Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Clinical and autopsy studies have shown an association between pulmonary microembolism and acute respiratory failure after trauma or sepsis. Prophylaxis and treatment with the aim of decreasing the fibrin deposition in the lungs were associated with a decrease in the incidence and death rate of this syndrome. Small fibrin degradation products (peptides) are accumulated in the lungs and are only slowly cleared from this organ, especially during states of fibrinolysis inhibition. These peptides may contribute to the pulmonary damage in several ways. They act by interfering with other vasoactive substances as bradykinin, histamine and products of the arachidonic acid cascade. Products of the cyclooxygenase pathways as thromboxane A2 play a major role in early microembolism whereas lipoxygenase products seem to be involved in delayed microembolism. Pulmonary microembolism thus seems to be one important, but certainly not the only pathogenetic factor in acute "idiopathic" respiratory failure. Other factors such as pulmonary contusion, aspiration of gastric contents or blood, or oxygen toxicity, might well be contributory in some cases. Pulmonary microemboli containing fibrin and leukocytes are probably also involved as contributory agents in some cases in the large group of acute respiratory failure due to "known factors".
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PMID:Pulmonary microembolism as a cause of acute respiratory failure. 696 76

The potential role of tumor necrosis factor alpha (TNF alpha) and eicosanoids in the pathogenesis of experimental neonatal sepsis models was investigated. Lethality was induced in neonatal rats by administration of heat killed group B streptococci (GBS, 7 mg kg-1 intracardially) or Salmonella enteritidis endotoxin (0.35 mg kg-1 intracardially). The relative efficacy of six compounds with putative TNF alpha and eicosanoid inhibitory actions were tested. These were: ibuprofen (3 and 20 mg kg-1), a cyclo-oxygenase inhibitor; CGS85515 (30 mg kg-1), a lipoxygenase inhibitor; LY203647 (30 mg kg-1), a leukotriene D4 receptor antagonist; pentoxifylline (10, 50 and 100 mg kg-1), a TNF inhibitor; cloricromene (2 and 10 mg kg-1), a thromboxane A2 synthetase inhibitor with TNF alpha inhibitory actions; and SKF86002 (2.5, 5, 10 and 20 mg kg-1), a dual cyclo-oxygenase/lipoxygenase inhibitor with TNF alpha inhibitory activity. Pentoxifylline, cloricromene and SKF86002, when given intraperitoneally 2 h before challenge, produced 45, 52 and 61% reductions, respectively, in plasma levels of TNF alpha at 2.5 h post-injection with killed GBS (P < 0.05). On the contrary, pretreatment with ibuprofen, CGS85515 or LY203647 did not significantly affect TNF alpha levels. All compounds significantly attenuated the lethality by killed GBS and S. enteritidis endotoxin. These data suggest that TNF alpha and eicosanoids contribute to the pathogenesis of shock induced by killed GBS and endotoxemia.
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PMID:Efficacy of tumor necrosis factor alpha and eicosanoid inhibitors in experimental models of neonatal sepsis. 792 Apr 63

Endotoxin (LPS) can cause hepatocellular injury under several circumstances, and leukotrienes have been implicated as a contributing factor. Since ion channel activation has been associated with cytotoxicity, the aim of this study was to determine the circumstances under which LPS and/or leukotrienes activate ionic conductances in hepatocytes. LPS treatment of rats increased Cl- conductance in hepatocytes from 232+/-42 to 1236+/-134 pS/pF. Voltage dependence and inhibitor specificity of this conductance were similar to that of a swelling-activated Cl- conductance, and internal dialysis with nucleoside analogues suggested control by an inhibitory G protein. The lipoxygenase inhibitor nordihydroguaiaretic acid, the specific leukotriene D4 (LTD4) receptor antagonist MK-571, and the 5-lipoxygenase activating protein inhibitor MK-886 all significantly inhibited the conductance. Intracellular dialysis with LTD4 (1.5 microM) elevated intracellular Ca2+ from 143+/-6.5 to 388+/-114 nM within 6 min and stimulated an outwardly rectifying conductance from 642+/-159 to 1669+/-224 pS/pF (n = 9, P < 0.001). In hepatocytes prepared from untreated rats, this concentration of intracellular LTD4 neither raised intracellular Ca2+ nor activated the conductance. The LTD4 response could be induced in normal hepatocytes by culture with either conditioned medium from LPS-treated macrophages or purified TNF-alpha. In conclusion, intracellular LTD4 activates a chloride conductance in hepatocytes isolated from rats treated with LPS or primed in vitro with TNF-alpha. Changes in the hepatocellular accumulation of leukotrienes therefore mediate channel activation and may contribute to liver injury during sepsis and other inflammatory conditions.
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PMID:Leukotriene D4 activates a chloride conductance in hepatocytes from lipopolysaccharide-treated rats. 918 15

Nitric oxide (NO) is a mediator that modulates vessel wall tone and hemostatic-thrombotic balance. Platelet function is regulated by NO generated from platelets, endothelial cells and leukocytes. Nitric oxide has been shown to inhibit platelet adhesion, aggregation, and stimulate disaggregation of preformed platelet aggregates. Many of the effects of NO are mediated by its stimulation of guanylate cyclase and the formation of cyclic GMP and its subsequent transduction mechanism. In vivo, NO is likely to interact with prostacyclin, metabolites of ecto-nucleotidase, and lipoxygenase to modulate platelet function in a synergistic manner. An imbalance of NO production (deficiency or overproduction) has been implicated in the pathogenesis of various vascular disorders including thrombosis, atherosclerosis, septicemia, and ischemia-reperfusion injury. It is likely that some of detrimental effects of NO are mediated through its reaction with superoxide anion to form the potent oxidant, peroxynitrite. Nitric oxide gas and NO donors are used for the pharmacological treatment of various vascular disorders. Because inhaled NO has been documented to improve systemic oxygenation and reduce the need for extracorporeal membrane oxygenation, it has been widely used in neonates with severe hypoxemia. An inhibition of platelet function, resulting in a prolonged bleeding time, has been shown in adults receiving inhaled NO. Because bleeding complications may occur in high-risk infants, it is important to evaluate the effect of inhaled NO on platelet function and its correlation with clinical consequences such as intracranial hemorrhage. For these reasons, hemostasis should be carefully monitored during the administration of inhaled NO to critically ill neonates.
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PMID:Nitric oxide and platelet function: implications for neonatology. 935 13

We have previously demonstrated that treatment of hepatocytes with IFN gamma results a series of cellular injury processes, including DNA synthesis arrest, membrane breakage and apoptosis. In the present work, we show that IFN gamma suppresses cellular respiration and protein synthesis in hepatocytes, and that cellular respiration suppression is an early event in the IFN gamma-induced cellular injuries. Polyunsaturated fatty acids (PUFAs) increased cellular respiration of hepatocytes, but only linoleic acid showed some protective effect against IFN gamma-induced cellular respiration suppression. Linoleic acid also reduced other IFN gamma-mediated cellular injuries, including membrane breakage and protein synthesis inhibition. Like linoleic acid, fetal bovine serum also inhibited IFN gamma-induced cellular damage. Increased NAD levels were found in both IFN gamma-treated and non-treated hepatocytes following the addition of PUFAs, but clofibrate, a peroxisome proliferator, bromophenacyl bromide (BPB), an inhibitor of phospholipase, nordihydroguaiaretic acid (NDGA), an inhibitor of lipoxygenase, and arachidonic acid, a metabolite of linoleic acid, did not inhibit IFN gamma-induced cellular injury. In addition, the combination of linoleic acid and IFN gamma induced nitric oxide (NO) synthesis in hepatocytes. These results suggest that fatty acid may play an important role in liver homeostasis during chronic inflammatory states and sepsis.
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PMID:Protective effect of linoleic acid on IFN gamma-induced cellular injury in primary culture hepatocytes. 953 94

Despite immense progress in intensive-care medicine, mortality rates of 30-70% in sepsis and SIRS are still an unresolved problem. Particularly the failure of respiratory and other vital functions is a major cause of death. Besides infectious stimuli (viruses, bacteria, fungi) a variety of non-infectious triggers (tissue damage, immune complexes, complement activation, etc.) can initiate the development of organ failure. These inflammatory reactions aim physiologically towards inactivation and removal of the stimulating agents as well as the induction of reparative processes. In states of prolonged activation of humoral and cellular mediator systems the natural host defence mechanisms react in an uncontrolled manner causing tissue damage and organ failure. So far there are no efficient therapeutic strategies to influence these complex inflammatory reactions. In the development of SIRS and sepsis, pro-inflammatory lipid mediators play a crucial role. Omega-3-fatty acids (omega-3-PUFAs) have shown anti-inflammatory and antithrombotic properties in a great number of experimental and clinical studies. These effects seem to be related to the uptake of eicosapentaenoic acid (EPA) into cellular membrane lipid pools and its subsequent metabolisation. After inflammatory activation EPA is released besides arachidonic acid (AA) and competes with AA for metabolisation via the cyclo- and lipoxygenase pathway. Compared to AA the derivatives of EPA have less pro-inflammatory and chemotactic characteristics. With regard to prophylactic and therapeutic consequences it appears reasonable to supplement omega-3-PUFAs to attenuate the inflammatory response by modulating the generation of lipid mediators during inflammation.
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PMID:[Pharmacologic aspects of polyunsaturated fatty acids in parenteral nutrition]. 955 31

During the past few decades, intensive collaborative research in the fields of chronic and acute inflammatory disorders has resulted in a better understanding of the pathophysiology and diagnosis of these diseases. Modern therapeutic approaches are still not satisfactory and shock, sepsis and multiple organ failure remain the great challenge in intensive care medicine. However, the treatment of inflammatory diseases like rheumatoid arthritis, ulcerative colitis or psoriasis also represents an unresolved problem. Many factors contribute to the complex course of inflammatory reactions. Microbiological, immunological and toxic agents can initiate the inflammatory response by activating a variety of humoral and cellular mediators. In the early phase of inflammation, excessive amounts of interleukins and lipid-mediators are released and play a crucial role in the pathogenesis of organ dysfunction. Arachidonic acid (AA), the mother substance of the pro-inflammatory eicosanoids, is released from membrane phospholipids in the course of inflammatory activation and is metabolised to prostaglandins and leukotrienes. Various strategies have been evaluated to control the excessive production of lipid mediators on different levels of biochemical pathways, such as inhibition of phospholipase A2, the trigger enzyme for release of AA, blockade of cyclooxygenase and lipoxygenase pathways and the development of receptor antagonists against platelet activating factor and leukotrienes. Some of these agents exert protective effects in different inflammatory disorders such as septic organ failure, rheumatoid arthritis or asthma, whereas others fail to do so. Encouraging results have been obtained by dietary supplementation with long chain omega-3 fatty acids like eicosapentaenoic acid (EPA). In states of inflammation, EPA is released to compete with AA for enzymatic metabolism inducing the production of less inflammatory and chemotactic derivatives.
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PMID:Lipid mediators in inflammatory disorders. 956 39

Escherichia coli hemolysin (HlyA) is a prototype of a large family of pore-forming proteinaceous exotoxins that have been implicated in the pathogenetic sequelae of severe infection and sepsis, including development of acute lung injury. In the present study in rabbit alveolar macrophages (AMs), subcytolytic concentrations of purified HlyA evoked rapid synthesis of platelet-activating factor, with quantities approaching those in response to maximum calcium ionophore challenge. In parallel, large quantities of leukotriene (LT) B(4) and 5-, 8-, 9-, 12-, and 15-hydroxyeicosatetraenoic acid (HETE) were liberated from HlyA-exposed AMs depending on exogenous arachidonic acid (AA) supply. Coadministration of eicosapentaenoic acid (EPA) dose dependently suppressed generation of the proinflammatory lipoxygenase products LTB(4) and 5-, 8-, 9-, and 12-HETE in parallel with the appearance of the corresponding EPA-derived metabolites LTB(5) and 5-, 8-, 9-, and 12-hydroxyeicosapentaenoic acid (HEPE). At equimolar concentrations, EPA turned out to be the preferred substrate over AA for these AM lipoxygenase pathways, with the sum of LTB(5) and 5-, 8-, 9-, and 12-HEPE surpassing the sum of LTB(4) and 5-, 8-, 9-, and 12-HETE by >80-fold. In contrast, coadminstration of EPA did not significantly reduce HlyA-elicited generation of the anti-inflammatory AA lipoxygenase product 15-HETE. We conclude that AMs are sensitive target cells for HlyA attack, resulting in marked proinflammatory lipid mediator synthesis. In the presence of EPA, lipoxygenase product formation is shifted from a pro- to an anti-inflammatory profile.
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PMID:E. coli hemolysin-induced lipid mediator metabolism in alveolar macrophages: impact of eicosapentaenoic acid. 1089 8

Rodent models of sepsis differ from clinical human disease in that humans make substantially less whole-body nitric oxide and have different cellular responses to endotoxin. Sheep, when exposed to endotoxin, behave in a manner more similar to humans. Many studies of rodent peripheral blood mononuclear cells (PBMCs) exposed to endotoxin demonstrate increased cationic amino acid transporter function (particularly through the y+ transporter) to supply arginine substrate to upregulated nitric oxide synthase. Whether this is true in sheep is not known. We have studied cationic amino acid transport in sheep PBMCs stimulated with endotoxin, using labelled lysine. PBMCs stimulated both in vitro and in vivo show an initial reduction in total and y+ lysine transport (after 1-2 h exposure to endotoxin): a previously undescribed effect of endotoxin. In in vitro activated cells, the reduction in y+ transport was prevented by the lipoxygenase inhibitor, nordihydroguaretic acid (NDGA), and the phospholipase inhibitor 4-bromophenacyl bromide (4-BPAB), but not cyclohexamide or a number of other inhibitors of intracellular second-messenger pathways. In contrast after 14 h incubation, the expected increase in total and y+ lysine transport was seen. The increase in y+ transport could be prevented by cyclohexamide, dexamethasone, ibuprofen, the protein kinase C inhibitor sphingosine, NDGA and 4-BPAB. These results suggest that in response to endotoxin exposure there is an initial decrease in y+ activity mediated by a lipoxygenase product, followed by a substantial increase in y+ activity mediated by the products of either cyclo-oxygenase or lipoxygenase. Cyclo-oxygenase and/or lipoxygenase inhibition might be useful in reducing arginine transport, and hence nitric oxide production, in these cells.
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PMID:Effects of endotoxin exposure on cationic amino acid transporter function in ovine peripheral blood mononuclear cells. 1262 25

Platelet-activating factor (PAF) is a potent lipid mediator that has been implicated in asthma, sepsis, acute lung injury and ischemia/reperfusion injury. Its actions in the lungs include vasoconstriction, bronchoconstriction, and edema formation. Despite the fact that PAF exerts these actions within minutes, they are mediated by other lipid mediators, in particular eicosanoids generated by cyclooxygenase and lipoxygenase enzymes and sphingolipids generated by acid sphingomyelinase.We will discuss the mechanisms of the PAF-induced pressor responses that are triggered by thromboxane A(2) and leukotrienes, as well the PAF-induced increase in vascular permeability that is mediated by prostaglandin E(2) (PGE(2)) and ceramide.
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PMID:Mechanisms of platelet-activating factor (PAF)-mediated responses in the lung. 1641 1


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