There were 27 patients with ARDS (16 patients with a septic etiology and nine patients with a nonseptic etiology) plus eight control patients with hydrostatic pulmonary edema.. IL-8 was present in the pulmonary edema fluid of all patients with ARDS, but the median IL-8 concentration was higher in the edema fluid of patients with ARDS associated with sepsis (84.2 ng/mL, n = 16) compared with the ARDS patients without sepsis (14.8 ng/mL, n = 11) (p < .05). In patients with cardiogenic edema, IL-8 concentration (5.0 ng/mL,n = 8, p < .05) was significantly lower than those values in patients with ARDS. Median plasma concentration of IL-8 was increased in septic individuals (1.3 ng/mL), but these concentrations were not significantly higher than in patients with a nonseptic etiology of ARDS (0.35 ng/mL) (p = .14) or those patients with cardiac failure (0.21 ng/mL).. The high concentrations of IL-8 in pulmonary edema fluid, coupled with the relatively low concentrations of IL-8 in the plasma, suggest that the lung was the primary source of IL-8 in the patients with ARDS. The markedly increased concentrations of IL-8 in the pulmonary edema fluid of patients with ARDS from sepsis suggests that this group of patients may be particularly suitable for potential trials directed at inhibiting the activity of this important chemokine.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Humans; Intensive Care Units; Interleukin-8; Lung; Middle Aged; Prospective Studies; Pulmonary Edema; Respiratory Distress Syndrome; Sepsis

We measured the levels of soluble intercellular adhesion molecule-1 (sICAM-1), CD11a, CD11b, CD18, endotoxin, and various inflammatory cytokines to clarify the relationship between adhesive molecules and cytokines in sepsis. We studied 21 patients with sepsis (sepsis group) and 13 patients with trauma not complicated by infection (trauma group). The mean sICAM-1 level was significantly higher in the sepsis group than in the trauma group. No significant difference was observed in the CD11a, CD11b, and CD18 levels between the two groups. The sICAM-1 levels significantly correlated with the levels of endotoxin, tumor necrosis factor alpha (TNF-alpha), and IL-8, but CD11a, CD11b, and CD18 levels did not correlate with endotoxin or cytokine levels. These findings suggest that ICAM-1 production is induced by endotoxins and cytokines produced in excess by inflammatory reactions and that endotoxins and cytokines are involved in qualitative, but not quantitative changes in LFA-1 (CD11a/CD18) and Mac-1 (CD11b/CD18).

Topics: Adult; Aged; Aged, 80 and over; Antigens, CD; Cell Adhesion Molecules; Cytokines; Endothelium, Vascular; Female; Humans; Interleukin-8; Male; Middle Aged; Sepsis; Tumor Necrosis Factor-alpha; Wounds and Injuries

Sepsis and septic shock lead to activation of the complement cascade and to the release of pro-inflammatory cytokines.. The effects of E coli infusion and of infusion of anti-TNF antibodies and a xanthine derivative (HWA 138) on complement activation and cytokine release was evaluated in 17 baboons. All animals received 5 x 10(8) live bacteria per kg body weight. Five animals received only bacteria, five received in addition 0.5 mg per kg body weight of anti-TNF-antibody, and seven received an infusion of 6 mg per kg body weight of HWA 138 in addition to the bacteria.. In baboons receiving 5 x 10(8) live E coli per kg body weight increased plasma levels of TCC, TNF-alpha and IL-8 were found. The release of TNF-alpha was lower in the group receiving HWA 138 at 2 h after the infusion. In baboons receiving an infusion of anti-TNF antibody the concentration of IL-8 was lower at 2 and 4 h than in animals receiving just E coli or HWA 138.. Infusion of anti-TNF-antibody before E coli infusion will decrease the formation of IL-8. Infusion of HWA 138 before the E coli infusion will also inhibit the formation of TNF-alpha.

Topics: Animals; Antibodies; Complement Activation; Complement Membrane Attack Complex; Escherichia coli Infections; Hemodynamics; Interleukin-8; Male; Papio; Pentoxifylline; Sepsis; Tumor Necrosis Factor-alpha; Xanthines

The present study was conducted to determine whether a plasma interleukin-1 receptor antagonist (IL-1ra) would reflect the severity of burn injury and to examine the relation between IL-1ra and the cytokines. We studied 24 burn patients in whom the total burn surface area (TBSA) accounted for at least 20% of the body surface, and in whom serial blood samples could be obtained beginning immediately after the burn injury. Plasma levels of IL-1ra were determined by enzyme-linked immunosorbent assay (ELISA). Plasma levels of tumor necrosis factor-alpha (TNF-alpha), IL-6, and IL-8 were also determined by ELISA. Endotoxin was measured by an endotoxin-specific synthetic substrate method. There was a significant correlation between the plasma levels of IL-1ra and TBSA during the first week following burn injury. The IL-1ra level was the highest immediately after the burn injury. The level decreased markedly thereafter, and again rose when infection occurred. The IL-1ra level was extraordinarily elevated in patients who developed concomitant sepsis, septic shock or the septic multiple organ dysfunction syndrome. The IL-1ra level on admission and the maximum IL-1ra level during the observation period were significantly higher in the patients who eventually died than in the survivors. There was a significant correlation between the level of IL-1ra and that of TNF-alpha, IL-6 or IL-8 during the observation period. No correlation was found between IL-1ra and endotoxin. The plasma IL-1ra level was closely correlated with the severity of inflammation and the clinical status of the burn patients, regardless of the infection. Results suggest that IL-1ra can serve as an index of the systemic inflammatory response syndrome (SIRS).

Topics: Adult; Aged; Burns; Endotoxins; Enzyme-Linked Immunosorbent Assay; Female; Humans; Interleukin 1 Receptor Antagonist Protein; Interleukin-6; Interleukin-8; Male; Middle Aged; Receptors, Interleukin; Sepsis; Sialoglycoproteins; Systemic Inflammatory Response Syndrome; Tumor Necrosis Factor-alpha

Different immunologic parameters were measured in cord blood to test their usefulness in the early diagnosis of early onset sepsis. Cord blood levels of circulating intercellular adhesion molecule-1 (cICAM-1), interleukin-6 (IL-6) and interleukin-8 (IL-8) were significantly elevated in septic compared to nonseptic neonates. No significant difference between either population was seen for cord blood C3a and elastase-alpha 1-proteinase inhibitor complex (E alpha 1 PI). Measured concentrations of cICAM-1, IL-6 and IL-8 in fetal and maternal blood did not correlate, indicating that the neonate's response to sepsis is clearly different from the mother. Our data suggest that cord blood measurements of cICAM-1, IL-6 and IL-8 might be useful in identifying neonates with early-onset sepsis.

Topics: Escherichia coli Infections; Fetal Blood; Haemophilus Infections; Haemophilus influenzae; Humans; Infant, Newborn; Intercellular Adhesion Molecule-1; Interleukin-6; Interleukin-8; Sepsis

Blood levels of various cytokines were determined in patients with burn injury immediately after the accident, and the relationship between cytokines and morbid condition was investigated. There was almost no marked elevation of cytokines in the early stage of burn injury. Throughout the entire course, tumour necrosis factor alpha, interleukin 6 and interleukin 8, as cytokines, showed high levels in patients with burn injury associated with sepsis and those who died. These levels well reflected the severity in the phase complicated with sepsis.

Topics: Accidents; Adult; Aged; Body Surface Area; Body Temperature; Burns; Cytokines; Female; Humans; Interleukin-6; Interleukin-8; Leukocyte Count; Male; Middle Aged; Prognosis; Sepsis; Survival Rate; Tumor Necrosis Factor-alpha; Wound Infection

We studied blood MIP-1 alpha and IL-8 in 38 septic patients and 5 healthy volunteers. Both chemokines were undetectable in the healthy volunteers. In sepsis, serum MIP-1 alpha was detected in 45% of the patients and Il-8 in 84%. The levels of MIP-1 alpha, but not of IL-8, correlated with CRP, IL-6 and TNF alpha levels. Complications, including various organ failures and mortality, showed no correlation with serum MIP-1 alpha levels. In contrast, we found increased levels of serum IL-8 in septic patients with disseminated intravascular coagulation, central nervous system (CNS) dysfunction or renal failure, and the mortality rate was higher in the IL-8 detectable group than in the IL-8 undetectable group (50% vs 0%, p < 0.05). In conclusion, the production of both MIP-1 alpha and IL-8 was increased and initially detectable levels of circulating IL-8 predicted high mortality in sepsis.. To determine the significance of the C-C chemokine MIP-1 alpha and the C-X-C chemokine IL-8 in sepsis.. Prospective study.. Clinical investigation, emergency department and general intensive care unit of university hospital.. 38 septic patients and 5 healthy volunteers were studied. Sepsis was diagnosed following the criteria formulated by ACCP/SCCM.. 10-20 ml of blood was drawn from each patient at the time of initial diagnosis of sepsis.. MIP-1 alpha and IL-8 were determined by sandwich ELISA. Both chemokines were undetectable in the healthy volunteers. In sepsis, serum MIP-1 alpha was detected in 45% of the patients and IL-8 was detected in 84%. The levels of MIP-1 alpha, but not of IL-8, correlated with CRP, IL-6 and TNF alpha levels. Complications, including various organ failures and mortality, showed no correlation with serum MIP-1 alpha levels. In contrast, we found increased levels of serum IL-8 in patients with disseminated intravascular coagulation (DIC) (p < 0.05), central nervous system (CNS) dysfunction (p < 0.05), renal failure (p < 0.01) and the mortality rates were higher in the IL-8 detectable group than in the IL-8 undetectable group (50% vs 0%, p < 0.05).. The production of MIP-1 alpha and IL-8 was increased in sepsis. Furthermore, an initially detectable level of circulating IL-8, but not MIP-1 alpha, predicted a high mortality in sepsis diagnosed according to the ACCP/SCCM criteria.

Topics: Biomarkers; Case-Control Studies; Chemokine CCL4; Disseminated Intravascular Coagulation; Female; Humans; Interleukin-8; Japan; Macrophage Inflammatory Proteins; Male; Middle Aged; Multiple Organ Failure; Prognosis; Prospective Studies; Sepsis; Statistics, Nonparametric

Large burns are followed by significant trauma-induced immunomodulation, and activated neutrophils can be demonstrated in the circulation of burn patients shortly after injury. Interleukin-8 (IL-8) is a recently described molecule with neutrophil activating properties and in the present study we have measured the concentration of this cytokine in plasma from 27 patients with large burns during hospitalization using an enzyme linked immunosorbent assay (ELISA). The mean patient plasma concentration of IL-8 at admission was about 60 times higher than that of healthy controls. Furthermore, patients with total body surface area burn of more than 40% had significantly higher IL-8 concentrations in plasma than patients with smaller burns. For patients without serious infectious complications, the IL-8 concentration fell gradually after injury, whereas in patients with complicating sepsis a second peak of IL-8 was demonstrated. Thus, the increased IL-8 concentrations seem to be related to burn size and to have a role in the pathophysiology of sepsis in patients with large burns. The large amounts of circulating IL-8 following thermal injury may contribute to the strong and sustained activation of neutrophils reported earlier in patients with large burns.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Body Surface Area; Burns; Case-Control Studies; Enzyme-Linked Immunosorbent Assay; Female; Follow-Up Studies; Humans; Interleukin-8; Leukocyte Count; Male; Middle Aged; Neutrophil Activation; Sepsis; Trauma Severity Indices

To determine whether continuous venovenous hemodialfiltration (CVVHD) is associated with the extraction of interleukin-6 (IL-6) and interleukin-8 (IL-8) from the circulation of critically ill patients with septic acute renal failure. To quantitate their clearance and assess any possible effect of CVVHD on these cytokines' serum concentrations.. Prospective controlled study of IL-6 and IL-8 removal by CVVHD in patients with septic acute renal failure.. Intensive care unit of a tertiary institution.. Ten critically ill patients with sepsis, acute renal failure, and multiorgan failure. A control group of five patients experiencing an acute illness while undergoing chronic hemodialysis.. Collection of blood samples before CVVHD. Simultaneous collection of prefilter blood and ultradiafiltrate after 4 and 24 h of treatment. IL-8 concentrations were measured in blood and ultradiafiltrate. Their clearances and daily extractions were calculated.. IL-6 and IL-8 were detected in the blood of all patients with septic acute renal failure prior to CVVHD. The median IL-6 blood level was 103 pg/mL (range: 19 to 900) and the median IL-8 blood level was 200 (range: 32 to 2925). Both cytokines were cleared by the hemofilter during CVVHD. The median hemofilter clearance of IL-6 were 1.99 L/day (range: 0 to 8.5) and the median clearance of IL-8 was 3.95 L/day (range: 0.31 to 42.8). These blood levels and clearances resulted in median daily extraction rates of 194 ng of IL-6 (range: 0 to 9031) and of 915 ng of IL-8 (range 47.5 to 3562). Control patients had negligible amounts of either IL-6 or IL-8 in their ultrafiltrate. The rate of extraction for IL-6 correlated with its blood levels (p < 0.0001). This was not true for IL-8. A correlation between IL-6 levels and the patients' white cell counts was found after 24 h of hemofiltration.. CVVHD is associated with the extraction of IL-6 and IL-8 from the circulation of patients with septic multiorgan and renal failure. The biological significance of such extraction is undetermined, but such cytokine removal highlights the complexity of the effect of continuous hemofiltration on the soluble mediators of inflammation activated during human sepsis.

Topics: Acute Kidney Injury; APACHE; Case-Control Studies; Female; Hemodiafiltration; Humans; Interleukin-6; Interleukin-8; Male; Middle Aged; Multiple Organ Failure; Prospective Studies; Sepsis

Because of their effects on monocytes, monocyte chemotactic proteins-1 and -2 (MCP-1 and MCP-2) may participate in the pathophysiology of sepsis. We measured circulating MCP-1 and MCP-2 levels in 42 septic patients having positive local or blood cultures. MCP-1 and MCP-2 levels were elevated in 24 (57%) and 25 (59%) of 42 septic patients, respectively, compared with healthy volunteers. Both patients with gram-positive and gram-negative infections had elevated MCP-1 plasma levels (P = .0001) and P < .0001), respectively; Mann-Whitney-U test), whereas patients with gram-positive infection, but not those with gram-negative infection, had increased MCP-2 plasma levels (P= .0182). No relative differences in MCP-1 and MCP-2 plasma levels were observed between several subgroups of patients (sepsis v septic shock; survivors v nonsurvivors), although levels of MCP-1 were the highest in patients with the more severe forms of sepsis, ie, those with shock or a lethal outcome. Serial observations showed that MCP-1 and MCP-2 plasma levels remained elevated for at least 48 hours. MCP-1 correlated weakly with interleukin-8 and MCP-2, the correlations for which were most pronounced in patients with septic shock. MCP-2 correlated with interleukin-8, and surprisingly, with the complement activation product C3a; these correlations further improved when analyzing patients with septic shock or when applying gram-positive infections. Thus, our results not only show increased MCP-1 and MCP-2 levels in patients with sepsis, but also suggest that the synthesis and release of MCP-1 and MCP-2 in sepsis are differently regulated in part.

Topics: Chemokine CCL2; Chemokine CCL8; Female; Follow-Up Studies; Gram-Negative Bacterial Infections; Gram-Positive Bacterial Infections; Humans; Interleukin-6; Interleukin-8; Male; Middle Aged; Monocyte Chemoattractant Proteins; Mycoses; Sepsis; Shock, Septic; Single-Blind Method; Survivors

Commercially available ELISA kits now make it possible to measure cytokines in biological samples and cell culture supernatants. We have compared the levels of IL-1 beta, IL-6, IL-8 and TNF-alpha in various pathological plasma and synovial fluids, and in supernatants of human monocytes activated by lipopolysaccharide (LPS). Measurements were performed using ELISA kits from different companies. A wide variation in values was obtained when measurements were deduced from the standard curves formed with the standard provided by the manufacturers. We also performed calibration curves for all ELISA kits, using the international standards provided by the NIBSC (UK). The coefficients of variation were then significantly improved for IL-6 and IL-8 measurements but not for IL-1 beta and TNF alpha assays. However, despite this attempt to obtain uniform measurements, none of the kits gave similar values for individual samples. These results suggest that the nature of the different pairs of monoclonal antibodies employed in each ELISA does not permit comparable recognition of cytokines in samples. Further work with the various kits is required to establish whether (i) denaturation of the recognized epitope within the natural cytokine, (ii) fragmentation of the cytokine following enzymatic cleavage, (iii) depolymerization, (iv) binding of cytokines to undefined ligands, (v) variable glycosylation of the natural cytokines (vi) recognition of precursor forms, interferes with the measurements.

Topics: Antibodies, Monoclonal; Arthritis; Cells, Cultured; Culture Media, Conditioned; Enzyme-Linked Immunosorbent Assay; Epitopes; False Negative Reactions; Humans; Interleukin-1; Interleukin-6; Interleukin-8; Interleukins; International Agencies; Leukocytes, Mononuclear; Lipopolysaccharides; Protein Denaturation; Reagent Kits, Diagnostic; Reference Standards; Reproducibility of Results; Sepsis; Synovial Fluid; Tumor Necrosis Factor-alpha

Septic shock is the major cause of treatment-related death in patients with acute myelogenous leukaemia (AML) undergoing intensive chemotherapy. Interleukins (IL)-1 beta, -6, -8, and tumour necrosis factor alpha (TNF-alpha) have been implicated as mediators of septic shock, with circulating leucocytes being considered a major source for their release. However, plasma cytokine levels of leucocytopenic patients with evolving sepsis have not been studied. We have prospectively measured plasma cytokines during chemotherapy-induced leucocytopenia (< 1 x 10(9)/l) in 50 patients with AML. Cytokine levels in patients with severe sepsis (n = 5) or septic shock (n = 8) were compared to those measured in 13 matched patients with uncomplicated febrile infections. In evolving septic shock, IL-6, IL-8 and TNF-alpha peaked within 48 h of fever onset at levels reported for non-leucocytopenic patients and distinctively higher than during uncomplicated febrile episodes (P < 0.05). Peak concentrations measured within 48 h after onset of fever were related to fatal outcome. IL-1 beta was detected in less than 5% of all samples. Cytokine concentrations were unrelated to leucocyte counts and markers of neutrophil or monocyte activation (elastase and neopterin levels, respectively). We conclude that cytokine release associated with evolving septic shock in patients with AML does not depend on circulating leucocytes.

Topics: Adult; Aged; Antineoplastic Agents; Biopterins; Cytokines; Female; Humans; Interleukin-6; Interleukin-8; Leukemia, Myeloid, Acute; Leukopenia; Male; Middle Aged; Neopterin; Pancreatic Elastase; Prospective Studies; Sepsis; Shock, Septic; Tumor Necrosis Factor-alpha

To clarify the relationship between cytokines and arachidonic acid metabolites, we measured tumor necrosis factor (TNF-alpha), interleukin 8 (IL-8), and leukotriene B4 (LTB4). The subjects consisted of 30 patients with sepsis. The results were compared between patients who died (Group A) and those who survived (Group B). All TNF-alpha, IL-8, and LTB4 levels were significantly higher in Group A than in Group B, reflecting the severity of the disease. The LTB4 levels were significantly correlated with the TNF-alpha level and the IL-8 level. These results suggest that inflammatory cytokines, excessively produced due to inflammatory reactions, stimulate as a mediator the release of arachidonic acid, increasing LTB4 production.

Topics: Adult; Aged; Aged, 80 and over; Enzyme-Linked Immunosorbent Assay; Female; Humans; Interleukin-8; Leukotriene B4; Male; Middle Aged; Sepsis; Tumor Necrosis Factor-alpha

The proteolytic enzyme elastase released by granulocytes (polymorphonuclear leukocytes [PMN]) in high concentrations during sepsis causes degradation of essential plasma proteins, endothelial damage, and tissue edema. This may result in organ dysfunction and organ failure during sepsis, since increased elastase plasma levels correlate with the mortality rate of patients with sepsis. In vitro studies demonstrated a regulatory role of inflammatory cytokines (tumor necrosis factor-alpha [TNF-alpha], interleukin 1 beta [IL-1 beta], IL-8]) upregulating protease release by PMN. In this light, the interactions between cytokine release by macrophages and altered elastase secretion during sepsis remain to be determined.. An ex vivo model consisting of lipopolysaccharide stimulation of human whole blood as a relevant physiological milieu was used. Heparinized blood was obtained from 20 patients with sepsis syndrome (APACHE II [Acute Physiology and Chronic Health Evaluation II] score 28.5 +/- 1.2 points [mean +/- SD]) on days 0 through 3, 5, 7, and 10 after sepsis diagnosis and from 20 control patients without infection. Blood was incubated with lipopolysaccharide (1 mg/L) for 8 hours. Plasma levels of elastase, TNF-alpha, IL-1 beta, and IL-8 were determined using enzyme-linked immunosorbent assay or bioassay (TNF-alpha), respectively.. Elastase plasma levels in whole blood from patients with sepsis were increased up to 188% (P < .01) above normal, while the release of TNF-alpha (-87%), IL-1 beta (-91%), and IL-8 (-51%) was markedly (P < .01) decreased compared with control patients. Neutralization of TNF-alpha or IL-1 beta did not attenuate the increased release of elastase.. These data indicate an increased release of elastase by PMN despite a reduced secretion of PMN-activating cytokines. Although priming effects of TNF-alpha, IL-1 beta, and IL-8 on protease secretion in vivo cannot be excluded completely, other mediators or mechanisms may be involved in the upregulation of detrimental protease release during sepsis.

Topics: Adult; Aged; Autoantibodies; Case-Control Studies; Cytokines; Humans; Interleukin-1; Interleukin-8; Leukocyte Elastase; Lipopolysaccharides; Middle Aged; Neutrophils; Pancreatic Elastase; Sepsis; Shock, Septic; Tumor Necrosis Factor-alpha

The role of tumor necrosis factor (TNF) in interleukin (IL)-8 release in septicemia in the baboon (2-h infusion of live Escherichia coli, 5 x 10(8) cfu/kg) was investigated. Four experiments were done: one control (n = 7) and three with pretreatment to reduce TNF plasma levels. Pretreatment was with anti-TNF antibody (anti-TNF) 15 mg/kg, which neutralized circulating TNF (n = 4); 0.5 mg/kg of anti-TNF, which reduced peak TNF from 6.2 ng/mL (controls) to 0.6 ng/mL (n = 4); and a xanthine derivate (HWA138), which reduced TNF to 1 ng/mL (n = 5). With TNF levels < 1 ng/mL, a significant reduction of circulating IL-8 from 10.4 ng/mL (peak) in controls to 1 ng/mL (peak) in anti-TNF-treated animals was found, but with HWA138 only some decrease in IL-8 was seen. Despite high endotoxin levels (10-30 ng/mL peak), neutralization of TNF resulted in diminished release of IL-8 and significantly lower levels of granulocyte elastase.

Topics: Animals; Escherichia coli Infections; Interleukin-8; Male; Papio; Sepsis; Tumor Necrosis Factor-alpha

Patients suffering from serious bacterial infection present to the hospital after early inflammatory events, such as release of tumor necrosis factor (TNF), have been initiated. The role of other cytokines, such as interleukin-8 (IL-8), a neutrophil chemoattractant and activator, in the pathophysiology of human sepsis is not well characterized, and there are only limited data on IL-6. We studied serial concentrations of TNF, IL-6 (involved in the acute-phase response), and IL-8 in plasma and leukocyte levels of mRNA for these cytokines in patients with localized and septicemic Pseudomonas pseudomallei infection on admission to the hospital and during a prolonged recovery phase (up to 30 days). Of 18 patients, 8 had detectable plasma IL-8 and all had raised plasma IL-6 concentrations. In patients who died median initial concentration of IL-8 (167 pg/ml; range, 97 to 362 pg/ml) and IL-6 (4,800 pg/ml; range, 60 to 9,245 pg/ml) in plasma were higher than those in survivors (P less than 0.008 and P = 0.007, respectively). Septic patients who survived and patients with localized disease had similar cytokine levels. Plasma IL-8 and IL-6 concentrations were elevated throughout the inpatient period of recovery. Circulating leukocytes contained mRNA for IL-8 but not for IL-6 and TNF, and they may secrete IL-8. An elevated plasma IL-6 concentration (greater than 1,000 pg/ml) had 75% mortality) was the best predictor of mortality in P. pseudomallei sepsis. Fifty percent of patients with detectable plasma IL-8 concentrations died. In contrast, plasma TNF bioactivity did not relate to outcome; 75% of patients who did never had detectable plasma TNF activity.

Topics: Adult; Aged; Burkholderia pseudomallei; Female; Humans; Interleukin-6; Interleukin-8; Leukocytes; Male; Middle Aged; Pseudomonas Infections; RNA, Messenger; Sepsis; Tumor Necrosis Factor-alpha

IL-8, a cytokine known for its potent and specific neutrophil activation and chemoattractant properties, has been recently detected in the circulation during septic shock, endotoxemia, and after IL-1 alpha administration. Because of its observed in vitro actions, it has been hypothesized that IL-8 may contribute to the dynamics of circulating granulocytes and to the pathologic sequelae seen in sepsis. Here, human rIL-8 is administered to healthy nonhuman primates as a single i.v. injection or as a continuous 8-h i.v. infusion. We demonstrate that both methods of i.v. administration result in a rapid but transient, severe granulocytopenia, followed by a granulocytosis that persists as long as IL-8 levels are detectable in the circulation. There were no hemodynamic changes after IL-8 administration, and animals remained clinically stable during the 24-h observation period. No detectable circulating TNF-alpha, IL-1 beta, or IL-6 response was induced by either IL-8 administration regimen. Histopathologic examination revealed mild to moderate neutrophilic margination in lung, liver, and spleen, of greater severity in baboons receiving the 8-h infusion. There was no associated neutrophilic infiltration or tissue injury. Thus, IL-8 modulates circulating granulocyte dynamics and likely directs their actions, but when administered i.v. to healthy animals, either as a bolus dose or as a continuous infusion for up to 8 h, does not induce the hemodynamic and metabolic aberrations or the acute organ damage seen during sepsis.

Topics: Animals; Cytokines; Female; Hemodynamics; Injections, Intravenous; Interleukin-8; Leukocyte Count; Papio; Recombinant Proteins; Sepsis; Spleen

A hyperdynamic sepsis model was set up in seven adult baboons to evaluate neutrophil-activating peptide-1/interleukin (IL)-8 (NAP-1/IL-8), IL-1 beta, IL-6, tumor necrosis factor-alpha (TNF alpha), and IFN-gamma in plasma. By continuous intravenous administration of 10(10) cfu/kg live Escherichia coli over 8 h with additional infusion therapy (less than or equal to 50 ml/kg/h), endotoxin plasma levels of 2.7-22.3 ng/ml were observed. In plasma the kinetics of NAP-1/IL-8 and IL-6 were similar to those of IL-1 at the end of the experiment (8 h) (peak median values, 34, 4197, and 230 ng/ml, respectively). Differences were greatest for IL-6. Monocyte activation during sepsis was confirmed by elevated plasma neopterin levels (91-139 mumol/mmol of creatine). Granulocyte activation was evident from both incipient neutropenia and the massive release of neutrophil elastase into the plasma as measured by a new immunoassay (peak level, 374 ng/ml). Thus, in primate bacteremia, early TNF release is followed by a concomitant increase of NAP-1/IL-8 with plasma kinetics similar to those of IL-6 and IL-1 and accompanied by massive activation of neutrophils.

Topics: Animals; Biopterins; Disease Models, Animal; Endotoxins; Escherichia coli Infections; Interferon-gamma; Interleukin-1; Interleukin-6; Interleukin-8; Leukocyte Elastase; Male; Neopterin; Pancreatic Elastase; Papio; Sepsis; Tumor Necrosis Factor-alpha

Topics: Animals; Biopterins; Endotoxins; Escherichia coli Infections; Humans; In Vitro Techniques; Infant, Newborn; Interleukin-1; Interleukin-6; Interleukin-8; Kidney; Leukocytes; Lipopolysaccharides; Lung; Male; Models, Biological; Neopterin; Pancreatic Elastase; Papio; Sepsis; Tumor Necrosis Factor-alpha