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)

Neutrophil (PMN) apoptosis regulates local and systemic inflammation during sepsis. Tumor necrosis factor receptor-associated factors (TRAFs) have been implicated as mediators of apoptosis; however, the signaling pathways for their production in stimulated PMN are unclear. We hypothesize that NF-kappaB translocation is necessary for the induction of TRAF-1 in PMNs with prolonged survival. Neutrophils were isolated from the blood of healthy volunteers by Ficoll gradient centrifugation and red blood cell sedimentation. Neutrophil NF-kappaB was inhibited with a proteasome inhibitor, PSI-I. Cells were treated with PSI-I (30 microM) or vehicle (DMSO 0.2%) for 50 min then incubated over an 18-h time course with LPS (10 to 1000 ng/mL), tumor necrosis factor alpha (TNFalpha) (2 to 20 ng/mL) or control media. In vitro apoptosis was quantified by propidium iodide FACS analysis. Total cellular TRAF-1 was detected by Western blot analysis of cell lysates. Steady state TRAF-1 mRNA was detected by RPA. NF-kappaB activity was determined by Western blot analysis for nuclear p65. Means and standard errors were calculated; data were analyzed by ANOVA. Lipopolysaccharide (LPS) and TNFalpha increased PMN nuclear p65 and steady state TRAF-1 mRNA. Apoptosis was inhibited by TNFalpha and LPS at 12 and 18 h (P < 0.01). Incubation of cells in the NF-kappaB inhibitor PSI-I blocked LPS and TNFalpha-induced inhibition of apoptosis (P < 0.05) and the induction of both nuclear p65 and TRAF-1 mRNA. These data demonstrate that inhibition of PMN apoptosis and TRAF-1 induction by LPS and TNFalpha is NF-kappaB dependent.
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PMID:Inhibited neutrophil apoptosis: proteasome dependent NF-kappaB translocation is required for TRAF-1 synthesis. 1102 45

Besides its central role in coagulatory pathways, thrombin is known to be a key mediator of macrophage and granulocyte activation in vitro. During recent years the concept of thrombin inhibition by the specific thrombin inhibitor, hirudin, has been established to treat septic disorders. Since basic mechanisms of sepsis include leukocyte/endothelial cell interaction and deterioration of capillary perfusion, we hypothesized that hirudin modulates leukocyte activation and microvascular injury. Severe endotoxemia was induced in Syrian hamsters by intravenous administration of endotoxin (lipopolysaccharide [LPS], E. coli, 2mg/kg) at 0 h. Hirudin (0.25 mg/kg/h) was substituted intravenously during the 4 h after the induction of endotoxemia (n = 7, hirudin). In control animals (n = 6, control) LPS was given without hirudin substitution. In skinfold chamber preparations leukocyte/endothelial cell interaction and functional capillary density (FCD, measure of capillary perfusion) were analyzed during a 24-h period after LPS injection using intravital fluorescence microscopy. Hirudin effectively normalized thromboplastin time and antithrombin activity when compared to controls (P < 0.05, ANOVA). However, hirudin did not attenuate LPS-induced arteriolar and venular leukocyte adherence, and even tended to increase leukocyte adherence after 24 h (P > 0.05, MANOVA). In parallel, addition of hirudin led to a significant deterioration of FCD over time when compared to controls (hirudin: baseline = 171 +/- 19 cm(-1) versus 16 +/- 9 at 24 h; control: baseline = 150 +/- 20 cm(-1) versus 62 +/- 18 at 24 h; P < 0.05). The fall in FCD in hirudin animals was associated with a significant increase of wet-to-dry weight ratios in lung, kidney, muscle, and small intestine (P < 0.05 versus control, ANOVA). Thus our study does not indicate a protective effect of hirudin on microcirculation during endotoxemia, despite an improvement of coagulatory parameters. This result may at least in part explain the lack of efficacy of hirudin on lethality during endotoxemia and sepsis.
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PMID:The thrombin antagonist hirudin fails to inhibit endotoxin-induced leukocyte/endothelial cell interaction and microvascular perfusion failure. 1109 85

The vascular endothelium has a central role in the control of microvascular tone, and it has been proposed that vascular endothelial damage occurs in septic shock, producing multiorgan failure. We have developed a method of detecting circulating endothelial cells (EC) that provides direct evidence of EC shedding in human sepsis. Human umbilical vein endothelial cells (HUVEC) were seeded in whole blood and recovered by isopycnic centrifugation to validate the technique. Blood samples were subsequently taken from 11 healthy volunteers, nine ventilated intensive care unit (ICU) control patients without sepsis, eight patients with sepsis but without shock, and 15 patients with septic shock. EC were identified by indirect immunofluorescence, using antibodies to von Willebrand factor (vWf) and the vascular endothelial growth factor receptor KDR. Mean HUVEC recovery was 86% for 20 to 100 seeded cells/ml of blood. vWf-positive EC counts per milliliter were significantly higher (analysis of variance [ANOVA], p < 0.0001) in patients with sepsis (16.1 +/- 2.7 [mean +/- SEM]) and septic shock (30.1 +/- 3.3) than in healthy (1.9 +/- 0.5) or ICU controls (2.6 +/- 0.6). KDR-positive EC counts per milliliter were also significantly higher (ANOVA, p < 0.0001) in patients with sepsis (4.2 +/- 1.1/ml) and septic shock (10.4 +/- 1.2/ml) than in healthy (0.7 +/- 0.3/ml) or ICU controls (0.5 +/- 0.2/ml). Cell counts made with anti-vWf antibody were consistently higher than those made with anti KDR antibody, but correlation between the two counts was high (r(2) = 0.93). The number of circulating KDR-positive EC was significantly higher in patients who died of septic shock than in survivors (12.0 +/- 1.6/ml versus 7.1 +/- 1.2/ml, p = 0.026). An increase in circulating EC can be identified during sepsis and septic shock. This supports the hypothesis that endothelial damage occurs in human sepsis.
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PMID:Circulating endothelial cells in patients with septic shock. 1120 46

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

Upon activation, polymorphonuclear leucocytes (PMN) release bactericidal/permeability-increasing protein, (BPI) from their azurophil granules. BPI selectively binds to the lipopolysaccharide (LPS) on gram-negative bacteria and induces their death. This study examined plasma BPI concentration levels in healthy newborns and in newborns with clinical sepsis, and the ability of PMN from preterm and term infants to release BPI. We also studied the release of myeloperoxidase (MPO), and the surface expression of adhesion molecule CD11b on PMN. In infants with clinical sepsis, plasma BPI concentration was higher, 27.8 microg/L [8.6-883; median (range)] (n = 11), than in healthy term infants 8.9 microg/L (3.9-179) (n = 17), and in adults 7.3 microg/L (0.7 -18.4) (n = 15); p = 0.014, Kruskal-Wallis. In preterm infants (n = 8), the ability of PMN to release BPI in vitro after stimulation with PMA was 8.8, in term infants it was 15.9 (n = 29; p > 0.05 vs. preterm infants) and in adults 23.4 ng/10(6) PMN (n = 15; p = 0.024 and p > 0.05 vs. preterm and term infants, respectively). The corresponding values of MPO were 20.0 ng/10(6) (11.3-46.7) in preterms, 19.0 ng/10(6) (2.2-223.7) in terms, and 27.8 ng/10(6) (9.1-80.7) in adults; p = 0.67 between groups. In infants with clinical sepsis, CD11b level was higher, 292 RFU (234-403) than the basal CD11b expression levels in healthy newborn infants, 116 RFU (76-145); P = 0.0001. FMLP-stimulated PMN CD11b expressions in preterm cord blood, 1071 RFU (552-1286) and in term cord blood, 918 (567-1472) were on the same level, but lower than that in adult blood, 1592 (973-1946); p < 0.001, ANOVA. Our findings suggest that in preterm infants the ability to release BPI is lower than in adults and term infants. These findings suggest that premature neonates have an impaired ability to mobilize BPI, possibly contributing to their marked susceptibility to infections with Gram-negative bacteria.
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PMID:Extracellular release of bactericidal/permeability-increasing protein in newborn infants. 1203 58

Adrenomedullin (AM) is a vasodilatory peptide hormone, playing a key role in the regulation of cardiovascular homeostasis. In view of the circulatory failure in sepsis, it is still debated as to whether the occurrence of vascular hyporeactivity against AM plays a causative or protective role. This study was designed as a prospective, controlled trial to elucidate the hemodynamic response following a titrating infusion of human AM in healthy and endotoxemic sheep. ANOVA demonstrated that AM infusion produced hypotension and tachycardia, and increased cardiac index in a dose-dependent manner, both in healthy and endotoxemic sheep. In addition, AM application reduced pulmonary vascular resistance index in ovine endotoxemia (P=0.02). These findings confirm that AM produces a hyperdynamic circulation, in the presence and absence of systemic inflammation. Further, exogenous AM could possibly be a useful adjunct in the common setting of sepsis-associated pulmonary hypertension.
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PMID:Hemodynamic effects of exogenous adrenomedullin in healthy and endotoxemic sheep. 1214 39

Procalcitonin (PCT) is one of the precursors in the synthesis of calcitonin in thyroidal C-cells and other neuroendocrine cells. PCT and other calcitonin precursors in serum are present at less than 50 pg/ml in healthy individuals, but are highly elevated in serum where conditions leading to systemic inflammatory response syndrome or sepsis prevail. We measured PCT concentrations in milk and serum samples taken from 9 healthy women after delivery. PCT concentrations were below 10 pg/ml in serum samples, but were more than 100 times as high in the corresponding milk samples. PCT in milk reached a maximum within the early days after delivery, with a median peak concentration of 2310 pg/ml (range 223 - 4224 pg/ml) at day one and 2442 pg/ml (range 952 - 4488 pg/ml) at day two, then declining over the next days to a median concentration of 747 pg/ml (range 443 - 1656 pg/ml) at day 10 (p = 0.012, by Friedman ANOVA). PCT values reached a steady state of 504 pg/ml median value. Mature calcitonin values measured in parallel with a specific assay were not above the normal range of 10 pg/ml in any samples measured. The strong discrepancy between serum and milk PCT suggests that PCT (but not mature calcitonin) is synthesised in the breast of healthy mothers after delivery. The precise mechanism and the physiological relevance are unclear. Since PCT levels increase drastically in serum from patients suffering from sepsis and related conditions, and since PCT has been ascribed a pro-inflammatory function, we propose that milk PCT might contribute to the activation of the developing neonatal immune system. Similar speculations were proposed for a variety of other pro-inflammatory cytokines, which had comparable kinetics in human milk.
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PMID:High concentrations of procalcitonin but not mature calcitonin in normal human milk. 1219 3

Sepsis is frequently associated with or complicates short-bowel syndrome (SBS). To investigate the effects of lipopolysaccharide (LPS) endotoxemia on enterocyte proliferation and death via apoptosis in a rat model of SBS, adult male Sprague-Dawley rats were divided into three experimental groups: sham rats underwent bowel transection and reanastomosis; SBS rats underwent 75% small-bowel resection; and SBS-LPS rats underwent 75% bowel resection and were given intraperitoneal injections of LPS 10 mg/kg. Parameters of intestinal adaptation (bowel and mucosal weights, mucosal DNA and protein, villus height, and crypt depth), enterocyte proliferation, and death via apoptosis were determined on day 15 after the operation. Statistical analysis was determined by Student's and ANOVA tests with a P less than 0.05 considered significant. SBS-LPS animals demonstrated a significant decrease (vs SBS rats) in duodenal (20%), jejunal (30%), and ileal (15%) overall weight, duodenal (20%), jejunal (27%), and ileal (18%) mucosal weight, jejunal (20%) and ileal (30%) mucosal DNA, jejunal (29%) and ileal (31%) villus height, and jejunal (14%) and ileal (29%) crypt depth. LPS endotoxemia led to reduced cell proliferation and enterocyte apoptosis compared to untreated SBS animals. Thus, in a rat model of SBS, LPS endotoxemia inhibits intestinal adaptation. A possible mechanism may be decreased cell proliferation. Decreased enterocyte loss via apoptosis may reflect a reduced number of enterocytes. Other mechanisms (necrosis) may be mainly responsible for cell death following LPS injection.
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PMID:Lipopolysaccharide endotoxemia reduces cell proliferation and decreases enterocyte apopotosis during intestinal adaptation in a rat model of short-bowel syndrome. 1247 77

Tissue factor (TF) initiates the extrinsic coagulation cascade on the surface of macrophages and endothelial cells. In septic patients, the extrinsic coagulation cascade is activated. When septic patients are febrile, mortality is decreased. The purpose of this study was to investigate the role of elevated temperatures on TF expression by endothelial cells during a sepsis-like challenge. Human endothelial vein cells (HUVECs) were incubated with lipopolysaccharide (LPS) or interleukin-1 beta (IL-1 beta) for 0, 2, 4, 6, or 8 h. At the 0-h time point, some HUVECs were heat shocked at 43 degrees C for 2 h and then recovered at 37 degrees C for 0, 2, 4, or 6 h. Heat-shocked and non-heat-shocked LPS-stimulated HUVECs were analyzed for TF-specific mRNA expression by ribonuclease protection assay (RPA), surface TF expression by flow cytometry, and TF activity by a two-stage clotting assay. Heat shocked LPS-stimulated HUVECs expressed significantly reduced TF-specific mRNA, TF surface protein levels, and TF surface activity when compared with non-heat-shocked, LPS-stimulated HUVECs (p < 0.0125, p < 0.0125, and p < 0.0001, respectively; repeated measures analysis of variance, ANOVA). If heat shock models elevated core temperature, these results suggest that fever may protect the host during sepsis by reducing TF activity on the surface of endothelial cells.
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PMID:The modulation of tissue factor by endothelial cells during heat shock. 1253 87

We investigated the effects of early and late sepsis on the actions of nondepolarizing neuromuscular blockers by using a rat sepsis model induced by cecal ligation and puncture. Isometric twitch tensions of nerve-hemidiaphragm preparations elicited by indirect (phrenic nerve) supramaximal stimulation at 0.1 Hz were evaluated. Rocuronium, pancuronium, and d-tubocurarine dose-dependently decreased the twitch tensions of the nonseptic, early septic, and late septic diaphragms (P < 0.01 each by analysis of variance [ANOVA]). Late sepsis shifted the concentration-twitch tension curves rightward from those of nonsepsis to larger degrees than did early sepsis, as indicated by increases in 50% inhibitory concentration (IC(50)) values (P < 0.01 each by ANOVA and P < 0.01 or 0.05 by the Scheffe F test). The standardized rightward shifts in early and late sepsis were largest for pancuronium, second largest for rocuronium, and smallest for d-tubocurarine (5.741, 2.979, and 1.660 times in late sepsis, respectively; P < 0.01 each by ANOVA and the Scheffe F test). Sepsis-induced increases in IC(50) values did not accompany the decreases in slopes. The results indicate that sepsis induces hyposensitivities to nondepolarizing neuromuscular blockers, the degree of which depends on the stage of sepsis and on the kind of neuromuscular blocker.
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PMID:Sepsis stage dependently and differentially attenuates the effects of nondepolarizing neuromuscular blockers on the rat diaphragm in vitro. 1572 74


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