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)

We assayed serial plasma samples from 86 patients, who were enrolled in a prospective randomized trial of the effects of methylprednisolone (MPSS) in septic shock, for the presence of cytokine tumor necrosis factor (TNF) using an enzyme-linked immunosorbent assay. TNF was present in the plasma of 27 of the 74 patients with septic shock, but in only 1 of the 12 patients with shock due to other causes. TNF was detected with equal frequency in patients with shock from gram-negative or from gram-positive bacillary sepsis. TNF levels were highest on the initial sample and decreased significantly over the subsequent 24 h in both the patients treated with MPSS and in those given placebo. Patients with detectable TNF had a higher incidence and severity of the adult respiratory distress syndrome and a higher mortality rate than did patients without detectable TNF.
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PMID:Plasma tumor necrosis factor in patients with septic shock. Mortality rate, incidence of adult respiratory distress syndrome, and effects of methylprednisolone administration. 229 91

The endogenously produced cytokine, tumor necrosis factor-alpha (TNF-alpha), has been shown in adult animal models to be associated with many of the pathophysiologic effects of sepsis, including systemic hypotension and hemorrhagic necrosis. TNF-alpha can induce the release of various vasoactive arachidonic acid metabolites, suggesting that TNF-alpha may act either directly or via intermediary substances in producing its effects. The pathophysiologic role of TNF-alpha in neonatal sepsis, especially its potential effect on pulmonary vascular tone, is presently unknown. To assess the role of TNF-alpha in neonatal sepsis, 19 piglets (19 +/- 5 d old) were anesthetized, intubated, paralyzed, mechanically ventilated, and catheterized to assess pulmonary and systemic vascular hemodynamics and pulmonary gas exchange. The multiple inert gas elimination technique was used to assess ventilation perfusion matching. A 30-min infusion of human recombinant TNF-alpha (250 micrograms/kg total dose) was administered to animals pretreated with either 10 mg/kg dazmegrel, a thromboxane synthase inhibitor (n = 9) or placebo (n = 10). TNF-alpha alone induced a prompt and sustained rise in pulmonary arterial pressure and pulmonary vascular resistance that continued at least for 2 h after onset of the infusion. In contrast, the animals pretreated with dazmegrel demonstrated no rise in pulmonary vascular resistance until 2 h after the onset of the infusion. Neither group of animals demonstrated a significant decline in arterial PO2 or evidence from inert gas analysis of VA/Q mismatching or increase in intrapulmonary shunt.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Tumor necrosis factor-induced neonatal pulmonary hypertension: effects of dazmegrel pretreatment. 234 73

Tumour necrosis factor-alpha (TNF-alpha)/cachectin is a multifunctional cytokine that has effects in inflammation, sepsis, lipid and protein metabolism, haematopoiesis, angiogenesis and host resistance to parasites and malignancy. TNF-alpha was first described in activated macrophages, but certain mouse or rat mast cell populations (reviewed in refs 4,5) and some in vitro-derived human cells with cytochemical features of mast cells-basophils may also contain products similar to TNF-alpha. Here we present evidence that resident mouse peritoneal mast cells constitutively contain large amounts of TNF-alpha bioactivity, whereas cultured, immature mast cells vary in their TNF-alpha content. IgE-dependent activation of cultured or peritoneal mast cells induces extracellular release of TNF-alpha and augments levels of TNF-alpha messenger RNA and bioactivity. These findings identify mouse mast cells as an important source of both preformed and immunologically inducible TNF-alpha, and suggest that release of TNF-alpha by mast cells may contribute to host defence, the pathophysiology of allergic diseases and other processes dependent on TNF-alpha.
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PMID:Mast cells as a source of both preformed and immunologically inducible TNF-alpha/cachectin. 237 92

Hemorrhage induces a severe suppression of the immune system resulting in increased susceptibility to sepsis. Although studies indicate beneficial effects of calcium channel blockers on cell and organ functions after low-flow conditions, it remains unknown whether such agents have any effects on different immune responses after hemorrhage. To study this, C3H/HeN mice were bled to a mean blood pressure of 35 mm Hg and were maintained for 60 minutes, followed by resuscitation with their own shed blood and adequate fluid. The mice received either the water-soluble calcium channel blocker diltiazem (400 or 2400 micrograms/kg body weight) or saline solution (vehicle). Peritoneal macrophages were obtained by lavage 24 hours later. Antigen presentation was measured by coculturing peritoneal macrophages with the D10.G4.1 helper T-lymphocyte clone. Immune associated antigen (Ia) expression was determined by direct immunofluorescence. Interleukin (IL)-1, 6, and tumor necrosis factor-alpha (TNF) levels in peritoneal macrophage supernatants were measured by use of cytokine-specific cellular assays. Hemorrhage caused a significant decrease in peritoneal macrophage antigen presentation function, Ia expression, and IL-1 and IL-6 synthesis in the vehicle-treated group, whereas TNF levels were increased. However, both doses of diltiazem significantly improved peritoneal macrophage antigen presentation, Ia expression, and IL-1 synthesis. IL-6 synthesis was only increased with high doses of diltiazem, whereas both diltiazem doses decreased TNF production. These results indicate that the calcium channel blocker diltiazem can markedly improve macrophage functions after hemorrhage. The use of diltiazem might offer a new therapeutic modality in the treatment of immunosuppression and in decreasing the susceptibility to sepsis after hemorrhagic shock.
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PMID:Immunoprotective effect of a calcium channel blocker on macrophage antigen presentation function, major histocompatability class II antigen expression, and interleukin-1 synthesis after hemorrhage. 238 17

Protein catabolic states (i.e., sepsis and trauma) are thought to be associated with accelerated oxidation of branched-chain amino acids (BCAA). Branched-chain alpha-keto acid dehydrogenase (BCKAD), the rate-limiting enzyme for BCAA oxidation by muscle, is regulated by phosphorylation/dephosphorylation. Skeletal muscle BCKAD was only 2-4% active in control rats. Intravenous injection of Salmonella enteritidis endotoxin (0.25-10 mg/kg) did not change total BCKAD activity, but increased the percent active enzyme in muscle three- to four-fold in 4-6 h. Identical results were observed in adrenalectomized rats pretreated with one dose of alpha-methylprednisolone (2.5 mg/kg i.p.) 30-60 min before saline or endotoxin injection, indicating that endotoxin's effect was not mediated by hypersecretion of adrenal hormones. Cortisone pretreatment of normal rats (100 mg/kg per d) for 2 d prevented endotoxin-induced activation of muscle BCKAD, suggesting that endogenous secretion products mediated BCKAD activation by endotoxin. Human recombinant tumor necrosis factor-alpha and/or IL-1 beta or alpha (50 micrograms/kg) increased muscle BCKAD activation two- to fourfold in normal rats 4-6 h after intravenous injection. We conclude that cytokine-mediated activation of muscle BCKAD may contribute to accelerated BCAA oxidation in septicemia.
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PMID:Administration of endotoxin, tumor necrosis factor, or interleukin 1 to rats activates skeletal muscle branched-chain alpha-keto acid dehydrogenase. 240 25

After injury, infection, or major operations a number of predictable metabolic responses occur. It has been proposed that the cytokine tumor necrosis factor (TNF)/cachectin is a primary mediator of these host responses. To test this hypothesis, we studied 16 tumor-bearing humans with normal renal and hepatic function, who received 24-hour continuous intravenous infusions of escalating doses of recombinant TNF (4 to 636/micrograms/m2/24 h). Serial measurements were made of vital signs and plasma concentrations of TNF, interleukin-1, adrenocorticotropic hormone, cortisol, iron, glucose, and C-reactive protein. Low doses of TNF had minimal metabolic effects, but infusions of greater than or equal to 545 micrograms/m2/24 hr (n = 8) resulted in fever, pituitary, and stress hormone release and acute phase changes. These alterations were compared with the changes that occurred in healthy humans (n = 13) receiving intravenous bolus injections of Escherichia coli endotoxin (4 ng/kg). TNF infusion in doses greater than or equal to 545 micrograms/m2/24 hr produced peak plasma TNF concentrations and metabolic responses that were similar to those after endotoxin injection. Interleukin-1 concentrations remained basal after TNF or endotoxin administration. TNF may represent the primary afferent signal that initiates many of the metabolic responses associated with sepsis and endotoxemia.
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PMID:Tumor necrosis factor and endotoxin induce similar metabolic responses in human beings. 245 28

Intestinal mucosal atrophy, as induced by total parenteral nutrition (TPN) and/or prolonged bowel rest, is hypothesized to enhance bowel endotoxin (LPS) translocation and may alter host responses to infection. To examine the effect of TPN-induced bowel atrophy on the response to LPS, 12 healthy volunteers were randomized to receive either enteral feedings (ENT, n = 6) or seven days of TPN without oral intake (TPN, n = 6). Enteral or TPN feedings were terminated 12 hours before the study period when a constant dextrose infusion (50 mg/kg/hour) was initiated and continued throughout the subsequent study period. After placement of arterial, hepatic vein, and femoral vein catheters, metabolic parameters were determined before and for six hours after an intravenous E. coli LPS challenge (20 U/kg). Subsequent peak levels of arterial glucagon (ENT, 189 +/- 39 pg/mL; TPN, 428 +/- 48; p less than 0.01), arterial epinephrine (ENT, 236 +/- 52 pg/mL; TPN, 379 +/- 49; p less than 0.05) and hepatic venous cachectin/tumor necrosis factor (cachectin/TNF) (ENT, 250 +/- 56 pg/mL; TPN, 479 +/- 136; p less than 0.05) were significantly higher in the TPN group than in the ENT group. The extremity efflux of lactate (ENT, -16 +/- 4 micrograms/min-100cc tissue; TPN, -52 +/- 13; t = 2 hours; p less than 0.05) and of amino acids (ENT, -334 +/- 77 nmol/min-100cc tissue; TPN, -884 +/- 58; t = 4 hours; p less than 0.05) were higher in the TPN subjects after the endotoxin challenge. Circulating C-reactive Protein (CRP) levels measured 24 hours postendotoxin were also significantly higher in the TPN subjects (ENT, 1.7 +/- 0.2 mg/dL; TPN, 3.2 +/- 0.3; p less than 0.01). Hence the counter-regulatory hormone and splanchnic cytokine responses to LPS were enhanced after TPN and bowel rest. This is associated with a magnified acute-phase response, peripheral amino acid mobilization, and peripheral lactate production. Thus antecedent TPN may influence the metabolic alterations seen in infection and sepsis via both an exaggerated counter-regulatory hormone response as well as an enhanced systemic and splanchnic production of cytokines.
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PMID:Total parenteral nutrition and bowel rest modify the metabolic response to endotoxin in humans. 250 83

The catastrophe theory evolved by Thom and Zeeman proposes a mathematical definition for the abrupt or 'catastrophic' changes that can suddenly occur in normally well-ordered and smooth-running systems. We have integrated this theory with our own PAF/cytokine feedback network hypothesis to explain the control and dysfunction of the inflammatory response. This process involves the activation of cells and factors such as proteases, and is coordinated by mediators such as PAF, cytokines and growth factors, minute amounts of which can prime cells to respond in an enhanced manner to subsequent agonistic stimuli. PAF and certain cytokines also possess the unique property of being able to induce the release of each other and their own generation in vivo. This 'singularity' may enable a self-generating feedback network to become established. The priming ability of these mediators indicates the extreme sensitivity of the inflammatory process and importance of a homeostatic equilibrium between the vectors involved in the priming and feedback processes and internal suppressive mechanisms. In pathological conditions, one can consider the phenomenon of PAF and cytokine autogeneration as a 'fold' in the feedback network and an expression of the singularity characteristic of the catastrophe hypothesis. This may lead to systemic toxicity and microcirculatory collapse, a characteristic feature of shock, sepsis, asthma, ischemia and graft rejection. A combination of drugs antagonizing the various feedback components may inhibit this catastrophic process and thus provide more successful therapy of these conditions.
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PMID:PAF/cytokine auto-generated feedback networks in microvascular immune injury: consequences in shock, ischemia and graft rejection. 251 89

The studies reviewed here represent but a fraction of those published in the field last year, but they serve to illustrate two important points: (1) the cytokine network possesses enormous diversity of biological function, and (2) it is redundant, such that overlapping and synergistic effects are observed between many different cytokines. The impact of this system on the host is pervasive and readily amplifiable, and integrates the diverse responses to infectious disease which may be either beneficial, protecting against infection, or deleterious, causing tissue injury and death. The example of cachectin/TNF illustrates this type of scenario: during local infection or inflammation, low levels of cachectin/TNF act to enhance immune responsiveness, stimulate blood-vessel growth, increase energy mobilization, induce the release of other cytokines, and promote wound-healing; when overwhelming infection occurs, as in septicemia, large quantities of cachectin/TNF reach the circulation and cause shock, MSOF, and death; if a persisting infection develops and cachectin/TNF is chronically secreted, it mediates a state of cachexia which may be fatal. Future studies will undoubtedly advance our understanding of these effects, and that of the other cytokines. The development of novel therapies for inflammation, septic shock, and cachexia may be based on such advances.
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PMID:Cachectin/tumor necrosis factor and other cytokines in infectious disease. 267 5

The protective effect of xanthines against E. coli-induced and cytokine-induced lung injury in guinea-pigs has been demonstrated recently. In the present study, the possible protective effects were examined of an analogue of pentoxifylline, HWA-138, a xanthine derivative, on lung injury in septic guinea-pigs. Three groups of animals were studied over a period of 8 hours: Group I animals--saline control injected intravenously with 3 ml 2% lysine/normal saline followed by a continuous lysine/saline infusion (1 ml/kg/hr); Group II--septic control injected intravenously with 2 x 10(9)/kg Escherichia coli followed by a continuous lysine/saline infusion (1 ml/kg/hr); and Group III--E. coli septicaemia plus HWA-138 continuous infusion (HWA-138 dissolved in lysine/saline) began with a bolus (10 mg/kg) followed by a HWA-138 continuous infusion (3 mg/kg/hr) started 60 minutes before injection of E. coli. Arterial blood pressure and white blood cell counts were monitored serially for 8 hours. Lung water (wet-to-dry ratio) and the concentration ratio of 125I-labelled albumin in bronchoalveolar lavage (BAL) fluid and lung tissue compared to plasma (125I-albumin BAL/plasma, 125I-albumin lung/plasma) were examined. Results demonstrated that an intravenous injection of E. coli caused an increased W/D ratio (p less than 0.01) and an increased 125I-albumin lung/plasma ratio (p less than 0.01). In contrast, the HWA-138-treated group did not demonstrate significantly increased W/D lung ratios (p less than 0.01) and 125I-albumin lung/plasma ratios (p less than 0.05). The data suggest a possible role for HWA-138 in attenuating sepsis-induced lung injury.
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PMID:Attenuation of acute lung injury in septic guinea-pigs by a new xanthine derivative (HWA-138). 268 96


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