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)

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.
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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.
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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.
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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.
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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.
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PMID:International union of pharmacology. XLV. Classification of the kinin receptor family: from molecular mechanisms to pathophysiological consequences. 1573 27

Sepsis is a complex clinical syndrome that results from a harmful host response to infection, in which foreign bacteria and lipopolysaccharide (LPS) are potent activators of different immune cells, including monocytes and macrophages. To date, there are currently few effective adjuvant therapies in clinical use except activated protein C focusing on the coagulation system. Mastoparans (MPs) are wasp venom cationic amphiphilic tetradecapeptides; these are capable of modulating various cellular activities, including stimulation of GTP-binding protein, phospholipase C and can bind to a phospholipid bilayer. Masroparan-1 (MP-1, INLKAIAALAKKLL-NH2), a tetradecapeptide toxin isolated from hornet venom, was synthesized chemically. In this study, Escherichia coli 25922 (E. coli 25922) and LPS were used to induce sepsis in an animal model. We found that MP-1 treatment at 3 mg/kg protected mice from otherwise lethal bacteria and LPS challenges. MP-1 has antibacterial capabilities against Gram-negative and Gram-positive bacteria. Its antibacterial action against E. coli may result from the destruction of bacterial membrane structures. In addition, treatment of murine peritoneal macrophages with MP-1 potently inhibited the respiratory burst. This effect maybe related to an inhibition of NADPH oxidase in the membrane. Furthermore, MP-1, bound with high-affinity to LPS and lipid A with dissociation equilibrium constants of 484 and 456 nM, respectively, and neutralized LPS in a dose-dependent manner. MP-1 also significantly reduced the expression of TLR4, TNF-alpha and IL-6 mRNA and the release of cytokines in LPS-stimulated murine peritoneal macrophages. Our results shows that the MP-1-mediated protection of mice from lethal challenge by live bacteria and LPS was associated with its bactericidal action and inhibition of inflammatory responses by macrophages to both bacteria and LPS (the release of cytokines and reactive oxygen species).
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PMID:A synthesized cationic tetradecapeptide from hornet venom kills bacteria and neutralizes lipopolysaccharide in vivo and in vitro. 1593 30

Staphylococcus aureus infections can result in sepsis and septic shock associated with vascular damage and multiple organ failure. Apoptosis appears to play a key role during sepsis, and the ability of S. aureus to induce apoptosis in endothelial cells might contribute to metastatic infection. In contrast to leukocytes, in human umbilical vein endothelial cells and two endothelial cell lines neither purified alpha-toxin nor staphylococcal supernatants were sufficient to induce apoptosis. Apoptosis induction instead required staphylococcal invasion as well as signals from metabolically active intracellular staphylococci. Only strongly haemolytic and invasive staphylococci, but not non-invasive strains induced apoptosis that was caspase-dependent but Fas-independent. However, only a subgroup of clinical isolates with an invasive and haemolytic phenotype induced apoptosis. Expression of alpha-toxin in a non-haemolytic strain partially restored apoptosis induction, suggesting a role of alpha-toxin as a trigger of apoptosis. Furthermore, infection of endothelial cells with isogenic mutants of various regulator genes revealed that apoptosis induction was dependent on the global regulator agr and the alternative sigma factor sigB, but not influenced by sarA. Together, our results indicate that the ability of S. aureus to induce apoptosis in endothelial cells is determined by multiple virulence factors.
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PMID:Multiple virulence factors are required for Staphylococcus aureus-induced apoptosis in endothelial cells. 1600 76

Infection with group B streptococcus (GBS) is the most common cause of early onset neonatal sepsis in many countries, leading to neonatal morbidity and mortality. There is much evidence for a direct involvement of platelets in the pathogenesis of inflammation and sepsis. Several bacteria are known to directly interact with platelets leading to activation and aggregation, a phenomenon also observed with GBS. Here, we demonstrate that GBS rapidly bound to platelets; however, only strains isolated from septic patients bound fibrinogen on their surface and induced platelet thromboxane synthesis, platelet aggregation, and P-selectin (CD62P) expression. In contrast, GBS strains isolated from healthy newborns or healthy pregnant women induced only shape change, but not platelet thromboxane synthesis, platelet aggregation, or CD62P expression. All GBS strains investigated were able to activate FcgammaRIIA receptor signaling pathways including phospholipase C gamma2 (PLCgamma2), as well as calcium/calmodulin-dependent myosin kinase II (CaMKII) and phosphorylation of myosin light chain (MLC). In contrast, protein kinase C (PKC) was exclusively activated by GBS strains isolated from septic patients, and p38 mitogen activated protein kinase (p38 MAP kinase) was preferentially activated by septic GBS strains. Furthermore, stress signaling kinase SEK1/MKK4 and focal adhesion kinase (FAK) were activated by all tested GBS strains in a FcgammaRIIA-independent way. This study demonstrates that septic, but not colonizing, GBS strains bind fibrinogen on their surface, and that septic GBS strains influence platelet function not only via the FcgammaRIIA receptor, but also via pathways distinct from IgG-mediated signalling. These mechanisms lead to platelet aggregation and secretion, thereby possibly modulating the pathophysiologic course of GBS infections.
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PMID:Group B streptococcus isolates from septic patients and healthy carriers differentially activate platelet signaling cascades. 1667 76

Abnormal production of inflammatory cytokines and chemokines is a key feature of bacterial endotoxin, lipopolysaccharide (LPS)-induced inflammation, and cytotoxicity; however, the mechanisms regulating production of inflammatory markers remain unclear. Herein, we show that inhibition of the aldehyde-metabolizing enzyme aldose reductase (AR; AKR1B3) modulates NF-kappaB-dependent activation of inflammatory cytokines and chemokines in mouse serum, liver, heart, and spleen. Pharmacological inhibition or small interfering RNA ablation of AR prevented the biosynthesis of tumor necrosis factor-alpha, interleukin 1beta, interleukin-6, macrophage-chemoattractant protein-1, and cyclooxygenase-2 and prostaglandin E(2) in LPS-activated RAW264.7 murine macrophages. The AR inhibition or ablation significantly attenuated LPS-induced activation of protein kinase C (PKC) and phospholipase C (PLC), nuclear translocation of NF-kappaB, and phosphorylation and proteolytic degradation of IkappaBalpha in macrophages. Furthermore, treatment of macrophages with 4-hydroxy-trans-2-nonenal (HNE), and cell-permeable esters of glutathionyl-4-hydroxynonanal (GS-HNE) and glutathionyl-1,4-dihydroxynonane (GS-DHN) activated NF-kappaB and PLC/PKC. Pharmacological inhibition or antisense ablation of AR that catalyzes the reduction of GS-HNE to GS-DHN prevented PLC, PKC, IKKalpha/beta, and NF-kappaB activation caused by HNE and GS-HNE, but not by GS-DHN, suggesting that reduced GS-lipid aldehydes catalyzed by AR propagate LPS-induced production of inflammatory markers. Collectively, these data provide evidence that inhibition of AR may be a significant therapeutic approach in preventing bacterial endotoxin-induced sepsis and tissue damage.
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PMID:Aldose reductase mediates the lipopolysaccharide-induced release of inflammatory mediators in RAW264.7 murine macrophages. 3071 8

Bacterial toxins cause cardiac dysfunction and death through an inflammatory process, but the mechanism remains unclear. Simvastatin is recognized as having anti-inflammatory properties beyond its lipid-lowering effects. We examined Staphylococcus aureus alpha-toxin in isolated heart and in vivo models and tested simvastatin's effects in sepsis. Isolated Langendorff-perfused rat hearts were exposed to a recirculating perfusate containing alpha-toxin (0.5 microg mL(-1)). Compared with controls, there was a significant increase in coronary perfusion pressure and fall in myocardial performance. Significant increases in p53 expression and apoptosis (1.3 +/- 0.5 to 7.1 +/- 1.4 terminal deoxynucleaotidyl transferase nick end labeling-positive cells; P < 0.05) compared with controls were observed, but markers of necrosis were similar. In parallel experiments, anaesthetized rats receiving alpha-toxin (40 microg kg(-1), i.v.) had in vivo hemodynamic parameters and serum markers of necrosis monitored for 4 h before the hearts were analyzed for histological change, p53 expression, and apoptosis. Over 4 h, alpha-toxin exposure produced substantial hemodynamic effects. In addition, p53 expression (0.2 +/- 0.2 to 7.1 +/- 0.5 p53-positive myocytes; P < 0.05), TNF-alpha levels, the degree of apoptosis, and markers of necrosis were all significantly increased compared with control animals. Pretreatment with simvastatin protected against alpha-toxin-induced sepsis associated with reduced p53, TNF-alpha, apoptosis, and necrosis. We found significant changes in systemic hemodynamics, coronary perfusion pressure, myocardial function, and increased p53 expression with apoptosis due to bacterial exotoxin. In vivo changes were significantly inhibited by pretreatment with simvastatin. We provide novel evidence for the mechanisms by which septicemia causes myocardial depression and hint at a potential role for simvastatin as an inhibitor of apoptosis in sepsis.
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PMID:Apoptosis contributes to septic cardiomyopathy and is improved by simvastatin therapy. 1859 4


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