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)

A number of key mediators are implicated in the pathophysiology of sepsis. In previous studies of a septic porcine model, ibuprofen pretreatment prevented the early but not the late rise in pulmonary vascular resistance index (PVRI) and the early but not the late fall in arterial PO2 (PaO2), whereas monoclonal antibody to tumor necrosis factor alpha (anti-TNF alpha) prevented the late but not the early rise in PVRI and the late but not the early fall in PaO2. This study examined the impact of pretreatment with combined ibuprofen and anti-TNF-alpha on the course of sepsis and acute lung injury (ALI) in pigs. Three groups were studied for 5 hours. Groups I (n = 9) and II (n = 5) received a 1-hour infusion of Pseudomonas aeruginosa. Group II received ibuprofen (12.5 mg/kg) and anti-TNF-alpha (5 mg/kg) before P. aeruginosa, and a further bolus of ibuprofen at 120 minutes. Group III (n = 11) received sterile saline. Group I demonstrated a significant (p < 0.05) rise in plasma TNF-alpha that was abolished in group II. The SVRI in group II did not change significantly from baseline through the study and the SVRI rose sharply in group I following onset of the infusion of P. aeruginosa, as did PVRI. There was no significant change in PVRI from baseline in group II, except for the final 60 minutes; PVRI in group II was significantly less than in group I throughout the study.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Combined ibuprofen and monoclonal antibody to tumor necrosis factor-alpha attenuate hemodynamic dysfunction and sepsis-induced acute lung injury. 809 75

Interleukin-8 (IL-8), a neutrophil chemoattractant and activating cytokine, has been implicated as a proinflammatory mediator in gram-negative sepsis. In vitro data support the notion of IL-8 as an endothelial adherence inhibitor. To evaluate this issue, we infused six volunteers with reference endotoxin and measured plasma levels of IL-8, neutrophil tumor necrosis factor alpha (TNF-alpha) receptors, TNF-alpha-induced adherence to fibronectin, and neutrophil chemotaxis to IL-8 and other attractants. We found that, at 3 h postinfusion, IL-8 but not TNF-alpha plasma levels were elevated. Neutrophils had shed L-selectin (mean channel fluorescence decrease, 79 +/- 9 to 49 +/- 7; P = 0.0625) and TNF-alpha receptors (decrease in number of receptors per cell, 1,596 +/- 340 to 574 +/- 93; P = 0.004). Cells were chemotactically desensitized to IL-8. TNF-alpha-induced adherence to fibronectin was suppressed from 69% +/- 5% of the phorbol myristate acetate response to 38% +/- 7% (P = 0.0154). These findings support the notion that release of IL-8 into the vascular space may be an in vivo mechanism for suppression of neutrophil accumulation at extravascular sites. L-Selectin loss would reduce the ability of neutrophils to adhere to activated endothelial cells. The specific loss of migratory response to IL-8 would impair neutrophil delivery to areas where IL-8 was the predominant chemoattractant. Loss of TNF-alpha-induced adherence to fibronectin would blunt those responses, including production of oxidants, capacitated by adherence.
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PMID:Alterations of neutrophil responses to tumor necrosis factor alpha and interleukin-8 following human endotoxemia. 811 67

Sepsis and lipopolysaccharide (LPS) trigger the systemic release of both cytokines and catecholamines. Cytokines are known to be capable of eliciting a stress hormone response in vivo. The present study sought insight into the effect of noradrenaline on LPS-induced release of tumor necrosis factor alpha (TNF) and interleukin 6 (IL-6) in human whole blood. Whole blood was incubated with LPS for 4 h at 37 degrees C in the presence and absence of noradrenaline and/or specific alpha and beta antagonists and agonists. Noradrenaline caused a dose-dependent inhibition of LPS-induced TNF and IL-6 production. This effect could be completely prevented by addition of the specific beta 1, antagonist metoprolol, while it was not affected by the alpha antagonist phentolamine. Specific beta-adrenergic stimulation by isoprenaline mimicked the inhibiting effect of noradrenaline on LPS-evoked cytokine production, whereas alpha-adrenergic stimulation by phenylephrine had no effect. Fluorescence-activated cell sorter analysis demonstrated that beta-adrenergic stimulation had no effect on LPS binding to and internalization into mononuclear cells or on the expression of CD14, the major receptor for LPS on mononuclear cells. In acute sepsis, enhanced release of noradrenaline may be part of a negative feedback mechanism meant to inhibit ongoing TNF and IL-6 production.
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PMID:Noradrenaline inhibits lipopolysaccharide-induced tumor necrosis factor and interleukin 6 production in human whole blood. 816 70

Certain phosphatidic/plasmanic/plasmenic acid (PA) species function as lipid intermediates in cell activation and may function directly as intracellular signaling molecules. PA can also be dephosphorylated to 1,2-diradyl-sn-glycerol by phosphatidate phosphohydrolase. Treatment of various cell types, including murine P388 monocytic leukemia cells, with bacterial lipopolysaccharide rapidly stimulates large increases in PA and PA-derived diradylglycerol. Pentoxifylline, 1-(5-oxohexyl)-3,7-dimethylxanthine, inhibits lipopolysaccharide-stimulated formation of PA in P388 cells at high concentrations (IC50 = 500 microM). Lisofylline [1-(5R-hydroxyhexyl)-3,7-dimethylxanthine] is a unique metabolite of pentoxifylline in humans and is > 800-fold more active as an inhibitor of PA formation than pentoxifylline (IC50 = 0.6 microM). Lisofylline does not inhibit lipopolysaccharide-induced activation of phosphatidylinositol-specific phospholipase C and generation of phosphatidylinositol-derived diradylglycerol. Lisofylline but not pentoxifylline protects BALB/c mice from endotoxin lethality when administered 4 hr after lipopolysaccharide. This protective effect is independent of either agent's effect on suppression of plasma tumor necrosis factor alpha. These data suggest that inhibitors of PA formation may have significant clinical potential in the treatment of sepsis and septic shock.
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PMID:Protection from endotoxic shock in mice by pharmacologic inhibition of phosphatidic acid. 817 Oct 2

Plasma levels of interleukin 1 beta (IL-1 beta), tumor necrosis factor alpha (TNF alpha), interleukin 6 (IL-6), and markers of protein metabolism were determined in 12 burn patients throughout the healing period (day 2 to 21 post-injury) to determine the pattern of variations in plasma cytokine concentration. To establish the relationship between cytokine production and the nutritional status a wide range of severity standpoints (burn surface area ranging from 9% to 82%) was chosen. Interleukin 6 levels were increased in all patients throughout the study period; maximum concentrations (615 +/- 198 pg/mL) were reached on day 4 and correlated (p < 0.01) with the extent of burn injury. Tumor necrosis factor alpha levels were also elevated; they were significantly higher on day 7 in the patients who developed sepsis than in the other patients (67 +/- 21 pg/mL vs. 20 +/- 7 pg/mL; p < 0.05) but did not correlate with the extent of burn injury. Interleukin 1 beta was rarely detected. Cortisolemia on day 7 was inversely correlated with levels of TNF alpha but not with those of IL-6. Interleukin 6 levels correlated positively with protein turnover (phenylalaninemia) and catabolism (3-methylhistidine/creatinine ratio) and negatively with levels of fibronectin and transthyretin. Our data indicate that the systemic cytokine response to burn injury is mainly represented by IL-6. These data also support the hypothesis that IL-6 is a key mediator of the variations in protein metabolism following burn injury.
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PMID:Cytokine response to burn injury: relationship with protein metabolism. 818 61

The pathophysiology of sepsis and septic shock is extremely complex and ultimately involves every physiological pathway. The initiating event is the entrance of endotoxin or similar substances into the blood which initiates the release of multiple mediators. These are designed to react locally and to protect the organism. Their constant release, however, sets in motion up- and down regulations, ultimately resulting in "metabolic anarchy". Tumor necrosis factor alpha and other cytokines trigger several systems, especially coagulation to yield DIC, and the complement system. Many treatment modalities have been developed, most recently those which substitute inhibitors of various systems. Antithrombin III concentrates and potentially protein C concentrates are designed to arrest DIC. C1-esterase inhibitor concentrates should intercept the activation of the complement system and the contact phase of coagulation and its relationship to kinin generation. Even newer approaches entail antibodies to tumor necrosis factor alpha or endotoxin itself. The complex process of sepsis will undoubtedly require a multifaceted therapeutic approach.
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PMID:Perspectives for the future. 822 36

We have cloned a full length complementary DNA (cDNA) of the porcine tumor necrosis factor alpha (pTNF-alpha) gene and expressed it in porcine and murine cells. Total RNA obtained from lipopolysaccharide (LPS) stimulated porcine peripheral blood mononuclear cells was reverse transcribed with a specific antisense pTNF-alpha primer to generate a single stranded cDNA which was subsequently amplified by the polymerase chain reaction utilizing an additional pTNF-alpha specific sense primer. The resulting double stranded cDNA was introduced into the pBMGNeo expression vector and transfected by electroporation in porcine (PK(15)) and murine (L929) cell lines. TNF-alpha bioactivity was detected in the supernatant of the transfected cells using a standard L929 bioassay or a PK(15) bioassay. The activity was zinc inducible as expected for a gene controlled by a metallothionein promoter. The bioactivity was not lowered by an anti-mouse TNF-alpha antiserum neutralizing murine, but not human TNF-alpha and a broad immunoreactive band of 17-19 kD was detected using an anti-mouse TNF-alpha serum suitable for immunoblotting. This newly developed tool will allow us to investigate the role of TNF-alpha in pathogenesis of viral infections and gram-negative sepsis.
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PMID:Cloning and expression in mammalian cells of porcine tumor necrosis factor alpha: examination of biological properties. 825 38

Pteridin neopterin production by monocytes/macrophages has been linked to the biologic activity of immune activation- and/or infection-related cytokines. In patients with thermal injuries who succumb to infections, serum levels of both interleukin-2 (IL-2) and neopterin are significantly increased. However, the relationship between these two markers of immune activation remains unclear. This study examines the role of IL-2 in the biosynthesis of neopterin after major burn. Up to 4 weeks after burn, the levels of plasma neopterin and endotoxin were elevated in all patients studied (N = 9, 30% to > 90% total body surface area). Intact (unsupplemented) peripheral blood mononuclear cell (PBMC) cultures from patients with sepsis secreted high levels of neopterin spontaneously. The spontaneous release of neopterin was significantly decreased (p < 0.05) after supplementation with exogenous IL-2. The reverse was observed in peripheral blood mononuclear cell cultures from infection-free or control groups where relatively low neopterin secretion was markedly augmented in the presence of IL-2. The effect of IL-2 in patient cultures was unrelated to the activity of endogenous interferon gamma, because the production of this cytokine was profoundly reduced. However, IL-2-induced alterations in neopterin secretion paralleled those in the production of tumor necrosis factor alpha. This suggests that after thermal injury, biologic responses of neopterin-secreting peripheral blood mononuclear cells are directly or indirectly regulated by IL-2.
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PMID:Thermal injury-associated neopterin production: regulation by interleukin-2. 830 Jun 96

In this study we have investigated the ability of lipopolysaccharide (LPS) to suppress binding and phagocytosis of erythrocytes via various receptors on mouse macrophages. Thioglycollate-elicited peritoneal macrophages were treated in vitro with LPS and the ability to bind and phagocytose radiolabeled sheep red blood cells was determined. We show that LPS can directly suppress phagocytosis of immunoglobulin G-opsonized and nonopsonized sheep red blood cells (SRBCs) by inflammatory macrophages. Suppression was dose dependent and was observed after 4 h of exposure. This effect lasted for at least 24 h following the removal of LPS. LPS suppressed the binding, rate, and absolute level of phagocytosis via Fc receptors. Phagocytosis via all Fc receptors (Fc gamma RI, Fc gamma RII, and Fc gamma RIII) was suppressed by LPS. Furthermore, suppression was not limited to Fc receptor-mediated phagocytosis because binding and uptake of C3bi-opsonized SRBCs to CR3 receptors was also decreased following LPS treatment. LPS did not exert its effects via the production of interleukin-1 (IL-1), IL-6, tumor necrosis factor alpha, or interferon alpha/beta, because antibodies to these cytokines did not abrogate the effect. The ability of LPS to suppress binding and phagocytosis of microorganisms may contribute to the toxic effects of LPS during gram-negative sepsis by preventing or delaying elimination of bacteria by host macrophages.
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PMID:Lipopolysaccharide-induced suppression of erythrocyte binding and phagocytosis via Fc gamma RI, Fc gamma RII, Fc gamma RIII, and CR3 receptors in murine macrophages. 833 82

The growing knowledge on the pathophysiological role of cytokines in septic shock stimulated efforts to control their synthesis and action pharmacologically in clinical situations. Among the various compounds elaborated by monocytes/macrophages in response to endotoxins, tumor necrosis factor alpha (TNF) and interleukin-1 (IL-1) have been recognized to be of particular importance for endotoxic effects. Therefore, therapeutic strategies in septic shock may benefit from antagonism or inhibition of these mediators. Anti-TNF-antibodies as well as pentoxifylline, an inhibitor of TNF synthesis, attenuated lethality provoked by endotoxin or sepsis in experimental animals. Furthermore, application of IL-1 receptor antagonist was able to counteract endotoxicity in animals. Based on these promising findings, controlled clinical studies have been started to define the precise clinical efficacy of the a.m. therapeutic strategies.
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PMID:[Therapeutic strategies against mediators of septic shock]. 834 Jan 37


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