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)

Prostaglandins (PGs) released by cultured rat Kupffer cells in response to stimulation with lipopolysaccharide (LPS) or ethanol were extracted from culture media, separated by HPLC and measured by radioimmunoassay. LPS (0.5-5 micrograms/ml) enhanced, after a 3-4 hrs lag period, the production of PGE2 (7-10 fold by 24 hrs), thromboxane B2 (2-3 fold) and PGD2. PG 6-keto-F1 alpha, PGF2 alpha (20-50% each). This effect was not inhibited by 30 microM aspirin but was reduced by dexamethasone. Ethanol (25-85 mM) gradually increased the release of PGE2 (40-90% by 24 hrs) and other PGs (10-30%), with 30 microM aspirin eliminating this effect. When added together with LPS, ethanol potentiated the endotoxin action. We suggest that LPS causes synthesis of the inducible cyclooxygenase-2 form in Kupffer cells, whereas ethanol exerts its effect via the pre-existing cyclooxygenase-1 mainly by increasing the free arachidonic acid content.
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PMID:Secretion of prostaglandins elicited by lipopolysaccharide and ethanol in cultured rat Kupffer cells. 748 10

The effect of aniso-osmotic exposure on the level of inducible cyclooxygenase (Cox-2) and on prostanoid synthesis was studied in cultured rat liver macrophages (Kupffer cells). In lipopolysaccharide (LPS)- or phorbol 12-myristate 13-acetate-stimulated Kupffer cells, hyperosmotic (355 mosmol/l) exposure, due to addition of NaCl or impermeant sugars, markedly increased prostaglandin (PG) E2, D2 and thromboxane B2 synthesis in a time- and osmolarity-dependent manner. Increased prostanoid production was observed about 8 h after exposure to LPS in hyperosmotic medium compared to Kupffer cells treated with LPS under normotonic (305 mosmol/l) conditions. A similar stimulatory effect of hyperosmolarity on PGE2 production was also seen when arachidonate was added exogenously. Hyperosmotic stimulation of PGE2 production was accompanied by a strong induction of Cox-2 mRNA levels and an increase in immunoreactive Cox-2, whereas the levels of immunoreactive phospholipase A2 and cyclooxygenase-1 did not change significantly. Dexamethasone, indomethacin and the selective Cox-2 inhibitor, NS-398, abolished the hypertonicity-induced stimulation of PGE2 formation; dexamethasone also prevented the increase in Cox-2 mRNA and protein. The increase of immunoreactive Cox-2 lasted for about 24 h and was also blocked by actinomycin D or cycloheximide, but not by brefeldin A. Tunicamycin or treatment with endoglucosidase H reduced the molecular mass of hypertonicity-induced Cox-2 by 5 kDa. Tunicamycin treatment also suppressed the hypertonicity-induced stimulation of PGE2 production. The hyperosmolarity/LPS-induced stimulation of prostaglandin formation was partly sensitive to protein kinase C inhibition but was not accompanied by an increase in the cytosolic free Ca2+ concentration. The data suggest that osmolarity may be a critical factor in the regulation of Cox-2 expression and prostanoid production in activated rat liver macrophages.
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PMID:Hyperosmolarity stimulates prostaglandin synthesis and cyclooxygenase-2 expression in activated rat liver macrophages. 749 3

The discovery of a second cyclooxygenase has provided fresh impetus to the search for new anti-inflammatory drugs. The second enzyme is effectively absent from healthy tissues but its levels rise dramatically during inflammation. It can be induced in migratory cells by bacterial lipopolysaccharide, cytokines and growth factors. The constitutive cyclooxygenase-1 (COX-1) can thus be considered a "housekeeping" enzyme, in contrast to cyclooxygenase-2 (COX-2) which is activated by tissue damage. Both enzymes have a molecular weight of around 70 kDa and similar Km and Vmax values for their reaction with arachidonic acid. Several non steroid anti-inflammatory drugs which have more than 1,000 fold selectivity for COX-2 over COX-1 are in the early stages of drug development.
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PMID:New insights into the mode of action of anti-inflammatory drugs. 766 22

To examine the possible role of increased vascular permeability in the circulatory shock induced by endotoxin (lipopolysaccharide), we examined whether lipopolysaccharide elicits plasma extravasation in the skin of ddY strain mice. We also studied whether nitric oxide (NO) and prostaglandins may mediate the lipopolysaccharide-induced increase in vascular permeability. Subcutaneous injection of lipopolysaccharide (100-400 micrograms/site) induced a dose-related and delayed increase in vascular permeability at the injection site as determined by the leakage of pontamine sky blue. Concurrent administration of aminoguanidine (a putative inducible NO synthase inhibitor) (10 mg/kg, i.v.) inhibited the lipopolysaccharide (400 micrograms/site)-induced dye leakage by 71%. N(G)-Nitro-L-arginine methyl ester (an inhibitor for both constitutive and inducible NO synthase) (10 and 20 mg/kg, i.v.) inhibited the lipopolysaccharide-induced dye leakage by 36% and 54%, respectively, whereas the inactive enantiomer, N(G)-nitro-D-arginine methyl ester (10 mg/kg, i.v.), had no effect. Pretreatment with an intraperitoneal injection of dexamethasone (500 micrograms/kg) or indomethacin (a cyclooxygenase-1 and -2 inhibitor) (5 mg/kg) almost completely inhibited the response induced by lipopolysaccharide, by 96% and 84%, respectively. [N-(2-Cyclohexyloxy-4-nitrophenyl) methanesulphonamide (a cyclooxygenase-2-specific inhibitor) (0.01-1 mg/kg, i.p.) also induced a dose-related inhibition of dye leakage elicited by lipopolysaccharide: 38% and 80% suppression at the doses of 0.1 and 1 mg/kg, respectively. Cycloheximide (a protein biosynthesis inhibitor) (35 mg/kg, s.c.) suppressed the effect of lipopolysaccharide by 74%. These results suggest that the increase in vascular permeability induced by lipopolysaccharide is mediated by both NO and prostaglandins and that synthesis of inducible NO synthase and cyclooxygenase-2 may be involved in this effect of lipopolysaccharide.
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PMID:Role of nitric oxide and prostaglandins in lipopolysaccharide-induced increase in vascular permeability in mouse skin. 866 58

Cyclooxygenase (COX) is the key rate-limiting enzyme in the synthesis of prostanoids from arachidonic acid. Two isoforms of COX have been described in mammalian cells, referred to as cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). COX-1 is a constitutively expressed enzyme; COX-2 is an inducible enzyme that appears to be expressed in inflamed tissue and following exposure to growth factors or cytokines, such as interleukin-1 (IL-1). The aim of the present study was to test if the antagonism on the binding of IL-1 to its cell-surface receptor by human recombinant IL-1 receptor antagonist (hrIL-1ra) may control the COX mRNA expression and prostaglandin E2 (PGE2) production by human monocyte cultures. Northern blot studies showed that hrIL-ra (500 ng/ml) had a strong inhibitory effect on inducible COX activity. The effect was evident after 6 hr incubation (2.7-fold decrease of mRNA COX-2 transcripts); and about a threefold decrease at 24hr incubation. A non-significant effect was observed with COX-1 transcripts. Induced PGE2 production by monocyte cultures treated with lipopolysaccharide (LPS) or interleukin-1 beta (IL-1 beta) was strongly inhibited in the presence of hrIL-1ra (500 ng/ml). In addition, a significant inhibition of COX-2 protein expression, as evaluated by Western blotting, was also observed. These data suggest that hrIL-1ra may be the key mediator in the down-regulation of the COX-2 inducible pathway.
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PMID:Down-regulation of cyclooxygenase-2 (COX-2) by interleukin-1 receptor antagonist in human monocytes. 895 57

The anti-pyretic effect of a selective cyclooxygenase-2 inhibitor, DFU (5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl-2(5H)-furano ne), was examined in conscious, un-restrained squirrel monkeys (Saimiri sciureus) using a radio telemetric system. Injection of bacterial endotoxin (lipopolysaccharide, 6 microg kg(-1), i.v.) in squirrel monkeys caused a gradual increase in core body temperature reaching a plateau of 2.07 +/- 0.17 degrees C above baseline at 2 h post-injection. Oral administration of DFU (1 mg kg(-1)) reduced, and DFU (3 mg kg(-1)) completely reversed the lipopolysaccharide-induced pyretic responses. The onset of action of DFU (about 30 min) is in good agreement with the pharmacokinetic profile of this compound in squirrel monkeys. The effect of DFU is comparable to that of a conventional non-selective non-steroidal anti-inflammatory drug (NSAID), diclofenac (3 mg kg(-1)). Since the plasma levels achieved for DFU at the dose employed in the present study are below the threshold required for inhibition of cyclooxygenase-1, it is concluded that the anti-pyretic effect of DFU can be attributed predominantly to an inhibitory action on cyclooxygenase-2. Thus, lipopolysaccharide-induced pyresis in squirrel monkeys can be used as a model for evaluation of anti-pyretic activity of cyclooxygenase inhibitors.
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PMID:A selective inhibitor of cyclooxygenase-2 reverses endotoxin-induced pyretic responses in non-human primates. 920 May 63

Macrophages exudating into inflammatory sites (thioglycollate-elicited macrophages, TGM) have a diminished ability to synthesize prostaglandins (PG) as compared with resident peritoneal macrophages (RM). Constitutive expression of cyclooxygenase-1 (COX-1) was lower in TGM than in RM but the releasability of arachidonic acid was not significantly different. Thus, the differences in expression of COX-1 were primarily responsible for the abilities of TGM and RM to synthesize PGE2 upon calcium ionophore (CaI) stimulation. COX-1 expression in RM and TGM was also correlated with their ability to synthesize PGE2 from exogenously added arachidonic acid. When exposed to lipopolysaccharide (LPS), the induction of COX-2 and the enhancement of PGE2 synthesis upon CaI were much lower in TGM as compared with RM the releasability of arachidonic acid upon CaI stimulation was relatively unchanged in RM but was reduced in TGM Thus, in TGM as compared with RM, a lower level of COX-1 expression and a lower level of COX-2 induction, and the reduction of arachidonate releasability by LPS exposure, are mainly responsible for lower PGE2 synthetic ability upon CaI stimulation. However, the different COX-2 induction by LPS in RM and TGM was not reflected in their increase in the ability to synthesize PGE2 from exogenously added arachidonic acid.
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PMID:Absence of relation between the expression of cyclooxygenase isoforms and the synthesis of prostaglandin E2 in resident and thioglycollate-elicited macrophages in rats. 967 17

Several enzymes play a role in vasodilation, including cyclooxygenase, which converts arachidonic acid into prostaglandins, and nitric oxide synthase, which converts arginine to citrulline and yields nitric oxide. The effects of endogenous and exogenous estrogen and lipopolysaccharide on uterine artery production of prostacyclin, and levels of cyclooxygenase and nitric oxide synthase were examined. Uterine arteries collected from ewes during the follicular (Day -1 to 0, Day 0 = estrus) or luteal (Day 10) phase were treated in vitro with lipopolysaccharide. In addition, ovariectomized ewes were treated in vivo with estradiol-17beta (5 microg/kg; 120 min) or a vehicle control; arteries from the uteri were treated in vitro with lipopolysaccharide. After 24 h of lipopolysaccharide treatment, culture media were collected for measurement of 6-keto-prostaglandin F1alpha (the stable metabolite of prostacyclin). These uterine arteries were homogenized, and the level of cyclooxygenase and nitric oxide synthase was determined by Western analysis. Lipopolysaccharide stimulated (p < 0.02) prostacyclin production by uterine arteries from both follicular- and luteal-phase sheep although phase of the estrous cycle did not affect prostacyclin responses (p = 0.56) to lipopolysaccharide. In contrast, uterine arteries from ovariectomized sheep treated with estradiol-17beta produced more prostacyclin (p < 0.001) in response to lipopolysaccharide than did uterine arteries from ovariectomized sheep treated with the vehicle control. There was no effect of phase (follicular or luteal) of the estrous cycle on either cyclooxygenase-1 or -2 gene expression. Lipopolysaccharide increased (p = 0.0002) gene expression of cyclooxygenase-2, but not cyclooxygenase-1, in both follicular- and luteal-phase ewes, which was significantly correlated (r2 = 0.91, p = 0.003) with uterine artery production of prostacyclin. Uterine arteries from follicular-phase sheep expressed significantly more nitric oxide synthase-III after lipopolysaccharide exposure than did uterine arteries from luteal-phase ewes (p = 0.03). In contrast, nitric oxide synthase-II was not detected in uterine arteries after lipopolysaccharide exposure. These results suggest that estrogen plays a role in regulating uterine artery responses to lipopolysaccharide.
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PMID:Estrogen and lipopolysaccharide stimulation of prostacyclin production and the levels of cyclooxygenase and nitric oxide synthase in ovine uterine arteries. 974 55

The enzymes cyclooxygenase-1 and cyclooxygenase-2 (COX-1 and COX-2) catalyze the conversion of arachidonic acid to prostaglandin (PG) H2, the precursor of PGs and thromboxane. These lipid mediators play important roles in inflammation and pain and in normal physiological functions. While there are abundant data indicating that the inducible isoform, COX-2, is important in inflammation and pain, the constitutively expressed isoform, COX-1, has also been suggested to play a role in inflammatory processes. To address the latter question pharmacologically, we used a highly selective COX-1 inhibitor, SC-560 (COX-1 IC50 = 0.009 microM; COX-2 IC50 = 6.3 microM). SC-560 inhibited COX-1-derived platelet thromboxane B2, gastric PGE2, and dermal PGE2 production, indicating that it was orally active, but did not inhibit COX-2-derived PGs in the lipopolysaccharide-induced rat air pouch. Therapeutic or prophylactic administration of SC-560 in the rat carrageenan footpad model did not affect acute inflammation or hyperalgesia at doses that markedly inhibited in vivo COX-1 activity. By contrast, celecoxib, a selective COX-2 inhibitor, was anti-inflammatory and analgesic in this model. Paradoxically, both SC-560 and celecoxib reduced paw PGs to equivalent levels. Increased levels of PGs were found in the cerebrospinal fluid after carrageenan injection and were markedly reduced by celecoxib, but were not affected by SC-560. These results suggest that, in addition to the role of peripherally produced PGs, there is a critical, centrally mediated neurological component to inflammatory pain that is mediated at least in part by COX-2.
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PMID:Pharmacological analysis of cyclooxygenase-1 in inflammation. 978 85

Lipopolysaccharide is an inflammatory agent and interleukin-1 is a cytokine. Their pro-inflammatory effects may be mediated by prostanoids produced by inducible cyclooxygenase-2. The aim of this study was to determine the prostanoids produced by lipopolysaccharide and interleukin-1 stimulated enterocytes through the cyclooxygenase-1 and 2 pathways. Cultured enterocytes were stimulated with lipopolysaccharide or interleukin-1beta with and without cyclooxygenase inhibitors. Low concentrations of indomethacin and valerylsalicylic acid (VSA) were evaluated as cyclooxygenase-1 inhibitors and their effects compared with the effects of a specific cyclooxygenase-2 inhibitor, SC-58125. Prostaglandin E2, 6-keto prostaglandin F1alpha, prostaglandin D2 and leukotriene B4 levels were determined by radioimmunoassay. Immunoblot analysis using isoform-specific antibodies showed that the inducible cyclooxygenase enzyme (COX-2) was expressed by 4 h in LPS and IL-1beta treated cells while the constitutive COX-1 remained unaltered in its expression. Interleukin-1beta and lipopolysaccharide stimulated the formation of all prostanoids compared with untreated cells, but failed to stimulate leukotriene B4. Indomethacin at 20 microM concentration, and VSA inhibited lipopolysaccharide and interleukin 1beta stimulated prostaglandin E2, but not 6-keto prostaglandin F1alpha formation. SC-58125 inhibited lipopolysaccharide and interleukin-1beta stimulated 6-keto prostaglandin F1alpha but not prostaglandin E2 release. The specific cyclooxygenase-2 inhibitor also inhibited lipopolysaccharide produced prostaglandin D2 but not interleukin-1beta stimulated prostaglandin D2. While SC-58125 inhibited basal 6-keto prostaglandin-F1alpha formation it significantly increased basal prostaglandin E2 and prostaglandin D2 formation. As SC-58125 inhibited lipopolysaccharide and interleukin-1beta induced 6-keto prostaglandin F1alpha production but not prostaglandin E2 production, it suggests that these agents stimulate prostacyclin production through a cyclooxygenase-2 mediated mechanism and prostaglandin E2 production occurs through a cyclooxygenase-1 mediated mechanism. Prostaglandin D2 production appeared to be variably produced by cyclooxygenase-1 or cyclooxygenase-2, depending on the stimulus.
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PMID:The role of cyclooxygenase-1 and cyclooxygenase-2 in lipopolysaccharide and interleukin-1 stimulated enterocyte prostanoid formation. 983 94


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