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)

In this study, we hypothesized that tumor necrosis factor alpha (TNF alpha) is an important mediator of sepsis-related impairment in diaphragm contractility (1-2). In 12 anesthetized, ventilated dogs, bipolar stimulating electrodes were placed on the phrenic nerves and diaphragm electromyographic activity (EMG) and shortening were recorded with needle electrodes and piezoelectric crystals, respectively. Transdiaphragmatic pressure (Pdi) was also recorded using esophageal (Pes) and abdominal balloon catheters (Pdi = Pab-Pes). Dogs were randomized to receive saline injection (n = 6), or TNF alpha 60 micrograms/kg (n = 6). All parameters were recorded hourly for 6 h. Mean arterial blood pressure decreased 1 h after infusion in TNF alpha animals (p < 0.05) with no significant change thereafter. Cardiac output increased early after TNF alpha infusion (p < 0.05) and remained at greater than baseline values at study termination. Diaphragm pressure generation and costal shortening decreased progressively from 3 to 6 h post TNF alpha infusion (p < 0.05) with no significant change in control animals. Compound diaphragm action potential in response to supramaximal phrenic stimulation decreased in TNF alpha animals (p < 0.01) with no significant change in control animals 3 and 6 h postinfusion. We conclude that TNF alpha infusion was associated with significant declines in isotonic and quasi-isometric diaphragm contraction and that this could be explained, at least in part, by impaired neuromuscular transmission.
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PMID:Tumor necrosis factor alpha decreases in vivo diaphragm contractility in dogs. 795 66

This study explored the relationship between cytokines (TNF, IL-1, IL-6), coagulation and fibrinolytic factors in the early stage of sepsis syndrome and the relation between these factors with the severity of inflammatory illness as measured by the Simplified Acute Physiology Score (SAPS). Twenty-one normal controls were compared to 34 patients divided into three categories ranging from uncomplicated postoperative patients, to patients with severe infectious conditions including septic shock. A major hemostatic imbalance was demonstrated with particularly marked reduction in fibrinolytic activity [drop of antithrombin III (ATIII) and protein C with an increase of plasminogen activator inhibitor (PAI-1) levels] which were directly correlated with the severity of the inflammatory state. Both ATIII and PAI-1 levels were correlated with the levels of TNF and IL-6 and the severity of illness as measured by SAPS. We established an index, ATIII/PAI-1 antigen that is significantly different among the four groups (p < 0.001) and strongly correlated with the SAPS (p < 0.001). As PAI-1 could be secreted not only by TNF activating endothelial cells but also by hepatocytes activated by insulinemia, treatment of sepsis with cytokine-specific agents might be of limited effect.
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PMID:Coagulation/fibrinolysis balance in septic shock related to cytokines and clinical state. 795 54

The aim of this study was to compare the ability of both a 55- and 75-kD soluble tumor necrosis factor receptor immunoglobulin G fusion protein (sTNFR-IgG) in protecting against death in a murine model of gram-negative sepsis. Pretreatment with 250 micrograms of the p75 construct delayed but did not avert death in this model, reducing peak bioactive TNF-alpha levels after infection from 76.4 ng ml-1 in control mice to 4.7 ng ml-1 in the treated group (p < 0.05, two-sample t test). However, these low levels of bioactive TNF-alpha persisted in the p75 fusion protein-treated animals compared with the controls and were sufficient to mediate delayed death. In contrast, pretreatment with 200 micrograms of the p55 sTNFR-IgG gave excellent protection against death with complete neutralization of circulating TNF. Studies of the binding of TNF-alpha with the soluble TNFR fusion proteins showed that the p75 fusion construct exchanges bound TNF-alpha about 50-100-fold faster than the p55 fusion protein. Thus, although both fusion proteins in equilibrium bind TNF-alpha with high affinity, the TNF-alpha p55 fusion protein complex is kinetically more stable than the p75 fusion construct, which thus acts as a TNF carrier. The persistent release of TNF-alpha from the p75 fusion construct limits its therapeutic effect in this model of sepsis.
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PMID:Protective effect of 55- but not 75-kD soluble tumor necrosis factor receptor-immunoglobulin G fusion proteins in an animal model of gram-negative sepsis. 796 92

Mild infection or sublethal dose of endotoxin elicits a brief elevation of GH and PRL in the serum. These hormones have proinflammatory and immunostimulatory effect. In severe trauma, sepsis and shock, GH and PRL are suppressed, whereas glucocorticoids and catecholamines are elevated. Under these conditions an acute phase response is initiated by tissue derived (cytokine) hormones, namely IL-1, IL-6, TNF alpha, and several others, which elicit a neuroendocrine response and initiate major metabolic alterations. There is fever and catabolism prevails, whereas the synthesis of acute phase proteins in the liver, cell proliferation in the bone marrow, and protein synthesis by leukocytes is elevated. This is an emergency reaction to save the organism after the local immune/inflammatory response has failed to contain and eliminate the infectious agent. During sepsis and endotoxin shock the systemic activation of the complement system and of leukocytes releasing enzymes and highly toxic cytokines seriously threaten survival. Glucocorticoids suppress proinflammatory cytokine production and potentiate the secretion of acute phase proteins. Some of these proteins, such as C reactive protein, or LPS binding protein, are designed to combine with microorganisms and trigger their destruction by the activation of complement system and of phagocytes. The increased production of some complement components also helps host resistance. The rise in serum fibrinogen promotes blood clotting which can serve to isolate the invading agent by triggering thrombosis in infected tissues. A number of enzyme inhibitors are produced as acute phase proteins, which are likely to serve to curb the nonspecific damage inflicted by enzymes released from activated phagocytes and from damaged cells into the circulation during sepsis and shock. Catecholamines are also elevated, which serve to inhibit inflammatory responses and to promote, even initiate, the acute phase response. If the acute phase reaction fails to protect the host, shock will develop. Patients with subclinical adrenal insufficiency succumb to septic shock almost invariably if glucocorticoid therapy is not given. However, glucocorticoid treatment of septic patients with normal adrenal function has not been helpful. The use of antibiotics to control infection did not lead to spectacular success either because of the emergence of resistant bacterial strains or the enhanced release of endotoxin by this therapy. The new approaches to prevent and treat septic shock involve the use of antibodies capable of neutralizing LPS and of cytokines and the inhibition of cytokine action by antagonist agents.
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PMID:Neuroendocrine defence in endotoxin shock (a review). 797 6

Biomaterials in the peritoneal cavity disrupt the physiology of the host and may cause bacterial translocation. The current study was performed to determine whether biomaterials exacerbate intra-abdominal infections. Adult male rats were divided into four groups: group 1, celiotomy+intraperitoneal (i.p.) saline; group 2, celiotomy+i.p. Escherichia coli (3 x 10(8) cfu); group 3, i.p. rubber+i.p. saline; and group 4, i.p. rubber+i.p. E. coli (3 x 10(8) cfu). Twelve h after the challenge, enteric bacterial translocation, bacterial population levels in the cecum and serum levels of IL-6 and TNF were measured. Bacterial translocation to mesenteric lymph nodes and the liver was observed in animals from groups 2 and 3, but significantly increased in group 4 with a concomitant elevation of serum levels of TNF and IL-6, as compared with group 1. Histological examination revealed a more pronounced inflammatory reaction in the peritoneum and distal ileum in group 4 than in groups 2 and 3. These results suggest that the presence of rubbers in the peritoneal cavity aggravates intra-abdominal sepsis.
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PMID:Abdominal rubber drain piece aggravates intra-abdominal sepsis in the rat. 798 41

In experimental animals, injection of gram-negative endotoxin (LPS) decreases hepatic cytochrome P450-mediated drug metabolism. To evaluate this phenomenon in a human model of gram-negative sepsis, LPS was administered on two consecutive days to healthy male volunteers during which time a cocktail of antipyrine (AP-250 mg), hexobarbital (HB-500 mg), and theophylline (TH-150 mg) was ingested and the apparent oral clearance of each drug determined. Each subject had a control drug clearance study with saline injections. In the first experiment, six subjects received the drug cocktail 0.5 h after the first dose of LPS. In the second experiment, another six subjects received the drug cocktail 0.5 h after the second dose of LPS. In both experiments, LPS caused the expected physiologic responses of inflammation including fever with increases in serum concentrations of TNF alpha, IL-1 beta, IL-6, and acute phase reactants. In the first experiment, only minor decreases in clearances of the probe drugs were observed (7-12%). However in the second experiment, marked decreases in the clearances of AP (35, 95% CI 18-48%), HB (27, 95% CI 14-34%), and TH (22, 95% CI 12-32%) were seen. The decreases in AP clearance correlated with initial peak values of TNF alpha (r = 0.82) and IL-6 (r = 0.86). These data show that in humans the inflammatory response to even a very low dose of LPS significantly decreases hepatic cytochrome P450-mediated drug metabolism and this effect evolves over a 24-h period. It is likely that septic patients with much higher exposures to LPS have more profound inhibition of drug metabolism.
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PMID:Endotoxin administration to humans inhibits hepatic cytochrome P450-mediated drug metabolism. 798 76

Two types of cellular IL-1Rs have been characterized and cloned from both human and murine sources. The type II IL-1R has a very short cytoplasmic domain and does not seem to participate in IL-1 signaling. We demonstrate that type II IL-1Rs are released from the surface of neutrophils in response to treatment with TNF or endotoxin. In addition, serum from patients with sepsis syndrome contains elevated levels of soluble type II IL-1Rs. Neutrophils isolated from patients with sepsis have greatly enhanced expression of type II IL-1R mRNA and cell surface receptors and are therefore a likely source for the shed receptors in serum. Of the three forms of IL-1, soluble type II IL-1R binds IL-1 beta with highest affinity and also selectively inhibits IL-1 beta activity. We propose that increased cell surface expression and rapid release of preformed type II IL-1R from neutrophils, as a soluble IL-1 beta binding protein, represents a mechanism that has evolved for regulating IL-1 activity in sepsis.
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PMID:Elevated levels of shed type II IL-1 receptor in sepsis. Potential role for type II receptor in regulation of IL-1 responses. 798 76

We hypothesized that treatment of experimental sepsis with bactericidal antibiotics, known to enhance microbial toxin release, would alter tumor necrosis factor-alpha production and the hemodynamic response to the syndrome. In the rat, after cecal ligation and puncture (CLP), elevated serum TNF levels and cardiac output were observed following antibiotic treatment. TNF and cardiac output were elevated to a greater extent in bactericidal-treated than bacteriostatic-treated or antibiotic-untreated rats. Animals treated with bactericidal antibiotics also had significantly greater cardiac outputs than untreated rats. Despite increases in circulating TNF with antibiotic administration, the mortality rate at 96 hr decreased after either bactericidal or bacteriostatic antibiotics. We conclude that elevated TNF after CLP in rats treated with antibiotics is associated with enhanced hemodynamic responses to CLP, but does not increase early mortality. In this model of polymicrobial sepsis, bactericidal and bacteriostatic antibiotics led to different hemodynamic effects without compromising survival.
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PMID:Bactericidal antibiotics increase tumor necrosis factor-alpha and cardiac output in rats after cecal ligation and puncture. 801 63

Conflicting reports concerning the hepatic effects of interleukin-1 beta (IL-1 beta) and tumor necrosis factor alpha (TNF alpha) in the metabolic response to injury led us to investigate the influence of physiological concentrations of these cytokines on amino acid metabolism in the isolated perfused rat liver. IL-1 beta was ineffective at a concentration of 1 ng/mL, whereas TNF alpha (0.7 ng/mL) reduced the uptake of some of the main gluconeogenic amino acids (alanine, -55.3 +/- 4.9 v -72.9 +/- 13.7 nmol.min-1.g-1 in controls, P < .05) without affecting urea synthesis. TNF alpha increased glucose uptake by 237% and inhibited that of free fatty acids (-1.6 +/- 1.4 v -9.9 +/- 6.7 nmol.min-1.g-1 in controls, P < .05). IL-1 beta and TNF alpha potentiated glucagon-induced total amino acid uptake by 56% and 87%, respectively. They also affected glucagon-activated gluconeogenesis, leading to an initial potentiation of glucose release. Thereafter, IL-1 beta inhibited glucagon action, leading to an hepatic uptake of glucose. These results indicate that (1) in the conditions of the study, IL-1 beta has no direct effect on hepatic amino acid exchanges and utilization; (2) TNF alpha which exerted an inhibitory effect on these parameters, could be involved in the reduced amino acid exchanges during the end stage of sepsis; (3) the TNF alpha-induced increase in glucose uptake could be related to an inhibition of gluconeogenesis and/or to the activation of glucose utilization by Kupffer cells; (4) IL-1 beta and TNF alpha both potentiate the action of glucagon on hepatic amino acid uptake and utilization; and (5) complex interactions between Kupffer cells and hepatocytes on the one hand and between cytokines and hormones on the other hand could account for the differences in hepatic metabolism according to the stage of the response to injury.
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PMID:Independent and combined actions of interleukin-1 beta, tumor necrosis factor alpha, and glucagon on amino acid metabolism in the isolated perfused rat liver. 802 4

Tumor necrosis factor (TNF alpha), both by direct action and by trafficking cells of the immune system, is implicated in cardiopulmonary derangements and PMN-mediated microvascular injury associated with gram-negative sepsis. We examined the effects of pretreatment with a monoclonal antibody to TNF alpha on PMN function, hemodynamic derangements, and alveolar capillary membrane damage in a septic porcine model. Anti-TNF alpha profoundly improved hemodynamic consequences in this model. Reduction in PMN CD11/18 receptor expression, lung myeloperoxidase activity, and attenuation of peripheral neutropenia (all P < 0.05) indicate that pretreatment significantly reduced lung sequestration of PMNs seen in septic controls. In contrast, PMN oxygen radical (O2-) generation was not significantly different from unprotected septic animals. Despite the presence of circulating PMNs primed for O2- burst, alveolar capillary membrane damage, assessed by bronchoalveolar lavage protein content and arterial PO2 was markedly attenuated in the treatment group (P < 0.05). We conclude that anti-TNF alpha suppresses systemic hemodynamic actions of TNF alpha. Further, it prevents upregulation of PMN adhesion receptors inhibiting PMN/endothelial cell interaction. This prevents formation of a "microenvironment," protected from circulating oxidant scavengers, into which sepsis-activated PMNs release their toxic products. Pretreatment with anti-TNF alpha monoclonal antibody thus affords global protection in porcine Gram-negative sepsis.
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PMID:Tumor necrosis factor-alpha blockade prevents neutrophil CD18 receptor upregulation and attenuates acute lung injury in porcine sepsis without inhibition of neutrophil oxygen radical generation. 809 6


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