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)

Attempts to augment immune function in infants or children with overwhelming sepsis or immune deficiency have focused on recombinant cytokines and interferons. Although early in their clinical use, the proinflammatory and antiinflammatory effects of the interleukins show promise in regulating the acute inflammatory response. The hematopoietic growth factors have demonstrated considerable clinical effect, especially in individuals with distinct hematopoietic disorders and in patients receiving immunosuppressive chemotherapy. The interferons gamma and alpha have received considerable attention over the last decade as potential immunomodulators. The stimulatory effects of INF-gamma on human neutrophils suggest its therapeutic usefulness in children with specific neutrophil dysfunction, and INF-alpha has shown broad clinical application both as an antitumor as well as an antiviral agent. The most recent studies of the integrins and selectins implicate their potential role in regulating a number of infectious disease states. As we learn more about the complexity of interactions and the delicate balance these molecules have in regulating the immune response, we will be better able to implement their use in regulating disease states in infants and children.
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PMID:Immunomodifiers applicable to the prevention and management of infectious diseases in children. 812 25

Patients with advanced cancer and cachexia typically demonstrate modestly increased rates of energy expenditure in the presence of diminished food intake due to anorexia and to gastrointestinal disturbances. Rates of glucose production by the liver, gluconeogenesis and glycolysis to lactate (Cori cycle) are increased, fat mobilisation and oxidation are accelerated. There is a redistribution of body proteins away from muscle towards visceral proteins, resulting in marked muscle protein loss. Cancer cachexia differs from simple starvation and demonstrates metabolic similarities to sepsis or polytrauma. The metabolic response in the patient with cancer is largely due to mediators released by the tumour or by the host; recently the role of cytokines such as tumour necrosis factor alpha (TNF alpha), interleukin-1 (IL-1) and -6 (IL-6) and interferon gamma (INF gamma) has been emphasized. Catabolic hormones such as glucocorticoids and adrenaline have also been implicated. Cytokines have the potential to reproduce experimentally the clinical syndrome of cancer cachexia. There is evidence of increased production of several of them in certain types of cancer. There are overlapping activities of the cytokines TNF alpha, IL-1, IFN gamma and IL-6. The contribution of each of them to cancer cachexia remains unclear. Inhibition of cytokine activity using specific antibodies in cancer-bearing experimental animals demonstrated partial prevention of cachexia. A positive feedback between macrophage-derived IL-1 and tumour-derived IL-6 has been demonstrated recently in experimental cancer cachexia. Cytokines may support tumour growth by acting as growth factors.
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PMID:Pathophysiology of cancer cachexia. 815 43

Sepsis induces metabolic disorders that include loss of body weight, muscle wasting, and acute-phase protein synthesis in liver. Cytokines are generally recognized as active mediators of these disorders, and the implication of tumor necrosis factor (TNF) has been frequently discussed in the recent past. However, the identity of the active agent in alterations of protein metabolism is still controversial. To improve our understanding of the role of cytokines in mediating muscle wasting observed in sepsis, we investigated muscle and liver protein metabolism in the following three groups of rats: infected control rats (INF-C); infected rats pretreated with pentoxifylline (PTX-INF), which is a potent inhibitor of TNF secretion; and pair-fed rats for the PTX-INF group pretreated with pentoxifylline. Pentoxifylline nearly completely suppressed TNF secretion but did not influence the transient fall in rectal temperature, the decreased hematocrit, and the increased liver protein mass and synthesis observed in INF-C rats. Pentoxifylline decreased the anorexia, the loss of body weight and muscle protein observed in INF-C animals, and partially prevented the decrease in muscle protein synthesis induced by infection. The overall data indicate that pentoxifylline is an effective agent in mitigating the characteristic muscle protein wasting induced by sepsis and confirm the limited role of TNF in the mediation of the acute-phase protein synthesis. Our results suggest a probable implication of TNF in the regulation of protein balance in muscle but do not allow discarding possible implication of other mediators that would be inhibited by pentoxifylline.
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PMID:Pentoxifylline decreases body weight loss and muscle protein wasting characteristics of sepsis. 823 42

The inducible nitric oxide synthase (iNOS) gene is expressed by hepatocytes in a number of physiologic and pathophysiologic conditions affecting the liver including septic and hemorrhagic shock. The molecular regulation of iNOS expression is complex and occurs at multiple levels in the gene expression pathway. The cytokines TNF-alpha, IL-1beta, and INF-gamma synergistically activate iNOS expression in the liver, and the human iNOS gene was first cloned from cytokine-stimulated hepatocytes. iNOS expression requires the transcription factor NF-kappaB and is down-regulated by steroids, TGF-beta, the heat shock response, p53, and nitric oxide (NO) itself. In vivo, hepatic iNOS induction is differentially regulated from the typical acute-phase reactants and is not expressed as a mandatory component of the acute phase response. Thus, numerous mechanisms have evolved to regulate iNOS expression during hepatocellular injury. Studies of the effects of NO in the liver demonstrate that induced NO synthesis plays an important role in hepatocyte function and protects the liver during sepsis and ischemia reperfusion. Its cytoprotective role is best exemplified in a rodent model of endotoxemia. Here the addition of the nonspecific NOS inhibitors significantly increased hepatic damage. NO exerts a protective effect through its ability to prevent intravascular thrombosis by inhibiting platelet adhesion and neutralizing toxic oxygen radicals. NO also exerts a protective effects both in vivo and in vitro by blocking TNF-alpha-induced apoptosis and hepatotoxicity, in part by a thiol-dependent inhibition of caspase-3-like protease activity. These studies demonstrate the cytoprotective effects of NO in the liver and suggest hepatic iNOS expression functions as an adaptive response to minimize inflammatory injury. In addition, NO has anti-tumor effects as well as known mutagenic effects, is involved in the systemic vasodilatation of cirrhosis, and has potent antimicrobial properties.
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PMID:Inducible nitric oxide synthase in the liver: regulation and function. 972 29

Innate immunity not only mediates early host defenses to infection, but also contributes to septic hemodynamic compromise through nitric oxide synthase (NOS2) induction and inhibition of cardiovascular adrenergic responses. Because of increased age-related susceptibility to sepsis, we hypothesized that hearts from old (28-29 months) adult rats would exhibit greater beta-adrenergic hyporesponsiveness than young (6-8 months) following lipopolysaccharide (LPS, 6 mg/kg) with and without interferon gamma (INF-gamma, 5000 units). LPS/INF-gamma depressed baseline +dP/dt and isoproterenol-stimulated inotropy in both old and young hearts. beta-adrenergic inotropic (+dP/dt) and lusitropic responses were more depressed in old v young LPS/INF-gamma hearts. Additionally isoproterenol-stimulated cAMP elaboration was less in old (1950+/-160 fmol/min/g) v young (2440+/-170 fmol/min/g, P=0.05) LPS/INF-gamma hearts. LPS alone also depressed basal +dP/dt and prolonged myocardial relaxation in old and young hearts, but suppressed isoproterenol +dP/dt responses only in old hearts. Depressed beta-adrenergic inotropic responses were augmented with the selective NOS2 inhibitor N-iminoethyl-L-lysine. To establish biochemical mechanisms for this, we tested whether induction of NOS2 and innate immune system receptors (CD14 and Toll-like receptor 4, TLR4) were enhanced in old v young hearts. Induction of myocardial NOS2 and CD14 (not present in control) by LPS/INF-gamma was approximately 2-3-fold greater in old compared to young animals. TLR4 was constitutively expressed in old and young hearts and was unaffected by LPS/INF-gamma. These findings indicate that advanced age is associated with augmented cardiac beta-adrenergic depression and enhanced CD14-NOS2 signaling in response to cytokines. Upregulation of cardiovascular innate immunity may have clinical implications for increased mortality in older individuals with systemic inflammatory response syndromes.
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PMID:Augmented age-associated innate immune responses contribute to negative inotropic and lusitropic effects of lipopolysaccharide and interferon gamma. 1160 26

We hypothesized that the dietary threonine demand for the anabolic response may be increased more than that of other essential amino acids during sepsis. Using a flooding dose of either L-[1 -13C]valine or L-[U -13C]threonine, we measured valine and threonine utilization for syntheses of plasma proteins (minus albumin), and wall, mucosal, and mucin proteins of the small intestine in infected (INF; d 2 and d 6 of postinfection) and control pair-fed (PF) rats. At d 2, the protein absolute synthesis rate (ASR) of INF rats was 21% (mucins) to 41% (intestinal wall) greater than that of PF when measured using valine as tracer, and 45% (mucosa) to 113% (mucins) greater than that of PF when measured with threonine as tracer. Plasma protein ASR was higher in INF than in PF rats, reaching 5- to 6-fold the value of PF. The utilization of both amino acid tracers for the protein synthesis was significantly increased by the infection in all compartments studied. The daily increased absolute threonine utilization for protein synthesis in gut wall plus plasma proteins was 446 micromol/d compared with 365 micromol/d for valine, and it represented 2.6 times the dietary threonine intake of rats at d 2. Most changes in protein ASR and threonine utilization observed at d 6 of postinfection were limited. In conclusion, sepsis increased the utilization of threonine for the anabolic splanchnic response. Because this threonine requirement is likely covered by muscle protein mobilization, increasing the threonine dietary supply would be an effective early nutritional management for patients with sepsis.
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PMID:Threonine utilization for synthesis of acute phase proteins, intestinal proteins, and mucins is increased during sepsis in rats. 1758 34

Spontaneous remission of acute myeloid leukaemia (AML) is extremely rare and usually of short duration. We report two patients with documented AML who developed spontaneous remission of their leukaemia shortly after an episode of severe sepsis and respiratory failure requiring mechanical ventilation. The underlying mechanisms of spontaneous remission remain unclear but an association with preceding blood transfusions and severe systemic infections has been reported. An overwhelming immune response due to sepsis and leading to raised levels of TNF-alpha, INF-gamma, IL -2 and an increased activity of NK cells, cytotoxic T-cells and macrophages are thought to play an important role. Better insights into the mechanisms of spontaneous remission of AML after recovery from sepsis could help in developing new therapies for AML.
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PMID:Spontaneous remission of acute myeloid leukaemia after recovery from sepsis. 1765 12

The relative role of complement and CD14 in E. coli-induced cytokine synthesis in an in vitro human whole blood model of sepsis was examined. Fresh lepirudin-anticoagulated whole blood was incubated with E. coli for 2h. Monoclonal antibodies or a C5a receptor antagonist were used to block complement. Inflammatory mediators (n=27) were measured by multiplex technology, selected cytokine mRNA by real time PCR, and CD11b, oxidative burst and phagocytosis by flow cytometry. E. coli significantly increased 18 of the 27 inflammatory mediators, including proinflammatory cytokines (TNF-alpha, IL-6, INF-gamma and IL-1beta), chemokines (IL-8, MCP-1, MIP-1alpha, MIP-1beta, eotaxin and IP-10), growth factors (VEGF, FGF-basic, G-CSF and GM-CSF) and other interleukins (IL-9, IL-15 and IL-17). Notably, the increases in all mediators were abolished by a combined inhibition of CD14 and complement using anti-C2 and anti-factor D in combination, whereas the relative effect of the inhibition of complement and CD14 varied. In comparison, a C5a receptor antagonist and anti-CD14 in combination reduced cytokine synthesis less efficiently. Real time PCR analysis confirmed that the cytokine synthesis was blocked at the mRNA level. Similarly, E. coli-induced CD11b up-regulation, oxidative burst and phagocytosis was totally inhibited by CD14, anti-C2 and anti-factor D in combination after 2h incubation. In conclusion, the combined inhibition of complement using anti-C2, anti-factor D and CD14 almost completely inhibits the E. coli-induced inflammatory response. The combined approach may therefore be a new treatment regimen in Gram-negative sepsis.
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PMID:Combined inhibition of complement and CD14 abolish E. coli-induced cytokine-, chemokine- and growth factor-synthesis in human whole blood. 1860 53

We evaluated the role of IL-1 during Pseudomonas aeruginosa bacteremia by intravenously injecting P. aeruginosa strain D4 into IL-1-deficient and WT mice. The two strains showed equivalent mortality rates. However, when the mice were pretreated with cyclophosphamide, bacteremia-induced mortality was significantly greater in the IL-1-deficient mice than in the WT mice (P < 0.01). We then investigated the role of neutrophils and macrophages in protecting IL-1-deficient mice from bacteremia by administering anti-Gr-1 antibody or liposomes containing dichloromethylene diphosphonate, respectively. After P. aeruginosa inoculation survival was significantly lower in the macrophage-depleted IL-1-deficient mice than in the WT mice. In contrast, neutrophil depletion did not have this effect. Compared to the macrophage-depleted WT mice, the macrophage-depleted IL-1-deficient bacteremic mice had higher bacterial counts in various organs 48 and 72 hr post-infection. They also had lower TNF-alpha, IL-6, and INF-gamma concentrations in their livers during the early phase of sepsis. Thus, IL-1 deficiency becomes disadvantageous during P. aeruginosa bacteremia when it is accompanied by immunosuppression, particularly when macrophage functions are seriously impaired.
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PMID:Interleukin-1 deficiency in combination with macrophage depletion increases susceptibility to Pseudomonas aeruginosa bacteremia. 1970 44

The purpose of this study was to assess lipopolysaccharide (LPS)-stimulated cytokine production in the presence of linezolid (LZD) in comparison with the drug effect on the plasma endotoxin level. Peripheral venous whole-blood samples collected from five healthy subjects were stimulated with 10 microg/ml of LPS. LZD was then added to the LPS-stimulated blood samples at concentrations of 0, 2, 4, and 15 microg/ml , followed by incubation for 24 h at 37 degrees C in a 5% CO(2)-95% air atmosphere. Supernatants of the resultant cultures were assayed to determine the levels of tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, interleukin (IL)-10, monocyte chemoattractant protein (MCP)-1, and endotoxin. Significant decreases in the levels of TNF-alpha and IFN-gamma were observed in the LZD 2, 4, and 15 microg/ml groups as compared with that in the 0 microg/ml group (Dunnett's procedure; P < 0.05). The level of IL-10 tended to increase irrespective of the LZD concentration; however, no significant intergroup differences were observed [analysis of variance (ANOVA); P = 0.68]. No significant decrease of the endotoxin level was observed in the LZD 2, 4, or 15 microg/ml groups as compared with that in the 0 microg/ml group, with no significant intergroup differences (ANOVA; P = 0.83). No change in the MCP-1 levels was observed irrespective of the LZD concentration (ANOVA; P = 0.82). To conclude: (1) it appears possible that LZD inhibits the production of INF-gamma and TNF-alpha to a limited extent; (2) LZD did not exert any inhibitory effect on endotoxin production by bacteria, while suppressing cytokine production. The results indicate that LZD may have a significant role in saving the lives of patients with sepsis.
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PMID:Effect of linezolid on cytokine production capacity and plasma endotoxin levels in response to lipopolysaccharide stimulation of whole blood. 2009 52


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