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: UNIPROT:P43026 (lipopolysaccharide)
62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Both tumor necrosis factor (TNF) and platelet-activating factor (PAF) are released during sepsis and are important mediators of septic lung injury. I investigated the interactions of TNF and PAF on vasoactive responses in the pulmonary circulation. In isolated rat lungs perfused with a cell- and plasma-free physiological salt solution, PAF (0.01- and 0.1-micrograms boluses) caused transient dose-dependent pulmonary arterial and venous constrictions. In vivo pretreatment of the rats with TNF (0.02 or 0.2 mg/kg i.v.) 1 h before lung isolation increased lung myeloperoxidase activity and markedly enhanced PAF-induced pulmonary vasoconstriction without affecting the pressor responses to angiotensin II or hypoxia. In contrast, pretreatment with lipopolysaccharide (10 mg/kg), which increased lung myeloperoxidase to the same extent as TNF, caused only a modest enhancement of PAF-induced vasoconstriction associated with reduced pressor responses to angiotensin II and hypoxia. Ex vivo perfusion of isolated lungs with TNF for 1 h did not affect PAF vasoconstriction. The TNF-induced potentiation of PAF vasoconstriction was not altered by depletion of circulating neutrophils with vinblastine but was blocked by Dazmegrel, a thromboxane synthase inhibitor. Thus, TNF potentiates PAF-induced pulmonary vasoconstriction by an in vivo mechanism that is neutrophil independent but thromboxane dependent. This TNF-PAF interaction likely contributes to the development of pulmonary hypertension during sepsis.
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PMID:TNF potentiates PAF-induced pulmonary vasoconstriction in the rat: role of neutrophils and thromboxane A2. 789 27

Tumor necrosis factor alpha (TNF alpha) and thromboxane A2 (TXA2) are major products of the activated alveolar macrophage and serve as key mediators of lung injury. In order to determine if the synthesis of TXA2 and the release of TNF alpha are associated, the production of these inflammatory agents by the human alveolar macrophage (AM), as a result of activation by lipopolysaccharide (LPS), was assessed in the absence and presence of the thromboxane synthase inhibitors UK 38,485 (Dazmegrel) and OKY 046. UK 38,485 and OKY 046 inhibited both LPS-stimulated TXA2 production and TNF alpha release in a dose-dependent manner. Prostaglandin E2 (PGE2) production was not increased by UK 38,485 or OKY 046. Neither LPS nor UK 38,485 had any effect on LTB4 production by AM. Neither UK 38,485 or OKY 046 had any effect on LPS-stimulated interleukin-1 beta release. However, the TXA2 mimetic, U46619, did not stimulate TNF alpha release by AM either in the absence or presence of UK 38,485. These findings suggest that 1) UK 38,485 and OKY 046 are inhibitors of both TXA2 production and TNF alpha release by activated human AM, 2) UK 38,485 probably does not exert its inhibitory action on TNF alpha release through effects on eicosanoid production and 3) the possibility that TNF alpha- and TXA2-induced lung injury may be subject to amelioration by imidazole-based compounds should be further evaluated.
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PMID:An inhibitor of thromboxane production attenuates tumor necrosis factor release by activated human alveolar macrophages. 823 28

G 619 is 3-carbamyl-(3'-picolyl)-4-methoxy-1-benzamide. The compound is structurally related to picotamide, a previously reported dual thromboxane synthase inhibitor/thromboxane A2 receptor antagonist, which displays inhibitory activity on tumor necrosis factor-alpha. The aim of the present work was to study the effect of G 619 on tumor necrosis factor-alpha synthesis both in vivo and in vitro. Salmonella enteritidis lipopolysaccharide was used to induce tumor necrosis factor-alpha production. Septic shock was produced in male rats by a single intravenous (i.v.) injection of 20 mg/kg (LD90) of Salmonella enteritidis lipopolysaccharide. Rats were pretreated with G 619 (50 mg/kg, i.v.) or vehicle (1 ml/kg, i.v.) 1 h before endotoxin challenge. Salmonella enteritidis lipopolysaccharide administration dramatically reduced survival rate (0%, 72 h after endotoxin administration), reduced mean arterial blood pressure, increased plasma levels of thromboxane B2 and 6-keto-prostaglandin F1 alpha and enhanced serum levels of tumor necrosis factor. Furthermore, endotoxic shock produced characteristic gastric damage, consisting of haemorrhagic infiltrates. Pretreatment with G 619 in vivo significantly protected against Salmonella enteritidis lipopolysaccharide-induced lethality (80% survival rate and 60% survival rate 24 h and 72 h after Salmonella enteritidis lipopolysaccharide injection, respectively), reduced hypotension, decreased plasma thromboxane B2 and serum tumor necrosis factor-alpha levels and enhanced blood levels of 6-keto-prostaglandin F1 alpha. In rat peritoneal macrophages, G 619 in vitro (25, 50 and 100 microM) significantly blunted (P < 0.001) Salmonella enteritidis lipopolysaccharide-stimulated production of tumor necrosis factor-alpha, whereas it increased 6-keto-prostaglandin F1 alpha and cyclic AMP levels. The present data indicate that G 619 may be useful during disease states characterized by elevated tumor necrosis factor-alpha levels.
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PMID:G 619, a dual thromboxane synthase inhibitor and thromboxane A2 receptor antagonist, inhibits tumor necrosis factor-alpha biosynthesis. 856 49

Thromboxane A2(TxA2) is a potent vasoconstrictor associated with cerebrovascular disease and is thought to be synthesized within tissues of the brain. In order to determine the cellular sources of TxA2 in the central nervous system (CNS), we measured the release of the stable metabolite TxB2 in cultures of mixed or highly enriched populations of brain glia. Using techniques which isolated large numbers of highly enriched microglia and astroglia, we found that only microglia release TxB2. Moreover, microglia, not astroglia, contain the requisite synthetic enzyme thromboxane synthase. Phagocytic signals and lipopolysaccharide are potent stimulants of microglial release of thromboxane, with lesser effects shown by platelet activating factor and substance P. We conclude that microglia, when activated, are the principal source of brain-derived thromboxane and may help to control vascular flow at sites of acute CNS injury.
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PMID:Activated microglia are the principal glial source of thromboxane in the central nervous system. 880 90

Using morphological, immunocytochemical, and functional parameters we have previously shown that highly purified adult rat microglial cells undergo a process of "activation" when cultured in a serum-containing medium in the absence of added proinflammatory substances or other factors (Slepko and Levi: Glia 16:241-246, 1996). Here we studied the lipopolysaccharide (LPS)-evoked production of two prostanoids, thromboxane A2 (measured as thromboxane B2) (TXB2) and prostaglandin E2 (PGE2), as a function of microglial "activation." LPS induced a greater time- and dose-dependent release of TXB2, compared to PGE2, in the less "activated" cells. Further "activation" led to amplified synthesis of PGE2 and not of TXB2, so that the TXB2/PGE2 ratio changed from 2.2 to 0.25 between the 2nd and 4th day in culture. Western blot experiments showed that the LPS-evoked expression of the inducible form of cyclooxygenase (COX) was markedly higher in cells exhibiting a more "activated" phenotype. The expression of the constitutive isoform of COX was low in all conditions, was slightly greater in more "activated" cells, and was not affected by LPS. Neither progression in microglial "activation" nor LPS treatment enhanced thromboxane synthase activity. We hypothesize that reorientation of prostanoid synthesis toward a major production of PGE2 in the more "activated" cells can be largely attributed to an increased inducibility of cellular COX expression, combined with the inability of thromboxane synthase to cope with the increased availability of the COX product prostaglandin H2 (PGH2), the common precursor of TXA2 and PGE2. In view of the different, and at times opposite, functional activity of TXB2 and PGE2, the described change in prostanoid production pattern may contribute to the role of "activated" microglia in inflammation and host defense.
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PMID:Reorientation of prostanoid production accompanies "activation" of adult microglial cells in culture. 926 Jul 40

Both nitric oxide and arachidonic acid metabolites have been implicated in pathogenesis of septic shock. We have recently described a model of endotoxin-induced acute lung injury in rats in which nitric oxide synthase is inhibited. The possible interplay between nitric oxide and eicosanoids (thromboxane A2, prostacyclin) in this model have been presently studied. Animals were randomly assigned to four experimental groups which received the following treatment. 1. Lipopolysaccharide (LPS) infusion only, 2 mg.kg-1min-1 during 10 min (LPS group). 2. N omega-Nitro-L-Arginine 10 mg.kg-1 (L-NNA, nitric oxide synthase inhibitor) pretreatment followed by LPS infusion (L-NNA + LPS group). 3. L-NNA and camonagrel 25 mg.kg-1 (CAM, thromboxane synthase inhibitor) pretreatment followed by LPS infusion (L-NNA + CAM + LPS group). 4. L-NNA and iloprost 0.3 microgram.kg-1.min-1(ILO, stable analog of prostacyclin) pretreatment followed by LPS infusion (L-NNA + ILO + LPS group). LPS infusion resulted in a biphasic response in mean arterial blood pressure. A transient but deep fall in arterial blood pressure was followed by a long-lasting hypotension that led to death after 278 +/- 49 min. L-NNA + LPS rats died within 22 +/- 5 min among the symptoms of systemic hypotension and acute lung injury. In L-NNA + CAM + LPS group a significant attenuation of early phase of hypotension occurred and survival time was comparable with that of the LPS group (298 +/- 68 min). In rats of the L-NNA + ILO + LPS group survival time increased insignificantly to 48 +/- 41 min. It is concluded that immediate deleterious effects of lipopolysaccharide in NO-deficient rats are at least partially mediated by thromboxane A2 while prostacyclin cannot replace NO in its pneumoprotective action.
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PMID:Pneumotoxicity of lipopolysaccharide in nitric oxide-deficient rats is limited by a thromboxane synthase inhibitor. 944 13

We present for the first time direct continuous assay of NO concentration (porphyrinic sensor) in the lung parenchyma of Sprague-Dawley rats in vivo during endotoxemia. Intravenous infusion of lipopolysaccharide (LPS, 2 mg x kg(-1) x min(-1) for 10 minutes) stimulated an acute burst of NO from constitutive NO synthase (NOS) that peaked 10 to 15 minutes after the start of LPS infusion, mirroring a coincident peak drop in arterial pressure. NO concentration declined over the next hour to twice above pre-LPS infusion NO levels, where it remained until the rats died, 5 to 6 hours after LPS infusion. The chronic drop in arterial pressure observed from 70 minutes to 6 hours after the start of LPS infusion was not convincingly mirrored by a chronic increase in NO concentration, even though indirect NO assay (Griess method, assaying NO decay products NO2-/NO3-) showed that NO production was increasing as a result of continuous NO release by inducible NOS. A NOS inhibitor, N(omega)-nitro-L-arginine (L-NNA, 10 mg/kg i.v.) injected 45 minutes before LPS infusion, resulted in sudden death accompanied by macroscopically/microscopically diagnosed symptoms similar to acute respiratory distress syndrome <25 minutes after the start of LPS infusion. Pharmacological analysis of this L-NNA+LPS model by replacing L-NNA with 1-amino-2-hydroxy-guanidine (selective inhibitor of inducible NOS) or by pretreatment with S-nitroso-N-acetyl-penicillamine (NO donor), camonagrel (thromboxane synthase inhibitor), or WEB2170 (platelet-activating factor receptor antagonist) indicated that in the early acute phase of endotoxemia, LPS stimulated the production of cytoprotective NO, cytotoxic thromboxane A2, and platelet-activating factor.
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PMID:Protective role of pulmonary nitric oxide in the acute phase of endotoxemia in rats. 956 42

In the present study, we have investigated the effects of nitric oxide (NO) synthase inhibition on mortality in lipopolysaccharide (LPS)-induced sepsis in mice. Serum nitrite levels peaked at 15 h after an injection of LPS (10 mg kg-1, i.p.). Aminoguanidine, a selective inducible NO synthase (iNOS) inhibitor, at a dose of 100 mg kg-1 significantly reduced the LPS-induced increase in nitrite levels and improved mortality. Econazole, iNOS inhibitor, calmodulin antagonist, 5-lipoxygenase and a specific thromboxane synthase inhibitor, at a 1 mg kg-1 dose significantly decreased the LPS-induced increase in nitrite levels, but increased mortality 4. 9-fold when compared to the LPS group (control). Indomethacin, a putative iNOS and non-selective cyclo-oxygenase (COX) inhibitor, of 1, 10 and 100 mg kg-1, dose dependently decreased the LPS-induced increase in nitrite levels. This decrease was significantly different from the control at 10 and 100 mg kg-1 dose levels. When indomethacin (100 mg kg-1) was combined with aminoguanidine (100 mg kg-1), LPS-induced nitrite levels were significantly attenuated. NO precursor, L-arginine, was added to this combination in order to test the inhibition of iNOS activity which resulted in no change in nitrite levels. An indomethacin and aminoguanidine combination increased mortality twofold when compared to the control. The addition of L-arginine to the combination enhanced the mortality rate to 1.5-fold. These results suggest that NO appears to play a role in the LPS-induced septic shock model in mice. The improvement in sepsis-induced mortality enhanced by aminoguanidine by the inhibition of iNOS but not with the other agents or combinations should be re-evaluated in order to make an appropriate choice of the therapeutic target. In addition, it may also suggest that other mediators, such as arachidonic acid products and cytokines play a role in septic shock pathogenesis as well. (c) 1998 The Italian Pharmacological Society.
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PMID:Effects of nitric oxide synthase inhibition in lipopolysaccharide-induced sepsis in mice. 980 22

Enhanced prostanoid generation has been implicated in vascular abnormalities occurring during endotoxemia and sepsis, and the lung is particularly prone to such events. Prostanoids are generated from arachidonic acid (AA) via cyclooxygenase (COX)-1 or -2, both isoenzymes recently demonstrated to be expressed in different lung cell types. Upregulation of COX may underlie the phenomenon that endotoxin [lipopolysaccharide (LPS)]-exposed lungs show markedly enhanced vasoconstrictor responses to secondarily applied stimuli (priming). Isolated rat lungs were perfused with a physiological salt buffer solution in the absence and presence of 1.5% rat plasma and exposed to different concentrations of LPS (1,000 or 10,000 ng/ml) during a 2-h priming period. No change in physiological variables was noted during this period, although enhanced baseline liberation of both thromboxane (Tx) A(2) and PGI(2) as well as of tumor necrosis factor (TNF)-alpha was evident compared with that in control lungs in the absence of LPS. LPS priming caused a significant elevation in AA-induced pulmonary arterial pressure, ventilation pressure, and lung weight gain. Concomitant increased levels of TxA(2) were found in the buffer perfusate. All changes were largely suppressed by three selective, structurally unrelated COX-2 inhibitors (NS-398, DUP-697, and SC-236) in both buffer- and buffer-plasma-perfused lungs. Anti-TNF-alpha neutralizing antibodies were ineffective under conditions of buffer perfusion. In the presence of plasma components, manyfold augmented TNF-alpha generation was noted, and anti-TNF-alpha antibodies significantly suppressed the increase in ventilation pressure but not in the vascular pressor response and lung edema formation. We conclude that the propensity of LPS-primed lungs to respond with enhanced vasoconstriction, edema formation, and bronchoconstriction to a secondarily applied stimulus proceeds nearly exclusively via COX-2 and increased Tx formation, with TNF-alpha generation being involved in the change in bronchomotor reactivity in the presence of plasma constituents. In context with recent immunohistological investigations, LPS-induced upregulation of the COX-2-thromboxane synthase axis in vascular and bronchial smooth muscle cells is suggested to underlie these events.
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PMID:Endotoxin priming of the cyclooxygenase-2-thromboxane axis in isolated rat lungs. 1083 25

Intravenous administration of lipopolysaccharide to rats that had been immunized with lipopolysaccharide induced hemorrhagic damage in the large intestine. We investigated the role of 5-lipoxygenase and thromboxane synthase products in the damage of the large intestine induced by lipopolysaccharide. In the large intestine of lipopolysaccharide-immunized rats, intravenous injection of lipopolysaccharide increased the vascular permeability, production of leukotriene B(4), leukotriene C(4)/D(4), thromboxane B(2) and prostaglandin E(2), and also increased the activity of myeloperoxidase, a marker enzyme of neutrophils. Oral administration of E3040 (6-hydroxy-5,7-dimethyl-2-(methylamino)-4-(3-pyridylmethyl)benzothiazole), a novel dual inhibitor of 5-lipoxygenase and thromboxane synthase, at 30 and 100 mg/kg inhibited the increase in vascular permeability induced by lipopolysaccharide in the large intestine. E3040 inhibited the production of leukotriene B(4) and thromboxane B(2) and tended to increase the production of prostaglandin E(2) in the large intestine. Sulfasalazine (500 mg/kg) and prednisolone (10 mg/kg), drugs used for the treatment of inflammatory bowel disease, had no significant effect on eicosanoid production and vascular permeability. These results indicate that E3040 inhibits the production of both leukotriene B(4) and thromboxane B(2) and prevents lipopolysaccharide-induced damage in the large intestine of lipopolysaccharide-immunized rats.
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PMID:Effect of E3040, an inhibitor of 5-lipoxygenase and thromboxane synthase, on rat bowel damage induced by lipopolysaccharide. 1155 69


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