UMLS:C0243026 - FACTA Search

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)

Exotoxins such as listeriolysin (LLO) and phosphatidylinositol-specific phospholipase C (PIcA) have been implicated in listerial infection and sepsis. Employing different Listeria strains, mutated in individually known virulence genes, we examined exotoxin-related induction of endothelial cell signaling. Listeria monocytogenes was a potent inductor of phosphatidylinositol (PtdIns) metabolism in HUVEC. This effect was completely absent in a LLO-negative strain. Using a recombinant Listeria innocua strain, engineered to produce high levels of LLO, PtdIns metabolism was restored to approximately 30% of that produced by the parental L. monocytogenes strain. A recombinant L. innocua strain expressing only PIcA did not induce any PtdIns metabolism. Even higher than wild-type levels of PtdIns hydrolysis products were, however, evoked when engineered bacteria secreted both LLO and PIcA. These effects occurred in the absence of bacterial uptake by the endothelial cells. Corresponding results were observed with regard to endothelial diacylglycerol (DAG) generation. The amplification of endothelial cell signaling could be reproduced by engaging purified LLO and PIcA in the absence of bacteria. In these experiments, the unrelated pore-forming agent staphylococcal alpha-toxin, a very weak stimulus for endothelial phosphoinositide metabolism by itself, substituted for LLO to allow marked PtdIns hydrolysis when co-applied with PIcA. We conclude that the listerial exotoxins LLO and PIcA cooperate to provoke potent second messenger synthesis in endothelial cells, in the absence of cell invasion by the bacteria. This is an impressive example of synergism between a pore-forming and an enzymatic bacterial exotoxin in provoking cell signaling and inflammatory events.
...
PMID:The listerial exotoxins listeriolysin and phosphatidylinositol-specific phospholipase C synergize to elicit endothelial cell phosphoinositide metabolism. 889 39

The complex pathway seen in patients with the systemic inflammatory response syndrome (SIRS) does not readily respond to mediator blockade. All such trials conducted in SIRS patients have shown no benefit in reducing mortality. We have shown experimentally that in sepsis, the administration of beta 2-adrenoceptor agonists reduces hepatic cellular injury, whereas administration of an alpha 1-adrenoceptor agonist increases hepatic cellular injury. Inflammatory mediators can cause a dose-related reversible change in target endothelial cells (ECs). There is a substantial body of literature describing the anti-inflammatory effects of beta 2-adrenoceptor agonists. They reduce both the increased permeability and the production of inflammatory mediators from ECs. Cellular transduction processes are involved when adrenergic receptor agonists modify either the anti-inflammatory or proinflammatory response to sepsis in ECs. Inflammatory mediators and alpha 1-adrenoceptor agonists stimulate their trimeric G protein-linked receptors to produce diacylglycerol (DAG) and increase the intracellular concentration of calcium. DAG is involved in the production of both inflammatory proteins and lipids. In addition, mitogen-activated protein kinase (MAPK) is activated which is also involved in the production of inflammatory proteins and lipids. beta 2-adrenoceptor agonists activate their trimeric G protein-linked receptors to produce the stimulatory G protein (Gs). Gs stimulates adenyl cyclase to form cyclic adenosine monophosphate (cAMP) and activate protein kinase A (PKA). PKA is involved in activating gene transcription agents to produce anti-inflammatory proteins such as interleukin-10. PKA also inhibits phospholipase C and MAPK. Although promising, the use of beta-adrenoceptor agonists or agonists that increase cellular cAMP to activate the cells' endogenous anti-inflammatory pathway requires further study.
...
PMID:Cell surface adrenergic receptor stimulation modifies the endothelial response to SIRS. Systemic Inflammatory Response Syndrome. 896 76

Escherichia coli hemolysin (HlyA) and Staphylococcus aureus alpha-toxin are membrane-perturbating bacterial exotoxins that have been implicated as significant virulence factors in human diseases. We investigated the capacity of these toxins to cause cell activation and mediator release in human endothelial cells, compared with the efficacies of thrombin and the Ca2+ ionophore A23187. Concentration ranges tested were 1 to 1000 ng/ml (HlyA), 0.01 to 10 micro/ml (alpha-toxin), 0.01 to 10 U/ml (thrombin), and 0.01 to 10 microM (A23187). All stimuli caused dose-dependent generation of platelet-activating factor, nitric oxide, and prostaglandin I2. HlyA and thrombin effected time- and dose-dependent accumulation of large quantities of inositol phosphates, with maximum effects at 100 ng/ml and 1 U/ml, respectively. Corresponding time course and dose dependency were noted for HlyA-elicited diacylglycerol formation. In contrast, only the highest concentrations of alpha-toxin (10 microg/ml) and A23187 (10 microM) effected some moderate inositol phosphate accumulation, and this was suppressed in the presence of the platelet-activating factor antagonist WEB 2086. Metabolic and secretory responses elicited by alpha-toxin were dependent on the presence of extracellular Ca2+. We conclude that both HlyA and alpha-toxin are potent inductors of inflammatory and vasodilatory mediators in human endothelial cells. HlyA-elicited effects may proceed predominantly via activation of the phosphatidylinositol hydrolysis-related signal transduction pathway, whereas transmembrane Ca2+ flux appears to be the major event underlying the release of mediators in response to alpha-toxin. These toxin properties may contribute to vasoregulatory and inflammatory disturbances encountered in states of severe infection and sepsis.
...
PMID:Human endothelial cell activation and mediator release in response to the bacterial exotoxins Escherichia coli hemolysin and staphylococcal alpha-toxin. 925 56

A critical feature of sepsis-induced adult respiratory distress syndrome (ARDS) is the release of cytokines (such as interleukin [IL]-6, IL-8, and tumor necrosis factor [TNF]) from endotoxin (lipopolysaccharide [LPS])-activated alveolar macrophages (AM). Nuclear factor kappa B (NF-kappaB) is activated in AM from patients with ARDS, and it is essential for the transcription of many cytokine genes. In these studies, we evaluated the regulation of LPS-induced cytokine release and the activation of NF-kappaB in human AM. We found that the activation of NF-kappaB and the release of IL-6, IL-8, and TNF from AM exposed to LPS was protein kinase C-independent and tyrosine kinase- and phosphatidylcholine-specific phospholipase C-dependent. We also found that LPS-induced activation of NF-kappaB was enhanced in AM cultured in serum or in the presence of LPS-binding protein, simulating conditions in the lung that are present in ARDS. In addition, LPS triggered the activation of several different NF-kappaB complexes in AM, and different forms of NF-kappaB bound to the IL-6, IL-8, and TNF promoter sequences. These observations suggest that physiologic abnormalities present in the lungs of patients with ARDS facilitate the activation of NF-kappaB and local release of cytokines.
...
PMID:Lipopolysaccharide-induced NF-kappaB activation and cytokine release in human alveolar macrophages is PKC-independent and TK- and PC-PLC-dependent. 949 Jun 56

During Gram-negative bacterial infections, lipopolysaccharide (LPS) interacts with monocyte/macrophage receptors, resulting in a host defense response. Activation of intracellular signal transduction pathways implicating various protein kinase and phospholipases is crucial in activating the transcription of genes encoding proinflammatory cytokines and inducible nitric oxide synthase (iNOS). In this article, we demonstrate that in mouse, endotoxin shock activation of phosphatidylcholine-specific phospholipase C (PC-PLC) plays a major role in controlling the inflammatory response. Inhibition of PC-PLC by the specific inhibitor tricyclodecan-9-yl-xanthogenate (D609) before LPS reduced the release of interleukin-1 beta, interleukin-6 and nitric oxide (NO) in vivo. In contrast, tumor necrosis factor-alpha serum levels were not altered by the pretreatment with D609. Consequently, survival from endotoxin shock of D609-treated animals was significantly improved compared with control animals (45% vs. 20%). Thus, inhibition of PC-PLC can reduce the inflammatory response to LPS and may serve as a novel approach to therapy of sepsis.
...
PMID:Modulation of mouse endotoxin shock by inhibition of phosphatidylcholine-specific phospholipase C. 958 Jun 29

1. We investigated the effect of adrenergic receptor stimulation or inhibition on the hepatic ultrastructural changes in a porcine faecal peritonitis model of multi-organ failure. We infused either the alpha1 adrenergic receptor agonist methoxamine or the beta2 adrenergic receptor antagonist ICI 118551 during 8 h of the study.2. Anaesthetized pigs (25-30 kg) were divided into four non-septic groups (control, non-septic, non-septic methoxamine and non-septic ICI 118551) and three septic groups (septic, septic methoxamine and septic ICI 118551).3. Changes in hepatic ultrastructure were measured by morphometric analysis. The septic group was significantly worse than all the non-septic groups. Septic methoxamine and septic ICI 118551 were significantly worse than the septic group.4. Septic methoxamine and septic ICI 118551 had a significantly increased perisinusoidal space; septic methoxamine had significant hepatocyte vacuolation.5. Hepatic ultrastructural changes were independent of hepatic blood flow.6. Septic methoxamine had significant myocardial depression.7. The alpha1 adrenergic receptor agonist methoxamine or the beta2 antagonist ICI 118551 both amplified the hepatic injury normally found during sepsis in our porcine model.8. These findings suggest that during sepsis a protective endogenous beta2 adrenergic receptor-mediated anti-inflammatory response is activated via cell membrane transduction to stimulate the trimeric G-protein complex Gs and activate the second cell messenger cAMP.9. In addition, it is likely that alpha1 adrenergic receptor agonists amplify the inflammatory response by stimulating the cell-surface receptor-linked trimeric G-protein complex to activate Gq and the second cell messenger phospholipase C.
...
PMID:Porcine hepatic response to sepsis and its amplification by an adrenergic receptor alpha1 agonist and a beta2 antagonist. 974 23

The first reported case of Clostridium septicum myonecrosis in an adult with aplastic anemia is described. The patient presented with sepsis, a parapharyngeal abscess that necessitated emergent intubation, and severe intravascular hemolysis attributed to clostridial alpha-toxin production. Despite prompt recognition and treatment, the patient died of his infection. C. septicum myonecrosis should be considered in any immunocompromised patient with sepsis, especially when accompanied by evidence of multiple sites of tissue infection.
...
PMID:Clostridium septicum myonecrosis presenting as a parapharyngeal abscess in a patient with aplastic anemia. 979 92

The interaction of Listeria monocytogenes with endothelial cells represents a crucial step in the pathogenesis of listeriosis. Incubation of human umbilical vein endothelial cells (HUVEC) with wild-type L. monocytogenes (EGD) provoked immediate strong NO synthesis, attributable to listerial presentation of listeriolysin O (LLO), as the NO release was missed upon employment of a deletion mutant for LLO (EGD hly mutant) and was reproduced by purified LLO. Studies of conditions lacking extracellular Ca(2+) suggested LLO-elicited Ca(2+) flux as the underlying mechanism. In addition, HUVEC incubation with EGD turned out to be a potent stimulus for sustained (>12-h) upregulation of proinflammatory cytokine generation (interleukin 6 [IL-6], IL-8, and granulocyte-macrophage colony-stimulating factor). Use of deletion mutants for LLO (EGD hly mutant), listerial phosphatidylinositol-specific phospholipase C (EGD plcA mutant), broad-spectrum phospholipase C (EGD plcB mutant) and internalin B (EGD inlB mutant), as well as purified LLO, identified LLO as largely responsible for the cytokine response. Endothelial cells responded with diacylglycerole and ceramide generation as well as nuclear translocation of NF-kappa B to the stimulation with the LLO-producing strains EGD and Listeria innocua. The endothelial PC-phospholipase C inhibitor tricyclodecan-9-yl-xanthogenate as well as two independent inhibitors of NF-kappa B activation, pyrolidine dithiocarbamate and caffeic acid phenethyl ester, suppressed both the NF-kappa B translocation and the upregulation of cytokine synthesis. We conclude that L. monocytogenes is a potent stimulus of NO release and sustained upregulation of proinflammatory cytokine synthesis in human endothelial cells, both events being largely attributable to LLO presentation. LLO-induced transmembrane Ca(2+) flux as well as a sequence of endothelial phospholipase activation and the appearance of diacylglycerole, ceramide, and NF-kappa B are suggested as underlying host signaling events. These endothelial responses to L. monocytogenes may well contribute to the pathogenic sequelae in severe listerial infection and sepsis.
...
PMID:Human endothelial cell activation and mediator release in response to Listeria monocytogenes virulence factors. 1115 83

This study was first designed to investigate systematically the kinetics of surface expression of scavenger receptors (SRs) and CD14 on alveolar macrophages in vivo and in vitro and their relation with local pro- and antiinflammatory responses in endotoxemia. The expression of SR and CD14 in lungs was down- and up-regulated, respectively, in the presence of endotoxemia, which might be due to decreased expression of SR and increased expression of CD14 on the surface of the resident macrophages. Down-regulation of SRs on alveolar macrophages not only induces decreased defensive function of the macrophages, it also enhances lipopolysaccharide (LPS)-induced activation of alveolar macrophages possibly through increasing LPS binding to CD14. Although CD14 is a key receptor responsible for LPS to activate macrophages, both phospholipase C and anti-CD14 antibody can completely inhibit activation of alveolar macrophages initiated by only LPS 1 ng/ml, as determined by tumor necrosis factor-alpha (TNFalpha) production, but it does not significantly change TNFalpha release upon cell stimulation by LPS 10 microg/ml. There was an intrinsic relation of enhanced intrapulmonary pro- and antiinflammatory responses with changes in SR and CD14 expression, which suggests that the down-regulation of SR and up-regulation of CD14 might be an important mechanism for the lung to change from a defense organ to an effector organ during sepsis.
...
PMID:Intrapulmonary expression of scavenger receptor and CD14 and their relation to local inflammatory responses to endotoxemia in mice. 1255 30

Kinins are proinflammatory peptides that mediate numerous vascular and pain responses to tissue injury. Two pharmacologically distinct kinin receptor subtypes have been identified and characterized for these peptides, which are named B1 and B2 and belong to the rhodopsin family of G protein-coupled receptors. The B2 receptor mediates the action of bradykinin (BK) and lysyl-bradykinin (Lys-BK), the first set of bioactive kinins formed in response to injury from kininogen precursors through the actions of plasma and tissue kallikreins, whereas the B(1) receptor mediates the action of des-Arg9-BK and Lys-des-Arg9-BK, the second set of bioactive kinins formed through the actions of carboxypeptidases on BK and Lys-BK, respectively. The B2 receptor is ubiquitous and constitutively expressed, whereas the B1 receptor is expressed at a very low level in healthy tissues but induced following injury by various proinflammatory cytokines such as interleukin-1beta. Both receptors act through G alpha(q) to stimulate phospholipase C beta followed by phosphoinositide hydrolysis and intracellular free Ca2+ mobilization and through G alpha(i) to inhibit adenylate cyclase and stimulate the mitogen-activated protein kinase pathways. The use of mice lacking each receptor gene and various specific peptidic and nonpeptidic antagonists have implicated both B1 and B2 receptors as potential therapeutic targets in several pathophysiological events related to inflammation such as pain, sepsis, allergic asthma, rhinitis, and edema, as well as diabetes and cancer. This review is a comprehensive presentation of our current understanding of these receptors in terms of molecular and cell biology, physiology, pharmacology, and involvement in human disease and drug development.
...
PMID:International union of pharmacology. XLV. Classification of the kinin receptor family: from molecular mechanisms to pathophysiological consequences. 1573 27

<< Previous 1 2 3 4 5 Next >>