interleukin-8 and Shock--Septic

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

Sepsis is still a major cause of postoperative morbidity and mortality. Numerous biochemical indicators have been evaluated regarding their potential in predicting prognosis in sepsis. Generally, one must differentiate between indicators: those for preoperative detection of patients at risk for lethal sepsis and those for early prediction of lethal outcome of septic complications. The first include the analysis of mononuclear phagocyte interleukin (IL)-12-synthesizing capability. Reduced IL-12 levels were associated with higher lethality. Cytokine-associated gene polymorphisms such as the loss of monocyte HLA-DR expression and homozygotism for the tumor necrosis factor B2 allele have a place in preoperative risk evaluation, as they were associated with worse prognosis in sepsis. Among the most important biochemical indicators for early prediction of lethal outcome in sepsis are decreased L-selectin and elevated IL-18, IL-6, and PCT plasma concentrations. Increased nuclear factor kappaB activity in mononuclear phagocytes and elevated calcitonin gene-related protein plasma concentrations were associated with unfavourable prognosis.

Topics: Calcitonin; Hospital Mortality; Humans; Interleukin-12; Interleukin-18; Interleukin-8; L-Selectin; Postoperative Complications; Predictive Value of Tests; Prognosis; Protein Precursors; Risk Factors; Shock, Septic; Surgical Wound Infection; Systemic Inflammatory Response Syndrome

Myocardial dysfunction is common in sepsis but optimal treatment strategies are unclear. The inodilator, levosimendan was suggested as a possible therapy; however, the levosimendan to prevent acute organ dysfunction in Sepsis (LeoPARDS) trial found it to have no benefit in reducing organ dysfunction in septic shock. In this study we evaluated the effects of levosimendan in patients with and without biochemical cardiac dysfunction and examined its non-inotropic effects.. Two cardiac biomarkers, troponin I (cTnI) and N-terminal prohormone of brain natriuretic peptide (NT-proBNP), and five inflammatory mediators were measured in plasma from patients recruited to the LeoPARDS trial at baseline and over the first 6 days. Mean total Sequential Organ Failure Assessment (SOFA) score and 28-day mortality were compared between patients with normal and raised cTnI and NT-proBNP values, and between patients above and below median values.. Levosimendan produced no benefit in SOFA score or 28-day mortality in patients with cardiac dysfunction. There was a statistically significant treatment by subgroup interaction (p = 0.04) in patients with NT-proBNP above or below the median value. Those with NT-proBNP values above the median receiving levosimendan had higher SOFA scores than those receiving placebo (mean daily total SOFA score 7.64 (4.41) vs 6.09 (3.88), mean difference 1.55, 95% CI 0.43-2.68). Levosimendan had no effect on the rate of decline of inflammatory biomarkers.. Adding levosimendan to standard care in septic shock was not associated with less severe organ dysfunction nor lower mortality in patients with biochemical evidence of cardiac dysfunction.

Topics: Aged; Biomarkers; Chemokine CCL2; Double-Blind Method; Female; Heart Diseases; HSP90 Heat-Shock Proteins; Humans; Intensive Care Units; Interleukin-10; Interleukin-6; Interleukin-8; Male; Middle Aged; Natriuretic Peptide, Brain; Organ Dysfunction Scores; Peptide Fragments; Prognosis; Shock, Septic; Simendan; Troponin I; United Kingdom

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

Plasma interleukin-8 levels of <220 pg/mL have an excellent negative predictive value (94% to 95%) for death at 28 days in children with septic shock and thus may be useful for risk stratification in clinical trial enrollment in this population. Whether plasma interleukin-8 would have similar utility in adults with septic shock is unknown.. Analysis of plasma interleukin-8 levels and prospectively collected clinical data from patients enrolled in two large randomized controlled trials of ventilator strategy for acute lung injury.. Intensive care units of university hospitals participating in the National Institutes of Health Acute Respiratory Distress Syndrome Network.. One hundred ninety-two adult patients with vasopressor-dependent septic shock.. None.. Plasma interleukin-8 levels > or =220 pg/mL were significantly associated with death at 28 days in this cohort (odds ratio, 2.92; 95% confidence interval, 1.42 to 5.99; p = .001). However, in contrast to the findings in pediatric septic shock, a plasma interleukin-8 cutoff <220 pg/mL had a negative predictive value for death of only 74% (95% confidence interval, 66% to 81%) in adults with septic shock. Receiver operating characteristic analysis found an area under the curve of 0.59 for plasma interleukin-8, indicating that plasma interleukin-8 is a poor predictor of mortality in this group. In adults aged <40 yrs, a plasma interleukin-8 cutoff <220 pg/mL had a negative predictive value of 92%.. In contrast to similar pediatric patients, plasma interleukin-8 levels are not an effective risk stratification tool in older adults with septic shock. Future studies of biomarkers for risk stratification in critically ill subjects will need to be replicated in multiple different populations before being applied in screening for clinical trials.

Topics: Acute Lung Injury; Adult; Aged; Biomarkers; Cohort Studies; Critical Care; Female; Humans; Interleukin-8; Male; Middle Aged; Predictive Value of Tests; Respiration, Artificial; Risk Assessment; ROC Curve; Shock, Septic; Vasoconstrictor Agents

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

To compare the hemodynamic and biological effects of high-adsorption continuous veno-venous hemofiltration (CVVH) with standard CVVH in septic shock.. In a randomized cross-over clinical trial twelve patients with septic shock and multiple organ failure were enrolled at a tertiary intensive care unit. Patients were allocated to either 9 hours of high-adsorption hemofiltration (CVVH with 3 hourly filter change using AN69 hemofilters - 3FCVVH) or 9 hours of standard hemofiltration (CVVH without filter change - 1F-CVVH).. Changes in hemodynamic variables, dose of noradrenaline required to maintain a mean arterial pressure greater than 75 mmHg and plasma concentrations of cytokines (IL-6, IL-8, IL-10 and IL-18) were measured. A 9-hour period of 3F-CVVH was associated with greater reduction in noradrenaline dose than a similar period of 1F-CVVH (median reduction: 16 vs. 3.5 microg/min, p=0.036; median percentage reduction: 48.1% vs. 17.5%, p=0.028). Unlike 1F-CVVH, 3F-CVVH was associated with a reduction in the plasma concentration of IL-6, IL-10 and IL-18 at 9 hours and a significant decrease 30 minutes after additional filter changes (IL-6: p<0.01, p<0.01; IL-10: p=0.03, p=0.016 and IL-18: p=0.016, p<0.01, respectively). Both, 3F-CVVH and 1F-CVVH were associated with decreased plasma concentrations of IL-8 at 9 hours (p<0.01, p<0.01, respectively). In a confirmatory ex-vivo experiment IL-6 concentrations substantially decreased during 3F-CVVH (at baseline 511 pg/mL and at end: 21 pg/mL) whereas IL-6 concentrations increased in control blood (at baseline 511 pg/mL and at end: 932 pg/mL).. High-adsorption CVVH appears more effective than standard CVVH in decreasing noradrenaline requirements and plasma concentrations of cytokines in septic shock patients.

Topics: Acute Kidney Injury; Adult; Aged; Aged, 80 and over; Blood Pressure; Female; Heart Rate; Hemofiltration; Humans; Interleukin-10; Interleukin-6; Interleukin-8; Male; Middle Aged; Multiple Organ Failure; Norepinephrine; Renal Dialysis; Shock, Septic

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

Stress doses of hydrocortisone are known to have immunomodulatory effects in patients with hyperdynamic septic shock. The prognosis correlates with the presence and severity of septic encephalopathy. However, neurological evaluation is influenced by the use of analgesia sedation during artificial ventilation. The objective of this study was to demonstrate the effect of stress doses of hydrocortisone during the initial phase of human septic shock on the serum values of the neurospecific protein S-100B in comparison to the inflammation markers interleukin (IL)-8 in serum and polymorphonuclear (PMN) elastase in plasma. A total of 24 consecutive patients, who met the American College of Chest Physicians/Society of Critical Care Medicine criteria for septic shock, were enrolled in this prospective, randomized, double-blind, single-center trial. The severity of illness at recruitment was graded using the Acute Physiology and Chronic Health Evaluation II and the Simplified Acute Physiology Score II scoring systems. Multi-organ dysfunction syndrome was described by the Sepsis-related Organ Failure Assessment (SOFA) score. All patients were prospectively randomized to receive either stress doses of hydrocortisone or placebo. Hydrocortisone was started in 12 patients with a loading dose of 100 mg and followed by a continuous infusion of 0.18 mg/kg/h for 6 days. Median S-100B serum levels of the hydrocortisone group decreased from 0.32 ng/mL at study entry to 0.07 ng/mL 6 days later without significant differences compared to the placebo group. Initial IL-8 serum levels were significantly higher in the hydrocortisone group up to 12 h after study entry, and significantly decreased from 715 to 17 pg/mL at the end of the observation period. Median PMN elastase plasma levels were not affected by hydrocortisone infusion. Patients with initial S-100B serum levels > 0.50 ng/mL revealed significantly higher SOFA scores up to 30 h, IL-8 serum levels up to 12 h, and PMN elastase plasma levels up to 36 h after study entry than those patients with < or = 0.50 ng/mL. These effects were independent of the amount of fluid correction for hemodilution. Starting S-100B, IL-8 and PMN elastase values of the hydrocortisone group were within the ranges already known in patients with out-of-hospital cardiac arrest or severe traumatic brain injury. Stress doses of hydrocortisone resulted in a significant reduction in IL-8 serum, but not in S-100B serum and PMN elastase plasma concentration

Topics: Adult; Aged; Anti-Inflammatory Agents; Dose-Response Relationship, Drug; Double-Blind Method; Female; Germany; Humans; Hydrocortisone; Intensive Care Units; Interleukin-8; Leukocyte Elastase; Male; Middle Aged; Multiple Organ Failure; Nerve Growth Factors; Placebos; Prognosis; Prospective Studies; S100 Calcium Binding Protein beta Subunit; S100 Proteins; Sensitivity and Specificity; Severity of Illness Index; Shock, Septic; Time Factors

Endothelial damage accounts greatly for the high mortality in septic shock. Higher expression of mediators (IL-6, IL-8, soluble intercellular adhesion molecule 1 [sICAM-1], soluble endothelial-linked adhesion molecule 1 [sELAM-1]) have been described for non-survivors in comparison with survivors. We investigated the predictive value of the mediators IL-6, IL-8, sELAM-1 and sICAM-1 and their time course in intensive care unit patients who developed septic shock with respect to outcome.. We measured serum levels of IL-6, IL-8, sELAM-1 and sICAM-1 in 40 intensive care unit patients who developed septic shock. Measurements were performed until death or until resolution of septic shock. Clinical and laboratory data were also recorded.. After 48 hours the levels of sELAM-1 and sICAM-1 increased in non-survivors and decreased in survivors. sELAM-1 was predictive for outcome on the third day (P = 0.02) and the fourth day (P = 0.02) after diagnosis of septic shock. This difference in the time course between survivors and non-survivors occurred 7 days before death of the patients (median, 10 days). sICAM-1 levels increased significantly in non-survivors over the study period (P < 0.001). sELAM-1 (P = 0.04), IL-6 (P = 0.04) and IL-8 (P = 0.008) were significantly higher in non-survivors over the whole study period. The age and norepinephrine dose >0.5 mug/kg/min were significantly different between the groups.. sELAM-1 showed a markedly opposing course after 48 hours of septic shock. This adhesion molecule may be a useful early predictor of disease severity in the course of septic shock after early initial treatment of the patients, and might suggest considering endothelial-restoring therapy.

Topics: Adult; Aged; Aged, 80 and over; Area Under Curve; Biomarkers; Cell Adhesion Molecules; Endothelium, Vascular; Female; Humans; Interleukin-6; Interleukin-8; Male; Middle Aged; Predictive Value of Tests; Shock, Septic; Survival Analysis; Time Factors

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

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

To assess the effects of adjunctive treatment with N-acetyl-L-cysteine (NAC) on hemodynamics, oxygen transport variables, and plasma levels of cytokines in patients with septic shock.. Prospective, randomized, double-blind, placebo-controlled study.. A 24-bed medicosurgical ICU in a university hospital.. Twenty-two patients included within 4 h of diagnosis of septic shock.. Patients were randomly allocated to receive either NAC (150 mg/kg bolus, followed by a continuous infusion of 50 mg/kg over 4 h; n= 12) or placebo (n=10) in addition to standard therapy.. Plasma concentrations of tumor necrosis factor-alpha (TNF), interleukin (IL)-6, IL-8, IL-10, and soluble tumor necrosis factor-alpha receptor-p55 (sTNFR-p55) were measured by sensitive immunoassays at 0, 2, 4, 6 and 24 h. Pulmonary artery catheter-derived hemodynamics, blood gases, hemoglobin, and arterial lactate were measured at baseline, after infusion (4 h), and at 24 h.. NAC improved oxygenation (PaO2/FIO2 ratio, 214+/-97 vs 123+/-86; p<0.05) and static lung compliance (44+/-11 vs 31+/-6 L/cm H2O; p<0.05) at 24 h. NAC had no significant effects on plasma TNF, IL-6, or IL-10 levels, but acutely decreased IL-8 and sTNFR-p55 levels. The administration of NAC had no significant effect on systemic and pulmonary hemodynamics, oxygen delivery, and oxygen consumption. Mortality was similar in both groups (control, 40%; NAC, 42%) but survivors who received NAC had shorter ventilator requirement (7+/-2 days vs 20+/-7 days; p<0.05) and were discharged earlier from the ICU (13+/-2 days vs 32+/-9 days; p<0.05).. In this small cohort of patients with early septic shock, short-term IV infusion of NAC was well-tolerated, improved respiratory function, and shortened ICU stay in survivors. The attenuated production of IL-8, a potential mediator of septic lung injury, may have contributed to the lung-protective effects of NAC.

Topics: Acetylcysteine; Adult; Aged; Aged, 80 and over; Antigens, CD; Double-Blind Method; Female; Hemodynamics; Humans; Infusions, Intravenous; Interleukin-10; Interleukin-6; Interleukin-8; Interleukins; Lactic Acid; Lung Compliance; Male; Middle Aged; Oxygen Consumption; Prospective Studies; Receptors, Tumor Necrosis Factor; Receptors, Tumor Necrosis Factor, Type I; Shock, Septic; Tumor Necrosis Factor-alpha

We tested the effects of NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) synthesis, on plasma levels of interleukin (IL) IL-6, IL-8, tumor necrosis factor-alpha (TNFalpha) and nitrite/nitrate (NO2-/ NO3-) in patients with severe septic shock.. Prospective clinical study.. Surgical intensive care unit at a university hospital.. 11 consecutive patients with severe septic shock.. Standard hemodynamic measurements were made and blood samples taken at intervals before, during, and after a 12-h infusion of L-NAME 1 mg x kg(-1) x h(-1) for determination of plasma IL-6, IL-8, TNFalpha and NO2-/NO3- concentration.. Patients with sepsis had increased plasma levels of IL-6, IL-8, TNFalpha and NO2-/NO3- (p < 0.05). Plasma levels of IL-6. IL-8, and NO2-/NO- were negatively correlated with systemic vascular resistance (r = -0.62, r = -0.65, and r = -0.78, respectively, all p < 0.05). Continuous infusion of L-NAME increased mean arterial pressure and systemic vascular resistance, with a concomitant reduction in cardiac output (all p < 0.01). No significant changes were seen in levels of plasma IL-6, IL-8, and NO-/NO3- during the 24-h observation period. Plasma levels of TNFalpha were significantly reduced during L-NAME infusion compared to baseline (p < 0.05).. NO plays a role in the cardiovascular derangements of human septic shock. Inhibition of NO synthesis with L-NAME does not promote excessive cytokine release in patients with severe sepsis.

Topics: APACHE; Drug Monitoring; Female; Hemodynamics; Humans; Infusions, Intravenous; Interleukin-6; Interleukin-8; Male; NG-Nitroarginine Methyl Ester; Nitrates; Nitric Oxide Synthase; Nitrites; Prospective Studies; Shock, Septic; Survival Analysis; Tumor Necrosis Factor-alpha

Plasma levels of interleukin 12 (IL-12), a cytokine consisting of two different polypeptide subunits (p40 and p35), were measured together with interferon gamma (IFN-gamma) and other cytokines in 46 children with septic shock and purpura. The median (range) plasma IL-12 p40 level on admission was 457 (244-2677) pg/ml in non-survivors vs 189 (< 40-521) pg/ml in survivors (P = < 0.001). IL-12 p70 levels were elevated in only nine patients. IL-12 p40 plasma levels were positively correlated with tumour necrosis factor alpha (TNF-alpha), IL-6, IL-8, IL-10 and PRISM-score, whereas they were negatively correlated with C-reactive protein (CRP), whole blood cell (WBC) and serum glucose levels. Twelve (29%) of the patients had detectable levels of IFN-gamma. Thus, circulating levels of IL-12 p40 and to a lesser extent those of IL-12 p70, are elevated in children with septic shock and purpura, and correlate with severity of disease and outcome.

Topics: Adolescent; Blood Glucose; C-Reactive Protein; Child; Child, Preschool; Female; Humans; Infant; Interferon-gamma; Interleukin-10; Interleukin-12; Interleukin-6; Interleukin-8; Male; Purpura; Severity of Illness Index; Shock, Septic; Tumor Necrosis Factor-alpha

To determine whether a continuous intravenous infusion of pentoxifylline, a methylxanthine derivative, alters the serum cytokine concentrations and/or hemodynamic measurements in patients with septic shock.. A prospective, randomized, double-blind, placebo-controlled study.. Medical intensive care unit in a university hospital.. Sixteen patients with septic shock.. Patients were randomly assigned to receive either pentoxifylline (1 mg/kg) followed by an infusion of 1.5 mg/kg/hr for 24 hrs (n = 8), or placebo (n = 8).. Tumor necrosis factor (TNF) and interleukin (IL)-6 concentrations were measured by radioimmunoassays; IL-8 concentrations by an enzyme-linked immunosorbent assay (ELISA) and pentoxifylline concentrations by high-performance liquid chromatography at 0, 3, 6, 12, 18, 24 and 48 hrs after study entry. Pulmonary artery catheter-derived hemodynamics were measured at 0, 0.75, 3, 6, 12, 18, and 24 hrs. In pentoxifylline-treated patients, at 24 hrs, serum concentrations of TNF were significantly lower compared with controls (12 +/- 2 vs. 42 +/- 12 pg/mL, respectively, p = .04). Serum concentrations of IL-6 and IL-8 did not differ between the two treatment groups. There were also no significant differences in any hemodynamic and oxygenation measurements comparing the two treatment groups. Pentoxifylline concentrations were 1,544 +/- 241 ng/mL after the initial dose, and 5,776 +/- 1,781 ng/mL at the end of the 24-hr infusion. Five patients in the pentoxifylline group and four patients in the placebo group died.. Pentoxifylline is able to decrease serum TNF but not IL-6 or IL-8 serum concentrations during septic shock. Pentoxifylline was well tolerated by all eight patients with no adverse effect. Further studies are needed to determine if pentoxifylline's ability to lower circulating TNF concentration without altering hemodynamics will improve outcome in septic shock.

Topics: Adult; Aged; Aged, 80 and over; Cytokines; Double-Blind Method; Female; Hemodynamics; Humans; Infusions, Intravenous; Interleukin-6; Interleukin-8; Male; Middle Aged; Pentoxifylline; Prospective Studies; Shock, Septic; Tumor Necrosis Factor-alpha; Vasodilator Agents

Proinflammatory cytokines (tumor necrosis factor [TNF]-alpha and interleukin [IL]-6 and -8), counterinflammatory compounds (IL-10 and soluble TNF receptors p55 and p75 [sTNFR-55 and -75]), and hemostatic parameters were determined in 38 patients with meningococcal septic shock. Eleven patients (29%) died. Serum levels of pro- and counterinflammatory compounds and plasma levels of plasminogen activator inhibitor (PAI)-1 were significantly higher in nonsurvivors. The interval between appearance of petechiae and blood sampling was shorter in nonsurvivors than in survivors (3.6 +/- 2.4 vs. 6.1 +/- 3.3 h; P = 0.4). This interval correlated strongly with the levels of TNF-alpha, IL-6, -8, and -10, sTNFR-55 and -75, and PAI-1. However, with the exception of PAI-1, differences between concentrations of these mediators disappeared after adjustment for the interval. PAI-1 levels correlated with TNF-alpha concentrations (r = .75; P < .001) and were 1.9 (P = .01) times higher in nonsurvivors at a similar TNF-alpha concentration. Thus, an increased PAI-1 response to TNF-alpha may be associated with fatality, probably because of polymorphism of the PAI-1 gene.

Topics: Adolescent; Antigens, CD; Blood Coagulation; Child; Child, Preschool; Cytokines; Female; Fibrinolysis; Humans; Infant; Interleukin-10; Interleukin-6; Interleukin-8; Male; Meningococcal Infections; Plasminogen Activator Inhibitor 1; Prospective Studies; Purpura; Receptors, Tumor Necrosis Factor; Receptors, Tumor Necrosis Factor, Type I; Receptors, Tumor Necrosis Factor, Type II; Shock, Septic; Tumor Necrosis Factor-alpha

To investigate the involvement of nitrite/nitrate oxide (NOx) in septic shock, and to evaluate the relationships between NOx and cytokines in patients with this disorder, we evaluated 11 patients with septic shock and 12 patients with sepsis unassociated with shock. NOx were measured with an automated system based on the Griess reaction. The plasma concentrations of various cytokines were determined by enzyme-linked immunosorbent assay. Endotoxin was determined by a specific assay after the plasma samples were processed by a perchloric acid method. The mean plasma levels of NOx in the group with shock significantly exceeded those in the group without shock. Significant correlations were observed between the plasma levels of NOx and those of endotoxin, tumor necrosis factor-alpha, and interleukin 8 in both groups. NOx appeared to be involved in the development of septic shock in humans. Endotoxin and cytokines appeared to be involved in the production of NOx.

Topics: Cytokines; Endotoxins; Enzyme-Linked Immunosorbent Assay; Female; Humans; Interleukin-6; Interleukin-8; Male; Middle Aged; Nitric Oxide; Nitrites; Shock, Septic; Tumor Necrosis Factor-alpha

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

This study aims to investigate the early changes in the immune systems of patients with septic shock. A total of 243 patients with septic shock were included in this study. The patients were classified as survivors (n = 101) or nonsurvivors (n = 142). Clinical laboratories perform tests of the immune system's function. Each indicator was studied alongside healthy controls (n = 20) of the same age and gender as the patients. A comparative analysis of every two groups was conducted. Univariate and multivariate logistic regression analyses were performed to identify mortality risk factors that are independent of one another. In septic shock patients, neutrophil counts, infection biomarkers (C-reactive protein, ferritin, and procalcitonin levels), and cytokines (IL-1β, IL-2R, IL-6, IL-8, IL-10, and TNF-α) increased significantly. Lymphocyte and their subset counts (T, CD4+ T, CD8+ T, B, and natural killer cell counts), lymphocyte subset functions (the proportions of PMA/ionomycin-stimulated IFN-γ positive cells in CD4+ T cells), immunoglobulin levels (IgA, IgG, and IgM), and complement protein levels (C3 and C4) decreased significantly. Compared to survivors, nonsurvivors had higher levels of cytokines (IL-6, IL-8, and IL-10) but lower levels of IgM, complement C3 and C4, and lymphocyte, CD4+, and CD8+ T cell counts. Low IgM or C3 concentrations and low lymphocyte or CD4+ T cell counts were independent risk factors for mortality. These alterations should be considered in the future development of immunotherapies aimed at treating septic shock.

Topics: Cytokines; Humans; Immune System; Immunoglobulin M; Interleukin-10; Interleukin-6; Interleukin-8; Shock, Septic

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

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

We have previously demonstrated that the activation of the spleen tyrosine kinase (Syk)/inhibitory-κB (IκB)-α/nuclear factor-κB (NF-κB) p65 signalling pathway contributes to hypotension and inflammatory response in a rat models of zymosan (ZYM)-induced non-septic shock. The purpose of this study was to further examine the possible mechanism underlying the effect of inhibition of Syk by BAY61-3606 via NF-κB activity at the level of nuclear translocation regarding the production of vasodilator and proinflammatory mediators in lipopolysaccharide (LPS) (septic)- and ZYM (non-septic)-induced shock. Administration of LPS (10 mg/kg, ip) or ZYM (500 mg/kg, ip) to male Wistar rats decreased mean arterial pressure and increased heart rate that was associated with an increase in the activities of cyclooxygenase and nitric oxide synthase, tumour necrosis factor-α, and interleukin-8 levels, and NF-κB activation and nuclear translocation in sera and/or cardiovascular and renal tissues. BAY61-3606 (3 mg/kg, ip), the selective Syk inhibitor, given 1 hour after LPS- or ZYM injection reversed all the above-mentioned effects. These results suggest that Syk contributes to the LPS- or ZYM-induced hypotension and inflammation associated with transactivation of NF-κB in septic and non-septic shock.

Topics: Animals; Cyclooxygenase 2; Disease Models, Animal; Gene Expression Regulation; Gene Expression Regulation, Enzymologic; Hypotension; Inflammation; Interleukin-8; Lipopolysaccharides; Male; NF-kappa B; NF-KappaB Inhibitor alpha; Niacinamide; Nitric Oxide Synthase Type II; Protein Kinase Inhibitors; Pyrimidines; Rats; Rats, Wistar; Shock, Septic; Syk Kinase; Tumor Necrosis Factor-alpha; Zymosan

In septic patients, both systemic inflammation and splanchnic hypoperfusion may cause enterocyte damage. Catecholamines may exert additional detrimental effects on mesenteric blood flow in these patients, and thereby contribute to this damage. Enterocyte damage itself results in impairment of gut barrier function and consequent translocation of bacteria/toxins. This may contribute to multiple organ failure and death by sustaining or amplifying the systemic inflammatory response. The aim of the study was 2-fold: to investigate which factors contribute to enterocyte damage in septic patients, and to assess whether enterocyte damage is associated with a sustained or amplified systemic inflammatory response.. In this prospective observational cohort study in 129 patients with septic shock admitted to the ICU, we serially measured plasma levels of Intestinal Fatty Acid-Binding Protein (I-FABP, a marker for enterocyte damage) and of cytokines Tumor Necrosis Factor (TNF)-α, Interferon (IFN)-y, Interleukin (IL)-1β, IL-6, IL-8, IL-1 Receptor Antagonist (RA), and IL-10. Clinical data were collected from electronic patient files.. A total of 129 patients were included in the study. The median age of the patients was 67 years [56-74]. The median norepinephrine infusion rate was 0.2 μg/kg/min [0.1-0.5]. Overall, 28-day mortality was 31 (24%). Similar to previous work, I-FABP levels at admission were independently associated with mortality (odds ratio 3.101 [1.138-8.448]). Acute Physiology and Chronic Health Evaluation II score and an increase in norepinephrine infusion rate between days 1 and 3 were independently associated with area under curve I-FABP levels, whereas mean arterial pressure and creatinine levels were not. No correlations were found between any of the measured cytokines and plasma I-FABP levels. Furthermore, high I-FABP levels were not related with the subsequent course of cytokine levels.. In patients with septic shock, norepinephrine use is associated with more enterocyte damage. Although enterocyte damage is associated with increased 28-day mortality, it is not associated with a sustained or amplified systemic inflammatory response.

Topics: Aged; Cohort Studies; Enterocytes; Fatty Acid-Binding Proteins; Female; Humans; Interleukin-10; Interleukin-1beta; Interleukin-6; Interleukin-8; Male; Middle Aged; Norepinephrine; Prospective Studies; Shock, Septic; Tumor Necrosis Factor-alpha

We previously derived and validated the Pediatric Sepsis Biomarker Risk Model (PERSEVERE) to estimate baseline mortality risk in children with septic shock. The PERSEVERE biomarkers are serum proteins selected from among the proteins directly related to 80 mortality risk assessment genes. The initial approach to selecting the PERSEVERE biomarkers left 68 genes unconsidered.. To determine if the 68 previously unconsidered genes can improve upon the performance of PERSEVERE and to provide biological information regarding the pathophysiology of septic shock.. We reduced the number of variables by determining the biological linkage of the 68 previously unconsidered genes. The genes identified through variable reduction were combined with the PERSEVERE-based mortality probability to derive a risk stratification model for 28-day mortality using classification and regression tree methodology (n = 307). The derived tree, PERSEVERE-XP, was then tested in a separate cohort (n = 77).. Variable reduction revealed a network consisting of 18 mortality risk assessment genes related to tumor protein 53 (TP53). In the derivation cohort, PERSEVERE-XP had an area under the receiver operating characteristic curve (AUC) of 0.90 (95% confidence interval, 0.85-0.95) for differentiating between survivors and nonsurvivors. In the test cohort, the AUC was 0.96 (95% confidence interval, 0.91-1.0). The AUC of PERSEVERE-XP was superior to that of PERSEVERE.. PERSEVERE-XP combines protein and mRNA biomarkers to provide mortality risk stratification with possible clinical utility. PERSEVERE-XP significantly improves on PERSEVERE and suggests a role for TP53-related cellular division, repair, and metabolism in the pathophysiology of septic shock.

Topics: Biomarkers; Chemokine CCL3; Child; Child, Preschool; Cohort Studies; Female; Granzymes; HSP70 Heat-Shock Proteins; Humans; Infant; Interleukin-8; Male; Matrix Metalloproteinase 8; Reproducibility of Results; Risk Assessment; RNA, Messenger; ROC Curve; Shock, Septic

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

During septic shock, tumor necrosis factor alpha (TNFα) is an early response gene and induces a plethora of genes and signaling pathways. To identify robust signals in genes reliably upregulated by TNFα, we first measured microarray gene expression in vitro and searched methodologically comparable, publicly available data sets to identify concordant signals. Using tag single-nucleotide polymorphisms in the genes common to all data sets, we identified a genetic variant of the TNFAIP2 gene, rs8126, associated with decreased 28-day survival and increased organ dysfunction in an adult cohort in the Vasopressin and Septic Shock Trial. Similar to this cohort, we found that an association with rs8126 and increased organ dysfunction is replicated in a second cohort of septic shock patients in the St. Paul's Hospital Intensive Care Unit. We found that TNFAIP2 inhibits NF-x03BA;B activity, impacting the downstream cytokine interleukin (IL)-8. The minor G allele of TNFAIP2 rs8126 resulted in greater TNFAIP2 expression, decreased IL-8 production and was associated with decreased survival in patients experiencing septic shock. These data suggest that TNFAIP2 is a novel inhibitor of NF-x03BA;B that acts as an autoinhibitor of the TNFα response during septic shock.

Topics: Adult; Canada; Cytokines; Datasets as Topic; Genotyping Techniques; Humans; Immunity, Innate; Interleukin-8; Microarray Analysis; Multiple Organ Failure; NF-kappa B; Polymorphism, Single Nucleotide; Randomized Controlled Trials as Topic; Shock, Septic; Signal Transduction; Survival Analysis; Tumor Necrosis Factor-alpha

Glutamine has been shown to promote the release of heat shock protein 70 (HSP70) both within experimental in vitro models of sepsis and in adults with septic shock. This study aimed to investigate the effects of 2 mM glutamine and an inhibitor of HSP70 (KNK437) on the release of HSP70 and inflammatory mediators in healthy adult volunteers.. An in vitro whole blood endotoxin stimulation assay was used.. The addition of 2 mM glutamine significantly increased HSP70 levels over time (P < 0.05). HSP70 release had a positive correlation at 4 h with IL-1 β (r = 0.51, P = 0.03) and an inverse correlation with TNF-α (r = -0.56, P = 0.02) and IL-8 levels (r = -0.52, P = 0.03), and there were no significant correlations between HSP70 and IL6 or IL-10 or glutamine. Glutamine supplementation significantly (P < 0.05) attenuated the release of IL-10 at 4 h and IL-8 at 24 h, compared with conditions without glutamine. In endotoxin-stimulated blood there were no significant differences in the release of IL-6, TNF-α, and IL-1 β with glutamine supplementation at 4 and 24 h. However, glutamine supplementation (2 mM) appeared to attenuate the release of inflammatory mediators (IL-1 β, IL-6, TNF-α), although this effect was not statistically significant. The addition of KNK437, a HSP70 inhibitor, significantly diminished HSP70 release, which resulted in lower levels of inflammatory mediators (P < 0.05).. Glutamine supplementation promotes HSP70 release in an experimental model of sepsis. After the addition of KNK437, the effects of glutamine on HSP70 and inflammatory mediator release appear to be lost, suggesting that HSP70 in part orchestrates the inflammatory mediator response to sepsis. The clinical implications require further investigation.

Topics: Adult; Benzhydryl Compounds; Body Mass Index; Dietary Supplements; Endotoxins; Glutamine; HSP70 Heat-Shock Proteins; Humans; Interleukin-10; Interleukin-1beta; Interleukin-6; Interleukin-8; Middle Aged; Pyrrolidinones; Shock, Septic; Tumor Necrosis Factor-alpha

Prognostic and predictive enrichment strategies are fundamental tools of precision medicine. Identifying children with septic shock who may benefit from corticosteroids remains a challenge. We combined prognostic and predictive strategies to identify a pediatric septic shock subgroup responsive to corticosteroids.. We conducted a secondary analysis of 288 previously published pediatric subjects with septic shock. For prognostic enrichment, each study subject was assigned a baseline mortality probability using the pediatric sepsis biomarker risk model. For predictive enrichment, each study subject was allocated to one of two septic shock endotypes, based on a 100-gene signature reflecting adaptive immunity and glucocorticoid receptor signaling. The primary study endpoint was complicated course, defined as the persistence of two or more organ failures at day 7 of septic shock or 28-day mortality. We used logistic regression to test for an association between corticosteroids and complicated course within endotype.. Among endotype B subjects at intermediate to high pediatric sepsis biomarker risk model-based risk of mortality, corticosteroids were independently associated with more than a 10-fold reduction in the risk of a complicated course (relative risk, 0.09; 95% CI, 0.01-0.54; p = 0.007).. A combination of prognostic and predictive strategies based on serum protein and messenger RNA biomarkers can identify a subgroup of children with septic shock who may be more likely to benefit from corticosteroids. Prospective validation of these strategies and the existence of this subgroup are warranted.

Topics: Adrenal Cortex Hormones; Biomarkers; Chemokines, CC; Female; Granzymes; HSP70 Heat-Shock Proteins; Humans; Intensive Care Units, Pediatric; Interleukin-8; Logistic Models; Male; Matrix Metalloproteinase 8; Precision Medicine; Prognosis; Prospective Studies; Risk Assessment; Shock, Septic

Secreted factors of Staphylococcus aureus can activate host signaling from the epidermal growth factor receptor (EGFR). The superantigen toxic shock syndrome toxin-1 (TSST-1) contributes to mucosal cytokine production through a disintegrin and metalloproteinase (ADAM)-mediated shedding of EGFR ligands and subsequent EGFR activation. The secreted hemolysin, α-toxin, can also induce EGFR signaling and directly interacts with ADAM10, a sheddase of EGFR ligands. The current work explores the role of EGFR signaling in menstrual toxic shock syndrome (mTSS), a disease mediated by TSST-1. The data presented show that TSST-1 and α-toxin induce ADAM- and EGFR-dependent cytokine production from human vaginal epithelial cells. TSST-1 and α-toxin also induce cytokine production from an ex vivo porcine vaginal mucosa (PVM) model. EGFR signaling is responsible for the majority of IL-8 production from PVM in response to secreted toxins and live S. aureus. Finally, data are presented demonstrating that inhibition of EGFR signaling with the EGFR-specific tyrosine kinase inhibitor AG1478 significantly increases survival in a rabbit model of mTSS. These data indicate that EGFR signaling is critical for progression of an S. aureus exotoxin-mediated disease and may represent an attractive host target for therapeutics.

Topics: ADAM Proteins; Animals; Epithelial Cells; ErbB Receptors; Female; Humans; Interleukin-8; Rabbits; Shock, Septic; Signal Transduction; Staphylococcal Infections; Vagina

The Pediatric Sepsis Biomarker Risk Model (PERSEVERE), a pediatric sepsis risk model, uses biomarkers to estimate baseline mortality risk for pediatric septic shock. It is unknown how PERSEVERE performs within distinct septic shock phenotypes. We tested PERSEVERE in children with septic shock and thrombocytopenia-associated multiple organ failure (TAMOF), and in those without new onset thrombocytopenia but with multiple organ failure (MOF).. PERSEVERE-based mortality risk was generated for each study subject (n = 660). A priori, we determined that if PERSEVERE did not perform well in both the TAMOF and the MOF cohorts, we would revise PERSEVERE to incorporate admission platelet counts.. Multiple PICUs in the United States.. Standard care.. PERSEVERE performed well in the TAMOF cohort (areas under the receiver operating characteristic curves [AUC], 0.84 [95% CI, 0.77-0.90]), but less well in the MOF cohort (AUC, 0.71 [0.61-0.80]). PERSEVERE was revised using 424 subjects previously reported in the derivation phase. PERSEVERE-II had an AUC of 0.89 (0.85-0.93) and performed equally well across TAMOF and MOF cohorts. PERSEVERE-II performed well when tested in 236 newly enrolled subjects. Sample size calculations for a clinical trial testing the efficacy of plasma exchange for children with septic shock and TAMOF indicated PERSEVERE-II-based stratification could substantially reduce the number of patients necessary, when compared with no stratification.. Testing PERSEVERE in the context of septic shock phenotypes prompted a revision incorporating platelet count. PERSEVERE-II performs well upon testing, independent of TAMOF or MOF status. PERSEVERE-II could potentially serve as a prognostic enrichment tool.

Topics: Biomarkers; Chemokine CCL3; Child; Child, Preschool; Female; Granzymes; HSP70 Heat-Shock Proteins; Humans; Infant; Intensive Care Units, Pediatric; Interleukin-8; Male; Matrix Metalloproteinase 8; Models, Statistical; Multiple Organ Failure; Platelet Count; Prognosis; Risk Assessment; Shock, Septic; Thrombocytopenia; United States

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

Mortality from septic shock is highly heritable. The identification of causal genetic factors is insufficient. To discover key contributors, we first identified nonsynonymous single-nucleotide polymorphisms in conserved genomic regions that are predicted to have significant effects on protein function. We then test the hypothesis that these nonsynonymous single-nucleotide polymorphisms across the genome alter clinical outcome of septic shock.. Genetic-association study plus in vitro experiment using primary cells plus in silico analysis using genomic DNA and protein database.. Twenty-seven ICUs at academic teaching centers in Canada, Australia, and the United States.. Patients with septic shock of European ancestry (n = 520).. Patients with septic shock were genotyped for 843 nonsynonymous single-nucleotide polymorphisms in conserved regions of the genome and are predicted to have damaging effects from the protein sequence.. The primary outcome variable was 28-day mortality. Secondary outcome variables were organ dysfunction. Productions of adhesion molecules including interleukin-8, growth-regulated oncogene-α, monocyte chemoattractant protein-1, and monocyte chemoattractant protein-3 were measured in human umbilical vein endothelial cells after SVEP1 gene silencing by RNA interference. Patients with septic shock having the SVEP1 C allele of nonsynonymous single-nucleotide polymorphism, SVEP1 c.2080A>C (p. Gln581His, rs10817033), had a significant increase in the hazard of death over the 28 days (hazard ratio, 1.72; 95% CI, 1.31-2.26; p = 9.7 × 10-5) and increased organ dysfunction and needed more organ support (p < 0.05). Silencing SVEP1 significantly increased interleukin-8, growth-regulated oncogene-α, monocyte chemoattractant protein-1, monocyte chemoattractant protein-3 production in human umbilical vein endothelial cells under lipopolysaccharide stimulation (p < 0.01).. C allele of SVEP1 c.2080A>C (p. Gln581His) single-nucleotide polymorphism, a non-synonymous single-nucleotide polymorphism in conserved regions and predicted to have damaging effects on protein structure, was associated with increased 28-day mortality and organ dysfunction of septic shock. SVEP1 appears to regulate molecules of the leukocyte adhesion pathway.

Topics: Aged; Cell Adhesion Molecules; Chemokines; Conserved Sequence; Female; Genetic Association Studies; Genome-Wide Association Study; Humans; Interleukin-8; Male; Middle Aged; Polymorphism, Single Nucleotide; 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

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

We previously derived and validated a risk model to estimate mortality probability in children with septic shock (PERSEVERE; PEdiatRic SEpsis biomarkEr Risk modEl). PERSEVERE uses five biomarkers and age to estimate mortality probability. After the initial derivation and validation of PERSEVERE, we combined the derivation and validation cohorts (n = 355) and updated PERSEVERE. An important step in the development of updated risk models is to test their accuracy using an independent test cohort.. To test the prognostic accuracy of the updated version PERSEVERE in an independent test cohort.. Study subjects were recruited from multiple pediatric intensive care units in the United States. Biomarkers were measured in 182 pediatric subjects with septic shock using serum samples obtained during the first 24 hours of presentation. The accuracy of PERSEVERE 28-day mortality risk estimate was tested using diagnostic test statistics, and the net reclassification improvement (NRI) was used to test whether PERSEVERE adds information to a physiology-based scoring system.. Mortality in the test cohort was 13.2%. Using a risk cut-off of 2.5%, the sensitivity of PERSEVERE for mortality was 83% (95% CI 62-95), specificity was 75% (68-82), positive predictive value was 34% (22-47), and negative predictive value was 97% (91-99). The area under the receiver operating characteristic curve was 0.81 (0.70-0.92). The false positive subjects had a greater degree of organ failure burden and longer intensive care unit length of stay, compared to the true negative subjects. When adding PERSEVERE to a physiology-based scoring system, the net reclassification improvement was 0.91 (0.47-1.35; p<0.001).. The updated version of PERSEVERE estimates mortality probability reliably in a heterogeneous test cohort of children with septic shock and provides information over and above a physiology-based scoring system.

Topics: Biomarkers; Chemokine CCL3; Child; Child, Preschool; Female; Granzymes; HSP70 Heat-Shock Proteins; Humans; Intensive Care Units; Interleukin-8; Male; Matrix Metalloproteinase 8; Models, Statistical; Predictive Value of Tests; Prognosis; Risk Assessment; Shock, Septic; Survival Analysis

To identify biomarkers which distinguish severe sepsis/septic shock from uncomplicated sepsis in the Emergency Department (ED).. Patients with sepsis underwent serial blood sampling, including arrival in the ED and up to three subsequent time points over the first 24 hours. Messenger RNA (mRNA) levels of 13 genes representing arms of the innate immune response, organ dysfunction or shock were measured in peripheral blood leucocytes using quantitative PCR, and compared with healthy controls. Serum protein concentrations of targets differentially expressed between uncomplicated sepsis and severe sepsis/septic shock were then measured at each time point and compared between the two patient groups.. Of 27 participants (median age 66 years, (IQR 35, 78)), 10 had uncomplicated sepsis and 17 had sepsis with organ failure (14 septic shock; 3 had other sepsis-related organ failures). At the time of first sample collection in the ED, gene expression of Interleukin (IL)-10 and Neutrophil Gelatinase Associated Lipocalin (NGAL) were significantly higher in severe sepsis than uncomplicated sepsis. Expression did not significantly change over time for any target gene. Serum concentrations of IL-6, IL-8, IL-10, NGAL and Resistin were significantly higher in severe sepsis than uncomplicated sepsis at the time of first sample collection in the ED, but only IL-8, NGAL and Resistin were consistently higher in severe sepsis compared to uncomplicated sepsis at all time points up to 24 h after presentation.. These mediators, produced by both damaged tissues and circulating leukocytes, may have important roles in the development of severe sepsis. Further work will determine whether they have any value, in addition to clinical risk parameters, for the early identification of patients that will subsequently deteriorate and/or have a higher risk of death.

Topics: Acute-Phase Proteins; Adult; Aged; Biomarkers; Case-Control Studies; Chemokine CCL2; Emergency Service, Hospital; Female; Gene Expression Profiling; Humans; Interleukin-10; Interleukin-6; Interleukin-8; Lipocalin-2; Lipocalins; Male; Middle Aged; Proto-Oncogene Proteins; Resistin; RNA, Messenger; Shock, Septic; Time Factors

The vaginal epithelium provides a barrier to pathogens and recruits immune defenses through the secretion of cytokines and chemokines. Several studies have shown that mucosal sites are innervated by norepinephrine-containing nerve fibers. Here we report that norepinephrine potentiates the proinflammatory response of human vaginal epithelial cells to products produced by Staphylococcus aureus, a pathogen that causes menstrual toxic shock syndrome. The cells exhibit immunoreactivity for catecholamine synthesis enzymes and the norepinephrine transporter. Moreover, the cells secrete norepinephrine and dopamine at low concentrations. These results indicate that norepinephrine may serve as an autocrine modulator of proinflammatory responses in the vaginal epithelium.

Topics: Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Adrenergic beta-Antagonists; Cell Line, Transformed; Dopamine; Epithelial Cells; Female; Humans; Immunomodulation; Interleukin-6; Interleukin-8; Neuroimmunomodulation; Neuropeptide Y; Norepinephrine; Peptide Fragments; Phentolamine; Propranolol; Shock, Septic; Staphylococcal Infections; Superantigens; Vagina; Vasoactive Intestinal Peptide

Catecholamines have been suggested to modulate innate immune responses in experimental settings. The significance hereof in the treatment of human septic shock is unknown. We therefore sought if and how vasopressor/inotropic doses relate to pro-inflammatory mediators during treatment of septic shock. We prospectively studied 20 consecutive septic shock patients. For 3 days after admission, hemodynamic variables, lactate and plasma levels of interleukins (IL)-6 and 8, tumor necrosis factor (TNF)-α, and elastase-α(1)-antitrypsin were measured six hourly. Doses of vasoactive drugs were recorded. Of the 20 patients, nine died in the intensive care unit. Dobutamine doses were positively associated and related to TNF-α plasma levels, independently of disease severity, hemodynamics, and outcome, in multivariable models. Dopamine doses were positively associated with IL-6, and norepinephrine was inversely associated with IL-8 and TNF-α levels. Our observations suggest that catecholamines used in the treatment of human septic shock differ in their potential modulation of the innate immune response to sepsis in vivo. Dobutamine treatment may contribute to circulating TNF-α and dopamine to IL-6, independently of activated neutrophils. Conversely, norepinephrine may lack pro-inflammatory actions.

Topics: Adult; Aged; Aged, 80 and over; alpha 1-Antitrypsin; Cardiotonic Agents; Dobutamine; Dopamine; Female; Humans; Immunity, Innate; Interleukin-6; Interleukin-8; Leukocyte Elastase; Male; Middle Aged; Neutrophils; Norepinephrine; Shock, Septic; Tumor Necrosis Factor-alpha; Vasoconstrictor Agents; Young Adult

The aim of this study was to better characterise the biological effects of Lactobacillus salivarius ssp. salivarius CECT5713, a probiotic with immunomodulatory properties.. Live or dead probiotic was assayed in the TNBS model of rat colitis to determine whether viability was a requisite to exert the beneficial effects. In vitro studies were also performed in Caco-2 cells to evaluate its effects on epithelial cell recovery and IL-8 production. Finally, the probiotic was assayed in the LPS model of septic shock in mice to establish its effects when there is an altered systemic immune response.. The viability of the probiotic was required for its anti-inflammatory activity. The probiotic inhibited IL-8 production in stimulated Caco-2 cells and facilitated the recovery of damaged intestinal epithelium. In LPS-treated mice, the probiotic inhibited the production of TNFα in plasma and lungs and increased the hepatic glutathione content. These effects were associated with an improvement in the altered production of the T-cell cytokines in splenocytes, by reducing IL-2 and IL-5 and by increasing IL-10. Finally, it reduced the increased plasma IgG production in LPS-treated mice.. The anti-inflammatory effects of viable L. salivarius ssp. salivarius CECT5713 are not restricted to the gastrointestinal tract.

Topics: Animals; Anti-Inflammatory Agents; Caco-2 Cells; Colitis; Female; Glutathione; Humans; Immunoglobulin G; Immunologic Factors; Interleukin-10; Interleukin-5; Interleukin-8; Intestinal Mucosa; Intestine, Large; Lactobacillus; Lipopolysaccharides; Liver; Male; Mice; Mice, Inbred BALB C; Probiotics; Rats; Rats, Wistar; Shock, Septic; Tumor Necrosis Factor-alpha

Staphylococcus aureus initiates infections and produces virulence factors, including superantigens (SAgs), at mucosal surfaces. The SAg, Toxic Shock Syndrome Toxin-1 (TSST-1) induces cytokine secretion from epithelial cells, antigen presenting cells (APCs) and T lymphocytes, and causes toxic shock syndrome (TSS). This study investigated the mechanism of TSST-1-induced secretion of proinflammatory cytokines from human vaginal epithelial cells (HVECs) and determined if curcumin, an anti-inflammatory agent, could reduce TSST-1-mediated pathology in a rabbit vaginal model of TSS. TSST-1 caused a significant increase in NF-κB-dependent transcription in HVECs that was associated with increased expression of TNF- α, MIP-3α, IL-6 and IL-8. Curcumin, an antagonist of NF-κB-dependent transcription, inhibited IL-8 production from ex vivo porcine vaginal explants at nontoxic doses. In a rabbit model of TSS, co-administration of curcumin with TSST-1 intravaginally reduced lethality by 60% relative to 100% lethality in rabbits receiving TSST-1 alone. In addition, TNF-α was undetectable from serum or vaginal tissue of curcumin treated rabbits that survived. These data suggest that the inflammatory response induced at the mucosal surface by TSST-1 is NF-κB dependent. In addition, the ability of curcumin to prevent TSS in vivo by co-administration with TSST-1 intravaginally suggests that the vaginal mucosal proinflammatory response to TSST-1 is important in the progression of mTSS.

Topics: Animals; Bacterial Toxins; Cell Line, Transformed; Chemokines; Curcumin; Disease Models, Animal; Enterotoxins; Epithelial Cells; Female; Humans; In Vitro Techniques; Inflammation Mediators; Interleukin-8; Mucous Membrane; NF-kappa B; Protective Agents; Rabbits; Shock, Septic; Signal Transduction; Staphylococcus aureus; Superantigens; Sus scrofa; Vagina

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

Interleukin-8 (IL-8) is a central chemokine in acute respiratory distress syndrome (ARDS), and the IL-8 gene contains a functional single nucleotide polymorphism (SNP) -251A/T in its promoter region. We hypothesized that IL-8 -251A/T SNP is associated with PaO(2)/FiO(2) in critically ill patients.. We conducted genetic-association studies in intensive care units at academic teaching centres using a derivation septic shock cohort (vasopressin and septic shock trial (VASST), n = 467) and a validation post-cardiopulmonary bypass surgery cohort (CPB, n = 739) of Caucasian patients. Patients in both cohorts were genotyped for IL-8 -251A/T. The primary outcome variable in both cohorts was the fraction of patients who had a PaO(2) /FiO(2) < 200. IL-8 mRNA expression was measured in genotyped lymphoblastoid cells in vitro.. The frequency of the patients with PaO(2)/FiO(2) <200 was significantly greater in patients who had the AA genotype of -251A/T than in patients who had the AT or TT genotypes in both VASST (AA = 60.8% vs AT and TT = 53.8% and 48.0%, P = 0.038) and the CPB cohort (AA = 37.0% vs AT and TT = 27.0% and 26.0%, P = 0.039). Patients having the AA genotype had a higher probability to remain on mechanical ventilation (P = 0.047) in the first 14 days. Lymphoblastoid cells having the AA genotype had significantly higher IL-8 mRNA expression than cells having the AT or TT genotype (P = 0.022).. Critically ill Caucasian patients who had the AA genotype of IL-8 -251A/T had an increased risk of PaO(2)/FiO(2) <200. The AA genotype was associated with greater IL-8 mRNA expression than the AT or TT genotypes.

Topics: Aged; Cardiopulmonary Bypass; Cells, Cultured; Cohort Studies; Critical Illness; Female; Gene Frequency; Genetic Association Studies; Genotype; Humans; Intensive Care Units; Interleukin-8; Male; Middle Aged; Oxygen; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Respiration, Artificial; Respiratory Distress Syndrome; Severity of Illness Index; Shock, Septic

Pulsed-field gel electrophoresis (PFGE) clonal type USA200 is the most widely disseminated Staphylococcus aureus colonizer of the nose and is a major cause of toxic shock syndrome (TSS). Exoproteins derived from these organisms have been suggested to contribute to their colonization and causation of human diseases but have not been well-characterized. Two representative S. aureus USA200 isolates, MNPE (α-toxin positive) and CDC587 (α-toxin mutant), isolated from pulmonary post-influenza TSS and menstrual vaginal TSS, respectively, were evaluated. Biochemical, immunobiological, and cell-based assays, including mass spectrometry, were used to identify key exoproteins derived from the strains that are responsible for proinflammatory and cytotoxic activity on human vaginal epithelial cells. Exoproteins associated with virulence were produced by both strains, and cytolysins (α-toxin and γ-toxin), superantigens, and proteases were identified as the major exoproteins, which caused epithelial cell inflammation and cytotoxicity. Exoprotein fractions from MNPE were more proinflammatory and cytotoxic than those from CDC587 due to high concentrations of α-toxin. CDC587 produced a small amount of α-toxin, despite the presence of a stop codon (TAG) at codon 113. Additional exotoxin identification studies of USA200 strain [S. aureus MN8 (α-toxin mutant)] confirmed that MN8 also produced low levels of α-toxin despite the same stop codon. The differences observed in virulence factor profiles of two USA200 strains provide insight into environmental factors that select for specific virulence factors. Cytolysins, superantigens, and proteases were identified as potential targets, where toxin neutralization may prevent or diminish epithelial damage associated with S. aureus.

Topics: Animals; Chromatography, High Pressure Liquid; Cytotoxins; Electrophoresis, Gel, Pulsed-Field; Enterotoxins; Epithelial Cells; Exotoxins; Female; Humans; Immunoblotting; Immunoglobulin G; Interleukin-8; Lung; Rabbits; Shock, Septic; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Staphylococcal Infections; Staphylococcus aureus; Superantigens; Swine; Vagina; Virulence Factors

We evaluated the relations among the arterial carbon monoxide (CO) concentration, heme oxygenase (HO)-1 expression by monocytes, oxidative stress, plasma levels of cytokines and bilirubin, and the outcome of patients with severe sepsis or septic shock.. Thirty-six patients who fulfilled the criteria for severe sepsis or septic shock and 21 other patients without sepsis during their stay in the intensive care unit were studied. HO-1 protein expression by monocytes, arterial CO, oxidative stress, bilirubin, and cytokines were measured.. Arterial blood CO, cytokine, and bilirubin levels, and monocyte HO-1 protein expression were higher in patients with severe sepsis/septic shock than in non-septic patients. Increased HO-1 expression was related to the arterial CO concentration and oxidative stress. There was a positive correlation between survival and increased HO-1 protein expression or a higher CO level.. Arterial CO and monocyte HO-1 protein expression were increased in critically ill patients, particularly those with severe sepsis or septic shock, suggesting that oxidative stress is closely related to HO-1 expression. The HO-1/CO system may play an important role in sepsis.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Bilirubin; Carbon Monoxide; Critical Care; Deoxyguanosine; Female; Heme Oxygenase-1; Humans; Intensive Care Units; Interleukin-1beta; Interleukin-6; Interleukin-8; Male; Oxidative Stress; Severity of Illness Index; Shock, Septic

Topics: Acute Lung Injury; Adult; Biomarkers; Child; Humans; Interleukin-8; Predictive Value of Tests; Risk Assessment; Shock, Septic; Vasoconstrictor Agents

Topics: Animals; Anti-Inflammatory Agents; Cell Line, Tumor; Dansyl Compounds; Glucose; Humans; Interleukin-8; Lipopolysaccharides; Mice; Shock, Septic; Sodium-Glucose Transporter 1

The objective of this study was to establish a porcine analog of human meningococcal sepsis for pathophysiological investigations and possible future therapy in severe sepsis. Heat-killed Neisseria meningitidis was continuously infused in sublethal concentrations into 10 anesthetized 30-kg pigs (sepsis group). The dose was doubled every 30 min. Six pigs received saline only (control group). The changes described in the succeeding paragraphs were observed in the sepsis group but not in the control group. MAP was aimed to be kept normal by fluid infusion but declined after 3 h in parallel with a decrease in systemic vascular resistance. Pulmonary arterial pressure increased considerably after 30 to 45 min. A massive plasma extravasation was shown by increased hematocrit and a 50% reduction in plasma albumin content. Fluid accumulated in lungs, muscles, and jejunum, as shown by increased wet-dry ratios. Peak inspiratory pressures and fraction of inspired oxygen had to be increased. The cytokines TNF-alpha, IL-1beta, IL-6, IL-8, IL-10, and IL-12 increased markedly. Neutrophils fell to zero-levels, and platelets were markedly reduced. Thrombin-antithrombin complexes increased notably after 120 min. This is the first large animal model of sepsis using whole Neisseria meningitidis. The model simulates well central aspects of human meningococcal sepsis and could be used for future interventional studies.

Topics: Animals; Disease Models, Animal; Female; Interleukin-10; Interleukin-12; Interleukin-6; Interleukin-8; Male; Meningococcal Infections; Neisseria meningitidis; Random Allocation; Shock, Septic; Swine; Tumor Necrosis Factor-alpha

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

Interventional clinical trials involving children with septic shock would benefit from an efficient preenrollment stratification strategy.. To test the predictive value of interleukin (IL)-8 for 28-day mortality in pediatric septic shock.. A training data set (n = 40) identified a serum IL-8 of greater than 220 pg/ml as having a 75% sensitivity and specificity for predicting 28-day mortality. This cutoff was then subjected to a series of validation steps.. Subjects were drawn from two large, independent pediatric septic shock databases. Prospective application of the IL-8 cutoff to validation data set 1 (n = 139) demonstrated 78% sensitivity and 64% specificity for 28-day mortality. A serum IL-8 level of 220 pg/ml or less, however, had a negative predictive value for 28-day mortality of 95% in validation data set 1, which was subsequently applied to an independently generated data set of children with septic shock (validation set 2, n = 193). A serum IL-8 level of 220 pg/ml or less had a negative predictive value for 28-day mortality of 94% when applied to validation set 2.. A serum IL-8 level of 220 pg/ml or less, obtained within 24 hours of admission, predicts a high likelihood of survival in children with septic shock. We propose that IL-8 can be used to exclude such patients from interventional clinical trials and ultimately derive a study population with a more favorable risk to benefit ratio when subjected to a study agent.

Topics: Biomarkers; Child; Child, Preschool; Databases, Factual; Female; Humans; Infant; Interleukin-8; Male; Predictive Value of Tests; ROC Curve; Severity of Illness Index; Shock, Septic; Survival Analysis

Superantigens interact with T lymphocytes and macrophages to cause T lymphocyte proliferation and overwhelming cytokine production, which lead to toxic shock syndrome. Staphylococcus aureus superantigen toxic shock syndrome toxin-1 is a major cause of menstrual toxic shock syndrome. In general, superantigen-secreting S. aureus remains localized at the vaginal surface, and the superantigen must therefore penetrate the vaginal mucosa to interact with underlying immune cells to cause toxic shock syndrome. A dodecapeptide region (toxic shock syndrome toxin-1 amino acids F119-D130), relatively conserved among superantigens, has been implicated in superantigen penetration of the epithelium. The purpose of this study was to determine amino acids within this dodecapeptide region that are required for interaction with vaginal epithelium. Alanine mutations were constructed in S. aureus toxic shock syndrome toxin-1 amino acids D120 to D130. All mutants maintained superantigenicity, and selected mutants were lethal when given intravenously to rabbits. Toxic shock syndrome toxin-1 induces interleukin-8 from immortalized human vaginal epithelial cells; however, three toxin mutants (S127A, T128A, and D130A) induced low levels of interleukin-8 compared to wild type toxin. When carboxy-terminal mutants (S127A to D130A) were administered vaginally to rabbits, D130A was nonlethal, while S127A and T128A demonstrated delayed lethality compared to wild type toxin. In a porcine ex vivo permeability model, mutant D130A penetrated the vaginal mucosa more quickly than wild type toxin. Toxic shock syndrome toxin-1 residue D130 may contribute to binding an epithelial receptor, which allows it to penetrate the vaginal mucosa, induce interleukin-8, and cause toxic shock syndrome.

Topics: Alanine; Amino Acids; Animals; Bacterial Toxins; Base Sequence; Binding Sites; Cell Membrane Permeability; Culture Techniques; Enterotoxins; Epithelial Cells; Female; Injections, Intravenous; Interleukin-8; Lymphocyte Activation; Mutation; Peptides; Rabbits; Shock, Septic; Superantigens; Swine; Vagina

Based on the implication of soluble triggering receptor expressed on myeloid cells (sTREM-1) in the septic cascade, it was investigated whether it participates or not in posttraumatic systemic inflammatory response syndrome (SIRS).. Blood was sampled on days 1, 4, 7, and 15 from 69 patients with SIRS after multiple injuries and upon presentation of a septic complication. Concentrations of sTREM-1, tumor necrosis factor-alpha (TNFalpha), interleukin (IL)-6, IL-8, and interferon-gamma were determined by an enzyme immunoassay. Samples drawn on day 1 from 10 trauma patients without SIRS served as controls.. In 26 patients with SIRS without septic complication, sTREM-1, TNFalpha, and IL-8 remained stable over follow-up; IL-6 decreased and interferon-gamma increased on days 4 and 7 compared with day 1. TNFalpha was the only variable being higher upon advent of septic shock compared with patients without SIRS and upon presentation of SIRS, sepsis, and severe sepsis (p of comparisons with all subgroups <0.0001). Mortality of patients with sTREM-1 greater than 180 pg/mL was 5.3% compared with 28.0% of those with sTREM-1 lower than 180 pg/mL (p 0.035). sTREM-1 higher than 40 pg/mL had sensitivity 56.5% and specificity 91.7% for the differential diagnosis between SIRS and sepsis after multiple injuries.. This is the first study providing evidence about the participation of sTREM-1 in posttraumatic SIRS. Its levels are increased and remain constant over time in patients who did not develop any complications whereas it seems to behave as an anti-inflammatory mediator.

Topics: Adult; Aged; Bacteremia; Cross Infection; Diagnosis, Differential; Enzyme-Linked Immunosorbent Assay; Female; Gram-Negative Bacterial Infections; Humans; Injury Severity Score; Interferon-gamma; Interleukin-6; Interleukin-8; Male; Membrane Glycoproteins; Middle Aged; Multiple Organ Failure; Multiple Trauma; Pneumonia, Bacterial; Predictive Value of Tests; Prognosis; Prospective Studies; Pyelonephritis; Receptors, Immunologic; Shock, Septic; Systemic Inflammatory Response Syndrome; Time Factors; Triggering Receptor Expressed on Myeloid Cells-1; Tumor Necrosis Factor-alpha

The susceptibility of neonates to pulmonary and systemic infection has been associated with the immaturity of both lung structure and the immune system. Surfactant protein (SP) D is a member of the collectin family of innate immune molecules that plays an important role in innate host defense of the lung.. We tested whether treatment with recombinant human SP-D influenced the response of the lung and systemic circulation to intratracheally administered Escherichia coli lipopolysaccharides.. After intratracheal lipopolysaccharide instillation, preterm newborn lambs were treated with surfactant and ventilated for 5 h.. Survival rate, physiologic lung function, lung and systemic inflammation, and endotoxin level in plasma were evaluated.. In control lambs, intratracheal lipopolysaccharides caused septic shock and death associated with increased endotoxin in plasma. In contrast, all lambs treated with recombinant human SP-D were physiologically stable and survived. Leakage of lipopolysaccharides from the lungs to the systemic circulation was prevented by intratracheal recombinant human SP-D. Recombinant human SP-D prevented systemic inflammation and decreased the expression of IL-1beta, IL-8, and IL-6 in the spleen and liver. Likewise, recombinant human SP-D decreased IL-1beta and IL-6 in the lung and IL-8 in the plasma. Recombinant human SP-D did not alter pulmonary mechanics following endotoxin exposure. Recombinant human SP-D was readily detected in the lung 5 h after intratracheal instillation.. Intratracheal recombinant human SP-D prevented shock caused by endotoxin released from the lung during ventilation in the premature newborn.

Topics: Animals; Animals, Newborn; Cause of Death; Disease Models, Animal; Endotoxins; Escherichia coli; Female; Gestational Age; Humans; Interleukin-1; Interleukin-6; Interleukin-8; Intubation, Intratracheal; Lipopolysaccharides; Lung; Male; Pneumonia; Pulmonary Surfactant-Associated Protein D; Pulmonary Surfactants; Respiration, Artificial; Respiratory Mechanics; Sheep; Shock, Septic; Survival Rate

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

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

To examine the hypothesis that neutrophil chemotaxis to interleukin-8 (IL-8) is reduced in septic shock. Surface expression of neutrophil CXC chemokine receptors and the adhesion molecule CD11b were also examined and associations between disease severity, gas exchange and receptor expression were studied.. Prospective cohort clinical study. SETTING. Intensive care unit in a tertiary referral teaching hospital.. Patients with septic shock ( n=15) and healthy controls ( n=8) were studied.. Daily (for 5 consecutive days) flow cytometric measurements of chemokine and beta integrin surface expression. "In vitro" neutrophil chemotaxis to IL-8 was also compared between patients with sepsis and healthy controls. CXCR2 expression significantly fell, CD11b expression increased and CXCR1 expression was unchanged throughout the study in the septic group compared with healthy controls. CD11b positively correlated with increasing APACHE II scores ( p<0.0001) and worsening PaO(2)/FIO(2) ratios ( p<0.0001). CXCR2 expression negatively correlated with both APACHE II scores ( p=0.016) and PaO(2)/FIO(2) ratios ( p=0.01). There was no correlation between CXCR1 expression and either APACHE II score or PaO(2)/FIO(2) ratios. Chemotaxis to IL-8 was reduced in patients with sepsis compared with healthy volunteers.. Surface expression of the chemokine receptor CXCR2 and the beta-integrin CD11b, but not CXCR1, were reduced on neutrophils isolated from patients with septic shock compared with healthy controls. Chemotaxis to IL-8 was also reduced in neutrophils from septic patients compared with healthy controls. The changes in receptor expression correlated with measures of disease severity.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; CD11b Antigen; Chemotaxis, Leukocyte; Cohort Studies; Female; Flow Cytometry; Hospitals, Teaching; Humans; Intensive Care Units; Interleukin-8; Linear Models; Male; Middle Aged; Neutrophils; Prognosis; Prospective Studies; Receptors, Chemokine; Severity of Illness Index; Shock, Septic; Survival Rate

The aim of the present study was to determine whether the presence of an infectious focus or of fever alone can predict bloodstream infection and whether levels of C-reactive protein, procalcitonin, interleukin (IL)-6, IL-8, and soluble IL-2 receptor (sIL-2R) improve the diagnosis of community-acquired bloodstream infection. Markers of systemic inflammation were studied in 92 patients with community-acquired infection. On admission to hospital, 54 patients had an infectious focus, 25 had fever without an infectious focus, and 13 had neither. The presence of focus or fever predicted bloodstream infection (n=13 patients) with a sensitivity of 100% (95% confidence interval, 75-100), a specificity of 16% (95%CI, 9-26), a negative predictive value of 100% (95%CI, 75-100), and a positive predictive value of 16% (95%CI, 9-26). Positive predictive values of C-reactive protein, procalcitonin, IL-6, IL-8, and sIL-2R, all measured on admission, were also low (33-44%). Eight febrile patients in whom an infectious focus was found during a 3-day follow-up period had higher on-admission IL-6 (P=0.005) and sIL-2R (P=0.046) levels than did 17 febrile patients without an infectious focus. In conclusion, markers of systemic inflammation do not improve the diagnosis of community-acquired bloodstream infection; however, they may aid in identifying patients with fever due to occult infection.

Topics: Acute Disease; Adolescent; Adult; Aged; Aged, 80 and over; Bacteremia; Biomarkers; Blood-Borne Pathogens; C-Reactive Protein; Cohort Studies; Confidence Intervals; Critical Illness; Emergency Service, Hospital; Female; Finland; Humans; Inflammation; Interleukin-6; Interleukin-8; Male; Middle Aged; Predictive Value of Tests; Prognosis; Receptors, Interleukin-2; Risk Assessment; ROC Curve; Sampling Studies; Sensitivity and Specificity; Shock, Septic; Survival Rate

Chronic alcoholic patients have a threefold to fourfold increased risk for developing a severe infection or septic shock after surgery, which might be due to altered immune response. The aim of this outcome matched study was to investigate proinflammatory and anti-inflammatory immune parameters during the course of infection and subsequent septic shock in chronic alcoholic patients, and to compare these parameters with those in nonalcoholic patients.. Twenty-eight patients from a cohort of fifty-six with either pneumonia or peritonitis and subsequent septic shock were selected. Fourteen patients were chronic alcoholics whereas fourteen were nonalcoholic patients. Chronic alcoholic patients met criteria (Diagnostic and Statistical Manual of Mental Disorders IV, of the American Psychiatric Association) for alcohol abuse or dependence. Measurements were performed during the onset of infection (within 24 hours after the onset of infection), in early septic shock (within 12 hours after onset of septic shock) and in late septic shock (72 hours after the onset). Blood measurements included proinflammatory and anti-inflammatory cytokines.. Chronic alcoholic patients exhibited significantly lower plasma levels of IL-8 (P < 0.010) during the onset of infection than did matched nonalcoholic patients. In early septic shock, chronic alcoholic patients had significantly decreased levels of IL-1beta (P < 0.015), IL-6 (P < 0.016) and IL-8 (P < 0.010). The anti-inflammatory parameters IL-10 and tumour necrosis factor receptors I and II did not differ between alcoholic and nonalcoholic patients.. At the onset of infection and during early septic shock, chronic alcoholic patients had lower levels of proinflammatory immune parameters than did nonalcoholic patients. Therefore, immunomodulatory therapy administered early may be considered in chronic alcoholic patients at the onset of an infection because of their altered proinflammatory immune response.

Topics: Adult; Aged; Alcoholism; Case-Control Studies; Chronic Disease; Humans; Interleukin-1; Interleukin-10; Interleukin-8; Middle Aged; Peritonitis; Pneumonia; Predictive Value of Tests; Receptors, Tumor Necrosis Factor; Risk Factors; Shock, Septic; Tumor Necrosis Factor-alpha

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

The effects of a monoclonal antibody (mAb) to tumor necrosis factor-alpha (TNF-alpha) were examined in a rabbit model of endotoxic shock. Intravenous administration of lipopolysaccharide (100 microg/kg/hr) for 6 hours (n = 11) increased TNF-alpha levels. Fibrinogen was partially consumed, and fibrin deposits were seen in kidney and lungs at 24 hours. Mortality at 24 hours was 64%. Levels of interleukin-8 (aka CXCL-8) were notably increased. Mean arterial pressure (MAP) and leukocyte counts decreased, whereas creatinine levels were enhanced. The anti-TNF-alpha mAb (20 mg/kg i.v. bolus + 5 mg/kg/h i.v. for the first 90 minutes) (n = 10) efficiently inhibited the TNF-activity. Rabbits exhibited lower CXCL-8 levels; MAP improved, the decrease in leukocyte counts was partially prevented and creatinine levels were lower, but fibrinogen, fibrin deposits in kidneys and lungs and mortality, 55%, were similar to the LPS group. Rabbits that did not survive exhibited lower fibrinogen levels, more fibrin in kidneys and lungs and higher CXCL-8 and creatinine levels than survivors, while there were no differences in TNF-alpha, MAP and leukocytes. Thus, the inhibition of TNF-alpha, although beneficial through lowering CXCL-8 levels, is not enough to improve the outcome, which could be partly due to the inability to prevent the fibrin deposits formation in kidneys and lungs.

Topics: Animals; Antibodies, Monoclonal; Blood Pressure; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Fibrin; Fibrinogen; Interleukin-8; Kidney; Leukocytes; Lipopolysaccharides; Lung; Male; Rabbits; Shock, Septic; Survival Rate; Tumor Necrosis Factor-alpha

Aim of the study was to characterize different functions of circulating and emigrated, intra-abdominal polymorphonuclear leukocytes (cPMNs, ePMNs) during human secondary peritonitis.. In patients (n=25) with diffuse secondary peritonitis circulating and emigrated PMNs were characterized intra- and until 96 h postoperatively. Patients were allocated to two different groups, e. g. patients with septic complications (shock, organ failure, n=11) and patients without complications (n=14) during peritonitis. In addition a control group of patients (n=10) with abdominal surgery but without peritonitis was investigated. The lucigenin- and luminol-enhanced chemiluminescence was used to determine extra- and intracellular oxygen radical generation of PMNs. Besides spontaneous oxygen radical generation of PMNs, stimulated radical production was investigated after the addition of ionophores A23 187 and C3-coated zymosan. Phagocytosis by PMNs was characterized with opsonized E. coli bacteria and fluorescence-activated cell analysis.. Especially patients with complicated peritonitis had strong and long-lasting changes of PMNs functions. The toxic and tissue-destroying production of extracellular oxygen radicals by circulating PMNs was enhanced (e. g., A23 187 - stimulated oxygen radical generation 433 +/- 89 cpm/cPMNs (peritonitis with complications) versus 90 +/- 30 cpm/cPMNs (peritonitis without complications) versus 110 +/- 44 cpm/cPMNs (controls), p < 0.05). Phagocytosis (58 +/- 9 % (ePMNs, peritonitis with complications) versus 81 +/- 6 % (ePMNs, peritonitis without complications) versus 82.2 +/- 1.6 % (ePMNs, controls), p < 0.05) and phagocytosis-associated intracellular oxygen radical generation (8.23 +/- 1.6 x 10(3) cpm/ePMNs (peritonitis with complications) versus 25.2 +/- 5.2 x 10(3) cpm/ePMNs (peritonitis without complications) versus 11.7 +/- 2.8 cpm x 10(3) cpm/ePMNs (controls) p < 0.05) were suppressed.. Not for all patients with peritonitis does it seem favourable to modulate PMNs-functions. If immunomodulation would be able to down-regulate exaggerated functions of circulating PMNs and to up-regulate the suppressed functions of emigrated PMNs patients with complicated peritonitis might benefit from this therapy.

Topics: Colectomy; Free Radicals; Gastrectomy; Humans; Interleukin-8; Luminescent Measurements; Multiple Organ Failure; Neutrophils; Peritoneum; Peritonitis; Postoperative Complications; Prognosis; Reactive Oxygen Species; Shock, Septic; Tumor Necrosis Factor-alpha

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

Up to now there is no treatment for staphylococcal toxic shock syndrome, a disease mainly induced by toxic shock syndrome toxin-1(TSST-1). There is great demand in finding means to control the disease, one of them is the development of an effective and safe vaccine against TSST-1. In this study we constructed a series of vaccine candidates and investigated their biological activity, toxicity, and potential to invoke an immune response. TSST-1 was isolated from Stahylococcus aureus supernatants and recombinantly expressed as a N-terminal 6x histidine-tagged protein in Escherichia coli. In order to obtain molecules with minimal toxicity we constructed single mutants (G31R and H135A) and one double mutant (G31R/H135A) with both residues exchanged. We also detoxified native TSST-1 isolated from S. aureus, and recombinantly expressed TSST-1 by treatment with formaldehyde. Functional activity of native and recombinant TSST-1 and grade of inocuity of mutants and toxoids was determined by investigating mitogenity, T-cell activation, and cytokine release upon stimulation of human mononuclear cells with the vaccine candidates. All substances were tested in a rabbit immunization study. After primary immunization and three additional boosts all vaccinated animals developed antibody titers against TSST-1 and were protected against challenge with a lethal doses of superantigen potentiated with lipopolysaccharide.

Topics: Animals; Antibodies, Bacterial; Bacterial Toxins; Enterotoxins; Female; Formaldehyde; Interleukin-8; Lymphocyte Activation; Mitogens; Mutation; Rabbits; Receptors, Antigen, T-Cell, alpha-beta; Shock, Septic; Staphylococcal Vaccines; Superantigens; Tumor Necrosis Factor-alpha; Vaccines, Inactivated; Vaccines, Synthetic

Intra-abdominal infection is one of the major causes of septic shock and multiple organ failure. To date, what causes the disease's progression remains unclear and therefore the relevance of immune modulating therapies remains speculative. The primary outcome measure of this study was to investigate immune modulating mediators at the onset of peritonitis before the development of subsequent septic shock. The secondary outcome measure was to investigate the usefulness of these immune parameters in predicting progression from peritonitis to septic shock. Fifty-eight peritonitis patients were included in this study: 14 patients subsequently developed septic shock. All patients were examined on "diagnosis of peritonitis" (<4 h within establishment of diagnosis), during "early septic shock" (<12 h following the onset of septic shock), and once again during "late septic shock" (within 72-98 h following the onset of septic shock). The immune modulating parameters tumor necrosis factor-alpha (TNF-alpha), the soluble TNF-alpha receptors I and II (sTNF-alpha RI and sTNF-alpha RII), interleukines (IL) -1beta, -6, -8, and -10, and the adhesions molecules endothelial-leukocyte-adhesion-molecule (E-Selectin), intercellular-adhesion-molecule-1 (ICAM-1), and vascular-adhesion-molecule-1 (VCAM-1), in addition to nitrate and nitrite, were determined. In the peritonitis group with subsequent septic shock, TNF-alpha, sTNF-alpha RI + RII IL-1beta, IL-8, IL-10, and nitrate were significantly increased before the onset of septic shock. TNF-alpha had an area under the receiver operating characteristics curve (AUC) of 0.84 and was reliable in predicting the progression from peritonitis to septic shock. The AUC of the other immune modulating parameters, despite being significantly elevated, ranged from 0.71 to 0.76. The AUC of the conventional laboratory markers such as leukocytes and C-reactive protein ranged from 0.64 to 0.68. In peritonitis that progressed to septic shock, an early immune response had already occurred before the onset of septic shock. The progression was best predicted by TNF-alpha. Therefore, mediator therapy might be considered in high-risk peritonitis patients who show an exaggerated immune response before the progression to septic shock.

Topics: Adult; Aged; Aged, 80 and over; Area Under Curve; Disease Progression; Female; Humans; Interleukin-1; Interleukin-10; Interleukin-8; Male; Middle Aged; Peritonitis; Predictive Value of Tests; Receptors, Tumor Necrosis Factor; Shock, Septic; Tumor Necrosis Factor-alpha

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

Priming of the polymorphonuclear neutrophil (PMN) response has been implicated in the activation of oxidative burst and tissue injury in patients with septic shock and acute renal failure (ARF). This study evaluated whether hemofiltration (HF) removes substances able to enhance the oxidative burst of PMNs.. Chemiluminescence (CL) priming activity induced by sera and ultrafiltrates of seven patients with septic shock, multiorgan dysfunction syndrome, and ARF (ARF/HF group) and of 10 uremic stable patients (Control/HF group) was evaluated on normal human PMNs stimulated with bacterial formyl-methionyl-leucyl-phenylalanine (FMLP). Patients submitted to HF were studied by determining blood and ultrafiltrate interleukin-8 (IL-8), platelet-activating factor (PAF), and CL priming activity at the beginning (T0), and after four hours (T4) of treatment.. Preincubation of normal human PMNs with sera and ultrafiltrates from septic patients induced a potent priming of CL activity in subsequent FMLP stimulation. In the ARF/HF group, the prefilter blood concentrations of IL-8 and CL PMN-priming activity significantly decreased during the four hours of HF treatment, with a loss of IL-8 in the ultrafiltrate of 6930 (median, range 4292 to 9282) ng per four hours. PAF detected in the ultrafiltrate and associated with the membrane (7.3 ng, range 1.45 to 9.89) was minimal. In the ARF/HF group, a significantly positive correlation between CL PMN-priming activity and IL-8 concentrations was observed. The CL priming activity in blood and ultrafiltrates was reduced to 55 and 46% by preabsorption with monoclonal antibody (mAb) anti-IL-8. In contrast, the PAF receptor antagonist WEB 2170 did not affect CL priming activity. In the control/HF group, the CL PMN-priming activity was significantly lower than in the ARF/HF group and was independent of IL-8.. Sera from septic patients demonstrate an enhanced CL priming activity on PMNs. This activity is reduced by ultrafiltration and is due, at least in part, to ultrafiltered IL-8.

Topics: Acute Kidney Injury; Aged; Blood Physiological Phenomena; Hemofiltration; Humans; Interleukin-8; Luminescent Measurements; Middle Aged; Multiple Organ Failure; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Platelet Activating Factor; Reference Values; Respiratory Burst; Shock, Septic; Uremia

The chemokine interleukin-8 (IL-8) has chemoattractant activity for neutrophils and is able to activate and degranulate these cells. We investigated whether IL-8 may exert these effects in children with dengue virus infection. Circulating levels of IL-8, neutrophilic elastase (a constituent of the azurophilic granula of neutrophils), and lactoferrin, released from specific granula, were measured in 186 children with dengue virus infection, 33 healthy children as negative controls and 11 children with bacterial infections as positive controls. Levels of IL-8 on admission were elevated in 71% of the dengue patients, while the elastase and lactoferrin levels were increased in 68 and 17% of patients, respectively. These levels were significantly higher than in healthy children (P < 0.05) for IL-8 and elastase but not for lactoferrin (by the Wilcoxon-Mann-Whitney [WMW] U test). Similar levels of IL-8 were found in patients with bacterial infections. Levels of IL-8 and elastase in patients with shock were significantly higher than in patients without shock (P = 0.02; WMW), but those of lactoferrin were not. IL-8 correlated with elastase and lactoferrin (r = 0.19 and P = 0.009 versus r = 0.24 and P = 0.001, respectively; two-tailed Spearman rank correlation). Thus, IL-8 levels are increased in most patients with dengue virus infection and correlate with degranulation of neutrophils as well as with some clinical and hemodynamic variables. These findings suggest a role for IL-8 in the pathogenesis of dengue virus infection.

Topics: Cell Degranulation; Child; Dengue; Humans; Inflammation Mediators; Interleukin-8; Lactoferrin; Leukocyte Elastase; Neutrophils; Shock, Septic

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

Nitric oxide (NO) acts as a vasorelaxant. We investigated the relationship between nitrite/nitrate (NOx), which are the final metabolites of NO, and hemodynamics during septic shock. We also examined tumor necrosis factor alpha (TNF-alpha), interleukin-8 (IL-8), and endotoxin. A significant negative correlation was observed between NOx levels and pulmonary capillary wedge pressure (PCWP; r = -0.6075, P = 0.0028). A significant positive correlation was noted between NOx levels and the cardiac index (CI; r = 0.5934, P = 0.0038). A significant negative correlation was found between NOx levels and the systemic vascular resistance index (SVRI; r = -0.4354, P = 0.0485). A significant positive correlation was observed between NOx levels and the stroke volume index (SVI; r = 0.5040, P = 0.0186). A significantly close positive correlation was also observed between TNF-alpha levels and NOx levels (r = 0.7848, P < 0.0001). These findings suggest that NOx levels are closely associated with hemodynamics during septic shock, resulting in a vascular relaxing effect.

Topics: Adult; Aged; Endotoxins; Female; Hemodynamics; Humans; Interleukin-8; Male; Middle Aged; Nitrates; Nitric Oxide; Nitrites; Regression Analysis; Shock, Septic; Stroke Volume; Tumor Necrosis Factor-alpha; Vascular Resistance

To determine the effect of the nitric oxide synthase inhibitor, L-N(G)-monomethylarginine, on interleukin-6 and interleukin-8 accumulation, and nuclear factor-kappaB expression in an endothelial cell model of sepsis.. Controlled cell culture experiments examining the immunomodulatory effects of nitric oxide synthase inhibition.. A human endothelial cell line (EA.hy926).. Cells were incubated with tumor necrosis factor-alpha and interleukin (IL)-1beta in the presence of L-N(G)-monomethylarginine (L-NMMA). IL-6 and IL-8 were measured in culture supernatants using enzyme immunoassay. Nuclear factor-kappaB was measured using electrophoretic mobility shift assay and was quantified using phosphorimaging. IL-6 accumulation was decreased (p < .05) and IL-8 accumulation increased (p < .01) with L-NMMA. Increased nuclear factor-kappaB expression in stimulated cells was unaltered on exposure to L-NMMA. Cell viability was unaffected.. Excessive production of nitric oxide has been implicated in septic shock, and the use of nitric oxide synthase inhibitors has been suggested. The immunoregulatory actions of nitric oxide synthase inhibitors affects the profile of cytokine release. This effect is not mediated through modulation of nuclear factor-kappaB. These findings have implications for the use of nitric oxide synthase inhibiting agents in septic shock.

Topics: Cell Line; Culture Media; Drug Evaluation, Preclinical; Endothelium; Humans; Interleukin-1; Interleukin-6; Interleukin-8; NF-kappa B; Nitric Oxide Synthase; omega-N-Methylarginine; Shock, Septic; Time Factors; Tumor Necrosis Factor-alpha

Leukocyte interactions with vascular endothelium during inflammation depend on cascades of adhesion molecule engagement, particularly during selectin-mediated leukocyte rolling. Leukocyte rolling is also facilitated by members of the integrin and Ig families. Specifically, leukocyte rolling velocities during inflammation are significantly increased in ICAM-1-deficient mice, with ICAM-1 expression required for optimal P- and L-selectin-mediated rolling. Elimination of ICAM-1 expression in L-selectin-deficient mice significantly reduces leukocyte rolling. Whether disrupted leukocyte rolling in L-selectin and ICAM-1 double-deficient (L-selectin/ICAM-1-/-) mice affects leukocyte entry into sites of inflammation in vivo was assessed in the current study by using experimental models of inflammation; thioglycollate-induced peritonitis, chemokine-induced neutrophil migration to the skin, delayed-type hypersensitivity responses, rejection of allogeneic skin grafts, and septic shock. In many cases, the loss of both L-selectin and ICAM-1 expression dramatically reduced leukocyte migration into sites of inflammation beyond what was observed with loss of either receptor alone. In fact, the effects from loss of both L-selectin and ICAM-1 effectively eliminated multiple chronic inflammatory responses in L-selectin/ICAM-1-/- mice. By contrast, the combined loss of L-selectin and ICAM-1 expression had minimal effects on the generation of Ag-specific T cell responses or humoral immunity. Thus, members of the selectin and Ig families function synergistically to mediate optimal leukocyte rolling and entry into tissues, which is essential for the generation of effective inflammatory responses in vivo.

Topics: Animals; Cell Movement; Dermatitis, Contact; Graft Rejection; Immunity, Innate; Immunoglobulin G; Immunoglobulin M; Injections, Intradermal; Injections, Intraperitoneal; Intercellular Adhesion Molecule-1; Interleukin-8; L-Selectin; Lymphocyte Activation; Lymphocytes; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Peritonitis; Shock, Septic; Signal Transduction; Skin Transplantation; T-Lymphocytes; Thioglycolates

To obtain predictors of organ failure (OF), we studied markers of systemic inflammation [circulating levels of interleukin-6 (IL-6), IL-8, soluble IL-2 receptor (sIL-2R), soluble E-selectin and C-reactive protein, and neutrophil and monocyte CD11b expression] and routine blood cell counts in 20 patients with systemic inflammatory response syndrome and positive blood culture. Eight patients with shock due to community-acquired infection developed OF, whereas 11 normotensive patients and one patient with shock did not (NOF group). The first blood sample was collected within 48 h after taking the blood culture (T1). OF patients, as compared with NOF patients, had at T1 a lower monocyte count, a lower platelet count, higher levels of CD11b expression on both neutrophils and monocytes, and higher concentrations of IL-6, IL-8 and sIL-2R. C-reactive protein and soluble E-selectin concentrations did not differ between groups. No parameter alone identified all patients that subsequently developed OF. However, a sepsis-related inflammation severity score (SISS), developed on the basis of the presence or absence of shock and on the levels of markers at T1, identified each patient that developed OF. The maximum SISS value was 7. The range of SISS values in OF patients was 2-5, and that in NOF patients was 0-1. In conclusion, high levels of CD11b expression, depressed platelet and monocyte counts, and high concentrations of IL-6, IL-8 and sIL-2R predict OF in patients with community-acquired septic shock, and the combination of these markers may provide the means to identify sepsis patients who will develop OF.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; APACHE; Biomarkers; Blood Cell Count; C-Reactive Protein; Community-Acquired Infections; E-Selectin; Female; Humans; Interleukin-6; Interleukin-8; Macrophage-1 Antigen; Male; Middle Aged; Multiple Organ Failure; Receptors, Interleukin-2; Shock, Septic

To further improve the treatment of burn wound sepsis.. Eight patients with burn wound sepsis, of whom 6 with MODS and two with septic shock, were treated consecutively in our hospital from September 1997 to October 1998. The plasma concentrations of IL-6, IL-8 TNF and LPS were assayed before and after surgical intervention and at the time when the patients' vital signs became stable.. (1) The patients' conditions abruptly deteriorated when the burn wound sepsis emerged. (2) The major causative factor related to burn wound sepsis was extensive burn injuries, with large area of deep burn remained open. (3) Although colonization by multiple pathogenic bacteria was found, Pseudomonas aeruginosa was the most frequent bacteria isolated from the subeschar tissue. (4) The plasma concentrations of IL-6, IL-8, TNF and LPS before surgical intervention were significantly higher than those after surgical intervention (P < 0.05); (5) The lowest level of the inflammatory mediators were observed when the conditions of patients became stable, and the values were significantly lower compared with those before surgical intervention (P < 0.001).. The main cause of burn wound sepsis is the presence of a large area of infected open deep burn wounds, which should be excised and covered early. LPS and pro-inflammatory mediators play an important role in the pathogenesis of burn wound sepsis. Favorable results in the treatment attribute to appropriate application of multiple treatments, and early, aggressive and thorough surgical excision of invasive burn infectious tissue and closure of wounds play a crucial role.

Topics: Adolescent; Adult; Burns; Child; Female; Humans; Interleukin-6; Interleukin-8; Lipopolysaccharides; Male; Middle Aged; Multiple Organ Failure; Shock, Septic; Wound Infection

A 67-yr-old patient with septic shock caused by gram-positive infection fell into circulatory collapse. Direct hemoperfusion with an endotoxin-removing column was then carried out for 120 min. As a result, blood pressure and systemic vascular resistance increased significantly during this therapy. Cardiac output changed from hyperdynamic to normodynamic, and plasma endotoxin level decreased. After this treatment, the patient recovered. From this experience, we consider that the endotoxin-removing column may be effective for septic shock patients.

Topics: Aged; Anti-Bacterial Agents; Blood Pressure; Cardiac Output; Endotoxins; Gram-Positive Bacterial Infections; Hemoperfusion; Humans; Interleukin-1; Interleukin-2; Interleukin-6; Interleukin-8; Male; Oxygen; Oxygen Consumption; Polymyxin B; Shock, Septic; Tumor Necrosis Factor-alpha; Vascular Resistance

The impact of antibiotics on total endotoxemia and circulating tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-8 in 18 patients with severe bacteremic sepsis or septic shock due to gram-negative species was investigated. Endotoxemia, TNF-alpha, IL-6, and IL-8 were assayed before (H0) and 1 h (H1) and 4 h (H4) after the first antibiotic infusion. Endotoxemia decreased from H0 (median, 0.4 EU/mL; interquartile interval, 0.09-1.23) to H1 (median, 0.19 EU/mL; interquartile interval, 0.07-0.75; P = .03) and remained stable between H1 and H4 (median, 0.12 EU/mL; interquartile interval, 0.09-0.30; P = .4). IL-6 levels fell between H0 and H4 (P = .01) and between H1 and H4 (P = .03). IL-8 was higher at H0 than at H1 (P = .04) and at H4 (P = .01). These results suggest that endotoxemia is not increased by antibiotherapy of severe gram-negative bacteremia.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Bacteremia; Drug Therapy, Combination; Endotoxins; Female; Gram-Negative Bacterial Infections; Humans; Interleukin-6; Interleukin-8; Male; Middle Aged; Shock, Septic; Tumor Necrosis Factor-alpha

The acute respiratory distress syndrome (ARDS) is a frequent complication of severe sepsis and a major cause of death in patients with hematologic malignancy during chemotherapy-induced leukocytopenia. Inflammatory mediators are important modulators of host response to injury and have been found to be increased in the bronchoalveolar lavage (BAL) fluid of nonleukocytopenic patients with ARDS. Since inflammatory cytokines in plasma of nonleukocytopenic patients seem to be efficient predictors of the course of ARDS, we examined this hypothesis in leukocytopenic patients with septic shock-induced ARDS.. Prospective, observational study.. Intensive care unit (ICU) of a university hospital.. Nineteen patients with leukocytopenia (white blood cell count of <1/nL) following cytoreductive chemotherapy for malignant disorders and severe sepsis with shock-induced ARDS (Murray score of >2.5).. BAL and plasma sampling and ICU management.. The proinflammatory cytokines tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-8 were measured in the BAL aspirates and in plasma samples, both obtained within 18 hrs after onset of ARDS. Hemodynamic and oxygen metabolism data were measured immediately before plasma samples were taken and BAL was performed. Of the 19 patients studied, nine patients responded to ICU treatment (e.g., mechanical ventilation as indicated by PaO2/FIO2, FIO2, shunt volume, and course of pulmonary infiltrates), whereas ten patients did not respond. BAL cytokine concentrations were significantly increased in nonresponders in comparison with responding patients (TNF-alpha, p = .021; IL-6, p = .008; IL-8, p = .019). In contrast, we did not observe any differences between the groups in terms of plasma cytokine concentrations.. Determination of cytokine concentrations in BAL samples may be useful for evaluation of severity and course of ARDS in leukocytopenic patients, whereas measurement of plasma cytokines is not helpful.

Topics: Adult; Aged; Biomarkers; Bronchoalveolar Lavage Fluid; Critical Care; Cytokines; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Interleukin-6; Interleukin-8; Leukopenia; Male; Middle Aged; Prospective Studies; Respiratory Distress Syndrome; Shock, Septic; Tumor Necrosis Factor-alpha

This study tested the hypothesis that tissue factor pathway inhibitor (TFPI) would improve mortality and morbidity evoked by peritonitis-induced bacteremia in pigs. Secondarily, it sought to determine if TFPI treatment would attenuate cardiodynamic abnormalities produced by this septic model. 32 pigs were chronically instrumented with intracardiac transducers to measure left ventricular pressure and diameter, pulmonary and aortic pressures, and cardiac output. At least 5 days after surgery to implant transducers, basal cardiovascular readings and blood samples were obtained. Using a randomized, blinded study design, either purified, reconstituted TFPI (1 mg/kg bolus, 10 mg/kg/min for 48 h), placebo (arginine buffer), or saline was administered to pigs immediately after Escherichia coli 0111.B4 (3.0-11 x 10(9) colony-forming U/kg)-laden fibrin clots were implanted intraperitoneally, producing peritonitis and bacteremia. Pigs did not receive antibiotics or supportive therapy. No significant differences in primary or secondary endpoints were noted between the arginine and saline groups, so these data were combined into a control group (N = 20). 5 of 12 TFPI pigs survived (42%), while 5 of 20 control pigs survived (25%); this difference was not significant (p = .714, Fisher's exact test). TFPI treatment augmented cardiac output in surviving pigs, but did not affect any other cardiovascular performance variable (heart rate, % diameter shortening, or systemic and pulmonary vascular resistance). In controls, peritonitis induced rapid increase in plasma tumor necrosis factor-alpha (428 +/- 771 to 5,933 +/- 559 pg/mL at 2 h) and interleukin-8 (180 +/- 153 to 1,393 +/- 145 pg/mL at 2 h). TFPI treatment significantly attenuated cytokine responses to sepsis, reducing peak tumor necrosis factor-alpha to 2,103 +/- 813 pg/mL and reducing peak interleukin-8 levels to 534 +/- 211 pg/mL at 2 h (p < .05, Tukey test, two-way ANOVA). In conclusion, TFPI treatment attenuated important mediator components of the inflammatory response but did not provide significant survival benefit.

Topics: Animals; Blood Pressure; Drug Evaluation, Preclinical; Heart; Heart Rate; Interleukin-8; Lipoproteins; Placebos; Random Allocation; Shock, Septic; Single-Blind Method; Survival Rate; Swine; Time Factors; Tumor Necrosis Factor-alpha

Although high levels of interleukin-8 (IL-8) have been found in patients with sepsis and a monoclonal antibody (MoAb) against IL-8 has been successfully used in some animal models of inflammation, no specific therapeutic agent against IL-8 has been tested for the treatment of sepsis. We studied the effects of a MoAb against IL-8 in the treatment of endotoxic shock with a prospective randomized rabbit endotoxic shock model.. Twenty New Zealand white rabbits were anesthetized and divided into four groups: normal, anti-IL-8, control-Ab, and lipopolysaccharide (LPS). Anti-IL-8 and control-Ab groups received a MoAb (immunoglobulin G, 3 mg/kg) 5 minutes before the LPS injection. All groups, except the normal group, received a continuous 20-minute infusion of LPS (500 micrograms/kg). The normal group received NaCl (0.9%) rather than LPS.. The 7-day survival rates were 100% for normal group, 80% for anti-IL-8 group, 40% for control-Ab group, and 0% for LPS group. Compared with the LPS group, anti-IL-8 rabbits had a smaller decrease in mean arterial blood pressure (p < 0.05) and increased urinary volume (p < 0.05). Anti-IL-8 rabbits had lower plasmatic levels of IL-1 beta, less free radical production (p < 0.05), and a higher survival rate (p < 0.01).. IL-8 plays a significant role in endotoxic shock, and IL-8 blockage results in attenuation of the hypotensive and tachypneic effects of LPS, reduced free radical production, and an increased survival rate after lethal endotoxic shock.

Topics: Animals; Antibodies, Monoclonal; Diuresis; Female; Free Radicals; Hematocrit; Hemodynamics; Interleukin-1; Interleukin-8; Leukocyte Count; Lipopolysaccharides; Neutrophils; Rabbits; Reactive Oxygen Species; Shock, Septic; Survival Rate; 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 evaluate the effects of removing circulatory tumor necrosis factor (TNF) by immunoadsorption on endotoxin shock animals.. Sixty New Zealand white rabbits were injected intravenously with lethal dose of endotoxin (10 Billion cfu/kg E. Coli endotoxin) and randomly divided into 3 groups: perfusion group, hemoperfusion started at 1 hour after injecting endotoxin through immunoadsorbent columns against TNF; pseudoperfusion group, hemoperfusion through blank columns; and control group, injected with endotoxin only. The arterial pressure, microcirculation of the mesentery, plasma levels of TNF, IL-1, IL-6, IL-8, nitrite, endothelin-1 (ET-1), alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine were measured and analyzed and finally the survival rate was observed.. Plasma levels of TNF were sharply reduced after immunoadsorption. Moreover, release of IL-1, IL-6, IL-8, NO and ET-1 were also attenuated. Hemodynamic abnormalities could be improved and survival rate ameliorated significantly.. Specific immunoadsorption of circulating TNF might be a new and effective therapy for endotoxin shock.

Topics: Animals; Endothelin-1; Immunosorbent Techniques; Interleukin-1; Interleukin-6; Interleukin-8; Rabbits; Random Allocation; Shock, Septic; Tumor Necrosis Factor-alpha

Soluble CD14 (sCD14) mediates lipopolysaccharide (LPS) activation of epithelial cells in vitro and may thereby be harmful in sepsis. sCD14 function was analyzed in sera from 62 patients with septic shock and compared with data from appropriate controls. sCD14 function was measured as sCD14-dependent LPS-induced interleukin (IL)-8 release in the SW620 epithelial cell line. In these cells, IL-8 production correlated with LPS concentration and the amount of sCD14. The effect of natural recombinant sCD14 was maximal at 100 ng/mL and blocked by anti-CD14 antibodies. Patient and control sera (0.5% final concentration) promoted induction of IL-8 by 100 ng/mL LPS in SW620 cells. In sepsis patients (highest serum sCD14), values were significantly higher than in the other groups. The LPS-induced IL-8 response was blocked by anti-CD14 and correlated with the serum CD14 level in sepsis patients. Thus, sCD14 could play a pathogenic role in sepsis.

Topics: Adult; Aged; Base Sequence; Case-Control Studies; Cell Line; DNA Primers; Female; Hemoglobinuria, Paroxysmal; Humans; In Vitro Techniques; Interleukin-8; Lipopolysaccharide Receptors; Lipopolysaccharides; Male; Middle Aged; Molecular Sequence Data; Shock, Septic; Solubility

Interleukin (IL)-12 is thought to be a key factor for the induction of interferon gamma (IFN-gamma), a cytokine essential for the lethal effects of endotoxin. We report here on the release of the nonfunctional subunit of IL-12, p40, as well as biologically active heterodimeric IL-12, p70, after administration of a lethal (n = 5) or sublethal (n = 8) dose of live Escherichia coli to baboons. Remarkably, on lethal challenge, peak levels of p40 were observed at 3 hours that were about twofold lower than those elicited after sublethal challenge (2,813 +/- 515 pg/mL v 4,972 +/- 732 pg/mL, P < .05). This disparity was also observed, although to a lesser extent, for IL-12 p70 antigen, of which maximum levels of 91 +/- 47 pg/mL and 151 +/- 41 pg/mL were measured 6 hours after a lethal or sublethal dose of E coli, respectively. Circulating p70 antigen correlated with IL-12 biologic activity (r = 0.869; P < .001). When comparing lethal to sublethal conditions, lower peak levels of IL-12 on lethal E coli sharply contrasted with higher levels of other proinflammatory cytokines, such as tumor necrosis factor (TNF)-alpha, IL-1beta, IL-6, and IL-8 observed in these animals. Lower IL-12 concentrations in the lethal group may have resulted in part from the enhanced production of IL-10, a known inhibitor of IL-12 synthesis in vitro, as peak levels of this cytokine 3 hours postchallenge inversely correlated with peak levels of IL-12, in particular p40 (r = -0.802; P < .01). Contrary to what might be expected if IFN-gamma were solely induced by IL-12, lethally challenged baboons generated threefold more IFN-gamma at 6 hours than those receiving a sublethal dose (P < .05). Moreover, higher levels of IFN-gamma were associated with lower p40/p70 ratios, suggesting that, in agreement with observations in vitro, IFN-gamma may have preferentially upregulated the release of p70 over p40. These data show that IL-12 is released in experimental septic shock in nonhuman primates and suggest that IL-10 and IFN-gamma are involved in the regulation of this release. Furthermore, this study indicates that the systemic release of IL-12 might be essential, but is not likely sufficient, to promote lethal production of IFN-gamma in sepsis.

Topics: Animals; Bacteremia; Cytokines; Escherichia coli Infections; Gene Expression Regulation; Interferon-gamma; Interleukin-10; Interleukin-12; Interleukin-8; Killer Cells, Natural; Papio; Phagocytes; Shock, Septic; T-Lymphocytes; Tumor Necrosis Factor-alpha

The function of vascular endothelial cells is to adjust blood vessel tonus, which contributes to maintaining homeostasis within blood vessels. However, inflammatory cytokines are produced in response to invasion by stimulating vascular endothelial cells and sometimes lead to shock or multiple organ failure. In the present study, we assessed cytokines in sepsis and septic shock, and various factors that are said to have a damaging effect on vascular endothelium. Endotoxin was measured by endotoxin-specific methods. Tumor necrosis factor-alpha (TNF-alpha), interleukin 6 (IL-6), and interleukin 8 (IL-8) were measured by enzyme-linked immunosorbent assay (ELISA). Endothelin-I was measured by radioimmunoassay (RIA). Nitric oxide was measured as metabolites of nitrite and nitrate oxides (NOx) by a method based on the Griess method. Thromboxane B2 (TXB2) and 6-keto-prostaglandin F1 alpha (PGF 1 alpha) were both measured by RIA. All of the factors except endotoxin were significantly higher in the septic shock group than in the non-shock group and significantly higher in the non-survivor group than in the survivor group. Significant correlations were also found between endothelin-1 and NOx and between TXB2 and PG1 alpha. Significant correlations were also found between TNF-alpha and IL-6, endothelin-1, NOx and TXB2, but no significant correlations were detected between any of them and endotoxin. In serious diseases such as septic shock, the vascular endothelial constricting factors, endothelin and TXB2, and the blood vessel relaxing factors NOx and PGF1 alpha increase almost simultaneously. This suggests that the body's regulating mechanisms are disrupted in these serious conditions. The results of this study also suggest that inflammatory cytokines may be involved in stimulating the production of these factors.

Topics: Adult; Aged; Aged, 80 and over; Cytokines; Endothelium, Vascular; Endotoxins; Enzyme-Linked Immunosorbent Assay; Female; Humans; Interleukin-6; Interleukin-8; Male; Middle Aged; Shock, Septic; Tumor Necrosis Factor-alpha

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

We determined the plasma concentrations of interleukin 8 (IL-8), polymorphonuclear leukocyte elastase (PMNE), and endotoxin in patients with septic shock in order to investigate the role of IL-8 and PMNE in the development of septic shock, especially in septic adult respiratory distress syndrome (ARDS). The IL-8 concentration in patients with septic shock was 6.28 +/- 9.00 ng/mL (mean +/- SD, n = 29), which was significantly higher (P < 0.0001) than the concentration in septic patients without shock (0.35 +/- 0.35 ng/mL, n = 40). There was a significant correlation between the IL-8 concentration and the PMNE concentration at the onset of septic shock (r = 0.6916, P < 0.0001). The IL-8 concentration was also significantly correlated with the endotoxin concentration (r = 0.5584, P = 0.0016). There was a significant negative correlation (r = -0.8237, P < 0.0001) between the serum PMNE concentration and the oxygenation index (PaO2/FiO2) at the onset of septic shock. These results indicate that IL-8 and PMNE are produced in large quantities when septic shock occurs, and may play a role in the development of septic ARDS.

Topics: Adult; Endotoxins; Humans; Interleukin-2; Interleukin-8; Kinetics; Leukocyte Elastase; Male; Middle Aged; Oxygen; Pancreatic Elastase; Reference Values; Respiratory Distress Syndrome; Shock, Septic

The plasma levels of endotoxin, tumor necrosis factor- alpha (TNF-alpha), interleukin -1 beta (IL-beta), IL-6, IL-8 and the nitrites and nitrates (NO2-/NO3-) as stable metabolites of nitric oxide (NO) were studied in the plasma of 2 patients with the streptococci toxic shock syndrome (STSS) associated to necrotizing fasciitis. A plasma profile of inflammatory mediators with high cytokine concentrations and NO2-/NO3- were observed with circulating endotoxin not being detected in plasma. The first patient died of fulminant refractory shock while the second survived following subacute evolution. The mediators profile, which was much higher in the first case, coincided with clinical severity. These data suggest that the cytokines and NO may have a role in the physiopathology of STSS and the severity of it is related to the levels of these mediators in the acute phase.

Topics: Adult; Cytokines; Endotoxins; Female; Humans; Interleukin-1; Interleukin-6; Interleukin-8; Male; Middle Aged; Nitrates; Nitric Acid; Nitrites; Shock, Septic; Streptococcal Infections; Streptococcus pyogenes; Tumor Necrosis Factor-alpha

To further clarify the mechanism of polymorphonuclear leukocyte (PMN) recruitment into the liver associated with short term endotoxin infusion (1), we investigated the effect of a noval factor generated by hepatocytes of such endotoxic rats on the expression of PMN adhesion molecules CD11b/c and chemotactic activity. Conditioned medium of hepatocytes from endotoxin-infused rats shows a fast induction and dose-dependent activity for upregulating CD11b/c expression in and chemotactic activity for blood PMN of naive rats. Supernatants of naive control rats cultured in the presence of endotoxin and Kupffer cells and liver PMNs of endotoxic rats also produce activation, but to a much lesser extent. The upregulating activity can be reduced significantly by heat inactivation at 100 degrees C for 10 min and by pronase hydrolysis at 37 degrees C for 60 min. Generation of the activity does not depend on cyclooxygenase products or phospholipase A2 activity, and it does not seem to be associated with the complement pathway. The activity is associated with molecular masses of 9-12 and 27-32 kDa and cannot be reduced by antiserum to rat interleukin-8 in serial dilutions ranging from 1:50 to 1:25,600. The results show that hepatocytes from acutely endotoxin infused rats generate a small molecular weight protein factor (or factors) that is capable of upregulating PMN 11b/c expression and chemotactic activity and is seemingly different from rat interleukin-8. Thus, hepatocytes in endotoxemia may play an important role in modulating neutrophil function and contributing to the mechanism of neutrophil sequestration into the liver.

Topics: Animals; CD11 Antigens; Cells, Cultured; Chemotactic Factors; Endotoxins; Escherichia coli; Gene Expression; Immune Sera; Interleukin-8; Liver; Male; Neutrophils; Rats; Rats, Sprague-Dawley; Shock, Septic

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

Topics: Animals; Cytokines; Humans; Interleukin-8; Multiple Organ Failure; Shock, Septic

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

To evaluate the role of interleukin (IL)-8 in meningococcal disease, a solid-phase double-ligand ELISA was used to quantitate IL-8 in sera and cerebrospinal fluid (CSF) from patients with meningococcal meningitis, bacteremia, or both with or without septic shock. IL-8 was demonstrated in sera from 28 of 62 patients; levels were significantly higher in patients with septic shock without meningitis (median, 36.1 ng/mL) than in patients with other manifestations (median, < 0.02 ng/mL), and 4 of 5 patients who died had high levels. IL-8 was detected in all 27 CSF samples. Serum IL-8 levels correlated highly significantly with those of IL-6 (r = .83) and tumor necrosis factor (TNF; r = .64), while the correlations between corresponding CSF levels were less pronounced (r = .43 and r = .38, respectively) but still significant. Serum IL-8 levels were highest in patients with a symptom history < 12 h. The elimination rate of IL-8 from serum varied and was similar to that of IL-6 and TNF. IL-8 appears to participate in the complex cytokine network during the initial phase of systemic meningococcal infections.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Bacteremia; Child; Child, Preschool; Female; Humans; Interleukin-1; Interleukin-6; Interleukin-8; Kinetics; Leukocyte Count; Male; Meningitis, Meningococcal; Meningococcal Infections; Middle Aged; Neutrophils; Shock, Septic; Tumor Necrosis Factor-alpha

The present study was undertaken to evaluate the extent to which an endogenous interleukin-1 (IL-1) response contributes to the hemodynamic and metabolic consequences of sublethal endotoxemia or lethal Gram-negative septic shock. Young, healthy baboons received either a sublethal dose of lipopolysaccharide (LPS) or an LD100 of live Escherichia coli bacteria, and one half of the animals in each group were continuously infused with IL-1 receptor antagonist (IL-1ra). Plasma IL-1 beta was not detected in this model of endotoxemia. Administration of IL-1ra had only minimal effects on the modest hemodynamic and metabolic responses to sublethal endotoxemia, and did not attenuate the plasma cytokine response. In contrast, high circulating levels of IL-1 beta (range 300-800 pg/ml) were seen during lethal E. coli septic shock. IL-1ra treatment significantly attenuated the decrease in mean arterial blood pressure (MAP) (from -72 +/- 8 to -43 +/- 6 mm Hg; P less than 0.05) and cardiac output (from -0.81 +/- 0.17 to -0.48 +/- 0.15 liter/min; P less than 0.05), and significantly improved survival from 43 to 100% at 24 h (P less than 0.05). The plasma IL-1 beta and IL-6 responses to lethal E. coli septic shock were also significantly diminished by IL-1ra treatment (P less than 0.05), whereas tumor necrosis factor-alpha (TNF alpha) concentrations were unaffected. We conclude that an exaggerated systemic IL-1 beta response is characteristic of lethal E. coli septic shock, and contributes significantly to the hemodynamic and metabolic consequences of E. coli septic shock. IL-1ra can significantly attenuate the cytokine cascade and improve survival.

Topics: Animals; Endotoxins; Escherichia coli; Hemodynamics; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Interleukin-6; Interleukin-8; Papio; Proteins; Receptors, Immunologic; Receptors, Interleukin-1; Shock, Septic; Sialoglycoproteins; Tumor Necrosis Factor-alpha

Because of its neutrophil-activating properties, interleukin-8 (IL-8) may play an important role in the pathophysiology of sepsis. We measured circulating IL-8 levels in 47 patients with clinical sepsis. Levels on admission were elevated in 42 of the 47 patients (89%) and were comparable in patients with gram-positive or gram-negative infections. Patients with shock had significantly higher IL-8 levels than normotensive patients (P = 0.0014, Wilcoxon-Mann-Whitney test), whereas no differences in IL-8 levels were found between patients with or without adult respiratory distress syndrome. Patients who died had higher IL-8 levels on admission than the patients who survived. The largest differences in IL-8 levels between survivors and nonsurvivors was found when only patients with positive cultures were considered (P = 0.0342). IL-8 levels appeared to correlate significantly with lactate levels and inversely with leukocyte and platelet numbers and mean arterial pressure. In addition, the IL-8 level in the sepsis patients was found to correlate significantly with levels of IL-6, elastase-alpha 1-antitrypsin, and C3a. Serial observations revealed that in most patients IL-8 levels decreased, irrespective of the outcome. Thus, our results demonstrate that IL-8 levels are increased in most patients with sepsis and correlate with some important clinical, biochemical, and inflammatory parameters. These findings suggest a role for IL-8 in the pathophysiology of sepsis.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; alpha 1-Antitrypsin; Bacteremia; Blood Pressure; Complement C3a; Enzyme-Linked Immunosorbent Assay; Factor XII; Gram-Negative Bacterial Infections; Gram-Positive Bacterial Infections; Humans; Interleukin-6; Interleukin-8; Lactates; Lactic Acid; Lactoferrin; Leukocyte Elastase; Middle Aged; Pancreatic Elastase; Prekallikrein; Respiratory Distress Syndrome; Shock, Septic

Much effort has been directed toward elucidating the host response to sepsis and inflammation, resulting in the definition of a cascade of endogenous mediators that direct metabolic and immunological responses. Here we report that IL-8, a novel cytokine produced by a variety of cells in vitro in response to stimulation with bacterial LPS and the proinflammatory cytokines, appears in the circulation of primates in vivo during septic shock, sublethal endotoxemia, and after the administration of IL-1 alpha. The magnitude of the IL-8 response correlates with the severity of the insult, and levels of IL-8 peak relatively late, after those of TNF-alpha and IL-1 beta, and simultaneously with those of IL-6. IL-8 has been primarily defined as a selective activator and chemoattractant of neutrophils, and we demonstrate that after LPS or IL-1 alpha infusion, circulating neutrophil numbers rapidly recover from an initial neutropenia while IL-8 concentrations are maximal, supporting the hypothesis that IL-8 influences circulating leukocyte populations in vivo. We conclude that IL-8 is another participant in the cytokine cascade elicited by sepsis and inflammation and, as such, may play a significant role in host defense and disease.

Topics: Animals; Endotoxins; Female; Interleukin-1; Interleukin-6; Interleukin-8; Lipopolysaccharides; Male; Papio; Shock, Septic; Tumor Necrosis Factor-alpha