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)

Tumor necrosis factor alpha (TNF-alpha) is a pleiotropic cytokine with diverse biological actions. Studies originally identified TNF-alpha as a systemic mediator of endotoxemic shock, cachexia, and tumor regression. We now recognize that TNF-alpha is a member of a large family of proteins, including Fas ligand, whose actions are primarily paracrine in nature, and serve to regulate both cell proliferation and apoptotic death. Although clinical trials with TNF-alpha inhibitors in sepsis syndrome have been disappointing to date, and TNF-alpha administration has not proven widely successful as an antineoplastic agent, preliminary successes with TNF-alpha inhibition have been recently reported in more chronic inflammatory diseases, including rheumatoid arthritis and ulcerative colitis. The recent description of the TNF-alpha converting enzyme responsible for the processing of cell-associated to secreted TNF-alpha has opened a new therapeutic avenue to address inflammatory diseases dependent on the release of 17-kd secreted TNF-alpha. Similarly, inhibitors of nuclear factor kappa B activation can increase TNF-alpha-mediated apoptosis and have rejuvenated efforts to explore TNF-alpha's antineoplastic potential. The multiple and often conflicting TNF-alpha signaling pathways reveal a diversity to TNF-alpha's actions not fully appreciated in the past. Such investigations have opened a number of novel therapeutic interventions to either inhibit or potentiate the actions of TNF-alpha during surgical injury or acute inflammation.
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PMID:Revisiting the role of tumor necrosis factor alpha and the response to surgical injury and inflammation. 960 21

The trauma and sepsis that follow open fractures and wounds may lead to the production of various cytokines. Understanding wound healing requires a direct knowledge of the specific cytokines and the respective wound fluid levels that are present at the wound site. An animal model was designed that mimics the open fracture and the clinical repair of the human, high-energy open fracture. Canine right tibiae were fractured with a penetrating, captive-bolt device, then repaired in a standard clinical fashion using an interlocking intramedullary nail. Before primary wound closure, microdialysis probes were placed at the fracture site and in a muscle located at a contralateral site. Canines received one of the following experimental protocols: (1) tibial fracture (n = 5); (2) tibial fracture plus Staphylococcus aureus inoculation at the fracture site (n = 5); and (3) tibial fracture, S. aureus inoculation, and a rotational gastrocnemius muscle flap (n = 5). Microdialysis fluid samples were collected intermittently for 7 days. Tumor necrosis factor alpha (TNFalpha) levels at the fracture site were significantly elevated 3 to 34-fold (p<0.02), as compared with respective serum levels at all time points for all treatment groups. Fracture site TNFalpha levels were elevated (p<0.02) in days 1 through 6, as compared with the baseline and contralateral in all treatment groups. At days 1 through 6, the TNFalpha levels of the muscle flap group fracture site were significantly decreased by approximately 50 percent (p<0.05), as compared with the fractures without muscle flaps and regardless of additional S. aureus inoculation. On day 7, fracture site TNFalpha levels in all animal groups were similar, yet remained well above those of baseline TNFalpha. These results demonstrate that S. aureus does not further elevate TNFalpha levels in the presence of an open fracture and that a muscle flap reduces pro-inflammatory TNFalpha levels during early wound healing. This experimental model allows for the characterization of specific biological signals and cellular pathways that are influenced by bacterial infection and surgical closure. These data provide a scientific framework on which to judge or validate therapeutic regimens for open-fracture wound healing.
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PMID:The effect of muscle flap transposition to the fracture site on TNFalpha levels during fracture healing. 1072 59

Tumor necrosis factor alpha (TNF-alpha) has well-described effects on lipid metabolism in the context of acute inflammation, as in sepsis. Recently, increased TNF-alpha production has been observed in adipose tissue derived from obese rodents or human subjects and TNF-alpha has been implicated as a causative factor in obesity-associated insulin resistance and the pathogenesis of type 2 diabetes. Thus, current evidence suggests that administration of exogenous TNF-alpha to animals can induce insulin resistance, whereas neutralization of TNF-alpha can improve insulin sensitivity. Importantly, results from knockout mice deficient in TNF-alpha or its receptors have suggested that TNF-alpha has a role in regulating in vivo insulin sensitivity. However, the absence of TNF-alpha action might only partially protect against obesity-induced insulin resistance in mice. Multiple mechanisms have been suggested to account for these metabolic effects of TNF-alpha. These include the downregulation of genes that are required for normal insulin action, direct effects on insulin signaling, induction of elevated free fatty acids via stimulation of lipolysis, and negative regulation of PPAR gamma, an important insulin-sensitizing nuclear receptor. Although current evidence suggests that neutralizing TNF-alpha in type 2 diabetic subjects is not sufficient to cause metabolic improvement, it is still probable that TNF-alpha is a contributing factor in common metabolic disturbances such as insulin resistance and dyslipidemia.
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PMID:Potential role of TNF-alpha in the pathogenesis of insulin resistance and type 2 diabetes. 1087 50

Group B streptococci (GBS) are important pathogens in neonatal sepsis and pneumonia. GBS stimulate alveolar macrophages to produce inflammatory cytokines and free oxygen radicals, which can damage the lungs. In several studies, use of exogenous surfactant in term babies has improved outcome related to sepsis and respiratory failure. The role(s) of exogenous surfactant in modulating the inflammatory response produced by this microbe was examined. Tumor necrosis factor alpha (TNF-alpha) production and luminol-enhanced chemiluminescence (LCL), a measure of respiratory burst, were investigated. For measuring TNF-alpha release, RAW 264.7 murine macrophages were pre-incubated with bovine surfactant and stimulated with either lipopolysaccharide, live or heat-killed GBS type Ia. LCL was measured after macrophages were pre-incubated with or without surfactant overnight, then stimulated with GBS or phorbol myristate acetate. Lipopolysaccharide and GBS stimulated TNF-alpha secretion from macrophages that was suppressed by exogenous surfactant in a dose-dependent fashion. GBS and phorbol myristate acetate also increased LCL from macrophages, which was significantly suppressed by pre-incubation of macrophages with exogenous surfactant. We conclude that GBS type Ia stimulates TNF-alpha release and LCL from RAW 264.7 cells and that these responses are suppressed by surfactant. Suppression of inflammatory mediators by exogenous surfactant might improve respiratory disease associated with GBS.
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PMID:Immunomodulation by exogenous surfactant: effect on TNF-alpha secretion and luminol-enhanced chemiluminescence activity by murine macrophages stimulated with group B streptococci. 1133 43

Tumor necrosis factor alpha (TNF-alpha) is a critical mediator of myocardial dysfunction during acute inflammatory states. TNF-alpha is also present in the serum of patients with chronic cardiac diseases. In monocytes, TNF-alpha stimulates cells by activating distinct signaling pathways that involve nuclear translocation of NF kappa B. Since NF kappa B may also regulate the expression of genes that could contribute to myocardial dysfunction, the cardiomyocyte NF kappa B activation following acute or chronic TNF-alpha challenges was investigated. To accomplish this, the authors either acutely administered TNF-alpha to healthy mice, or used transgenic mice which chronically overexpress TNF-alpha exclusively in cardiac myocytes. Following acute administration of TNF-alpha, cardiac NF kappa B translocation was detected from 15 min to 2 h post-challenge. The time course of I kappa B alpha degradation was consistent with the kinetics of NF kappa B translocation. I kappa B beta degradation was slower and less dramatic. In transgenic mice chronically overexpressing TNF-alpha, myocardial NF kappa B activation was detected at all ages tested (21, 40, and 75 days). In contrast to acutely challenged animals, two distinct NF kappa B proteins were activated in chronically challenged animals, p50--65 heterodimers as well as p50 homodimers. Activation of both could be transiently blocked by administration of a recombinant chimeric TNF-alpha receptor antagonist (rhTNFR:Fc). I kappa B alpha, but not I kappa B beta, levels were elevated in transgenics when compared to wild-type animals. These data indicate that following acute TNF-alpha administration, which simulates bacterial sepsis, myocardial p50-p65 translocates within minutes. Chronic TNF-alpha exposure, which is thought to occur in long-standing congestive heart failure, results in translocation of transcriptionally inactive p50 homodimers in addition to transcriptionally active p50--65 heterodimers. It is speculated that activation of p50 homodimers constitutes an adaptive response to minimize the inflammatory consequences of chronic cardiac TNF-alpha exposure.
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PMID:Differential regulation of myocardial NF kappa B following acute or chronic TNF-alpha exposure. 1144 28

Clinical studies demonstrate a better outcome of sepsis in females. Elevated estrogen levels and plasma cytokine imbalance occur in septic patients. We propose that gender-different cytokine secretion by the peripheral blood mononuclear cells (PBMCs) in sepsis determines the clinical outcome. A 2 x 10(6) PBMC sample from healthy volunteers (10 males and 10 females) was incubated with 1 ng/mL of lipopolysaccharide (LPS), estradiol (E2; 0, 0.03, 0.3, 3.0, 30 ng/mL), or 1 ng/mL of LPS + E2 (0, 0.03, 0.3, 3.0, 30 ng/ml), and supernatant cytokine levels were measured. Tumor necrosis factor alpha (TNF alpha) and interleukin (IL)-6 production by PBMCs from both sexes was time-dependently stimulated by LPS. At 6 h after LPS challenge, the TNF alpha level of male PBMCs was significantly higher but IL-6 secretion by female PBMCs was higher (two-way ANOVA: P < 0.05). E2 alone stimulated cytokine secretion by male PBMCs. Addition of the same E2 concentration as in sepsis patients' plasma modulated LPS-induced cytokine production. No significant sex differences in LPS-stimulated TNF alpha or IL-6 secretion by PBMCs were found, but IL-10 secretion by male PBMCs was significantly suppressed. This study demonstrated a gender difference in PBMCs responsiveness to LPS and E2 stimulation and E2-modulated cytokine secretion. In this PBMCs model of sepsis, only the supernatant IL-10 level was significantly lower in males. These ex vivo findings may partially explain the mechanism underlying the poorer outcome of male sepsis patients.
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PMID:Gender differences in cytokine secretion by human peripheral blood mononuclear cells: role of estrogen in modulating LPS-induced cytokine secretion in an ex vivo septic model. 1169 70

Tumor necrosis factor alpha (TNFalpha) appears to be the main mediator causing the systemic manifestations of sepsis and septic shock associated with edema. In vitro it augments movement of permeability tracers across endothelial cell monolayers. Herein we describe a method which permits quantification and assessment of changes in the integrity of endothelial monolayers by measuring transendothelial flux (luminal to subluminal) of tracer macromolecules in the absence of hydrostatic and oncotic pressure gradients. The system consists of two compartments separated by a polycarbonate filter and permits highly controlled conditions.
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PMID:Assessment of TNFalpha-induced endothelial damage through the loss of its barrier function. 1506 37

Tumor necrosis factor alpha (TNF-alpha) blocking drugs improve therapy for rheumatic diseases, but the risk of additional immunosuppression and infection is unclear. We report on a patient with rheumatoid arthritis treated with etanercept for 2 years, in addition to methotrexate and prednyliden, who developed fulminant pneumococcal pneumonia with rapid progression to fatal acute respiratory distress syndrome (ARDS) and septic shock. In patients receiving anti-TNF-alpha therapy, especially in combination with corticosteroids, signs of pulmonary infection should be regarded as very serious, as fulminant pneumonia with ARDS and severe sepsis may develop within 24 h.
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PMID:Lethal acute respiratory distress syndrome during anti-TNF-alpha therapy for rheumatoid arthritis. 1620 Mar 83

Cardiopulmonary bypass (CPB) is associated with immune paresis, which predisposes to the development of postoperative sepsis. The aims of this study were to characterize the ex vivo cytokine responses to bacterial cell wall components in whole blood from patients undergoing CPB and to determine whether altered leukocyte expression of Toll-like receptors (TLRs) is involved in immune paresis after CPB. We recruited 6 patients undergoing routine cardiac surgery with CPB. Preoperatively, at the end of CPB and 20 h later, blood was obtained, anticoagulated, and leukocyte surface expression of CD14, TLR2, and TLR4 was quantified by flow cytometry. In addition, blood was incubated at 37 degrees C in the presence of peptidoglycan (PepG) and/or lipopolysaccharide (LPS), and plasma cytokines were measured by enzyme immunoassay. At the end of CPB, ex vivo production of tumor necrosis factor alpha, interleukin (IL) 1beta, IL-8, and IL-10 in response to PepG or LPS was virtually abolished (P < 0.05). The following day, there was recovery of all cytokine responses to PepG. Tumor necrosis factor alpha and IL-1beta responses to LPS partially recovered, whereas IL-8 and IL-10 responses recovered. At the end of CPB, there was more than 50% reduction in neutrophil TLR2 and TLR4 expression (P < 0.05), with recovery to baseline the following day. There was a 29% reduction in monocyte TLR4 expression at the end of CPB (P < 0.05) and more than 120% increase in monocyte TLR2 and 4 expression the following day (P < 0.05). In conclusion, reduced ex vivo production of cytokines cannot be fully accounted for by downregulation of TLR expression, although receptor upregulation may contribute to the later recovery of responsiveness.
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PMID:Alterations in inflammatory capacity and TLR expression on monocytes and neutrophils after cardiopulmonary bypass. 1743 50

Glutamine may have benefits during neonatal sepsis, but its effects on systemic inflammation are unknown. Our aim was to determine whether glutamine affects inflammation in neonatal endotoxemia. Eleven-day rat pups were given intraperitoneal injections of saline (control; C), endotoxin (300 microg/g Escherichia coli lipopolysaccharide) (E), saline with glutamine (2 mmol/g; G), or endotoxin with glutamine (EG). Animals were killed after 2 or 6 hours. Plasma glutamine (mmol/L) was measured enzymatically, and both tumor necrosis factor alpha (pg/mL) and interleukin 10 (IL-10) were measured by enzyme-linked immunosorbent assay. Results, expressed as mean +/- SEM, were analyzed by analysis of variance. Endotoxemia caused a rapid significant decrease in plasma glutamine at 2 hours (C, 0.73 +/- 0.06; E, 0.32 +/- 0.07; mean difference, 0.41 [95% confidence interval {CI, 0.17-0.64}]; P < .001), which was prevented by intraperitoneal glutamine (EG, 0.59 +/- 0.04; mean difference vs E, 0.27 mmol/L [95% CI, 0.03-0.50]; P < .05), indicating glutamine absorption, whereas CG animals had a plasma glutamine of 0.82 +/- 0.07. Tumor necrosis factor alpha was greatly increased by 2-hour endotoxemia (C, 27 +/- 7; E, 2247 +/- 43; mean difference, 2220 pg/mL [95% CI, 2012-2429]; P < .001), and this increase was partly prevented by glutamine (EG, 1991 +/- 91; P < .05 vs E; mean difference, 256; 95% CI, 47-465; P < .05). The effect of glutamine was more pronounced at 6 hours (C, 32 +/- 27; E, 799 +/- 193; EG, 219 +/- 75, C vs E mean difference, 767; 95% CI, 346-1188; P < .001; E vs EG mean difference, 580; 95% CI, 159-1001; P < .01). The IL-10 levels were also greatly increased by 2-hour endotoxemia (C = 55 +/- 21, E = 2429 +/- 58, EG = 1989 +/- 177; C vs E mean difference, 2374; 95% CI, 2740-2008; P < .001; E vs EG mean difference, 440; 95% CI, 74-807; P < .05). Glutamine administration partially prevents the sepsis-induced fall in plasma glutamine levels and reduces the concentration of both proinflammatory and antiinflammatory cytokines.
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PMID:Glutamine decreases inflammation in infant rat endotoxemia. 1930 52


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