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)

Sepsis is a systemic inflammatory response to a blood-borne infection that is associated with an extremely high rate of morbidity and mortality. The present study investigates the role of cyclooxygenase (COX)-2 in host responses to bacterial endotoxemia. After administration of Escherichia coli lipopolysaccharide, 50% of wild-type mice die within 96 h. COX-2 deficient mice displayed a dramatic improvement in survival with reduced leukocyte infiltration into critical organs (kidneys and lungs) and a blunted and delayed induction of the cytokine inducible genes nitric oxide synthase 2 and heme oxygenase-1. Translocation and activation of transcription factors important for signaling events during an inflammatory response, such as nuclear factor (NF)-kappaB, were also markedly reduced. While the absence of COX-2 did not alter the induction of several pro-inflammatory cytokines in tissue macrophages, induction of the anti-inflammatory cytokine IL-10 was exaggerated. Administration of IL-10 to wild-type mice reduced NF-kappaB activation. Taken together, our data suggest that COX-2 deficient mice are resistant to many of the detrimental consequences of endotoxemia. These beneficial effects occur, in part, by a compensatory increase in IL-10 that counterbalances the pro-inflammatory host response to endotoxemia.
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PMID:Cyclooxygenase-2-deficient mice are resistant to endotoxin-induced inflammation and death. 1273 99

The effects of selective ((5,5-dimethyl-3-(3-florophenyl)-4-(4-methylsulphonyl-2(5H)-furanon); DFU) and (N-(2-cyclohexyloxy-4-nitrophenyl)-methansulphonamide; NS 398)) or non-selective (diclophenac and proquazon) inducible cyclooxygenase (COX-2) inhibitors on the survival, nitrite (stable product of nitric oxide (NO) as an index for inducible NO synthase (iNOS) activity) and 6-keto-prostaglandin F(1alpha) (6-keto-PGF(1alpha), stable product of prostacyclin as an index for COX-2 activity) production in serum, lungs, brain and/or kidney were investigated in endotoxin-induced sepsis model in mice. Endotoxin (10 mg x kg(-1), i.p.)-induced mortality was prevented by DFU, NS 398 and proquazon (0.1, 10 and 1 mg x kg(-1), respectively) and enhanced 2.6-fold with 0.1mg x kg(-1) diclophenac. Endotoxin-induced increase in the serum levels of nitrite was only inhibited by 10 mg x kg(-1) diclophenac. Endotoxin caused a significant decrease only in the brain levels of nitrite without affecting 6-keto-PGF(1alpha) levels in all tissues. The decreased levels of nitrite induced by endotoxin is further reduced by 0.1mg x kg(-1) DFU and 1 and 10mg x kg(-1) diclophenac while 10 mg x kg(-1) DFU and 1mg x kg(-1) proquazon increased it. On the other hand, 1mg x kg(-1) diclophenac and proquazon, and 10 mg x kg(-1) NS 398 increased the endotoxin-induced lung levels of 6-keto-PGF(1alpha). The results suggest that the COX inhibitors may have different effects on the survival and NO production depending on tissue and dose.
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PMID:Effects of cyclooxygenase inhibitors on nitric oxide production and survival in a mice model of sepsis. 1277 May 13

Adrenomedullin (ADM) is upregulated in cardiac tissue under various pathophysiological conditions. However, the direct inotropic effect of ADM on normal and compromised cardiomyocytes is not clear. In rat ventricular myocytes, ADM produced an initial (<30 min) increase in cell shortening and Ca(2+) transient and, on prolonged incubation (>1 h), a marked decrease in cell shortening and Ca(2+) transient. Both effects were sensitive to inhibition by the ADM antagonist ADM-(22-52). The increase and decrease in cell shortening and Ca(2+) transient were attenuated by pretreatment with indomethacin [a nonspecific cyclooxygenase (COX) inhibitor], nimesulide and SC-236 (specific COX-2 inhibitors), and tranylcypromine (a prostacyclin synthase inhibitor); SQ-29548 (a thromboxane receptor antagonist) was without effect. Cells isolated from LPS-treated rats that were in the late, hypodynamic phase of septic shock also showed a marked decrease in cell shortening and Ca(2+) transient. Because ADM is overexpressed in sepsis, we repeated the above protocol in cells isolated from LPS-treated rats. At 4 h after LPS injection, ADM levels markedly increased in plasma, ventricles, and freshly isolated ventricular myocytes. Decreases in cell shortening and Ca(2+) transient in LPS-treated cells were reversed by pretreatment with ADM-(22-52). Anti-ADM (rat) IgG also reversed the decrease in cell shortening and other parameters of cell kinetics. Indomethacin, SC-236, and tranylcypromine restored cell contractility and the decrease in Ca(2+) transient, whereas SQ-29548 had no effect, implying that prostacyclin played a role in both effects. However, with regard to cell-shortening kinetics, indomethacin and SQ-29548 decreased the amount of time taken by the cells to return to baseline, whereas SC-236 and tranylcypromine did not, implying that not only prostacyclin, but also thromboxane, is involved. The results indicate that ADM interacts with COX to yield prostanoids, which mediate its negative inotropic effect in LPS-treated rat ventricular myocytes.
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PMID:Role of cyclooxygenase in ventricular effects of adrenomedullin: is adrenomedullin a double-edged sword in sepsis? 1476 77

Besides cyclooxygenase and NO-synthase, another distinct endothelial pathway, endothelium-dependent hyperpolarization (EDHF), is involved in the relaxation of the vascular smooth muscle cells. EDHF has been demonstrated unequivocally in various blood vessels from different species, including human, and is likely to play an important role in cardiovascular physiology. This alternative pathway involves the activation of two populations of endothelial potassium channels, the small conductance and intermediate conductance calcium-activated potassium channels (SK(Ca) and IK(Ca), respectively). EDHF-mediated responses are clearly altered in various pathological conditions (ageing, hypertension, atherosclerosis, hypercholesterolemia, heart failure, ischemia-reperfusion, angioplasty, eclampsia, diabetes, sepsis). Therapeutic or adjutant interventions (angiotensin converting enzyme inhibitors, antagonist of the angiotensin receptor, estrogen, omega-3 polyunsaturated fatty acids, polyphenol derivatives, potassium and/or calcium intake) can restore these responses, suggesting that the improvement of the EDHF pathway contributes to the observed beneficial effect of these various substances. However, the improvement or restoration of EDHF responses has not been, yet, the direct purpose of any pharmaceutical effort. Activating endothelial IK(Ca) and/or SK(Ca) or increasing their expression as well as improving myo-endothelial communication, for instance by increasing the expression of connexin(s), could become interesting therapeutic targets.
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PMID:EDHF: new therapeutic targets? 1502 34

The aim of this study was to test the hypothesis that ongoing aspirin therapy preserves neutrophil apoptosis after cardiac surgery with cardiopulmonary bypass (CPB) by a cyclooxygenase mechanism. Twenty patients undergoing coronary revascularization with CPB were enrolled in a prospective cohort study. Patients who had continued taking 300 mg of aspirin until the day before surgery (n = 10) were compared with 10 patients not taking aspirin or who had discontinued it more than 5 days before surgery. Neutrophils were isolated from arterial blood before and 6 h after surgery and apoptosis was measured after 24 h in culture using flow cytometry. Serum was collected and assessed for IL-6, IL-8 and PGE2 by enzyme-linked immunoabsorbant assay. Patients were followed for clinical indices of sepsis for 7 days postoperatively. Spontaneous rates of neutrophil apoptosis were significantly reduced in postoperative compared with preoperative samples. There was no difference between aspirin and control preoperative neutrophil apoptosis rates (23.0% +/- 11.3% vs. 23.0% +/- 20.7%, P = 0.99). Postoperative neutrophil apoptosis was delayed in control patients (3.6% +/- 1.2% apoptosis), but this was significantly (P = 0.045) reversed in the aspirin-treated group (7.2% +/- 5.1% apoptosis). There were lower postoperative PGE2 levels in the aspirin group (136 +/- 69 pg/mL vs. 372 +/- 210 pg/mL, P = 0.04). There was no difference in clinical indices of sepsis. We conclude that the delay in postoperative neutrophil apoptosis is significantly preserved in patients taking 300 mg of aspirin on the day before surgery. This was associated with greater inhibition of PGE2, consistent with the hypothesis that aspirin exerts its effect on apoptosis after CPB via a cyclooxygenase-mediated mechanism.
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PMID:Aspirin preserves neutrophil apoptosis after cardiopulmonary bypass. 1516 76

Epidemiologic studies have indicated that high intake of saturated fat and/or animal fat increases the risk of colon and breast cancer. Omega-3 PUFAs in fish oil (FO) can inhibit the growth of human cancer cells in vitro and in vivo. These effects are related to the uptake of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) into the cellular substrate pool and their competitive metabolism with arachidonic acid (AA) at the cyclooxygenase and 5-lipoxygenase levels. The metabolites of EPA and DHA have less inflammatory and immunosuppressant potency than the substances derived from AA. Based on previous experimental data, we hypothesized that FO supplementation after major abdominal cancer surgery would improve hepatic and pancreatic function. Ours was a prospective, randomized, double-blinded clinical trial on 44 patients undergoing elective major abdominal surgery, randomly assigned to receive total parenteral nutrition (TPN) supplemented with either soybean oil (SO 1.0 g/kg body weight daily, n = 20) for 5 days or a combination of FO and SO (FO 0.2 + SO 0.8 g/kg body weight daily, n = 24). Compared to pure SO supplementation in the postoperative period, FO significantly reduced ASAT [0.8 +/- 0.1 vs. 0.5 +/- 0.1 mmol/(l. sec)], ALAT [0.9 +/- 0.1 vs. 0.6 +/- 0.1 mmol/(l. sec)], bilirubin (16.1 +/- 5.3 vs. 6.9 +/- 0.6 mmol/l), LDH (7.7 +/- 0.4 vs. 6.7 +/- 0.4 mmol/(l. sec) and lipase (0.6 +/- 0.1 vs. 0.4 +/- 0.1 micromol/(l. sec) in the postoperative course. Moreover, patients with increased risk of sepsis (IL-6/IL-10 ratio >8) showed a tendency to shorter ICU stay (18 hr) under omega-3 PUFA treatment. Weight loss as encountered after the SO emulsion of 1.1 +/- 2.2 kg was absent in the FO group. After major abdominal tumor surgery, FO supplementation improved liver and pancreas function, which might have contributed to the faster recovery of patients.
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PMID:Omega-3 fatty acids improve liver and pancreas function in postoperative cancer patients. 1523 41

Sepsis is a systemic inflammatory response to a blood-borne infection that is associated with an extremely high rate of morbidity and mortality. The present article reviews our recent studies involving the role of cyclooxygenase (COX)-2 in host responses to bacterial endotoxemia and its role in the regulation of nitric oxide synthase (NOS)2 and heme oxygenase (HO)-1. COX-2-deficient (-/-) mice display a blunted and delayed induction of the cytokine-inducible genes NOS2 and HO-1 after administration of Escherichia coli lipopolysaccharide (LPS or endotoxin). Translocation and activation of transcription factors important for signaling events during an inflammatory response, such as nuclear factor-kappaB and activating protein-1, are also reduced. In addition, COX-2(-/-) mice have reduced leukocyte infiltration into critical organs (kidneys and lungs) after LPS administration. Interestingly, the absence of COX-2 does not alter the LPS induction of several proinflammatory cytokines in tissue macrophages, but induction of the antiinflammatory cytokine interleukin-10 is exaggerated. After LPS administration, 50% of wild-type (+/+) mice die; however, COX-2(-/-) mice display a dramatic improvement in survival during endotoxemia. Taken together, our findings suggest that COX-2(-/-) mice are resistant to many of the detrimental consequences of endotoxemia.
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PMID:Alteration in heme oxygenase-1 and nitric oxide synthase-2 gene expression during endotoxemia in cyclooxygenase-2-deficient mice. 1534 45

Prostacyclin (PGI(2)) has beneficial cytoprotective properties, is a potent inhibitor of platelet aggregation and has been reported to improve microcirculatory blood flow during sepsis. The formation of PGI(2) in response to proinflammatory cytokines is catalysed by the inducible cyclooxygenase (COX) isoform COX-2. Recombinant human activated protein C (rhAPC, drotrecogin alfa (activated)) was shown to have multiple biological activities in vitro and to promote resolution of organ dysfunction in septic patients. Whether rhAPC exerts its beneficial effects by modulating prostanoid generation is unknown up to now. It was therefore the aim of the study to examine the in vitro effect of rhAPC on COX-2-mRNA-expression and PGI(2) release from human umbilical vein endothelial cells (HUVEC). We found that rhAPC, at supra-therapeutical concentrations (500 ng/ml-20 microg/ml), upregulated the amount of COX-2-mRNA in HUVEC at t=3-9 h and caused a time- and dose-dependent release of 6-keto PGF(1 alpha), the stable hydrolysis product of prostacyclin. RhAPC further increased the stimulating effect of tumor necrosis factor-alpha (TNF-alpha) and thrombin on COX-2-mRNA-levels. Transcript levels of cyclooxygenase-1 (COX-1) and prostaglandin 12 synthase, however, were unaffected by the stimulation with rhAPC or thrombin. The upregulatory effect on COX2-mRNA levels was specific for rhAPC since the zymogen protein C in equimolar concentrations had no effect on COX-2-mRNA-levels or 6-keto PGF(1 alpha)-release. Western Blot analysis revealed an increase of COX-2-protein content in HUVEC after treatment with rhAPC. As shown by experiments using monoclonal antibodies against the thrombin receptor PAR-1 (mAb=ATAP2) and against the endothelial protein C receptor (EPCR; mAb=RCR-252), the effect of rhAPC on COX-2-mRNA upregulation was mediated by binding to the EPCR-receptor and signaling via PAR-1. These results demonstrate that induction of COX-2-expression is an important response of HUVEC to stimulation with rhAPC and may represent a new molecular mechanism, by which rhAPC promotes upregulation of prostanoid production in human endothelium.
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PMID:Recombinant human activated protein C upregulates cyclooxygenase-2 expression in endothelial cells via binding to endothelial cell protein C receptor and activation of protease-activated receptor-1. 1584 23

Bacterial endotoxin produces sepsis associated with alterations in body temperature (fever or hypothermia). The intraperitoneal administration of bacterial endotoxin, lipopolysaccharide (LPS; 50 microg/mouse) led to a decrease in colonic temperature starting 1 hr after the injection. The hypothermic effect was accompanied by a significant increase in hypothalamic leukotriene B4 (LTB4) and prostaglandin E2 (PGE2) levels. 5-lipoxygenase inhibitor, zileuton (200 and 400 mg/kg, po) administered 30 min before LPS challenge significantly prevented hypothermia. However, non-selective cyclooxygenase inhibitor, indomethacin (10, 20 mg/kg, po) did not reverse the hypothermic response. Further, pretreatment of mice with zileuton prevented LPS-stimulated increase in hypothalamic LTB4 levels and caused a relatively small increase in PGE2 levels. Indomethacin had no effect on LTB4 levels but it reduced PGE2 levels. These results suggest a possible involvement of leukotrienes in LPS-induced hypothermia and the potential protective role of 5-lipoxygenase inhibitors in endotoxemia.
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PMID:Effect of 5-lipoxygenase inhibitor against lipopolysaccharide-induced hypothermia in mice. 1635 26

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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