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)

Despite antibiotic therapy, the septic shock syndrome continues to have a high mortality. Tumor necrosis factor (TNF) and interleukin 1 (IL 1), two polypeptide cytokines produced during sepsis, are thought to mediate the hypotension and tissue damage of shock. In the present studies, rabbits were infused with Escherichia coli organisms to produce shock. The IL 1 receptor antagonist (IL 1ra), which competes with IL 1 for occupancy of the IL 1 cell-surface receptors without agonist properties, was given 15 min before the bacterial infusion and during the subsequent 4 h. In saline-treated controls, hypotension was sustained for 4 h and death occurred for two of five rabbits; in rabbits treated with the IL 1ra, however, blood pressure was only transiently decreased, returned to pre-E. coli levels, and no deaths occurred. The associated leukopenia was also reduced by treatment with the antagonist (P less than 0.05). Histological examination of lung tissues showed reduced infiltrating neutrophils in the IL 1ra treatment group. Despite the attenuated responses in animals treated with the IL 1ra, circulating TNF and IL 1 levels were nearly identical in both groups. We conclude that specific blockade of IL 1 at the receptor level demonstrates an essential role for this cytokine in the pathogenesis of septic shock.
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PMID:A specific receptor antagonist for interleukin 1 prevents Escherichia coli-induced shock in rabbits. 182 16

Tumor necrosis factor (TNF) was measured antigenically and functionally in serum and bronchoalveolar lavage fluid (BAL) of patients with ARDS and those at high risk for ARDS. Of 22 patients with ARDS, 14 had sepsis or serious infection as the major clinical predisposition, and 10 of 20 high-risk patients had sepsis or serious infection. Mean levels of TNF in serum of patients with ARDS and high risk showed a trend toward elevation but were not significantly higher than mean serum levels in normal subjects. Mean levels of TNF in BAL of ARDS patients (242 +/- 126 pg/ml) were significantly higher than in normal subjects (9 +/- 5 pg/ml), p less than 0.05. Antigenic levels of TNF were undetectable in approximately half the patients with ARDS or the high-risk state. Levels of TNF in BAL appeared to be highest in the first day of ARDS. There appeared to be no relationship between levels of TNF in serum or BAL and subsequent mortality. However, serum levels of TNF were significantly higher in septic patients than in nonseptic patients, whereas this difference was not apparent in BAL. These results show that functional and antigenic elevations of TNF are present in BAL and perhaps in serum of patients with ARDS or with the high-risk state.
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PMID:Tumor necrosis factor levels in serum and bronchoalveolar lavage fluid of patients with the adult respiratory distress syndrome. 185 48

Five patients with AIDS and Listeria monocytogenes infection (three cases of bacteremia and two of meningitis) are reviewed. Four patients had prior or concurrent gastrointestinal illness. Two patients received corticosteroids. A 7- to 21-day course of ampicillin was administered with or without a 7- to 14-day course of gentamicin. This regimen was effective, with no evidence of relapse 7-8 months after therapy was discontinued. The relative infrequency of infection with L. monocytogenes in AIDS patients is unexpected. Tumor necrosis factor (TNF) appears to be essential in the inhibition of Listeria in vivo. Elevated levels of TNF in AIDS patients may be protective against listeriosis and thus help explain the low prevalence of listerial infection in this population. Nonetheless, although L. monocytogenes is an uncommon cause of illness in patients infected with the human immunodeficiency virus, it cannot be dismissed as a cause of undefined meningitis or sepsis.
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PMID:Listeria monocytogenes infections in patients with AIDS: report of five cases and review. 186 44

Tumor necrosis factor (TNF) is a potent cytokine mediator of the shock states associated with sepsis and burn injury. This experimental study was done to determine whether circulating TNF plays a major role in the vasomotor collapse seen following experimental hemorrhage and blunt injury. Twenty anesthetized pigs were divided into two groups. Ten animals were bled 60% of their calculated blood volume in 15 minutes. Animals in Group IA (n = 5) had no treatment, and Group IB animals (n = 5) were given twice the shed volume as crystalloid 30 minutes after hemorrhage. The other animals, groups IIa and IIb (n = 5 each), were first subjected to a blunt injury to the thigh sufficient to cause a midshaft femur fracture, then bled and similarly treated. In both groups, mean arterial pressure (MAP), cardiac output (CO), and serum TNF activity by L929 bioassay were measured at 15-minute intervals for 120 minutes after hemorrhage or hemorrhage and blunt injury. An additional three animals were infused with 4 x 10(8)/kg heat-killed E. coli to validate the TNF assay. All bled animals sustained a fall in MAP and CO to a mean of 33% of baseline values, with or without fracture. Group IB and IIB animals responded to fluid resuscitation by restoration of MAP and CO to 85%-97% of the baseline values. Tumor necrosis factor was not detectable before injury and remained undetectable in all these animals during the 120 minutes of the experiment despite hemorrhage alone or combined hemorrhage and blunt trauma, with or without fluid resuscitation. The test animals receiving the E. coli responded with markedly elevated TNF levels, which peaked at 90 minutes after injection.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Experimental hemorrhage and blunt trauma do not increase circulating tumor necrosis factor. 187 32

Tumor necrosis factor (TNF) is an important mediator of the systemic response to gram-negative sepsis and endotoxemia. We studied the renal effects of a sublethal TNF infusion in dogs (0.54 = 10(5) international units per kilogram of body weight during a six hour period). The TNF-infused dogs (n = 4) had marked polyuria and natriuresis in comparison with those in the control group (n = 12) (urine output, 35.3 +/- 4.1 versus 3.7 +/- 0.5 millimeters per kilogram per six hours p less than 0.01; sodium excretion, 2.82 +/- 0.27 versus 0.75 +/- 0.19, p less than 0.01). To evaluate the role of the spleen in this response, seven dogs that had splenectomy were infused with TNF. Splenectomy abolished both the polyuria and the natriuresis; this could not be explained by the differences in fluid balance or in hemodynamic or metabolic alterations. Treatment with ibuprofen given intravenously (12.5 milligrams per kilogram 40 minutes before and three hours after the beginning of TNF infusion) in eight dogs that did not undergo splenectomy also abolished these renal effects. Prostaglandin 2 (PGE2) concentrations in selected blood samples from the splenic vein did not increase with TNF infusion, excluding circulating PGE2 as a possible mediator of the renal effects. The results of these studies indicate that, during septic challenge or severe inflammation, the spleen participates in signaling the kidney to increase water and sodium excretion. These renal events are mediated through the cyclo-oxygenase pathway.
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PMID:Splenectomy attenuates the inappropriate diuresis associated with tumor necrosis factor administration. 190 Sep 57

Endotoxemia remains the leading cause of death in horses, being intimately involved in the pathogenesis of gastrointestinal disorders that cause colic and neonatal foal septicemia. Endotoxins, normally present within the bowel, gain access to the blood across damaged intestinal mucosa, or endotoxemia occurs when gram negative organisms proliferate in tissues. Endotoxins are removed from the circulation by the mononuclear phagocyte system, and the response of mononuclear phagocytes to these lipopolysaccharides (LPS) play an important role in determining the severity of clinical disease. Macrophages become highly activated for enhanced secretory, phagocytic and cidal functions by LPS. Macrophage-derived cytokines are responsible for many of the pathophysiologic consequences of endotoxemia. The arachidonic acid metabolites, prostacyclin and thromboxane A2 likely mediate early hemodynamic dysfunction and the leukotrienes may potentiate tissue ischemia during endotoxemia. Interleukin 1 (IL-1) induces fever and is responsible for the inflammatory cascade, which constitutes the acute phase response. Tumor necrosis factor (TNF), an important proximal mediator of the effects of LPS, acts to initiate events and formation of other molecules that affect shock and tissue injury. Systemic administration of TNF produces most of the physiologic derangements that are associated with endotoxemia and antibodies that are directed against TNF significantly reduce LPS-induced mortality in experimental animals. In response to endotoxins, mononuclear phagocytes express thromboplastin-like procoagulant activity (PCA), which initiates microvascular thrombosis. Both IL-1 and TNF induce PCA expression, creating a positive feedback loop for LPS-induced coagulopathy. A macrophage-derived platelet activating factor contributes to coagulation dysfunction and further stimulates arachidonic acid metabolism. The ultimate consequences of endotoxemia are multiple system organ failure and death. The numerous feedback loops and intertwining cascades of mediators during endotoxemia defy simplistic methods of treatment. The optimal therapy likely involves methods to alter the generation of inflammatory mediators by mononuclear phagocytes.
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PMID:Endotoxemia in horses. A review of cellular and humoral mediators involved in its pathogenesis. 192 Feb 54

Endotoxin is composed of lipid A, the toxic moiety, of the core region, a conserved structure among Gram-negative bacteria, and of the O-side chains, a highly variable part responsible for the antigenic specificity. The concept of cross-protection afforded by antiserum raised against the core region of endotoxin is supported by the following data: experimentally antiserum protected against infections caused by a wide range of Gram-negative bacteria or endotoxins; in patients with Gram-negative bacteremia, survival was associated with high levels of anti-core antibodies, and mortality was reduced by the prophylactic or therapeutic use of immune serum or plasma. However, the proof that protection is afforded by cross-protective anti-core antibodies is still lacking. Furthermore, many experimental studies and clinical studies trials have shown controversial results. Ongoing experimental studies and recently completed clinical trials, using either polyclonal or monoclonal anti-core antibodies should help clarify the issues both of the clinical efficacy and of the mechanism of protection. Tumor necrosis factor/cachectin has been unequivocally shown, both in experimental animal models and in humans to be a pivotal mediator of the clinical and humoral manifestations of shock induced by endotoxin or by whole Gram-negative bacteria. In humans, TNF was been transiently detected in the blood of volunteers challenged with endotoxin, in a small proportion of patients with Gram-negative sepsis, but in the vast majority of patients with established septic shock. However, in patients the magnitude and the evolution of the blood concentration of TNF differed from that observed in animal models or in human volunteers after an acute challenge with either Gram-negative bacteria or endotoxin, probably reflecting differences in infectious stimuli. In children with meningococemia and in adults with Gram-negative septic shock, TNF was associated with the patient's outcome. Anti-TNF monoclonal antibodies are presently undergoing clinical investigation in patients with septic shock. However, one should keep in mind that TNF serves both beneficial and detrimental functions depending upon its concentration in body fluids.
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PMID:Anti-lipopolysaccharide and anti-tumor necrosis factor/cachectin antibodies for the treatment of gram-negative bacteremia and septic shock. 192 24

The cytokine response to major surgical trauma has been studied in six patients undergoing elective aortic surgery. Peripheral blood was sampled frequently before, during, and after surgery and the plasma cytokines interleukin-1, interleukin-6, tumor necrosis factor-alpha, and interferon-gamma were measured using enzyme-linked immunosorbent assays. These results were reviewed together with the operative details, clinical course, and C-reactive protein levels. Tumor necrosis factor-alpha and interferon-gamma were not detected in these patients. An early and short-lived interleukin-1 beta response to major surgery was detected only by intensively sampling the intraoperative period. This was a consistent finding that preceded the rise in interleukin-6. Interleukin-6 rose steeply from 2 h, peaking between 4 and 24 h. It had fallen sharply by 48-72 h in five patients who had an uneventful postoperative course. It remained high in one patient who developed complications and fell only when a severe septicemia was treated successfully. His interleukin-6 levels were considerably higher than the other patients even during the operation itself. There was no obvious relation between the interleukin-6 peak and the duration of operation. A sequential interleukin-1 beta and interleukin-6 response has not been noted before in vivo, and would seem to provide evidence supporting the in vitro observation that interleukin-1 induces interleukin-6 synthesis and release. It also provides evidence of an important role for interleukin-6 in the body's response to injury. A larger study is in progress.
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PMID:The release of interleukin-1 beta (IL-1) precedes that of interleukin 6 (IL-6) in patients undergoing major surgery. 193 68

Tumor necrosis factor (TNF), a macrophage product released in response to endotoxin and other stimuli, has been shown to be a central mediator of endotoxin or septic shock. However, its highly conserved and wide-ranging physiological effects suggest that it may also be an essential cytokine in the host defense against acute bacterial infection or sepsis. A single nontoxic dose of human recombinant TNF administered intravenously 24 h prior to a lethal infusion of Escherichia coli lipopolysaccharide (LPS) completely prevented acute LPS-induced hypotension, ameliorated tissue injury in the lungs and liver, and improved survival in male Fisher 344 rats. The protective effects of TNF were dose dependent and required a 24-h pretreatment interval. After the infusion of LPS, animals in both groups (TNF-treated animals and saline-pretreated controls) initially appeared acutely ill and had a similar severe metabolic acidosis, indicating that TNF did not inactivate or prevent the toxic effects of LPS. Twelve hours after the administration of TNF, the gene for manganous superoxide dismutase, a mitochondrial enzyme which scavenges toxic reactive oxygen species and is induced during conditions which generate a free radical stress, was expressed in liver tissue, suggesting that the induction of manganous superoxide dismutase may be an important in vivo protective mechanism against cellular injury during lethal endotoxemia.
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PMID:Single-dose tumor necrosis factor protection against endotoxin-induced shock and tissue injury in rats. 193 48

Using a model of sepsis induced by parenteral challenge of mice with bacterial lipopolysaccharide (LPS), the authors analyzed the in vivo expression of interleukin-1 (IL-1) alpha,beta and tumor necrosis factor (TNF). Both TNF and IL-1 alpha,beta were detected in hepatic sinusoidal macrophages (Kupffer cells), immunohistochemically. Kinetic analysis showed a clear sequence of synthesis. Tumor necrosis factor was produced first, reaching maximal expression at 1 hour after LPS challenge, then rapidly disappeared. IL-1 beta followed, reaching maximal expression at 2 to 3 hours, then dropped off by 6 hours. Interleukin-1 alpha expression reached a peak at 6 hours and had disappeared by 18 hours. Analysis of serum bioactivity also revealed sequential expression that correlated with immunohistochemical findings. Tumor necrosis factor was maximal at 1 hour and IL-1 at 6 hours. The IL-1 bioactivity was not due to interleukin-6 (IL-6), as this was depleted from specimens by immunoabsorption. Also IL-6 bioactivity reached maximal levels at 3 hours, earlier than IL-1. Pretreatment with 4 mg/kg dexamethasone significantly decreased Kupffer cell expression of TNF and IL-1 alpha (about 80% and 60% suppression, respectively) but had less effect on IL-1 beta expression (about 30% suppression). Accordingly, serum levels of TNF were suppressed by 75% while serum IL-1 was decreased by 39%, indicating differential sensitivity of these cytokines to glucocorticoids. Endogenous corticosteroid levels increased as TNF levels decreased, supporting the contention that glucocorticoids regulate TNF synthesis. In contrast, IL-1 levels rose concurrently with corticosterone. These data indicate a sequential activation of cytokine gene expression in vivo, which may be critical to the cascade of events leading to septic shock, and provide evidence that Kupffer cells are a major source of cytokines in endotoxemia. Finally, the differential sensitivity of cytokine expression to glucocorticoids may in part explain the inadequacy of the latter in the treatment of sepsis.
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PMID:In vivo biologic and immunohistochemical analysis of interleukin-1 alpha, beta and tumor necrosis factor during experimental endotoxemia. Kinetics, Kupffer cell expression, and glucocorticoid effects. 199 64


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