Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Host immunosuppression after trauma contributes to septic morbidity. The macrophage is a key element in the host immune response. This study evaluated glucan, a macrophage stimulant, in a prospective, randomized, double-blind study of 38 trauma patients undergoing surgery. Glucan (21 patients), 50 mg/m2, or placebo (17 patients) was given intravenously daily for 7 days. Delayed hypersensitivity skin testing was performed on days 1 and 7 after trauma. Serum interleukin-1 (IL-1) and tumor necrosis factor (TNF) were assayed after trauma. While the total mortality rate was significantly less in the glucan group (0% versus 29%) (p less than 0.05), the mortality rate from sepsis was not statistically different (0% versus 17.6%). Glucan therapy significantly decreased septic morbidity (9.5% versus 49%; p less than 0.05). Serum IL-1 had a greater increase in glucan patients on day 3 after trauma (143.4 +/- 19.3% versus 78.6 +/- 11.7%; p less than 0.05), but there was no difference thereafter. Serum TNF did not vary between groups. Early increase in IL-1 correlated with subsequent skin test conversion to positive. Neither serum IL-1 nor TNF was a reliable indicator of future sepsis. Further clinical trials are indicated to evaluate biologic response modifiers that activate macrophages in the trauma patient.
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PMID:Beneficial effect of enhanced macrophage function in the trauma patient. 211 Nov 26

Glucocorticoids almost completely inhibit the synthesis by isolated macrophages of cachectin/tumor necrosis factor (TNF), a cytokine implicated as a major endogenous mediator of septic shock. Despite this in vitro effectiveness, the clinical use of glucocorticoids has failed to demonstrate any clear benefit in the treatment of septic shock. In an effort to understand what other mechanisms might play a role in the patient with sepsis, we examined the effect of interferon-gamma (IFN gamma) on the synthesis of cachectin/TNF. We show here that IFN gamma, although unable by itself to induce cachectin/TNF synthesis, enhanced the endotoxin-induced production of cachectin/TNF in vitro. Furthermore, IFN gamma overcame the inhibition of cachectin/TNF synthesis caused by the glucocorticoid, dexamethasone. These effects of IFN gamma were accounted for by increased levels of cachectin/TNF mRNA. The in vivo implications of these studies are discussed with emphasis on their relevance in human sepsis.
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PMID:Interferon-gamma overcomes glucocorticoid suppression of cachectin/tumor necrosis factor biosynthesis by murine macrophages. 212 Feb 85

Respiratory tract infections are major causes of excessive morbidity and mortality in hospitalized patients. Persons with systemic sepsis have an especially high risk of acquiring these infections, which indicates that their lung antibacterial defenses are compromised. To evaluate the effects of sepsis on pulmonary antibacterial defenses, we injected either saline or 5 mg/kg of Escherichia coli lipopolysaccharide intravenously into Sprague-Dawley rats. Two hours later, the animals were challenged by aerosol inhalation with either Staphylococcus aureus or Pseudomonas aeruginosa. It is known that phagocytic defenses against aerosolized S. aureus challenges are provided solely by the alveolar macrophage; in normal animals challenged with P. aeruginosa, however, an intrapulmonary inflammatory response is elicited. Animals pretreated with endotoxin showed a significant decrease in pulmonary bactericidal activity against S. aureus with 31 +/- 3% bacteria remaining viable at 4 hr compared with 20 +/- 2% in the controls, which indicates a defect in alveolar macrophage antimicrobial activity. After P. aeruginosa challenge, saline-injected control animals developed a marked intrapulmonary inflammatory response and killed greater than 85% of their initial inoculum by 4 hr. By contrast, endotoxin-treated animals failed to recruit neutrophils into the alveoli in response to P. aeruginosa, resulting in a proliferation of this pathogen within the lung (212 +/- 6% bacteria remaining viable at 4 hr). Endotoxin is known to be a potent stimulus for the production of tumor necrosis factor (TNF) by the host. TNF is a potent inflammatory mediator and promotes neutrophil adhesion to the vascular endothelium. In these experiments, serum TNF peaked at 28,390 +/- 7,766 Units/ml. 90 min after intravenous endotoxin. Histopathology of the lungs in these animals showed considerable sequestration of the neutrophils within the pulmonary vasculature. These data show that systemic endotoxin significantly impairs lung host defenses against intrapulmonary bacterial challenges and suggest that TNF-mediated events may play a central role.
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PMID:Endotoxin-induced suppression of lung host defenses. 212 Mar 77

The etiology and mechanisms by which severe trauma or sepsis induce hepatic failure are unknown. Previously we showed that Kupffer cells (KC), the fixed macrophages of the liver, induce a profound decrease in hepatocyte (HC) total-protein synthesis when exposed to endotoxin. Furthermore we demonstrated that endotoxin-activated KCs induce these changes in HC protein synthesis through the induction of a novel L-arginine-dependent biochemical pathway within the HC. In this pathway, the guanido nitrogen of L-arginine is converted to the highly reactive molecule nitric oxide (NO.). To identify the KC factors that act as signals for induction of HC NO. biosynthesis, recombinant cytokines were added to HC cultures and HC nitrogen oxide production and protein synthesis levels were determined. We found that no single cytokine, but rather a specific combination of tumor necrosis factor, interleukin-1, interferon-gamma, and endotoxin, were required for maximal induction of HC nitrogen oxide production. This specific combination of cytokines induced a 248.8 +/- 26.0 mumol/L (micromolar) increase in HC nitrogen oxide production and simultaneously inhibited HC total protein synthesis by 36.1% +/- 3.1%. These data demonstrate that multiple cytokines, produced by endotoxin-activated KC, induce the production of NO. within HC, which in turn leads to the inhibition of HC total-protein synthesis.
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PMID:Multiple cytokines are required to induce hepatocyte nitric oxide production and inhibit total protein synthesis. 212 Nov 10

Endotoxemia was evoked by bolus injection of Escherichia coli endotoxin (2 ng/kg body weight) in six healthy subjects to investigate the early kinetics of cytokine release in relation to the development of clinical and hematologic abnormalities frequently seen in gram-negative septicemia. The plasma concentration of tumor necrosis factor (TNF) increased markedly after 30 to 45 minutes, and reached a maximal level after 60 to 90 minutes. In each volunteer, the initial increase of plasma interleukin 6 (IL-6) concentrations occurred 15 minutes after the initial TNF increase, and maximal IL-6 concentrations were reached at 120 to 150 minutes. A transient increase in body temperature and pulse rate occurred simultaneously with the initial TNF and IL-6 increases, whereas a significant decrease in blood pressure occurred after 120 minutes. These changes were proportional to the changes in TNF and IL-6 concentrations. Coagulation activation, as assessed by a rise of prothrombin fragments and thrombin-antithrombin III complexes, was noted after 120 minutes, in the absence of activation of the contact system. A two- to sixfold increase in the concentrations of tissue plasminogen activator (t-PA) and von Willebrand factor antigen indicated endothelial cell activation. This increase started at 120 and 90 minutes, respectively. The release of t-PA coincided with activation of the fibrinolytic pathway, as measured by plasmin-alpha 2-antiplasmin complexes. The fibrinolytic activity of t-PA was subsequently offset by release of plasminogen activator inhibitor, observed 150 minutes after the endotoxin injection, and reaching a peak at 240 minutes. No complement activation was detected. These results show that in humans endotoxin induces an early, rapidly counteracted fibrinolytic response, and a more long-lasting activation of thrombin by a mechanism other than contact system activation. In addition, our data suggest that endotoxin-induced leukopenia and endothelial cell activation are mediated by TNF.
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PMID:Experimental endotoxemia in humans: analysis of cytokine release and coagulation, fibrinolytic, and complement pathways. 212 34

Despite numerous reports, the role of tumor necrosis factor (TNF) in polymorphonuclear leukocyte (PMN) function remains controversial. We found TNF to be a potent, pertussis toxin-independent stimulator of PMN adhesion (ED50 2.6 pM). TNF-stimulated PMN under adherent conditions released up to 65% of their transcobalamine content (ED50 3.9 pM) and increased their burst activity 10-fold (ED50 3.2 pM) as measured by the hexose monophosphate shunt, whereas PMN held in suspension hardly degranulated at all and only little burst activity was demonstrable. However, preincubation of PMN with TNF in suspension led to a decrease in cellular adhesiveness, degranulation, and burst activity in response to a secondary stimulus of TNF under adherent conditions, although cells remained fully responsive toward phorbol myristate acetate. A concomitant dose-dependent decline of TNF receptor numbers that correlated well with the inhibition of PMN function (r = 0.91) suggests receptor down-regulation as the mechanism of functional PMN deactivation. Remarkably, preincubation with other PMN stimuli such as N-formyl-methionyl-leucyl-phenylalanine, platelet-activating factor, leukotriene B4, complement component fragment 5a (C5a)/C5a (desarginated), and endotoxin also led to a reduction of TNF-specific PMN responses (cross-deactivation) from 35% (LTB4) to 90% (endotoxin), corresponding with the down-regulation of TNF receptors. Deactivation and receptor down-regulation are independent of pertussis toxin-sensitive G proteins and protein kinase C but seemed to depend on changes in calcium metabolism. Granulocyte hyporesponsiveness towards TNF in sepsis (with elevated blood levels of endotoxin and TNF) might be a mechanism of self-protection or, to the contrary, might impair a possibly central mode of host defense.
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PMID:The tumor necrosis factor receptor and human neutrophil function. Deactivation and cross-deactivation of tumor necrosis factor-induced neutrophil responses by receptor down-regulation. 216 42

Five cancer patients undergoing intravenous infusions of human recombinant tumor necrosis factor (TNF)alpha were evaluated for the effects these infusions had on the priming of circulating neutrophils for hypochlorous acid (HOCl) production. These patients were also studied for changes in temperature, circulating white blood cell counts, blood pressure, and spontaneous monocyte interleukin 1 beta (IL-1 beta) and TNF production. As predicted by previous in vitro studies, patient neutrophils increased their HOCl production to unopsonized zymosan from a baseline of 29.2 +/- 5.9 nmol I- oxidized/4 x 10(6) cells to a peak of 64.2 +/- 9.8 nmol I- oxidized/4 x 10(6) cells at 4 h after TNF infusion (P less than 0.01). Similar increases were also seen at 4 h with phorbol myristic acetate and opsonized zymosan as the stimuli. The priming effect could be reproduced in neutrophils from a normal individual by incubating them with the 30-min serum samples from the infused patients. The ability of this serum to prime neutrophils was completely blocked by a monoclonal anti-TNF alpha-antibody but not by an anti-IL-1 beta antibody. In addition to the priming of their neutrophils, patients also experienced fever, marked hypotension, and an initial fall, followed by rebound to an elevation, in circulating white blood cell counts. The TNF infusions did not produce detectable circulating IL-1 beta nor did they induce significant production of TNF or IL-1 beta by circulating blood monocytes. These studies confirm the role of TNF in producing the signs of sepsis such as hypotension, fever, and leukopenia followed by leukocytosis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Tumor necrosis factor infusions in humans prime neutrophils for hypochlorous acid production. 217 55

Our laboratory has previously shown that the administration of tumor necrosis factor (TNF), a cytokine produced by activated mononuclear cells, to guinea pigs produces a syndrome similar to gram-negative sepsis or ARDS. Pentoxifylline (PTX), a methylxanthine, protects against TNF-induced and sepsis-induced acute lung injury in vivo. We now report on in vitro cellular studies of PMN-mediated cellular injury and its attenuation. We studied TNF-induced bovine pulmonary artery endothelial cell (EC) cytotoxicity both with and without PMN. A 51Cr release assay was used to measure EC damage. Further, we investigated PMN function in response to TNF by measuring chemiluminescence. Agents that attenuate EC damage and PMN activation were evaluated in the above assays. Results revealed that TNF causes EC injury (p less than 0.05) and PMN increase TNF-induced EC injury. Furthermore, PTX, aminophylline (AMPH), caffeine, and forskolin attenuate TNF-induced EC cytotoxicity only in the presence of PMN (p less than 0.05). Of interest, dibutyryl cAMP (DBcAMP) protects EC from TNF-induced injury both with and without PMN. Agents that may increase cAMP levels in PMN (PTX, DBcAMP, forskolin, isobutyl methylxanthine, and terbutaline) significantly attenuate TNF-induced PMN chemiluminescence (p less than 0.05). We conclude that TNF causes EC damage and PMN increase this damage. Furthermore, PTX, AMPH, caffeine, and forskolin can attenuate TNF-induced EC injury in the presence of PMN, whereas DBcAMP attenuates TNF-induced EC injury with and without PMN. In addition, agents that may increase intracellular cAMP levels in PMN can attenuate TNF-induced PMN chemiluminescence. Thus, these agents likely attenuate TNF-induced PMN-mediated EC injury through their inhibitory effects on PMN.
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PMID:Attenuation of tumor necrosis factor-induced endothelial cell cytotoxicity and neutrophil chemiluminescence. 217 54

We have investigated the effects of recombinant human tumor necrosis factor-alpha (rhTNF alpha) on polymorphonuclear leukocytes (PMNs), concentrating on the mechanisms involved in the alterations of PMN-directed migration and adherence by this cytokine. RhTNF alpha profoundly suppressed PMN chemotaxis toward FMLP by 80%. At similar concentrations, it enhanced adhesion to gelatin-coated plastic dishes by more than tenfold and increased the expression of the CD11b antigen to 182% of the control. The monoclonal antibody 60.1, which is directed against the alpha chain of the CD11b/CD18 complex, completely blocked rhTNF alpha, induced inhibition of the chemotactic response to FMLP, and rhTNF alpha induced hyperadherence, suggesting that these effects were related to rhTNF alpha's effects on CD11b antigen expression. The fluid state of the PMN membrane was also decreased by rhTNF alpha. N-butanol, a known membrane fluidizer, partially inhibited the effect of rhTNF alpha on membrane fluidity and chemotaxis and completely reversed its effects on adherence and the expression of the CD11b antigen. Pentoxifylline, an agent that has previously been studied for its ability to prevent some effects of rhTNF alpha on PMNs, completely prevented the effect of rhTNF alpha on chemotaxis, the expression of the CD11b antigen, and membrane fluidity. Pentoxifylline partially prevented changes in adherence caused by this cytokine. Increased CD11b antigen expression caused by rhTNF alpha may result in enhanced PMN adhesion and suppression of migration. These events may, in turn, lead to the accumulation of PMNs on the vascular endothelium, resulting in the extensive vascular and tissue damage that is seen in gram-negative sepsis.
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PMID:Mechanisms of tumor necrosis factor-alpha alteration of PMN adhesion and migration. 218 25

Tumor necrosis factor has been implicated in the activation of blood coagulation in septicemia, a condition commonly associated with intravascular coagulation and disturbances of hemostasis. To evaluate the early dynamics and the route of the in vivo coagulative response to tumor necrosis factor, we performed a controlled study in six healthy men, monitoring the activation of the common and intrinsic pathways of coagulation with highly sensitive and specific radioimmunoassays. Recombinant human tumor necrosis factor, administered as an intravenous bolus injection (50 micrograms per square meter of body-surface area), induced an early and short-lived rise in circulating levels of the activation peptide of factor X, reaching maximal values after 30 to 45 minutes (mean +/- SEM increase after 45 minutes, 34.2 +/- 18.2 percent; tumor necrosis factor vs. saline, P = 0.015). This was followed by a gradual and prolonged increase in the plasma concentration of the prothrombin fragment F1+2, peaking after four to five hours (mean increase after five hours, 348.0 +/- 144.8 percent; tumor necrosis factor vs. saline, P less than 0.0001). These findings signify the formation of factor Xa (activated factor X) and the activation of prothrombin. Activation of the intrinsic pathway could not be detected by a series of measurements of the plasma levels of factor XII, prekallikrein, factor XIIa-C1 inhibitor complexes, kallikrein-C1 inhibitor complexes, and the activation peptide of factor IX. The delay between the maximal activation of factor X and that of prothrombin amounted to several hours, indicating that neutralization of factor Xa activity was slow. We conclude that a single injection of tumor necrosis factor elicits a rapid and sustained activation of the common pathway of coagulation, probably induced through the extrinsic route. Our results suggest that tumor necrosis factor could play an important part in the early activation of the hemostatic mechanism in septicemia.
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PMID:Activation of coagulation after administration of tumor necrosis factor to normal subjects. 221 25


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