Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endotoxin-induced intercellular adhesion molecule-1 (ICAM-1) and interleukin 8 (IL-8) production in endothelial cells, which is mediated by Toll-receptor signaling, is essential for optimal neutrophil recruitment and migration during sepsis. Endotoxin also causes stress fiber polymerization that has recently been shown to affect intracellular signaling. However, the role of this polymerization process on endothelial-induced neutrophil adhesion and migration is unknown. Human umbilical vein endothelial cells (HUVEC) were stimulated with lipopolysaccharide (LPS). Selected cells were pretreated with cytochalasin D (CD) or lactrunculin A (LA), agents that disrupt actin polymerization. Cellular protein was extracted and analyzed by Westem blot for the phosphorylated form of IL-1-associated kinase (IRAK) and production of ICAM-1. Extracted nuclear protein was analyzed by Western blot and electrophoretic mobility shift assay (EMSA) for nuclear translocation and activity of NF-kappaB. IL-8 production was determined by enzyme-linked immunoabsorbant assay (ELISA). Neutrophil adhesion was assayed fluorometrically using calcein-AM-labeled neutrophils on treated endothelial cells. LPS treatment led to phosphorylation of IRAK, and subsequent NF-kappaB translocation and activation. This cellular signaling was followed by ICAM-1 expression and IL-8 production. Pretreatment of cells with CD or LA led to a significant inhibition of IRAK phosphorylation, and NF-kappaB nuclear translocation and activation. Actin depolymerization also significantly inhibited LPS-induced ICAM-1 and IL-8 production. HUVEC pretreated with CD or LA demonstrated significant inhibition of LPS-induced neutrophil adhesion. Endotoxin-induced actin polymerization is essential for optimal intracellular signaling through IRAK and NF-kappaB. Failure of these signaling events is associated with a marked reduction in adhesion molecule production, IL-8 production, and neutrophil adhesion. These findings support the necessity of stress fiber polymerization for optimal recruitment of neutrophils during sepsis.
 ...
PMID:Endotoxin-induced endothelial cell proinflammatory phenotypic differentiation requires stress fiber polymerization. 1274 86

The relative contribution of the pro-inflammatory cytokines tumour necrosis factor (TNF)-alpha and interleukin (IL)-1 beta and the lipopolysaccharide (LPS)-induced pathways that result in endothelial activation during sepsis are not fully understood. We have examined the effects of plasma obtained from LPS-treated human whole blood on the expression of E-selectin and intercellular adhesion molecule-1 (ICAM-1) on human endothelial cells. Stimulation of blood with 10 pg/ml of LPS is sufficient to produce plasma that induces E-selectin and ICAM-1 expression, while direct induction by LPS alone requires a 100-fold higher concentration. Characteristics for the plasma-induced adhesion molecule expression were similar to the LPS-induced production of TNF-alpha and IL-1 beta in blood. A complete inhibition of E-selectin and ICAM-1 expression was observed when antibodies against TNF-alpha and IL-1 beta were added to plasma prior to the incubation to endothelial cultures. Significant inhibition was even observed if antibodies were added to the cultures up until 3 h after LPS-conditioned plasma. The plasma-induced adhesion molecule response could also be prevented with inhibitors of nuclear factor (NF)-kappaB, such as pyrollidine dithiocarbamate. These findings emphasize the central role of TNF-alpha and IL-1 beta in LPS-induced endothelial activation and suggest that simultaneous neutralization of these cytokines or their common pathways may, even after the initial stimulus, prevent endothelial response during sepsis.
 ...
PMID:Modulation of adhesion molecule expression on endothelial cells after induction by lipopolysaccharide-stimulated whole blood. 1514 53

Infections caused by Gram-negative bacteria constitute one of the major causes of septic shock, which results from the inability of the immune system to limit bacterial spread during the ongoing infection. In the last decade, it has been demonstrated that vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are two endogenous immunopeptides, which together with three G protein-coupled receptors (VPAC1, VPAC2, and PAC1) exert a significant, therapeutic effect attenuating the deleterious consequences of septic shock by balancing pro- and anti-inflammatory factors. We have recently shown PAC1 receptor involvement in vivo as an anti-inflammatory receptor, at least in part, by attenuating lipopolysaccharide-induced production of proinflammatory interleukin-6. The present study deepens in the protective role of PAC1 receptor in septic shock, elucidating its involvement in the modulation of neutrophil recruitment and in the expression of different molecular sensors such as intercellular adhesion molecule-1, vascular cell adhesion molecule-1, fibrinogen, serum amyloid A, and nitric oxide as important, systemic players of the development of septic shock. Our results, using a mice deficient in PAC1 and a PAC1 antagonist, show that VIP and PACAP as well as the PAC1 receptor are involved in neutrophil recruitment in different target organs, in adhesion molecules expression, and in coagulation-related molecule fibrinogen synthesis. Thus, this study provides some important insights with respect to the involvement of PAC1 into the complexities of sepsis and represents an advantage for the design of more specific drugs complementing standard intensive care therapy in severe sepsis, confirming VIP and PACAP as candidates for multitarget therapy of septic shock.
 ...
PMID:Analysis of the role of the PAC1 receptor in neutrophil recruitment, acute-phase response, and nitric oxide production in septic shock. 1566 28

Sepsis is a leading cause of multiorgan dysfunction and death in hospitalized patients. Dysregulated inflammatory processes and apoptosis contribute to the pathogenesis of sepsis-induced organ dysfunction and death. A(1) adenosine receptor (A(1)AR) activation reduces inflammation and apoptosis after ischemia-reperfusion injury. Therefore, we questioned whether A(1)AR-mediated reduction of inflammation and apoptosis could improve mortality and organ dysfunction in a murine model of sepsis. A(1)AR knockout mice (A(1) knockout) and their wild-type (A(1) wild-type) littermate controls were subjected to cecal ligation and double puncture (CLP) with a 20-gauge needle. A(1) knockout mice or A(1) wild-type mice treated with 1,3-dipropyl-8-cyclopentylxanthine (a selective A(1)AR antagonist) had a significantly higher mortality rate compared with A(1) wild-type mice following CLP. Mice lacking endogenous A(1)ARs demonstrated significant elevations in plasma creatinine, alanine aminotransferase, aspartate aminotransferase, keratinocyte-derived chemokine, and tumor necrosis factor-alpha 24 h after induction of sepsis compared with wild-type mice. The renal corticomedullary junction from A(1) knockout mice also exhibited increased myeloperoxidase activity, intercellular adhesion molecule-1 protein, and mRNA encoding proinflammatory cytokines compared with renal samples from A(1) wild-type littermate controls. No difference in renal tubular apoptosis was detected between A(1) knockout and A(1) wild-type mice. We conclude that endogenous A(1)AR activation confers a protective effect in mice from septic peritonitis primarily by attenuating the hyperacute inflammatory response in sepsis.
 ...
PMID:A1 adenosine receptor knockout mice exhibit increased mortality, renal dysfunction, and hepatic injury in murine septic peritonitis. 1578 41

Hydroxyethyl starch (HES) is one of the most frequently used plasma substitutes. Recent studies have indicated that HES may reduce capillary leakage. The present in vivo study was performed to investigate the effects of HES on pulmonary capillary permeability, inflammatory mediators, and transcription factors in sepsis. Septic rats induced by cecal ligation and puncture (CLP) were treated with different doses of HES (7.5, 15, or 30 ml/kg, iv). At 5 or 12 hr after CLPq the rat lung tissues were collected. Pulmonary microvascular permeability, various cytokine levels (tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6), mRNA expressions (cytokine-induced neutrophil chemoattractant (CINC), P-selectin, CD 11b/CD18 (Mac-1), and intercellular adhesion molecule-1 (ICAM-1)), and activities of nuclear factor (NF)-kappaB and activator protein (AP)-1 were determined in each group. HES, in a dose-related manner, significantly reduced pulmonary capillary permeability in the CLP model of sepsis. HES also down-regulated pulmonary proinflammatory cytokines (TNF-alpha, IL-1beta, and IL-6) and mRNA expressions (CINC and P-selectin), and inhibited pulmonary activities of NF-kappaB and AP-1. The results suggest that during sepsis HES reduces pulmonary capillary permeability and this beneficial effect of HES may act through down-regulation of inflammatory mediators and suppression of NF-kappaB and AP-1 activation.
 ...
PMID:Mechanism of the effect of hydroxyethyl starch on reducing pulmonary capillary permeability in a rat model of sepsis. 1594 82

Endothelial cells are highly sensitive to changes in the extracellular milieu. Sepsis results in activation of inflammatory and coagulation pathways. We hypothesized that sepsis-associated mediators may alter the response capacity (so-called "set point") of endothelial cells. Human umbilical vein endothelial cells (HUVEC) were preincubated in the presence or absence of tumor necrosis factor (TNF)-alpha, lipopolysaccharide (LPS), hypoxia, hyperthermia, and/or high glucose; treated with or without thrombin for 4 h; and then processed for RNase protection assays of selected activation markers. Priming with TNF-alpha and LPS significantly inhibited thrombin-mediated induction of vascular cell adhesion molecule-1, intercellular adhesion molecule-1, tissue factor, and E-selectin, but not platelet-derived growth factor-A or CD44. In electrophoretic mobility shift assays, thrombin-treated HUVEC demonstrated inducible binding of p65 NF-kappaB, an effect that was significantly blunted by pretreatment of cells with TNF-alpha and LPS. Consistent with these results, TNF-alpha and LPS attenuated the effect of thrombin on IkappaB phosphorylation, total cytoplasmic IkappaB, and nuclear translocation of p65 NF-kappaB. The inhibitory effect of TNF-alpha on thrombin signaling persisted for up to 24 h following removal of the cytokine. Taken together, these data suggest that inflammatory mediators prime endothelial cells to modulate subsequent thrombin response.
 ...
PMID:Preconditioning of primary human endothelial cells with inflammatory mediators alters the "set point" of the cell. 1617 86

An intercellular adhesion molecule-1 polymorphism (ICAM-1(Kilifi)) is present at a high frequency across sub-Saharan Africa, and its presence may increase susceptibility to cerebral malaria. Here, we report that, compared with children in whom wild-type intercellular adhesion molecule-1 is present, the incidence of nonmalarial fever is significantly lower among those homozygous for ICAM-1(Kilifi). We propose that ICAM-1(Kilifi) may be associated with reduced rates of tissue damage and of death due to sepsis.
 ...
PMID:A polymorphism of intercellular adhesion molecule-1 is associated with a reduced incidence of nonmalarial febrile illness in Kenyan children. 1628 10

The mortality rate for septic patients with acute renal failure is extremely high. Since sepsis is often caused by lipopolysaccharide (LPS), a model of LPS challenge was used to study the development of kidney injury. Intravital video microscopy was utilized to investigate renal peritubular capillary blood flow in anesthetized male C57BL/6 mice at 0, 2, 6, 10, 18, 24, 36, and 48 h after LPS administration (10 mg/kg ip). As early as 2 h, capillary perfusion was dramatically compromised. Vessels with continuous flow were decreased from 89 +/- 4% in saline controls to 57 +/- 5% in LPS-treated mice (P < 0.01), and vessels with intermittent flow were increased from 6 +/- 2% to 31 +/- 5% (P < 0.01). At 2 h, mRNA for intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 were elevated 50- and 27-fold, respectively, suggesting that vascular inflammation is an early event that may contribute to capillary dysfunction. By 10 h, vessels with no flow increased from 5 +/- 2% in saline controls to 19 +/- 3% in LPS-treated mice (P < 0.05). By 48 h, capillary function was returning toward control levels. The decline in functional capillaries preceded the development of renal failure and was paralleled by induction of inducible nitric oxide synthase in the kidney. Using NAD(P)H autofluorescence as an indicator of cellular redox stress, we found that tubular cell stress was highly correlated with the percentage of dysfunctional capillaries (r(2) = 0.8951, P < 0.0001). These data show that peritubular capillary dysfunction is an early event that contributes to tubular stress and renal injury.
 ...
PMID:Peritubular capillary dysfunction and renal tubular epithelial cell stress following lipopolysaccharide administration in mice. 1692 42

Sepsis is associated with an activation of the coagulation system and multiorgan failure. The aim of the study was to examine the effects of selective thrombin inhibition with melagatran on renal hemodynamics and function, and liver integrity, during early endotoxemia. Endotoxemia was induced in thiobutabarbital-anesthetized rats by an intravenous bolus dose of lipopolysaccharide (LPS; 6 mg/kg). Sham-Saline, LPS-Saline, and LPS-Melagatran study groups received isotonic saline or melagatran immediately before (0.75 micromol/kg iv) and continuously during (0.75 micromol.kg(-1).h(-1) iv) 4.5 h of endotoxemia. Kidney function, renal blood flow (RBF), and intrarenal cortical and outer medullary perfusion (OMLDF) measured by laser-Doppler flowmetry were analyzed throughout. Markers of liver injury and tumor necrosis factor (TNF)-alpha were measured in plasma after 4.5 h of endotoxemia. In addition, liver histology and gene expression were examined. Melagatran treatment prevented the decline in OMLDF observed in the LPS-Saline group (P < 0.05, LPS-Melagatran vs. LPS-Saline). However, melagatran did not ameliorate reductions in mean arterial pressure, RBF, renal cortical perfusion, and glomerular filtration rate or attenuate tubular dysfunctions during endotoxemia. Melagatran reduced the elevated plasma concentrations of aspartate aminotransferase (-34 +/- 11%, P < 0.05), alanine aminotransferase (-21 +/- 7%, P < 0.05), bilirubin (-44 +/- 9%, P < 0.05), and TNF-alpha (-32 +/- 14%, P < 0.05) in endotoxemia. Melagatran did not diminish histological abnormalities in the liver or the elevated hepatic gene expression of TNF-alpha, intercellular adhesion molecule-1, and inducible nitric oxide synthase in endotoxemic rats. In summary, thrombin inhibition with melagatran preserved renal OMLDF, attenuated liver dysfunction, and reduced plasma TNF-alpha levels during early endotoxemia.
 ...
PMID:Effects of thrombin inhibition with melagatran on renal hemodynamics and function and liver integrity during early endotoxemia. 1706 59

This laboratory study tested new methods to analyze hemostasis alterations in septic patients. Samples of ethylenediamine tetraacetic acid (EDTA) plasma and citrated plasma were collected from 62 patients with clinical diagnosis of sepsis. Additionally, a subset of EDTA-plasma samples from each patient was stabilized 1 + 1 with 2.5 mol/l arginine, pH 8.6, to conserve the real hemostasis activation state. EDTA-arginine plasma, EDTA plasma and citrated plasma samples were tested in duplicate. The patients at admission to the intensive care unit had 36 +/- 26 (normal, 0.8 +/- 0.2) ng/ml global endotoxin reactivity, 188 +/- 66% (normal, 100 +/- 20%) fibrinogen function, 179 +/- 66% (normal, 100 +/- 20%) fibrinogen antigen, 4.0 +/- 3.6 (normal, 0.049 +/- 0.025) microg/ml D-dimer, 313 +/- 307% (normal, 100 +/- 30%) plasmin-antiplasmin complex, 8.7 +/- 11.4 (normal, 1.1 +/- 0.7) U/ml plasminogen activator inhibitor-1, 12.1 +/- 10.5 (normal, 1.3 +/- 0.4) ng/ml thrombin-antithrombin III complex, 173 +/- 62% (normal, 100 +/- 20%) thrombin, 568 +/- 225 (normal, 140 +/- 42) pg/ml tissue factor, and 2.56 +/- 2.48 (normal, 0.19 +/- 0.04) microg/ml soluble intercellular adhesion molecule-1. Endotoxin (lipopolysaccharide and/or beta-glucan) reactivity (EDTA plasma), fibrinogen function + antigen + ratio and plasminogen activator inhibitor-1 (citrated plasma), and D-dimer, soluble intercellular adhesion molecule-1, thrombin activity (EDTA-arginine-stabilized plasma) presented large aberrations in septic patients when compared with normal values and may therefore be particularly interesting as markers of hemostasis alteration. Whether the observed alterations are of clinical significance has to be determined in well defined patient groups.
 ...
PMID:Analysis of hemostasis alterations in sepsis. 1728 36


<< Previous 1 2 3 4 5 6 7 Next >>