Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Post-traumatic septic complications result from impaired cell-mediated immune function, which is caused in part by circulating T-cell suppressive factors (TSFs). We examined whether tumor necrosis factor alpha (TNF-alpha) antibody treatment in a baboon sepsis model influences the production of TSFs, including interleukin-10 (IL-10) and transforming growth factor-beta (TGF-beta). Sepsis was induced in anesthetized baboons by Escherichia coli infusion, and caused an increase in plasma levels of TNF, TSF activity, IL-10, and active TGF-beta, as well as a decrease in latent TGF-beta. TNF antibody pretreatment reduced TNF levels by 98%. Transient TSF activity (0-4 h) was only marginally influenced, while sustained TSF activity (8-24 h) was markedly reduced. TSF activity at 24 h correlated with peak TNF levels. IL-10 levels, coinciding with early TSF activity, remained unchanged by anti-TNF treatment. Levels of active TGF-beta and the drop in latent TGF-beta were decreased. We conclude that anti-TNF treatment reduces sustained TSF activity and may partially restore impaired cell-mediated immune function.
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PMID:Tumor necrosis factor antibody treatment of septic baboons reduces the production of sustained T-cell suppressive factors. 777 95

A rapidly increasing body of evidence is implicating endothelin and TNF in the pathogenesis of septic acute renal failure. TNF causes renal damage by recruiting leukocytes, accelerating fibrin accumulation, promoting cell lysis, stimulating the release of vasoconstrictor substances, and other mechanisms. ET-1 causes renal dysfunction in sepsis and endotoxaemia primarily by evoking severe reductions in RBF and GFR. While these are only two of the many agents that mediate renal dysfunction during sepsis, they stand out by virtue of their combined ability to modulate numerous inflammatory pathways and to elicit marked alterations in renal function. Clearly the development of specific TNF and endothelin antagonists holds out promise for the treatment and prevention of septic acute renal failure.
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PMID:Role of endothelin and tumour necrosis factor in the renal response to sepsis. 780 Feb 73

Tumor necrosis factor-alpha (TNF alpha) is recognized as a principal mediator of a variety of inflammatory conditions. In animal models, pentoxifylline attenuates the morbidity and mortality of bacterial sepsis, an effect which has been attributed to its ability to suppress the induction of TNF alpha. To determine whether pentoxifylline also directly inhibits the effects of TNF alpha, the ability to inhibit cytotoxicity on the TNF alpha-sensitive murine fibrosarcoma cell line, L929, was examined. Cell viability was assessed by crystal violet staining and cell proliferation was assessed by [3H]-thymidine uptake assay. TNF alpha induced dose-dependent cytotoxicity. At concentrations of TNF alpha of 1000 U/ml, viability at 3 days was approximately 35% of control. When L929 cells were co-incubated with TNF alpha (1000 U/ml) and pentoxifylline (1 mM), cell viability increased to approximately 75% of control (P = 0.001). At concentrations of TNF alpha of 10,000 U/ml, cell viability which was 11% of control with TNF alpha alone increased to 53% in the presence of pentoxifylline (P = 0.002). TNF alpha at 1000 and 10,000 U/ml concentrations decreased [3H]-thymidine uptake to approximately 5% of control values. Co-incubation with pentoxifylline significantly increased uptake to 13% of control at both TNF alpha concentrations (P = 0.002). Pentoxifylline did not affect the level of type I TNF alpha receptor--ligand cross-link product. However, in TNF alpha receptor binding assays, incubation with pentoxifylline 1 mM for 4 h was associated with an increase in the receptor affinity (control: KD = 0.42 nM vs pentoxifylline-treated: KD = 0.21 nM, P = 0.006), without significant change in number of type I TNF alpha receptors, suggesting that pentoxifylline affects post-receptor signalling events. We have observed that pentoxifylline prevents the TNF alpha-mediated activation of sn-2 arachidonic acid-specific cytosolic phospholipase A2, an important component of the signal transduction pathway of TNF alpha cytotoxicity. Because pentoxifylline does not inhibit all activities mediated by the type I TNF alpha receptor, its selective inhibition of post-receptor signalling may facilitate further study into the mechanisms underlying the diverse effects of TNF alpha.
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PMID:Pentoxifylline inhibits tumor necrosis factor-alpha-mediated cytotoxicity and cytostasis in L929 murine fibrosarcoma cells. 780 30

Acute necrotizing pancreatitis (ANP), which often progresses to infection, sepsis, and multisystem organ failure, runs a course remarkably similar to that seen frequently after severe burns, massive physical trauma, or major surgery. There is extensive evidence that the development of the sepsis response is mediated by immunocytes, particularly activated polymorphonuclear leukocytes (PMNLs) and their secretions (reactive oxygen species, lysosomal hydrolases, cytokines, and so on). Some years ago it was suggested that the high mortality of ANP may be related to an overaggressive immunological defense system of the host rather than to autodigestion of the gland. Recent investigations of the immunoregulatory responses following surgery or other trauma have not only furnished additional support for this concept, but also revealed some genetic factors that may critically influence the outcome of posttraumatic illness including ANP. The prognostic significance of abnormal, early polymorphonuclear leukocyte (PMNL) activation in the development of sepsis, high neutrophil expression of certain receptor molecules, low monocyte and lymphocyte expression of major histocompatibility antigen MHC-class II, and the influence of the genetically encoded TNF and IL-1 secretion on the course of the illness are discussed and related to ANP. Evidence is presented for the potential usefulness of some of these parameters in the prognosis and future treatment of ANP.
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PMID:Genetic determinants of mortality in acute necrotizing pancreatitis. 780 9

Macrophage tumour necrosis factor-alpha (TNF-alpha) production is thought to represent an important pathogenic mechanism by which Gram-negative sepsis is mediated. We compared the effects of caecal ligation and puncture (CLP) on endotoxin-sensitive (C3H/HeSnJ) and endotoxin-resistant (C3H/HeJ) mice. Mortality after CLP for C3H/HeSnJ mice compared with C3H/HeJ mice was not significantly different (32% and 55%, respectively). When survivors were injected with lipopolysaccharide intraperitoneally on the 7th day after CLP, the mortality rate was 82% for C3H/HeSnJ mice versus 0% for C3H/HeJ mice (P < 0.0001). Serum endotoxin levels at 24 h after CLP were only slightly elevated. Serum TNF levels and peritoneal macrophage TNF production were undetectable in C3H/HeJ mice and were only slightly elevated in C3H/HeSnJ mice by 24 h after CLP. Peritoneal macrophage mRNA levels for TNF-alpha, IL-1 beta, and I-A alpha displayed a similar pattern in the two strains of mice, with a 2- to 3-fold increase in TNF-alpha and IL-1 beta mRNA levels by 24 h and a sharp decrease in I-A alpha mRNA by 24 h. The cause of mortality in mice that undergo CLP cannot be attributed to overwhelming endotoxemia and/or TNF production.
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PMID:Endotoxin and tumour necrosis factor do not cause mortality from caecal ligation and puncture. 782 89

Cytokines seem to act predominantly in a paracrine manner when producing their deleterious effects during sepsis. Therefore, local TNF alpha release by pulmonary macrophages would have a central role in the pathogenesis of the adult respiratory distress syndrome (ARDS). By contrast, pentoxiphylline (PTXF) can reduce lung damage in septic animal models, and somatostatin (SS-14) has been shown to down-regulate TNF alpha-receptor expression in monocytes, suggesting an immunomodulatory action for this hormone. The aim of this work was to study the effect of PTXF and SS-14 on lipopolysaccharide (LPS)-induced TNF alpha release by human pulmonary macrophages. Macrophages were obtained from multiple organ donor lungs. Donors with either a recent history of tobacco smoking, more than 72 hr of mechanical ventilation, or any radiological pulmonary infiltrate were not included in this study. After 1 hr of culture, LPS stimulated TNF alpha release in a dose-dependent manner (2.34 +/- 0.20 and 11.32 +/- 1.38 pg/microgram protein, P < 0.01, in response to 2.5 and 10 micrograms/ml LPS, respectively). This response was significantly inhibited by both PTXF, 100 micrograms/ml (0.24 +/- 0.07 vs. 2.43 +/- 0.20, P < 0.01, and 1.30 +/- 0.08 vs. 11.32 +/- 1.38, P < 0.01, pg/micrograms protein, 2.5 and 10 micrograms/ml LPS, respectively) and SS-14, 0.4 ng/ml (0.26 +/- 0.07 vs. 2.43 +/- 0.20, P < 0.01, and 0.60 +/- 0.19 vs. 11.32 +/- 1.38, P < 0.01, pg/micrograms protein, 2.5 and 10 micrograms/ml LPS, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of pentoxifylline and somatostatin on tumour necrosis factor production by human pulmonary macrophages. 783 20

Heat treatments administered prior to the onset of sepsis or endotoxemia markedly increase survival. A potential mechanism for the beneficial effect of heat could be effects on IL-1 alpha and TNF-alpha, important mediators of sepsis and endotoxemia. Administration of IL-1 or TNF prior to development of sepsis and endotoxemia increases survival; thus, prophylactic heat treatments may protect by releasing IL-1 or TNF. Paradoxically, an alternative mechanism of protection of prophylactic heat treatments could be to decrease the amount of IL-1 and TNF released during sepsis or endotoxemia. Cells pretreated with heat do not produce as much IL-1 or TNF in response to endotoxin as cells that have not been pretreated with heat. The purpose of this investigation was to determine if hyperthermia caused release of cytokines and/or blunted the rise in cytokines occurring after endotoxin. Mice were anesthetized with ketamine/xylazine and immersed in a water bath at 37.0 or 42.0 degrees C for sham or heat treatments. At 6-7 h after recovery from anesthesia and immersion, sham and heat-treated mice were injected with Escherichia coli endotoxin. Both heat-treated and sham mice had elevated plasma IL-1 alpha 2 h after anesthesia and immersion but IL-1 alpha was approximately 3-fold greater in the heated mice, 732 +/- 50 vs. 256 +/- 76 pg/ml (p < 0.01). Blood samples obtained after endotoxin revealed no difference in levels of TNF-alpha (5477 +/- 742 vs. 6514 +/- 652 pg/ml) or IL-1 alpha (546 +/- 72 vs. 603 +/- 121 pg/ml) in the sham vs. heated mice.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Hyperthermia induces IL-1 alpha but does not decrease release of IL-1 alpha or TNF-alpha after endotoxin. 785 59

The cytokines interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF alpha) have been implicated in the pathophysiology of sepsis and the systemic inflammatory response syndrome (SIRS). The anti-endotoxin antibody, HA-1A (Centoxin), introduced as a treatment for sepsis, was withdrawn because of possible toxicity in some patients. There has been little investigation of the effects of HA-1A on cytokine production. Sixty-one whole blood samples from 15 intensive care unit (ICU) patients with SIRS were incubated for 24 h with HA-1A and concentrations of cytokines determined. Concentrations of IL-6 exceeded those in samples incubated without HA-1A by more than 25% in five patients, of whom four died. One death occurred among 10 patients for whom IL-6 concentrations did not increase (P = 0.03). Incubation with HA-1A did not increase concentrations of IL-1 beta or TNF alpha. HA-1A did not affect cytokine production in whole blood from healthy subjects. HA-1A may induce IL-6 production in whole blood from some ICU patients and this response is associated with increased mortality. Immune therapies for treatment of sepsis and SIRS require careful evaluation of their ability to affect cytokine production, before they are introduced for general use.
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PMID:In vitro effects of HA-1A (Centoxin) on cytokine production in whole blood from intensive care unit patients. 788 Jun 71

Macrophage inflammatory proteins 1 alpha and beta (MIP-1 alpha and beta) and macrophage inflammatory protein 2 (MIP-2) are approximately 6-8 kd, heparin binding proteins that exhibit a number of inflammatory and immunoregulatory activities. The MIP proteins are members of a superfamily of cytokines called chemokines, many of which have been shown to possess chemotactic activity for inflammatory and immune effector cells. While MIPs were originally identified as secretory products of endotoxin-stimulated mouse macrophages, these chemokines are produced by a variety of cell types including neutrophils, fibroblasts, and epithelial cells. In addition, proteins with a high degree of structural and functional homology to murine MIP-1 alpha and beta and MIP-2 have been identified in other species including humans. MIP-1 alpha and beta are chemotactic for monocytes and lymphocytes and MIP-2 is a potent chemotactic factor for neutrophils. MIPs likely also play a role in regulating hematopoiesis and stimulating production of other inflammatory mediators such as IL-1, TNF alpha, and histamine. Studies using animal models of lung injury and inflammation have implicated MIPs as important mediators of lung defense. Increased MIP expression has been observed in models of bacterial sepsis, silicosis, and oxidant-induced lung injury. Studies in humans indicate MIP-1 alpha contributes to the inflammatory cell response associated with sarcoidosis and idiopathic pulmonary fibrosis. Given the bioactivities of MIP-1 alpha and beta and MIP-2 and the recent studies demonstrating their association with lung inflammation, it is likely these chemokines play a significant role in respiratory tract defenses and may contribute to the pathogenesis of inflammatory lung disease.
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PMID:Macrophage inflammatory proteins: biology and role in pulmonary inflammation. 788 2

Among the important pathophysiologic alterations in the brain in bacterial meningitis are abnormalities of cerebral circulation and metabolism; however, the precise mechanisms by which these disturbances occur are not completely delineated. It has been recently recognized that cytokines are produced by tissues in the central nervous system in meningitis and play a critical role in the host inflammatory response. Because these mediators are involved in circulatory and metabolic disturbances in other tissues in sepsis, we investigated the role of tumor necrosis factor-alpha in the central nervous system in a rabbit model. We found that injection of recombinant human TNF into the cisterna magna in the rabbit led to an acute reduction in cerebral oxygen uptake and a more prolonged reduction in cerebral blood flow. This was accompanied by an increase in intracranial pressure and an increase in cerebrospinal fluid lactate. Reduction in oxygen uptake and increases in intracranial pressure and CSF lactate were blocked by pretreatment with L-NAME, an inhibitor of nitric oxide synthase. Reduction in cerebral blood flow was not affected by L-NAME treatment and was due to increased cerebrovascular resistance and reduced oxygen demand. These results suggest that TNF may be a critical mediator of changes in cerebral circulation and metabolism and that some of these changes occur via the nitric oxide pathway.
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PMID:Effect of recombinant human tumor necrosis factor-alpha on cerebral oxygen uptake, cerebrospinal fluid lactate, and cerebral blood flow in the rabbit: role of nitric oxide. 788 56


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