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

Report of a T-cell rich B-cell lymphoma (TCRBCL) in a 43 years old man with an associated haemophagocytic syndrome (HS). At presentation the haemophagocytic cells involved the same organs as the lymphoma, i.e. spleen, liver, abdominal lymph nodes and bone marrow. As supportive measure to alleviate chemotherapy-induced granulocytopenia the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) was given. After an initial improvement of the blood granulocyte count pancytopenia developed again, resulting in fatal sepsis. Autopsy demonstrated massive proliferation of macrophages in the bone marrow with haemophagocytosis as morphological correlation to the pancytopenia. The observation that exogenous GM-CSF enhanced the preexistent HS primarily reactive to the TCRBCL raises the question if endogenous GM-CSF may play a role in triggering a HS. The observed association of TCRBCL and HS has not been reported so far.
 ...
PMID:[T-cell rich B-cell lymphoma associated with hemophagocytic syndrome]. 128 41

Endotoxin (lipopolysaccharide [LPS])-induced cytokine release has been implicated in the pathogenesis of sepsis. Sublethal doses of LPS induce tolerance to a septic insult. This study evaluated pretreatment with interleukin 1 (IL-1) against an LPS challenge and examined its relationship to endotoxin tolerance. C3H/HeN mice (N = 100) were injected intraperitoneally with phosphate-buffered saline (control group), IL-1 (200 micrograms/kg), or LPS (1 mg/kg) for 3 days. On day 5, peritoneal macrophages were harvested and assayed for antimicrobial activity (superoxide anion production and Candida albicans phagocytosis). Serum cytokine levels and survival after an LPS challenge on day 5 were also assessed. Pretreatment with IL-1 or LPS significantly increased superoxide anion production, C albicans phagocytosis, and survival compared with pretreatment with phosphate-buffered solution. Interleukin 6 levels significantly decreased in the IL-1 and LPS groups. Peak levels of tumor necrosis factor significantly decreased only in the LPS group. Thus, pretreatment with IL-1 or low doses of LPS may exert protective effects by decreasing levels of interleukin 6 while increasing antimicrobial activity. Mice pretreated with IL-1 were protected from endotoxin despite elevated peak levels of tumor necrosis factor, suggesting a different mechanism for endotoxin tolerance than for tolerance to tumor necrosis factor.
 ...
PMID:Interleukin 1 and its relationship to endotoxin tolerance. 131 50

1. Administration of tumour necrosis factor (cachectin) and of interleukin-1-alpha increased the plasma level of nonesterified fatty acids in fed rats, and in the case of interleukin-1-alpha the blood glycerol level was also increased, suggesting stimulation of adipose tissue lipolysis. There were parallel increases in the plasma level of triacylglycerols. Neither cytokine had significant effects on blood or liver total ketone body (acetoacetate plus 3-hydroxybutyrate) concentrations. 2. In starved rats, the higher plasma non-esterified fatty acid concentration was not increased further by the cytokines. The plasma triacylglycerol level was increased, although the absolute change was less than in fed rats. The ketonaemia associated with starvation tended to be increased by the cytokines, but this was only significant in the case of interleukin-1-alpha. Parallel changes occurred in hepatic ketone bodies. 3. It is concluded that tumour necrosis factor-alpha and interleukin-1-alpha are not responsible for the hypoketonaemia associated with sepsis or other inflammatory states.
 ...
PMID:Acute administration of tumour necrosis factor-alpha or interleukin-1-alpha does not mimic the hypoketonaemia associated with sepsis and inflammatory stress in the rat. 131 59

Cytokines have been studied intensively to delineate their role in the altered pathophysiology observed in septic shock. We studied the role of TNF in the lethality of two well characterized models of septic shock by inhibiting TNF's activity with a specific antibody. In the first model, sepsis was induced by cecal ligation and puncture (CLP), and in the second model sepsis was induced by either an i.p. or i.v. injection of LPS. After CLP, plasma endotoxin was detectable within 4 h and reached a peak at 8 h (136 +/- 109 ng/ml). TNF bioactivity peaked at 12 h (528 +/- 267 pg/ml) at a significantly higher level than sham-operated control mice (64 +/- 31 pg/ml). After i.p. LPS, TNF peaked much more quickly (90 min) compared with CLP and at a significantly higher level (107,900 +/- 25,000 pg/ml). Another cytokine studied in septic shock, IL-6, peaked at 12 h after CLP at 1011 +/- 431 pg/ml, and at 90 min after lethal LPS at 16,300 +/- 3,700 pg/ml. Mice were treated with an anti-TNF antibody that has been shown previously to inhibit in vivo TNF activity. Antibody treatment of mice subjected to CLP significantly reduced TNF bioactivity but did not reduce mortality or pulmonary neutrophilic infiltration. In the i.v. LPS model, anti-TNF antibody treatment concomitant with LPS injection reduced plasma TNF activity from 80,000 +/- 20,000 pg/ml to undetectable levels. However, anti-TNF treatment immediately before either i.v. or i.p. LPS did not reduce mortality. Additionally, when the antibody was administered 4 h before the lethal i.v. LPS, there was no reduction in lethality. These data show that in two separate models of septic shock blockade of TNF biologic activity will not prevent lethality.
 ...
PMID:Anti-tumor necrosis factor antibody therapy fails to prevent lethality after cecal ligation and puncture or endotoxemia. 131 57

Tumor necrosis factor alpha (TNF alpha), a primary mediator of systemic responses to sepsis and infection, can be injurious to the organism when present in excessive quantities. Here we report that two types of naturally occurring soluble TNF receptors (sTNFR-I and sTNFR-II) circulate in human experimental endotoxemia and in critically ill patients and demonstrate that they neutralize TNF alpha-induced cytotoxicity and immunoreactivity in vitro. Utilizing immunoassays that discriminate between total sTNFR-I and sTNFR-I not bound to TNF alpha, we show that sTNFR-I-TNF alpha complexes may circulate even in the absence of detectable free TNF alpha. To investigate the therapeutic possibilities of sTNFR-I, recombinant protein was administered to nonhuman primates with lethal bacteremia and found to attenuate hemodynamic collapse and cytokine induction. We conclude that soluble receptors for TNF alpha are inducible in inflammation and circulate at levels sufficient to block the in vitro cytotoxicity associated with TNF alpha levels observed in nonlethal infection. Administration of sTNFR-I can prevent the adverse pathologic sequelae caused by the exaggerated TNF alpha production observed in lethal sepsis.
 ...
PMID:Tumor necrosis factor soluble receptors circulate during experimental and clinical inflammation and can protect against excessive tumor necrosis factor alpha in vitro and in vivo. 131 75

Several studies in human patients and in laboratory animals have revealed a correlation between serum interleukin (IL)-6 levels and outcome in clinical sepsis and in related animal models, respectively. In the present study, two monoclonal antibodies were used to investigate the contribution of IL-6 in the lethal action of tumor necrosis factor (TNF) and of lipopolysaccharide (LPS) in mice. We studied the potential protective properties of an anti-murine (m) IL-6 antibody and of an anti-mIL-6 receptor antibody. In controlled experiments, we observed that both monoclonal antibodies conferred a dose-dependent protection to a lethal dose of mTNF. Detailed studies with the monoclonal antibodies indicate, however, that protection was no longer observed when the mTNF dose was slightly higher than the lethal dose. Likewise, the anti-IL-6 monoclonal antibody protected against injections of LPS at a lethal-dose concentration, but here too failed to protect against higher doses of LPS. The anti-IL-6 monoclonal antibody was unable to protect against mTNF in mice sensitized by galactosamine, the corticoid receptor antagonist RU38486 or human (h) IL-1 beta. Protection did not correlate with the serum concentrations of IL-6. Finally, we demonstrate that hIL-6 injection did not change the sensitivity of mice towards mTNF. We conclude that, although IL-6 levels may be of value as a marker for the outcome in septic shock, this cytokine contributes only marginally in the pathogenesis leading to death. The small, but real, contribution of IL-6 in some situations might be due to its ability to up-regulate the level of TNF receptors.
 ...
PMID:Limited involvement of interleukin-6 in the pathogenesis of lethal septic shock as revealed by the effect of monoclonal antibodies against interleukin-6 or its receptor in various murine models. 132

Tumor necrosis factor-alpha (TNF) is a cytokine released by mononuclear cells in response to inflammation and sepsis. Since the biological effects of TNF are consistent with the systemic and intestinal features of ulcerative colitis, the role of TNF was examined in a rabbit model of chronic colitis. Peripheral blood mononuclear cells were isolated, stimulated with lipopolysaccharide, and cultured supernatants assayed for TNF levels using a cytotoxic assay on mouse fibrosarcoma L929 cells. Basal levels of TNF production by mononuclear cells from 13 normal rabbits (124.3 units/ml +/- 27.1 units/ml, mean +/- SE) were not different from nine rabbits with colitis (83.6 units/ml +/- 24.4 units/ml, P > 0.05). Treatment with lipopolysaccharide (100 micrograms/ml) induced increased TNF production by mononuclear cells isolated from both normals (672.0 units/ml +/- 197.5 units/ml, P < 0.05) and rabbits with colitis (1114.0 units/ml +/- 489.6 units/ml, P < 0.05). However, at all lipopolysaccharide concentrations stimulated TNF levels were comparable in experimental and control groups (P > 0.05). In light of the role of leukotrienes in inflammation, a separate group of rabbits with colitis was investigated following treatment with an oral leukotriene B4 receptor antagonist. Serum TNF levels in 15 control rabbits (32.5 units/ml +/- 7.6 units/ml, mean +/- SE) were not significantly different from rabbits with colitis receiving either leukotriene B4 receptor antagonist (35.7 units/ml +/- 9.2 units/ml, N = 13) or vehicle alone (50.3 units/ml +/- 10.2 units/ml, N = 14) (ANOVA, P > 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Systemic tumor necrosis factor-alpha production in experimental colitis. 133 Apr 61

The polypeptide cytokine interleukin-1 (IL-1) affects nearly every tissue and organ system. IL-1 is the prototype of the pro-inflammatory cytokines in that it induces the expression of a variety of genes and synthesis of several proteins which, in turn, induce acute and chronic inflammatory changes. Most studies on the biology of IL-1 have been carried out in animals, but human subjects have recently been injected with recombinant IL-1 and the results confirm IL-1 as being a mediator of disease as well as host defense. However, overproduction of IL-1 leads to debilitation of normal host functions; therefore, reduction of IL-1 synthesis or blockade of IL-1 activity becomes a target of therapy in many diseases. Agents for reducing the synthesis or antagonizing the effects of IL-1 have been sought, but the naturally occurring IL-1 receptor antagonist (IL-1Ra) has opened new experimental and clinical approaches. The ability of IL-1Ra to block IL-1 receptors without agonist activities has reduced the severity of diseases such as septic shock, lethal sepsis, inflammatory bowel disease, experimental arthritis, and the spontaneous proliferation of human leukemic cells.
 ...
PMID:The role of interleukin-1 in host responses to infectious diseases. 134 62

Interleukin 2, has frequent and important side effects. Toxic effects observed are systemic (fever, chills, malaise), hemodynamic (capillary leak syndrome, hypotension), cardiac (arrhythmia, infarction), renal (renal dysfunction), infectious (septicemia), cutaneous, hematologic, gastrointestinal, endocrinologic and metabolic. Side effects are dose-dependent, generally reversible, with a mortality from 1 to 3%. Regimens of administration and other cytokine combinations affect interleukin 2 toxicity. If the treatment of these side effects is well known, selection of patients and specialized care unit remain always necessary.
 ...
PMID:[Adverse effects of interleukin 2]. 136 55

There is an increasing incidence of sepsis among hospitalized patients. Also, high mortality associated with sepsis and septic shock persists despite appropriate antibiotic therapy. Recent investigations have demonstrated that bacterial antigens stimulate a cascade of cellular mediators or cytokine release. In sepsis and septic shock the response of these cytokines often exceeds natural downregulation and leads to multisystem organ failure and even death in an unacceptably high number of patients. Many investigative studies have shown that tumor necrosis factor (TNF) is the prime mediator of the inflammatory response seen in sepsis and septic shock. Sepsis management in the future will include immune modulating therapy directed against the deleterious effects of cytokines, specifically TNF. This article reviews the current problem of sepsis and the evidence to support the role of TNF in sepsis. also, recent studies employing monoclonal antibodies against TNF as well as considerations for future studies are discussed.
 ...
PMID:The role of tumor necrosis factor in sepsis. 137 Feb 62


1 2 3 4 5 6 7 8 9 10 Next >>