Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Production and release of proinflammatory mediators such as tumour necrosis factor-alpha and neopterin are common events following the activation of the cellular immune system. Concerning inflammatory disorders of the lung, e.g. sepsis or sarcoidosis, high serum neopterin levels have been reported to correlate well with the severity of the disease. These situations are often associated with an increased expression of ICAM-1 reported to be induced in type II alveolar epithelial cells. In our study we investigated the potential effects of neopterin on ICAM-1 synthesis in the type II-like pneumocyte cell line L2. Detection of ICAM-1 gene expression by reverse transcriptase-polymerase chain reaction revealed a dose-dependent effect of neopterin, with maximum impact following 12-h incubations. Comparable results were obtained when ICAM-1 protein synthesis was measured via a cell-based ELISA. In a second set of experiments we were able to show that coincubation of L2 cells with pyrrolidine dithiocarbamate (PDTC) significantly suppressed neopterin-induced ICAM-1 synthesis. Since PDTC is known to be a potent inhibitor of NF-kappaB, the stimulating effects of neopterin on ICAM-1 gene expression and protein generation may be mediated by activation of this transcription factor. From these data we conclude that neopterin stimulates ICAM-1 production in L2 cells. In vivo, these effects may contribute to the prolongation of the inflammatory response, including cytotoxic cell host defence mechanisms that impair the functions of the airway epithelium.
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PMID:Neopterin-induced expression of intercellular adhesion molecule-1 (ICAM-1) in type II-like alveolar epithelial cells. 1059 64

Background: At present, it is unclear whether in experimental endotoxemia, the pro-inflammatory response observed in healthy volunteers is followed by an anti-inflammatory response, as observed in patients with sepsis. We studied the evolution of a number of inflammatory parameters during a prolonged period (24 h) after infusion of endotoxin in healthy subjects. Methods: Six healthy male subjects received an infusion of endotoxin (4 ng/kg body weight). Blood was drawn before, and at various intervals up to and including 24 h after, endotoxin infusion. Circulating cytokine levels, leukocyte activation surface markers, plasma lactoferrin, and neopterin levels were measured, and clinical signs and symptoms were noted during a 24-h period. Monocyte and neutrophil activation after endotoxin infusion is investigated in relation to the inflammatory response. The extent of neutrophil and monocyte activation was correlated to clinical markers and blood levels of inflammatory mediators and cytokines. Results: Tumor necrosis factor-alpha appeared 30 min after infusion in the circulation, peaking (5665+/-1910 pg/ml) at 2 h. Interleukin-10 appeared 60 min after infusion, peaking (427+/-348 pg/ml) at 3 h. The expression of leukocyte activation markers increased significantly after infusion. Expression of HLA-DR on monocytes decreased significantly after 3 h (P=0.03). There was a correlation between the TNF-alpha:IL-10 ratio and the CD11b:HLA-DR ratio (P=0.03). Conclusions: During experimental human endotoxemia, an initial pro-inflammatory response is successfully compensated by an anti-inflammatory response, leading to homeostasis. This is in contrast to what happens in septic patients with compensatory anti-inflammatory response syndrome. The inflammatory balance, expressed as the cytokine pro:anti-inflammatory ratio, is reflected at a cellular level.
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PMID:Leukocyte activation and cytokine production during experimental human endotoxemia. 1074 52

Cardiopulmonary bypass increases the blood levels of various immune mediators, thereby leading to a systemic inflammatory response syndrome, e.g. sepsis, with some hemodynamic alterations, such as vasodilatation, tachycardia, and a decrease in systemic vascular resistance. Perioperative hemofiltration is one of the treatment modalities proposed to prevent this syndrome. Modified hemofiltration has been introduced recently by investigators who recommend that the former standard techniques are ineffective in eliminating the inflammatory mediators. The purpose of this study was to determine the effects of the modified technique on these mediators and on hemodynamic parameters. Forty patients undergoing coronary artery bypass grafting were randomized into equal control and hemofiltered groups. The hemodynamic parameters, as well as blood samples, were taken before and after hemofiltration to assess blood concentrations of interleukin-6, interleukin-8 and neopterin. The hemodynamic parameters and immune mediator levels did not differ between the two groups during the course of the study, except in the immediate postoperative periods, where cardiac output, cardiac index, and systemic vascular resistance values were significantly greater in the hemofiltered group while there were no differences in the immune mediators. The results of our study suggest that the effects of modified hemofiltration on immune mediators are still debatable. The improvement found in cardiac performance could be attributed to the prevention of hemodilution and hypervolemia.
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PMID:The effects of modified hemofiltration on inflammatory mediators and cardiac performance in coronary artery bypass grafting. 1078 69

Until recently, inflammation was believed to arise from events taking place exclusively in the periphery. However, it is now clear that central neurogenic influences can either enhance or modulate peripheral inflammation. Therefore, it should be possible to improve treatment of inflammation by use of antiinflammatory agents that reduce peripheral host responses and inhibit proinflammatory signals in the central nervous system (CNS). One such strategy could be based on alpha-melanocyte stimulating hormone (alpha-MSH). Increases in circulating TNF-alpha and nitric oxide (NO), induced by intraperitoneal administration of endotoxin in mice, were modulated by central injection of a small concentration of alpha-MSH. Inducible nitric oxide synthase (iNOS) activity and iNOS mRNA in lungs and liver were likewise modulated by central alpha-MSH. Increase in lung myeloperoxidase (MPO) activity was significantly less in lungs of mice treated with central alpha-MSH. Proinflammatory agents induced by endotoxin were significantly greater after blockade of central alpha-MSH. The results suggest that antiinflammatory influences of neural origin that are triggered by alpha-MSH could be used to treat systemic inflammation. In addition to its central influences, alpha-MSH has inhibitory effects on peripheral host cells, in which it reduces release of proinflammatory mediators. alpha-MSH reduces chemotaxis of human neutrophils and production of TNF-alpha, neopterin, and NO by monocytes. In research on septic patients, alpha-MSH inhibited release of TNF-alpha, interleukin-1 beta (IL-1 beta), and interleukin-8 (IL-8) in whole blood samples in vitro. Combined central and peripheral influences can be beneficial in treatment of sepsis.
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PMID:alpha-MSH in systemic inflammation. Central and peripheral actions. 1081 51

Infectious complications are still a major cause of morbidity and mortality after organ transplantation, and early therapy would certainly reduce the risk associated with severe infections. We therefore investigated the significance of polymorphonuclear leukocyte (PMN) functional tests as predictive markers for infection in transplant patients under immunosuppressive therapy in a longitudinal study. In 41 patients, blood PMN migration and reactive oxygen species release, the blood levels of PMN elastase, malondialdehyde, neopterin, sICAM-1 and sVCAM-1, and urine neopterine were measured in 3- and 4-day intervals after liver-, kidney-, kidney-pancreas-, and heart and lung transplantation. PMN migration was determined in whole blood and estimated by the amount of PMNs to penetrate into a membrane filter upon FMLP stimulation. Three groups of patients were formed according to their postoperative course. Group I patients (n = 23) had no or only minor local infection, group II patients (n = 11) had infections with distinct systemic involvement, and group III patients (n = 7) developed sepsis. A first elastase-level of over 100 mg/L after surgery, followed by a drop in the amount of blood PMNs ready to migrate, on FMLP stimulation, to below 12 %, turned out to be a marker for impending infection, whereas all other parameters tested were not predictive. In six of seven group III patients, this marker became positive (sensitivity 85.7 %) up to 15 days before clinical manifestation of sepsis. In group I (largely uneventful recovery) only one of 23 patients was positive (specificity 95.6 % ), whereas group II patients were in between (4 of 11 positive). By this method it seems possible to diagnose severe infections in the pre-clinical phase, which may help prevent them if treatment is begun promptly.
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PMID:Polymorphonuclear leukocyte functions as predictive markers for infections after organ transplantation. 1083 47

We examined whether procalcitonin (PCT) or neopterin (NT) are useful in predicting sepsis, multiple organ failure (MOF), or death after multiple trauma (MT). In a prospective clinical study, a total of 137 consecutive trauma patients (mean age 39 years, median injury severity score [ISS] 27 points) and 34 healthy volunteers were enrolled. Blood samples were collected on arrival in the emergency room until day 28 after trauma. Plasma NT was detected by enzyme-linked immunoassay and PCT plasma levels were determined using an immunoluminometric assay. The incidence of sepsis was 65%, MOF 48%, and death in hospital within 28 days 11%. After adjustment for age, gender, and ISS, PCT and NT levels during the first 2 days after injury were unable to differentiate between patients who developed sepsis or not. On the contrary, patients who developed MOF had higher PCT plasma levels on day 0 (0.60 vs. 0.15 ng/mL), and on days 1 and 2 combined (1.95 vs. 0.32 ng/mL). This difference remained significant in multivariate logistic regression (P = 0.01) and additional subgroup analyses for early and late MOF (P = 0.048 and 0.002). For NT, smaller differences were observed (4.39 vs. 3.68 nmol/L, and 7.20 vs. 5.79 nmol/L), which lost significance in multivariate analysis. On the basis of PCT, ISS, and age, a MOF prediction rule was developed and had a good predictive power (area under the curve: 0.77; P < 0.001). These findings demonstrate that high plasma concentrations of PCT in the early posttraumatic phase are an independent predictor of MOF but not of sepsis.
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PMID:The clinical value of procalcitonin and neopterin in predicting sepsis and organ failure after major trauma. 1456 Jan 5

Neopterin is a low-molecular mass substance synthesized from guanosine triphosphate (GTP) in monocytes/macrophages due to IFNgamma stimulation. The cellular immune system is involved in or affected by the disease process in various conditions such as viral infections (AIDS), autoimmune disorders (rheumatoid arthritis, systemic lupus erythematosis, Crohn's disease), malignancy and monitoring after solid organ transplants. Similar to procalcitonin, neopterin determination can assist in the differential diagnosis between viral and bacterial infection and as an indicator for impending septic complications (MODS vs. sepsis). Because of fact that reduced glamerular filtration rate neopterin accumulates in the blood, neopterin determination in multiorgan failure or sepsis patients are limited. The aim of this study was to evaluate the usefulness of neopterin in clinical diagnostics.
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PMID:[Role of neopterin in clinical diagnostics]. 1646 8

Multiple trauma patients have an impaired immune system and thus frequently develop life-threatening septic complications. Because there is an ongoing debate on which are the most predictive immunologic parameters of clinical outcome, we prospectively studied 19 multiple trauma patients with sepsis (mean age, 38.7 +/- 15.8 years; mean Injury Severity Score, 40.6 +/- 11.6) over a period of 14 days. The following parameters were measured daily after admission to the intensive care unit: ex vivo lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNF-alpha) production, monocyte human leukocyte antigen (HLA)-DR expression, constitutive interleukin (IL) 6 secretion, white blood cell count, and C-reactive protein. In addition, procalcitonin, neopterin, LPS-binding protein, and constitutive TNF-alpha secretion were measured every third day. Immediately after trauma, all patients had significantly lower levels of HLA-DR and ex vivo LPS-stimulated TNF-alpha secretion than healthy controls (n = 7; P < 0.001). On the day after clinical diagnosis of sepsis, before any other parameter differed between survivors (n = 13) and nonsurvivors (n = 6), ex vivo LPS-induced TNF-alpha secretion was significantly lower (P < 0.05) in nonsurvivors than in survivors. We conclude that ex vivo LPS-induced TNF-alpha production is an earlier predictor of clinical outcome in multiple trauma patients with sepsis than monocyte HLA-DR expression, constitutive IL-6 secretion, or any other parameter assessed.
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PMID:Lipopolysaccharide-induced tumor necrosis factor alpha production and not monocyte human leukocyte antigen-DR expression is correlated with survival in septic trauma patients. 1652 50

Increased blood concentrations of phenylalanine in patients with trauma and sepsis are common but unexplained. We examined the potential relationship between serum concentrations of phenylalanine and the immune activation marker neopterin in 84 specimens of 18 patients (14 males and 4 females) post-trauma during 12-14 days of follow up. Compared to healthy controls, average phenylalanine and neopterin concentrations were elevated in patients, and there existed a positive correlation between concentrations of the two analytes (r (s) = 0.375, p < 0.001). No such association existed between neopterin and tyrosine concentrations (r (s) = -0.018), but neopterin concentrations correlated to the phenylalanine to tyrosine ratio (r (s) = 0.328, p = 0.001). Increased phenylalanine implies insufficient conversion by phenylalanine (4)-hydroxylase (PAH). Oxidative stress due to immune activation and inflammation may destroy cofactor 5,6,7,8-tetrahydrobiopterin and impair PAH activity. This assumption is further supported by the correlation found between higher neopterin concentrations and higher phenylalanine to tyrosine ratio, which estimates efficacy of PAH.
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PMID:Serum phenylalanine in patients post trauma and with sepsis correlate to neopterin concentrations. 1816 76

We report an unusual case of delayed death due to sepsis following closed blunt injury to the neck. The victim was a 71-year-old male with a clinical history of hypertension, diabetes and gout. He was found dead about three weeks after being assaulted. He had not consulted a hospital after the assault. Forensic autopsy demonstrated a large liquefied subcutaneous hematoma on the right side of the neck, peri- and thrombophlebitis of the right internal jugular vein. Otherwise, there was no evidence of trauma. Histological examination showed dermal vesicles in the skin covering the hematoma, accompanied by marked inflammatory cell infiltration phagocytosing gram-positive streptococci, subcutaneous edema, panphlebitis with partially organized thrombi and bacterial colonies, pulmonary edema and multiple pulmonary microthrombi involving bacterial aggregates. Postmortem serum C-reactive protein and neopterin levels were markedly elevated. These findings suggest sepsis as the cause of death, induced by infected internal jugular vein thrombophlebitis following blunt neck injury involving impaired skin barrier.
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PMID:An autopsy case of internal jugular vein thrombophlebitis involving sepsis following blunt neck injury. 1820 29


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