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Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

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

Despite significant advances in intensive care unit technology and mechanical ventilatory support, mortality due to adult respiratory distress syndrome (ARDS) or multiorgan failure (MOF) has not changed significantly within the past two decades. The key to improving survival requires understanding and modifying (or eliminating) factors that may initiate (or modulate) these syndromes. Infection, and the host responses to infection, are major etiological factors responsible for the induction and perpetuation of the injury to the lung and microvasculature in ARDS and MOF, and contribute to late mortality. While the pathogenesis of ARDS and MOF-complicating sepsis remains to be elucidated, bacterially derived (eg, endotoxin or lipopolysaccharides [LPS]) and host-derived humoral and cellular mediators are of importance in both disease states. In fact, the host response to infection (or injurious stimuli) may be a more critical determinant of the outcome of sepsis and ARDS than the original inciting stimulus. The pleiotropic effects of LPS are largely indirect, and are orchestrated via its ability to trigger the release of an array of host-derived mediators of inflammation. Several potential mechanisms of injury in ARDS, sepsis, and MOF have been suggested and include a variety of inflammatory cells (neutrophils, mononuclear phagocytes, platelets), activated complement and coagulation components, vasoactive mediators (kinins, arachidonic acid metabolites, lipids, peptides), reactive oxygen radicals, and diverse cytokines. Interactions between these humoral and cellular mediators appear to set in motion an amplified cascade of events culminating in cellular and tissue injury. In this article, several of these putative inflammatory mediators are discussed in detail, and the importance of cytokine networking and the possible role of nonimmune cells in the orchestration of the inflammatory response associated with ARDS and MOF are explained. Finally, future therapeutic strategies aimed at blocking or suppressing the release or effects of endogenous mediators may be the key to improving the outcome of these disorders.
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PMID:Host responses in mediating sepsis and adult respiratory distress syndrome. 212 91

About five out of 1,000 patients admitted to hospital develop bacterial sepsis leading to shock, the mortality rate for which is high despite antibiotic therapy. The infection results in hypotension and poor tissue perfusion, and eventually leads to the failure of several organ systems. Bacterial endotoxin is thought to be the direct cause of shock in Gram-negative sepsis, because it can cause shock in animals, and antibodies against endotoxin prevent Gram-negative shock in animals and in humans. But, the symptoms of septic shock are the result of the actions of host cytokines induced by the endotoxin. The cytokine interleukin-1 has been implicated as an important mediator of septic shock because it can induce tachycardia and hypotension and act synergistically with tumour necrosis factor to cause tissue damage and death. We now report that a specific interleukin-1 receptor antagonist reduces the lethality of endotoxin-induced shock in rabbits, indicating that interleukin-1 does indeed play an important part in endotoxin shock.
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PMID:Interleukin-1 receptor antagonist reduces mortality from endotoxin shock. 214 33

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

The objective of this study was to analyze monokine production by peripheral blood mononuclear cells from patients with alcoholic cirrhosis. The capacity of peripheral blood mononuclear cells and purified monocytes from these patients to produce tumor necrosis factor alpha, interleukin 1 beta, and interleukin 6 was investigated. Spontaneous production of tumor necrosis factor alpha, interleukin 6 and interleukin 1 beta was similar in cirrhotic and healthy subjects, but serum levels of interleukin 6 (less than 2 U/ml vs. 9.5 +/- 3 U/ml) and tumor necrosis factor alpha (3.1 +/- 1.2 pg/ml vs. 12.0 +/- 1.2 pg/ml) were significantly higher in cirrhotic patients. However, peripheral blood mononuclear cells or purified monocytes from patients with alcoholic liver cirrhosis, stimulated in vitro with Escherichia coli lipopolysaccharide, displayed a marked increase of tumor necrosis factor alpha, interleukin 1 beta and interleukin 6 secretions compared with healthy controls. A striking feature of this overproduction was its reversibility as assessed by allowing cells to rest in vitro without lipopolysaccharide for 1 to 7 days before stimulation. In such conditions, tumor necrosis factor alpha and interleukin 6 secretions declined to levels present in healthy subjects in whom production remained stable, whereas interleukin 1 beta secretion markedly decreased in both groups to the point where no difference could be seen. This reversible oversecretion of cytokines after lipopolysaccharide stimulation, along with the lack of abnormality of spontaneous cytokine secretion, suggests that monocytes in these patients may have undergone an in vivo activation process analogous to a priming phenomenon. The in vitro activation with lipopolysaccharide may represent the correlate of in vivo endotoxemia observed during acute events such as sepsis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Excessive in vitro bacterial lipopolysaccharide-induced production of monokines in cirrhosis. 218 15

Tumor necrosis factor, a mononuclear phagocyte-derived peptide produced in response to lipopolysaccharide, has been shown to mediate certain aspects of septic shock and multiple organ failure resulting from gram-negative septicemia. In the present investigation, pretreatment of animals with pentoxifylline inhibited lipopolysaccharide-induced serum tumor necrosis factor in a dose-dependent fashion. Pentoxifylline prevented the sequestration of neutrophils seen in animals given intravenous lipopolysaccharide. Furthermore, pentoxifylline protected animals from the lethal effects of an intravenous challenge with lipopolysaccharide. These data indicate that pentoxifylline inhibits lipopolysaccharide-induced tumor necrosis factor and may be an effective agent in mitigating the lethal consequences of sepsis and other disease processes mediated by this cytokine.
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PMID:Pentoxifylline inhibits lipopolysaccharide-induced serum tumor necrosis factor and mortality. 223 23

Immobilization-related hypercalcaemia is an uncommon but important condition being associated not infrequently with both urolithiasis and osteoporosis. In this study 5 patients who had been immobilized for a mean of 3 months and had a mean adjusted serum calcium of 3.15 mmol/l were treated with doses of intravenous pamidronate ranging between 10 mg and 45 mg. All patients became normocalcaemic by day 3. Patients 1-3 mobilized shortly after treatment and remained normocalcaemic. In those patients who continued to be immobile hypercalcaemia recurred after an interval of several weeks. Retreatment with pamidronate again resulted in normocalcaemia. No side effects were noted with treatment. All of the patients studied had increased rates of bone resorption as shown by elevated urinary hydroxyproline/creatinine ratios (median:range) of 0.101:0.045-0.180 (normal less than 0.033) and elevated calcium/creatinine ratios of 2.50:0.69-3.63 (normal less than 0.50). None of the patients in this study had any of the usual risk factors for developing immobilization-related hypercalcaemia though all 5 patients had problems with significant sepsis which we postulate may have lead to cytokine release which in turn contributed to the development of hypercalcaemia. We conclude that pamidronate (at doses as low as 10 mg) is safe and effective in immobilization-related hypercalcaemia and suggest that sepsis should be added to the list of risk factors for development of this syndrome.
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PMID:Immobilization-related hypercalcaemia--a possible novel mechanism and response to pamidronate. 226 2

Several lines of evidence implicate tumor necrosis factor (TNF), a cytokine produced by monocytes-macrophages, in the systemic manifestations of shock induced by Gram-negative bacteria. Whether the increase of circulating TNF levels is specific to septic shock as compared to sepsis without shock or to non-septic shock is still unclear. Since TNF values recorded at the time of admission to the hospital vary widely, statistical analysis has not been possible. Therefore, we postulated that the evolution of a patient's TNF serum level as compared to his initial value may better distinguish the survivor from the non-survivor than a single initial determination. Using a radioimmunoassay, we measured the TNF concentrations in the sera of 7 patients with severe infections without shock, 16 patients with septic shock and 8 patients with non-septic shock. Blood samples were drawn within the first 12 hours after the onset of shock. Patients with cancer, HIV infection, or under steroid therapy were excluded. Repeated measurements were made during the first 3 days of septic shock in 10 patients. The circulating TNF level, determined upon admission, appears to be neither specific nor predictive of the outcome of septic shock. In contrast, persistently high levels of circulating TNF seem to be well correlated with a poor prognosis, since 5 out of 6 patients with elevated TNF values died of septic shock.
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PMID:[Specificity and serum concentrations of tumor necrosis factor in septic shock]. 228 4


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