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)

Apart from the diagnostic value of anti-neutrophil cytoplasmic antibodies (ANCA), their detailed characterization and that of their corresponding antigens have opened new ways for the exploration of the pathogenesis of primary systemic vasculitis. ANCA are now thought to play an important functional role via activation of phagocytic cells (e.g. polymorphonuclear neutrophils (PMN)). In this study we examined the mechanisms by which ANCA could gain access to proteinase 3 (PR3) in intact PMN, at two levels: ex vivo by analysing the presence of PR3 on the plasma membrane of PMN from patients with ANCA-associated vasculitis, and in vitro by stimulation of PMN using different cytokines, including recombinant tumour necrosis factor-alpha (rhTNF-alpha) and two forms of IL-8 (produced by monocytic and endothelial cells). Using immunocytochemical staining techniques (FACS and immunoelectronmicroscopy) PR3 has been detected on the plasma membrane of PMN from patients with active ANCA-associated vasculitis. However, this phenomenon is also seen in patients with sepsis who do not have ANCA. In addition, TNF-alpha and both forms of IL-8 act synergistically and induce a translocation of PR3 from the intragranular loci to the cell surface of PMN. These results provide strong evidence for the hypothesis that ANCA are directly pathogenic by binding to PR3 which is expressed on the cell surface of primed/activated PMN.
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PMID:Activated neutrophils express proteinase 3 on their plasma membrane in vitro and in vivo. 830 99

Costimulation of neutrophils and cytokines may play an important role in organ injury in sepsis. Pentoxifylline inhibits various neutrophil functions in vitro, and attenuates endotoxin-induced production of TNF in both in vitro and in vivo models. To assess the effect of pentoxifylline on neutrophil activation in endotoxemia, nine adult chimpanzees (Pan troglodytes) were i.v. injected with saline (n = 2), Escherichia coli endotoxin (4 ng/kg; n = 4), or E. coli endotoxin (4 ng/kg) in combination with pentoxifylline (500 mg/3 h, starting 30 min before the endotoxin injection; n = 3). Serial blood samples were obtained for measurements of leukocyte counts and the granulocytic proteinases elastase complexed with alpha 1-antitrypsin and lactoferrin, and cytokines during the next 5 h. No changes were observed in the saline-treated chimpanzees. Endotoxin induced a marked leukocytosis and neutrophilia, which were slightly reduced by pentoxifylline. In contrast, pentoxifylline almost completely prevented endotoxin-induced neutrophil degranulation: peak elastase-alpha 1-antitrypsin was 164 +/- 21 ng/ml (mean +/- SE) after endotoxin alone, vs 71 +/- 7 ng/ml after endotoxin with pentoxifylline (t = 3 h; p < 0.05); peak lactoferrin was 329 +/- 15 and 182 +/- 5 ng/ml, respectively (t = 5 h; p < 0.05). Pentoxifylline also inhibited the endotoxin-induced release of TNF (271 +/- 26 vs 55 +/- 23 pg/ml at t = 1.5 h; p < 0.05) and IL-6 (225 +/- 42 vs 73 +/- 25 pg/ml at t = 2 h; p < 0.05). IL-8 release was not significantly inhibited by pentoxifylline. In none of the animals activation of the C system could be detected. We conclude that pentoxifylline attenuates neutrophil activation in endotoxemia in chimpanzees, probably in part by inhibiting the release of TNF.
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PMID:Pentoxifylline attenuates neutrophil activation in experimental endotoxemia in chimpanzees. 834 9

The systemic inflammatory response syndrome (SIRS) is an acute illness characterized by generalized activation of the endothelium. The most severe form of the syndrome is found in patients with shock due to gram-negative sepsis. We examined both animal and limited human data for the contribution of cytokines to this syndrome. Cytokines are endogenously produced proteins of small molecular weight and multiple biological effects. The cytokines interleukin 1 (IL-1) and tumor necrosis factor (TNF), as well as interferon-gamma and interleukin 8, are discussed. Laboratory investigations suggest that these cytokines play a critical role in SIRS by promoting the biochemical and clinical characteristics of SIRS. The biochemical changes induced by TNF and IL-1 include increased synthesis of nitric oxide, prostaglandins, platelet-activating factor, and endothelial cell adhesion molecules. Specific blockade of TNF using neutralizing antibodies or soluble receptors to TNF in animal models of SIRS reduces mortality and severity of disease. Similar results have been observed blocking IL-1 using soluble IL-1 receptors or IL-1 receptor antagonists. Preliminary clinical studies suggest that blockade may be useful in treating human SIRS. The various strategies for blocking IL-1 and TNF are presented; in addition, their mechanism(s) of action and safety in humans are discussed. We conclude that based on animal studies and preliminary clinical trials, strategies to block IL-1 or TNF may benefit patients with the syndrome, although thorough clinical trials have not been completed.
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PMID:Anticytokine strategies in the treatment of the systemic inflammatory response syndrome. 845 16

Continuous hemofiltration is widely used for renal replacement therapy in patients with acute renal failure. It has been suggested that hemofiltration may also eliminate toxic mediators thought to be important in the pathophysiology of sepsis. The present study examined whether hemofiltration can activate or eliminate inflammatory mediators in patients with sepsis, and whether ultrafiltrate can alter specific functions of peripheral blood mononuclear leukocytes (PBMC) in vitro. Veno-venous hemofiltration was performed in 16 patients and in 5 healthy volunteers. Pre-filter (afferent), post-filter (efferent) and ultrafiltrate concentrations of cytokines (IL-1 beta, IL-6, IL-8, TNF alpha) and of complement components (C3, C3adesArg, C5adesArg, terminal complement complex) were measured after the beginning of hemofiltration (t0), and 60 minutes later (t60). PBMC, and monocyte and lymphocyte subfractions were incubated with ultrafiltrate, and cytokines were determined in the supernatants. Hemofiltration did not induce significant mediator activation. There was no evidence for significant cytokine elimination. However, pre-filter C3adesArg concentration showed a significant decline during hemofiltration (patients: t0 = 676.9 +/- 99.7 ng/ml, t60 = 545.4 +/- 83.2, P < 0.001; volunteers: t0 = 54.8 +/- 13.3 ng/ml, t60 = 33.9 +/- 10.7, P < 0.001). Ultrafiltrate from septic patients significantly stimulated PBMC and monocyte TNF alpha release, but suppressed lymphocyte IL-2 and IL-6 production. Ultrafiltrate from volunteers was without effect. Hemofiltration effectively eliminates certain mediators such as C3adesArg. Ultrafiltrate contains compounds with significant immunomodulatory qualities. Therefore, hemofiltration may represent a new modality for removal of immunomodulatory mediators.
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PMID:Hemofiltration in human sepsis: evidence for elimination of immunomodulatory substances. 854 15

The interaction between activated neutrophils and pulmonary endothelium is thought to contribute to the pathogenesis of the adult respiratory distress syndrome (ARDS), but its relation to ARDS severity, which may support a pathogenetic role, is unclear. Therefore, circulating inflammatory mediators, including the neutrophil chemoattractant and activator interleukin 8 (IL-8), the acute phase cytokine IL-6, and the neutrophil product elastase complexed to alpha 1-antitrypsin (alpha 1-AT), were measured prospectively, together with gas exchange, ventilatory and radiographic variables, in 13 mechanically ventilated patients with ARDS, mostly owing to sepsis, at admission into the intensive care unit. Measurements were repeated in the eight improving patients at the time that positive end-expiratory pressure could be reduced to 0 cm H2O. From the gas exchange, ventilatory and radiographic abnormalities, a lung injury score (LIS) was calculated. For pooled data, the LIS and the arterial PO2/inspiratory O2 fraction, the oxygenation ratio, correlated with plasma levels of IL-8 (rs = 0.60, P < 0.01 and rs = -0.65, P < 0.005, respectively), with levels of IL-6 (rs = 0.60, P < 0.01, and rs = -0.68, P < 0.005, respectively), and the oxygenation ratio related to elastase-alpha 1-AT (rs = -0.70, P < 0.005). Levels of IL-8 and IL-6 interrelated (rs = 0.61, P < 0.01) and related to the elastase complexes (rs = 0.45, P < 0.05). Hence, our data support a role of cytokine-induced activation of neutrophils in the clinical severity of ARDS.
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PMID:Interleukin 8-related neutrophil elastase and the severity of the adult respiratory distress syndrome. 858 Mar 86

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.
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PMID:Function of soluble CD14 in serum from patients with septic shock. 862 30

In severe sepsis, a network of proinflammatory cytokines (TNF, IL-1 beta, IL-6, IL-8) is activated and blood levels of these cytokines are elevated, albeit inconsistently and with large individual variations. In addition, elevated blood levels of anti-inflammatory cytokines (IL-10), as well as of soluble cytokine receptors (sTNF-RI and II, IL-1ra), have been found. They seem to have a regulatory function in the host response. Levels of TNF and IL-6 are usually highest at the time of admission, whereas the time course of IL-1 beta levels (when detectable) can vary considerably. Limited data on IL-8 levels suggest that they may remain elevated for longer periods. Elevated levels of sTNFR and IL-1ra may also persist for a prolonged period of time. The pathogenetic significance of these observations is still unclear, but persistingly high levels of proinflammatory cytokines may be associated with organ failure and mortality.
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PMID:Time course of cytokine levels in sepsis. 863 33

Acute inflammatory illnesses, including the sepsis syndrome, often include a component of coagulation. A human whole blood culture system was developed so that the relationship between coagulation activation and cytokine responses in the presence or absence of lipopolysaccharide (LPS) could be evaluated. In the absence of LPS stimulation, coagulation activation resulted in a novel pattern of cytokine production. During a 4-hour culture of coagulating blood, significant production of interleukin-8 (IL-8; >2,000 pg/mL) was observed, whereas other proinflammatory cytokines including IL-1 beta, IL-6, or tumor necrosis factor a were undetectable or less than 35 pg/mL. The cytokine profile was distinct from that of fully anticoagulated, LPS-stimulated blood, which showed levels of all the indicated proinflammatory cytokines > or = 2,000 pg/mL over the same time period. Over 24 to 48 hours, the coagulation-induced cytokine response was characterized by marked and sustained IL-8 production, limited IL-6 generation (with kinetics delayed relative to IL-8), and minimal or undetectable tumor necrosis factor alpha levels. The magnitude of the whole blood IL-8 response correlated with the level of coagulation activation as determined by measurement of thrombin-antithrombin III complex formation. The combined stimuli of coagulation activation and LPS challenge induced a synergistic enhancement of IL-8 production but not of IL-6. Coagulation-induced cytokine production and the synergistic production of IL-8 by coagulation and LPS could be attenuated by hirudin or tissue factor pathway inhibitor (TFPI). Studies to elucidate mechanisms implicated (1) the TFPI third Kunitz and carboxy-terminus as important structural components for TFPI regulation of coagulation activation and (2) thrombin as a candidate mediator of the mononuclear cell cytokine response to coagulation activation. In summary, a unique aspect of the crosstalk between the coagulation and cytokine cascades in whole blood is shown with the identification of IL-8 as a key proinflammatory participant.
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PMID:The proinflammatory cytokine response to coagulation and endotoxin in whole blood. 865 18

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.
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PMID:Release of interleukin-12 in experimental Escherichia coli septic shock in baboons: relation to plasma levels of interleukin-10 and interferon-gamma. 865 27

We studied paired bronchoalveolar lavage (BAL) in patients with sepsis-associated acute respiratory distress syndrome (ARDS). Patients were evaluated at one institution and underwent bronchoscopy with BAL within 48 h of the onset of ARDS. Patients were restudied with bronchoscopy and BAL after 4 d of treatment. Fifty-eight patients were initially studied, with 44 patients having follow-up bronchoscopy after 4 d. The overall 30-d survival for the ARDS group was 60%. In the initial lavage, there was no difference in the neutrophils between the survivors and nonsurvivors (survivors: 59 [0-98]%; Median [Range]; nonsurvivors: 55 [0-92]%). The follow-up lavage demonstrated a significant drop in the neutrophils for the survivors (36 [4-89]%, p < 0.002) which was not seen for the nonsurvivors (70 [26-95]%). Initial IL-8 concentrations in the BAL fluid were not significantly different between the two groups. In the follow-up lavage, there was a significant fall for the IL-8 concentrations for the survivors but not the nonsurvivors. We conclude that neutrophil influx in ARDS may rapidly resolve within a week of the onset of ARDS. The resolution of neutrophils was associated with a good prognosis.
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PMID:Changes in the inflammatory response of the lung during acute respiratory distress syndrome: prognostic indicators. 868 Jul 3


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