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)

The role of tumor necrosis factor (TNF-alpha) in the pathogenesis of septic shock has been assessed by daily measurements of serum TNF-alpha levels in 60 patients admitted to the medical intensive care unit. All patients in the study had infectious disease and were at risk for the development of sepsis and septic shock. Sepsis was diagnosed in 34 patients, 24 of whom died (six within the first 24 hours). The 26 patients who did not evolve toward sepsis served as a control group. The clinical condition of all patients was monitored by daily APACHE II scoring. Blood was drawn once a day and additional samples were taken in patients whose clinical condition underwent sudden deterioration. TNF-alpha levels were measured with a commercially available immunoradiometric assay. At time of patient admission, TNF-alpha levels were higher in the group with sepsis than in the control group (median 79 iqr 329 vs median 0.5 iqr 5; p less than 0.001). In the group with sepsis, extremely high TNF-alpha levels were found in patients who died within 24 hours. These patients had TNF-alpha levels of 917 iqr 755 pg/ml, whereas the patients who died more than 24 hours after admission had TNF-alpha levels of 58 iqr 59 pg/ml. Survivors had lower TNF-alpha levels (26 iqr 347 pg/ml). APACHE II scores correlated with TNF-alpha levels in the total sepsis group (Spearman rank correlation coefficient 0.477; p less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Serum tumor necrosis factor levels in patients with infectious disease and septic shock. 237 91

Glucose utilization of different tissues was investigated in vivo by the 2-deoxyglucose tracer technique. After infusion of a non-lethal dose of recombinant human TNF-alpha (150 micrograms/kg) to rats, glucose utilization was increased by 80-100% in spleen, liver, kidney, by 60% in skin and by 30-40% in lung and ileum. The largest increase (150%) was observed in the diaphragm. There was no significant change in glucose utilization by skeletal muscles, testis and brain. These data show that TNF exerts metabolic effects on macrophage-rich tissues, and suggest that enhanced secretion of TNF may be one of the important factors in eliciting the metabolic changes in sepsis and endotoxicosis.
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PMID:Tumor necrosis factor increases in vivo glucose utilization of macrophage-rich tissues. 368 7

Cytokine-inducible nitric oxide (NO) production has been implicated in the pathogenesis of septic shock. The present study was designed to determine which cytokines induce expression of the NO synthase gene in rat aortic vascular smooth muscle cells (VSMC) in vitro and whether NO synthase gene expression is inducible in vivo. NO synthase mRNA appeared after 4-h exposure to interleukin-1 beta (IL-1 beta), and levels continued to increase up to 24 h. Levels of NO synthase transcripts were greatest in VSMC treated with IL-1 beta (1 nM), lower in VSMC treated with Escherichia coli lipopolysaccharide (LPS; 100 micrograms/ml), and just detectable in VSMC treated with tumor necrosis factor-alpha (TNF-alpha; 1 nM). IL-1 beta, TNF-alpha, and LPS each induced NO synthase activity, assessed by release of nitrite, conversion of L-arginine to L-citrulline, and increased levels of guanosine 3',5'-cyclic monophosphate, whereas IL-2, IL-6, and interferon-gamma were ineffective. IL-1 beta was more potent and effective than TNF-alpha; however, submaximal concentrations of TNF-alpha acted synergistically with IL-1 beta to induce NO synthase gene expression and activity. Inducible NO synthase mRNA was present in aorta from rats 6 h after treatment with LPS (5 mg/kg), but not at 24 h. Synergistic activation of NO synthase gene expression in VSMC by IL-1 beta and TNF-alpha may contribute to hypotension in sepsis.
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PMID:Interleukin-1 beta and tumor necrosis factor-alpha synergistically induce NO synthase in rat vascular smooth muscle cells. 751 63

The L-arginine:nitric oxide (NO) biosynthetic pathway has been proposed as an important mediator in host defense mechanisms and may therefore play a role in the acute allograft response. We have studied NO generation in liver allograft rejection and determined its value in immunological monitoring. Stable end products of this pathway have been determined serially in 50 primary liver recipients and compared with 2 known mediators and markers of acute allograft rejection (IL-2R positive lymphocytes and circulating TNF alpha). Plasma concentrations of acid-labile nitrosocompounds (NOx), which increased during acute allograft rejection (P < 0.0001), correlated with rejection severity and were reduced after administration of supplemental high dose glucocorticoids. Concentrations were significantly lower in nonrejection graft complications but were elevated during episodes of sepsis. Correlations between plasma NOx levels and circulating TNF-alpha (r = 0.451, P < 0.001) and IL-2R-positive lymphocytes in peripheral blood (r = 0.781, P < 0.001) were demonstrated. In a logistic analysis of these variables, plasma NOx was the most predictive parameter of an episode of acute cellular rejection. Nitric oxide generation in FK506-treated patients was lower compared with patients receiving a CsA-based immunosuppression regimen and was associated with a reduced frequency of acute rejection in the FK506 group. These data are consistent with a role for NO in the cellular alloantigen immune response and indicate that monitoring of plasma levels of NOx may be useful in the detection of acute allograft rejection.
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PMID:Nitric oxide generation. A predictive parameter of acute allograft rejection. 752 65

LPS has been implicated in the pathogenesis of Gram-negative bacterial sepsis. Despite intensive efforts to define the LPS-signal transduction pathway, CD14 is the sole molecule clearly demonstrated to possess signaling capabilities. However, it remains unclear whether CD14 is the only LPS-signaling molecule expressed in phagocytes and how CD14-mediated signaling occurs. Compound SDZ 280.961 is a synthetic triacylated amino acid that structurally resembles the reducing sugar moiety of lipid A. SDZ 280.961 effectively stimulated TNF-alpha release from human PBMC. Co-incubation of PBMC with the specific LPS inhibitor Rhodobacter sphaeroides lipid A inhibited SDZ 280.961-mediated stimulation of TNF-alpha release, indicating that this analogue signals mononuclear cells via a LPS-activated signaling pathway. Induction of TNF-alpha release from mononuclear cells by SDZ 280.961 was strongly dependent on the presence of serum and was enabled by the presence of purified LPS-binding protein, characteristics of CD14-mediated signaling. In contrast, SDZ 280.961-mediated signaling was not inhibited by blocking anti-CD14 mAbs. A Chinese hamster ovary fibroblast line transfected with human CD14, which responds to LPS in a manner qualitatively similar to that of macrophage cell lines, failed to respond to SDZ 280.961. Taken together, these data suggest that the lipid A analogue SDZ 280.961 activates monocytes via a unique LPS-signal transduction pathway that appears to be independent of CD14.
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PMID:Acyclic analogue of lipid A stimulates TNF-alpha and arachidonate release via a unique LPS-signaling pathway. 752 28

Inducible nitric oxide (NO) produced by macrophages is cytotoxic to invading organisms and has an important role in host defense. Recent studies have demonstrated inducible NO production within the heart, and that cytokine-induced NO mediates alterations in cardiac contractility, but the cytotoxic potential of nitric oxide with respect to the heart has not been defined. To evaluate the role of inducible nitric oxide synthase (iNOS) on cardiac myocyte cytotoxicity, we exposed adult rat cardiac myocytes to either cytokines alone or to activated J774 macrophages in coculture. Increased expression of both iNOS message and protein was seen in J774 macrophages treated with IFN gamma and LPS and cardiac myocytes treated with TNF-alpha, IL-1 beta, and IFN gamma. Increased NO synthesis was confirmed in both the coculture and isolated myocyte preparations by increased nitrite production. Increased NO synthesis was associated with a parallel increase in myocyte death as measured by CPK release into the culture medium as well as by loss of membrane integrity, visualized by trypan blue staining. Addition of the competitive NO synthase inhibitor L-NMMA to the culture medium prevented both the increased nitrite production and the cytotoxicity observed after cytokine treatment in both the isolated myocyte and the coculture experiments. Because transforming growth-factor beta modulates iNOS expression in other cell types, we evaluated its effects on cardiac myocyte iNOS expression and NO-mediated myocyte cytotoxicity. TGF-beta reduced expression of cardiac myocyte iNOS message and protein, reduced nitrite production, and reduced NO-mediated cytotoxicity in parallel. Taken together, these experiments show the cytotoxic potential of endogenous NO production within the heart, and suggest a role for TGF-beta or NO synthase antagonists to mute these lethal effects. These findings may help explain the cardiac response to sepsis or allograft rejection, as well as the progression of dilated cardiomyopathies of diverse etiologies.
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PMID:The lethal effects of cytokine-induced nitric oxide on cardiac myocytes are blocked by nitric oxide synthase antagonism or transforming growth factor beta. 753 89

After severe burns, a wound revision is often done to remove devitalized tissue and minimize bacterial growth. After such revision, the patient may show signs of sepsis. In a group of burned patients we found a transient endotoxemia, and a subsequent leukocyte activation, monitored as increased expression of the beta 2-integrin CD11b, after such wound revision. In most patients we could detect elevated levels of plasma TNF-alpha before the operation, with no increases in these levels after the operation. Plasma levels of IL-6 were elevated in all patients and increased after the wound revision in all patients. They also had elevated plasma levels of soluble E-selectin, indicating systemic inflammation. The close relation between endotoxin levels and CD11b expression, and lack of evidence for additional production of TNF-alpha, suggests that up-regulation of the beta 2 adhesion protein during wound revision is mainly caused by endotoxin interaction with the leukocyte.
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PMID:Transient endotoxemia during burn wound revision causes leukocyte beta 2 integrin up-regulation and cytokine release. 755 50

Previous reports have suggested that the endotoxin-resistant C3H/HeJ strain of mouse is more susceptible to infection than is the endotoxin-sensitive parent strain, C3H/HeN, although they have never been compared in an i.v. model of sepsis. We therefore have used these mouse strains in an i.v. model of Gram-negative sepsis to compare their sensitivities to infection, their cytokine responses, and the levels of induction of the enzyme nitric oxide synthase assayed in their livers. By using i.v. infection with Escherichia coli we have found that both strains are approximately equally sensitive to this organism, despite the C3H/HeJ mice having a markedly attenuated TNF-alpha response. IFN-gamma levels after infection were identical in the two strains; the levels of nitric oxide synthase induced in their livers were about fourfold greater in the C3H/HeJ mice. This difference could not be explained by differences in bacterial load. These experiments suggest that factors other than TNF-alpha are important in determining outcome from Gram-negative sepsis and that TNF-alpha is not a major factor in the induction of hepatic nitric oxide synthase after infection in vivo.
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PMID:Differences in cytokine response and induction of nitric oxide synthase in endotoxin-resistant and endotoxin-sensitive mice after intravenous gram-negative infection. 768 16

Thirteen patients (median age, 20 years) with life-threatening primary septic shock (10 meningococcal, 3 pneumococcal infections) were studied prospectively. All had a short history of sepsis (< or = 24 h) and no severe underlying disease. Two (15%) died. The logarithm of the initial plasma levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 beta, IL-6, IL-1 receptor antagonist (ra), and plasminogen activator inhibitor (PAI)-1 correlated significantly with APACHE II scores (r2 = .67, .57, .68, .81, and .68, respectively). The plasma levels of endotoxin, TNF-alpha, IL-1 beta, and PAI-1 decreased toward normal levels within the first 24 h of treatment, but IL-6 and IL-1ra levels remained high until clinical recovery. On admission, the molar excess of IL-1ra to IL-1 beta was > 2000-fold in 11 of the 13 patients. Acute plasmapheresis in 11 of the 13 patients significantly increased the plasma clearance of TNF-alpha (P = .02).
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PMID:Plasma levels of cytokines in primary septic shock in humans: correlation with disease severity. 779 35

Major trauma and consecutively associated infectious complications have a major impact on the mechanisms of the specific immune response and the nonspecific inflammatory reaction. The trauma-induced host defense abnormalities become strikingly evident with the analysis of cytokine synthesis patterns. The dissociation of cell-mediated immune responses following trauma is based upon an overrepresentation of suppressor-active monocytes and inadequate T-cell help in parallel. Corresponding dysregulation of cytokine production appears within many facets. Complement, endotoxin and antigen antibody complexes cause a massive activation of monocytes with an abnormal release of essential mediators, like PGE2, IL-1, IL-6, IL-8, TGF-beta and TNF-alpha. The regulation of cytokine synthesis under stressful conditions is differentially regulated for the individual mediators, either on a transcriptional or a posttranscriptional level. In our opinion, the endogenous provisions of the organism for survival following major injury are inadequate and from this hypothesis we derive the necessity for a substantial exogenous therapeutic intervention. The primary target of modern immunotherapy must be to inhibit the conversion of a systemic inflammatory reaction in immunocompromised patients towards a status of bacterial sepsis. Different approaches appear to be feasible to avoid the development of late multiorgan failure. These interventions have to be utilized preventively in a controlled manner as early as possible after trauma has occurred, and they must effectively protect different cell systems (lymphocytes, monocytes, PMNs and endothelial cells).
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PMID:[Immune mechanisms of post-traumatic hyperinflammation and sepsis]. 782 50


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