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)

The effects of indomethacin, a cyclooxygenase inhibitor, upon plasma concentrations of prostaglandin E2 (PGE2), the febrile response, and metabolic and hematological alterations induced by lipopolysaccharide (LPS) were studied. Experimental endotoxemia was provoked via i.p. injection of 1.0 mg E coli LPS/kg in rats (group A). Indomethacin was introduced/os (2.5 mg/kg) 30 min prior to LPS challenge (group B). Pretreatment with this medication completely inhibited the hyperthermic response to LPS and eliminated the LPS-induced non-specific symptoms of anorexia, adipsia, reduced locomotory activity and gastrointestinal troubles. Plasma PGE2 concentrations increased as early as the 2nd h after the LPS challenge but were blocked when endotoxin application was preceded by indomethacin treatment. Indomethacin did not significantly influence hematological parameters. The dynamics of hematocrit and erythrocyte counts were similar in both groups with a decrease up to the 2nd h followed by an increase to maximum at post-treatment day 3. Pretreatment with indomethacin did not influence the endotoxin-induced leukopenia observed at the 2nd h or the accompanying neutropenia and left shift. Cyclooxygenase inhibition affected total protein concentrations; they were decreased in the early hours of the study (hours 4-6) in both groups. The later tendency towards increase in total protein concentrations was more expressed in animals from group B. Changes in blood glucose were characterized by a permanent tendency towards decrease after hour 2 of LPS challenge up to day 6 (group A). In group B, a similar tendency was observed, but glucose concentrations decreased between hours 2-6 and then returned to initial values.
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PMID:Effects of indomethacin on lipopolysaccharide-induced plasma PGE2 concentrations and clinical pathological disorders in experimental endotoxemia. 946 1

1 The characterization of the B1 kinin receptor, and some mediators involved in the inflammatory response elicited by intrathoracic (i.t.) administration of des-Arg9-bradykinin (BK) in the mouse model of pleurisy, was investigated. 2 An i.t. injection of des-Arg9-BK (10-100 nmol per site), a selective B1 agonist, caused a significant and dose-related increase in the vascular permeability observed after 5 min, which peaked at 1 h, associated with an increase in cell influx, mainly neutrophils, and, to a lesser extent, mononuclear cell influx, peaking at 4 h and lasting for up to 48 h. The increase in fluid leakage caused by des-Arg9-BK was completely resolved 4 h after peptide injection. I.t. injection of Lys-des-Arg9-BK (30 nmol per site) caused a similar inflammatory response. 3 Both the exudation and the neutrophil influx elicited by i.t. injection of des-Arg9-BK were significantly antagonized (P<0.01) by an i.t. injection of the selective B1 antagonists des-Arg9-[Leu8]-BK (60 and 100 nmol per site) or des-Arg9-NPC 17731 (5 nmol per site), administered in association with des-Arg9-BK (P<0.01), or 30 and 60 min before the cellular peak, respectively. In contrast, an i.t. injection of the B2 bradykinin selective receptor antagonist Hoe 140 (30 nmol per site), at a dose which consistently antagonized bradykinin (10 nmol per site)-induced pleurisy, had no significant effect on des-Arg9-BK-induced pleurisy. 4 An i.t. injection of the selective tachykinin receptor antagonists (NK1) FK 888 (1 nmol per site), (NK2) SR 48968 (20 nmol per site) or (NK3) SR 142801 (10 nmol per site), administered 5 min before pleurisy induction, significantly antagonized neutrophil migration caused by i.t. injection of des-Arg9-BK. In addition, FK 888 and SR 142801, but not SR 48968, also prevented the influx of mononuclear cells in response to i.t. injection of des-Arg9-BK (P<0.01). However, the NK3 receptor antagonist SR 142801 (10 nmol per site) also significantly inhibited des-Arg9-BK-induced plasma extravasation. An i.t. injection of the calcitonin gene-related peptide (CGRP) receptor antagonist CGRP8-37 (1 nmol per site), administered 5 min before pleurisy induction, inhibited des-Arg9-BK-induced plasma extravasation (P<0.01), without significantly affecting the total and differential cell migration. 5 The nitric oxide synthase inhibitors L-NOARG and L-NAME (1 pmol per site), administered 30 min beforehand, almost completely prevented des-Arg9-BK (i.t.)-induced neutrophil cell migration (P<0.01), and, to a lesser extent, mononuclear cell migration (P<0.01). The D-enantiomer D-NAME had no effect on des-Arg9-BK-induced pleurisy. At the same dose range, L-NOARG and L-NAME inhibited the total cell migration (P<0.01). L-NAME, but not L-NOARG caused significant inhibition of des-Arg9-BK-induced fluid leakage. Indomethacin (1 mg kg(-1), i.p.), administered 1 h before des-Arg9-BK (30 nmol per site), inhibited the mononuclear cell migration (P<0.05), but, surprisingly, increased the neutrophil migration at 4 h without interfering with plasma extravasation. The administration of terfenadine (50 mg kg(-1), i.p.), 30 min before des-Arg9-BK (30 nmol per site), did not interfere significantly with the total cell migration or with the plasma extravasation in the mouse pleurisy caused by i.t. injection of des-Arg9-BK. 6 Pretreatment of animals with the lipopolysaccharide of E. coli (LPS; 10 microg per animal, i.v.) for 24 h did not result in any significant change of the inflammatory response induced by i.t. injection of des-Arg9-BK compared with the saline treated group. However, the identical treatment of mice with LPS resulted in a marked enhancement of des-Arg9-BK induced paw oedema (P<0.01). 7 In conclusion, we have demonstrated that the inflammatory response induced by i.t. injection of desArg9-BK, in a murine model of pleurisy, is mediated by stimulation of constitutive B1 receptors. (These responses are largely mediated by release of neuropeptides such as substanceP or CGRP and also by NO, but products derived from cyclo-oxygenase pathway and histamine seem not to be involved. Therefore, these results further support the notion that the B1 kinin receptor has an important role in modulating inflammatory responses, and it is suggested that selective B1 antagonists may provide therapeutic benefit in the treatment of inflammatory and allergic conditions.
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PMID:Characterization of the receptor and the mechanisms underlying the inflammatory response induced by des-Arg9-BK in mouse pleurisy. 948 17

We hypothesized that endotoxin (LPS) would impair vasoconstrictor-agonist-induced calcium (Ca2+) mobilization by a nitric oxide (NO)-dependent mechanism. We incubated bovine aortic myocytes (passages 16 to 23) for 22 to 24 hours with 0 to 1.0 mg/ml Escherichia coli lipopolysaccharide (LPS). Medium (Dulbecco's modified Eagle's medium (DMEM) + 10% fetal bovine serum (FBS)) was assayed for nitrite (chemiluminescence), and myocytes were loaded with fura-2 acetoxymethyl ester (fura-2AM), after which we assessed basal and thrombin (10 U/ml)-induced peak Ca2+ mobilization by microspectrofluorimetry. LPS (0.01 to 1.0 mg/ml) led to dose-dependent nitrite accumulation, which was blocked by coincubation with N(omega)-nitro-L-arginine methyl ester (L-NAME, 1 mmol/L). LPS also impaired Ca2+ responses in a dose-dependent manner (from -13% at 0.1 mg/ml to -47% at 1.0 mg/ml, n = 8 to 43/dose). However, coincubation with L-NAME did not ameliorate the Ca2+ mobilization defect (peak Ca2+ increments: control = 419 +/-30 nmol/L, vs LPS (1 mg/ml) = 206+/-18 nmol/L (mean+/-SE), n = 15; p < 0.001; control/L-NAME: 417+/-31 nmol/L vs LPS/L-NAME: 212+/-19 nmol/L; n = 17 p < 0.001), despite inhibition of associated nitrite accumulation in the medium (control vs LPS: p < 0.001; control/L-NAME vs LPS/L-NAME: p > 0.05; LPS vs LPS/L-NAME: p < 0.001). Supplemental L-arginine augmented LPS-induced nitrite generation without affecting Ca2+ mobilization. Indomethacin failed to prevent the LPS-induced decrement in thrombin response, but did inhibit LPS-induced myocyte nitrite production, suggesting "crosstalk" between the NO-synthase and cyclo-oxygenase (COX) systems. These experiments suggest that LPS-induced vascular contractile impairment is at least partly mediated by an NO-independent impairment of agonist-induced myocyte Ca2+ mobilization. This further suggests that any important contribution of NO synthesis to LPS-induced contractile dysfunction must depend on impairment of the Ca2+ sensitivity of the contractile apparatus (i.e., pharmacomechanical coupling).
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PMID:Endotoxin impairs agonist-induced calcium mobilization in bovine aortic myocytes by a nitric oxide-independent mechanism. 957 87

Infections are associated with a specific behavioral pattern that includes hypomotility, hypophagia, increased sleep, decreased libido, and decreased exploration. This behavioral response is considered adaptive and important for the survival of the animal. A similar behavioral pattern was observed following treatment with endotoxin (lipopolysaccharide [LPS]) and cytokines, such as interleukin-1 (IL-1). Because the secretion of these cytokines is induced by LPS and infections, it is possible that they mediate the behavioral responses to infection. We have studied ingestive behavior and locomotor activity in mice following infection with influenza virus, or injection of LPS, IL-1, or IL-6. A lethal dose of influenza virus, LPS, IL-1a and IL-1b each decreased the intake of sweetened condensed milk and 24-hour food pellet intake and decreased locomotor activity. Mouse IL-6 was ineffective. A sublethal dose of influenza virus decreased food pellet intake and locomotor activity, but did not significantly alter milk intake. Indomethacin prevented the behavioral responses to IL-1, and attenuated those to LPS, but had only a very small effect on those to influenza virus. Similar results were obtained with the IL-1-receptor antagonist (IL-1ra); it completely prevented the responses to IL-1, attenuated those to LPS, but, even after chronic high dose administration, attenuated the effects of influenza virus infection only slightly. Our results suggest that while IL-1 may play an important role in the responses to infection, IL-6 does not. Moreover, IL-1 cannot be the only factor contributing to the altered behavior of LPS-injected or influenza virus-infected mice.
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PMID:The role of cytokines in infection-related behavior. 962 84

The interaction between endogenous nitric oxide (NO), elicited by administration of Escherichia coli lipopolysaccharide, and cyclooxygenase system, in ethanol-induced injury in rat gastric mucosa, was investigated. Administration of graded doses of lipopolysaccharide reduced the gastric mucosal injury in response to ethanol. The ex vivo production of both nitrite and prostaglandin E2 was increased in dose-related manner by lipopolysaccharide. Pretreatment with dexamethasone, L-N6-(1-Iminoethyl)lysine(dihydrochloride) and L-NG-nitro arginine methyl ester inhibited the protection associated with lipopolysaccharide treatment and the ex vivo production of both, nitrite and prostaglandin E2. The pretreatment with L-arginine counteracted the decrease of nitrite and prostaglandin E2 production in lipopolysaccharide-treated rats in which nitric oxide synthesis was blocked by L-N6-(1-Iminoethyl)lysine(dihydrochloride). Administration of sodium nitroprusside and S-nitroso-N-acetyl-D,L-penicillamine caused a dose related enhancement in the accumulation of prostaglandin E2. Indomethacin administration and N-(2-Cyclohexyloxy-4-nitrophenyl)methanesulfonamide were ineffective in suppressing lipopolysaccharide-mediated protection against ethanol-induced damage, and in suppressing ex vivo increase of nitrite whereas the ex vivo increase of prostaglandin E2 was prevented in a dose-related fashion. These results indicate that in ethanol-induced rat gastric injury, endogenous NO elicited by lipopolysaccharide or released by NO donors is able to activate the cyclooxygenase pathway, and the protective effect of lipopolysaccharide is dependent upon NO formation.
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PMID:Nitric oxide enhances prostaglandin production in ethanol-induced gastric mucosal injury in rats. 965 40

The inducible isoform of nitric oxide synthase (iNOS) is expressed after systemic administration of lipopolysaccharide (LPS). The importance of expression of iNOS in blood vessels is poorly defined. Because nitric oxide from iNOS may alter vasomotor function, we examined effects of LPS on vasomotor function in carotid arteries from iNOS-deficient mice. We studied contraction of the carotid artery from wild-type and iNOS-deficient mice in vitro 12 h after injection of LPS (20 mg/kg ip). Contractile responses to PGF2alpha (3-30 microM) and thromboxane A2 analog (U-46619; 3-100 nM) were evaluated using vascular rings from mice treated with vehicle or LPS. Maximum force of contraction generated by rings in response to PGF2alpha was 0.39 +/- 0.02 and 0.25 +/- 0.01 (SE) g (n = 14) in vehicle and LPS-treated wild-type mice, respectively (P < 0.001 vs. vehicle). Thus LPS reduced constrictor responses in wild-type mice. Thiocitrulline and aminoguanidine (inhibitors of iNOS) improved contractile responses from LPS-treated wild-type vessels. Indomethacin also improved constrictor responses in arteries from wild-type mice injected with LPS. In contrast, contraction of the carotid arteries in response to PGF2alpha and U-46619 was not impaired in LPS-treated iNOS-deficient mice, and contraction was not altered by inhibitors of iNOS. Expression of iNOS mRNA was confirmed using RT-PCR in carotid arteries from wild-type mice after injection of LPS but not vehicle. PCR products for iNOS were not observed in iNOS-deficient mice. These findings provide the first direct evidence that iNOS mediates impairment of vascular contraction after treatment with LPS.
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PMID:Vascular effects of LPS in mice deficient in expression of the gene for inducible nitric oxide synthase. 968 28

Inhibitors of cyclooxygenases prevent fever. The purpose of this study was to test the hypothesis that selective and dual inhibitors of the other enzyme systems of arachidonic acid oxygenation (i.e., lipoxygenase and epoxygenase) affect the time course or magnitude of fever in mice. Swiss Webster mice kept at 30 degreesC ambient temperature were implanted with biotelemeters to monitor body temperature. Fever was induced by intraperitoneal injection of lipopolysaccharide at doses from 10 micrograms/kg to 2.5 mg/kg. Phenidone (20-30 mg/kg ip), a dual lipoxygenase and cyclooxygenase inhibitor, prevented fever in these mice, but esculetin (1-10 mg/kg ip), a selective inhibitor of lipoxygenases, did not affect fever. Intramuscular injection of nordihydroguaiaretic acid (10-20 mg/kg), a dual lipoxygenase and epoxygenase inhibitor, as well as SKF-525A (5 mg/kg ip) and clotrimazole (20 mg/kg im), inhibitors of the cytochrome P-450/epoxygenase pathway, augmented fever in mice. Indomethacin (5 mg/kg ip), an inhibitor of cyclooxygenase, suppressed the exacerbation of fever due to clotrimazole, suggesting that the epoxygenase inhibitor-induced potentiation of fever in mice is a prostaglandin-mediated effect. From this study, we hypothesize that the cytochrome P-450/epoxygenase branch of the arachidonate cascade is involved in antipyresis and in controlling the upper limit of fever.
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PMID:Inhibitors of alternative pathways of arachidonate metabolism differentially affect fever in mice. 975 31

Nonsteroidal anti-inflammatory drugs (NSAIDs), which inhibit prostaglandin (PG) synthesis, augment production of tumor necrosis factor (TNF) in most experimental models. We investigated the effect of two NSAIDs, indomethacin and ibuprofen, on the production of TNF in the CNS induced by intracerebroventricular injection of lipopolysaccharide (LPS). Indomethacin and ibuprofen, administered intraperitoneally, augmented (three- to ninefold) the levels of TNF in serum and peripheral organs of mice injected intraperitoneally with LPS and in rats with adjuvant arthritis (up to a sevenfold increase). However, NSAIDs (intraperitoneally or intracerebroventricularly) did not increase brain TNF production induced by intravenous LPS. In fact, indomethacin decreased (1.4-1.8-fold) TNF levels in the spinal cord of rats with experimental autoimmune encephalomyelitis and in the cortex of rats with focal cerebral ischemia. Systemic administration of iloprost inhibited serum TNF levels after intraperitoneal LPS, whereas intracerebroventricular injection of iloprost or PGE2 did not inhibit brain TNF induced by intracerebroventricular LPS. Both peripheral and central TNF productions were inhibited by cyclic AMP level-elevating agents or dexamethasone. Thus, a PG-driven negative feedback controls TNF production in the periphery but not in the CNS.
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PMID:Nonsteroidal anti-inflammatory drugs increase tumor necrosis factor production in the periphery but not in the central nervous system in mice and rats. 979 31

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

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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