Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the pathogenesis of cholera, cyclic adenosine monophosphate, 5-hydroxytryptamine, prostaglandins, and the function of neuronal structures have been implicated. To elucidate the role of different isoforms of cyclooxygenase (COX)-1 and COX-2, selective COX-2 inhibitors were used. The selective COX-2 inhibitors NS-398 and DFU completely suppressed cholera toxin-induced prostaglandin E2 biosynthesis and caused a dose-dependent inhibition of cholera toxin-induced fluid secretion in the rat jejunum in vivo. Constitutive expression of COX-1 but also of COX-2 mRNA was found in mucosal scrapings of the rat jejunum. Cholera toxin had no effect on COX-1 as well as COX-2 mRNA expression. Treatment of rats with dexamethasone did not effect cholera toxin-induced prostaglandin E2 biosynthesis and did not influence the expression of COX-2 mRNA, further substantiating that cholera toxin does not cause an induction of COX-2 mRNA. Treatment of rats with E. coli lipopolysaccharide caused a marked increase in COX-2 mRNA expression that was inhibited by dexamethasone. In conclusion, the results provide evidence that cholera toxin, in addition to other mediators, uses prostaglandin E2 to exert its secretory effect and that in the case of cholera toxin prostaglandins are metabolized via COX-2.
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PMID:Mechanisms of cholera toxin-induced diarrhea. 1119 97

The mechanisms of diarrhea in Asiatic cholera have been studied extensively. Cyclic AMP, 5-hydroxytryptamine, prostaglandins, and the function of neuronal structures have been implicated in the pathogenesis of cholera. To elucidate the role of the different isoforms (COX-1 and COX-2) of cyclooxygenase in cholera toxin (CT)-induced fluid secretion and intraluminal prostaglandin E(2) (PGE(2)) release in the rat jejunum in vivo, the effects of the COX-2 inhibitors NS-398 ([N-(2-cyclohexaloxy-4-nitrophenyl)methanesulfonamide]) and DFU [5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl-2(5H)-furanone], and of the COX-1 inhibitor SC-560, were studied. Net fluid transport was measured gravimetrically and PGE(2) by radioimmunoassay. COX-1 and COX-2 mRNA expression were determined by reverse transcription-polymerase chain reaction (RT-PCR) and COX-2 protein by Western blot analysis in mucosal scrapings. CT caused profuse net fluid secretion in all control rats. The COX-2 inhibitors NS-398 and DFU, but not the COX-1 inhibitor SC-560 or dexamethasone, dose-dependently inhibited CT-induced fluid secretion and PGE(2) release. RT-PCR showed expression of COX-1 and of COX-2 mRNA in control rats. CT did not induce an increase and dexamethasone did not reduce COX-2 mRNA, whereas lipopolysaccharide caused a marked induction of COX-2 mRNA, which was inhibited by dexamethasone. A weak band of COX-2 protein was observed in controls; however, CT enhanced COX-2 levels, which remained unaffected by dexamethasone. It can be assumed that post-transcriptional modulation is responsible for CT-induced increase in COX-2 protein. COX-1 does not seem to be involved. Therefore, PGE(2) produced by COX-2 seems to be responsible for the profuse fluid secretion induced by CT, and COX-2 appears to be a specific target for the treatment of Asiatic cholera.
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PMID:Cholera toxin induces prostaglandin synthesis via post-transcriptional activation of cyclooxygenase-2 in the rat jejunum. 1135 14

The present study was designed in order to clarify the mechanisms of diminished phosphoinositide (PI) hydrolysis by lipopolysaccharide (LPS) in blood vessels. In vitro pretreatment of rat aortic strips with LPS (1 microg/ml) for 10 or 24 hrs inhibited 5-hydroxytryptamine (5-HT, 100 microM)-induced inositol monophosphate accumulation in a time-dependent manner. Coincubation of the aortas with N(G)-monomethyl-L-arginine (LNMMA, 1 mM) completely prevented the early diminution of 5-HT-stimulated PI hydrolysis after 10-hr exposure to LPS but did not affect the delayed diminution after 24-hr exposure. Coincubation with cycloheximide (1 microM) did not prevent the delayed LPS-induced diminution of phosphoinositide hydrolysis. Tetraethylammonium (10 mM) did not restore the diminished phosphoinositide hydrolysis after 24-hr exposure to LPS, suggesting that the diminution is not due to K+ channel activation. Sodium fluoride (10 mM)-induced inositol monophosphate accumulation was also decreased in the aortic strips after LPS incubation for 24 hrs, and this decrease was not prevented by coincubation with LNMMA. LPS incubation time-dependently increased nitric oxide (NO) production in the aortas, which was completely inhibited by LNMMA or cycloheximide. These results suggest that NO is mainly involved in the inhibitory action of LPS on stimulated-PI hydrolysis in the early stage, while in the later stage, a factor(s) besides NO causes attenuation of the stimulated-PI hydrolysis.
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PMID:Nitric oxide-dependent and -independent inhibition by lipopolysaccharide of phosphoinositide hydrolysis in vascular smooth muscle. 1172 88

We have explored the effects of bacterial endotoxin (lipopolysaccharide; LPS) on the response of the airways of Brown Norway (BN) rats to adenosine. Comparisons have been drawn with the effects on responses to methacholine and 5-hydroxytryptamine. In vehicle-challenged animals, adenosine, given i.v. was only a weak bronchoconstrictor. In contrast, 1 h following intratracheal administration of LPS, 0.3 mg kg-1, bronchoconstrictor responses to adenosine were markedly and selectively enhanced. At this time point, there were no significant changes in leukocyte numbers, eosinophil peroxidase and myeloperoxidase activities or protein concentrations in bronchoalveolar lavage (BAL) fluid. Twenty-four hours after challenge, the sensitivity of the airways to both adenosine and methacholine was reduced relative to the earlier time point and there were substantial increases in each marker of inflammation in BAL fluid. The bronchoconstrictor response to adenosine was blocked selectively by methysergide, disodium cromoglycate and the broad-spectrum adenosine receptor antagonist, 8-SPT, but not by DPCPX or ZM 243185, selective antagonists for the A1 and A2A receptors, respectively. Thus, the response to adenosine augmented following LPS is mast cell mediated and involves a receptor which can be blocked by 8-SPT but not by selective A1 or A2A receptor antagonists. It thus bears similarity to the augmented response to adenosine induced by allergen challenge in actively sensitized BN rats. Exposure to LPS could be a factor along with allergen in determining the increased sensitivity of the airways of asthmatics to adenosine.
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PMID:Airway hyperresponsiveness to adenosine induced by lipopolysaccharide in Brown Norway rats. 1197 75

The mechanism underlying lipopolysaccharide (LPS)-induced depression of phosphoinositide (PI) hydrolysis was investigated using rat aortas. In LPS-pretreated aortas, the 5-hydroxytryptamine-stimulated accumulation of inositol monophosphate and incorporation of exogenous myo-inositol into PIs were significantly less than those in control aortas. Both sodium-myo-inositol cotransporter (SMIT) and phosphatidylinositol transfer protein (PITP) genes were constituently expressed in rat aortas. The mRNA level of SMIT was remarkably lower in LPS-pretreated aortas, while that of PITP mRNA was not affected by LPS. These results suggest that LPS-induced depression of SMIT expression is involved in inhibition of agonist-stimulated PI hydrolysis by LPS.
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PMID:Involvement of decreased myo-inositol transport in lipopolysaccharide-induced depression of phosphoinositide hydrolysis in vascular smooth muscle. 1202 50

In order to provide additional insight into the in vivo significance of serotonin [5-hydroxytryptamine (5-HT)] in inflammation, we examined its effect on the production of tumor necrosis factor (TNF)-alpha, IL-1alpha, IL-1beta, IL-6, IL-10 and IL-1 receptor antagonist in lipopolysaccharide (LPS)-stimulated human peripheral blood mononuclear cells (PBMC). 5-HT inhibited TNF-alpha production and increased IL-1beta production in PBMC. The level of IL-1beta-converting enzyme/caspase-1 remained unchanged, suggesting that the effect of 5-HT is not directly related to the IL-1beta maturation process. TNF-alpha mRNA and IL-1beta mRNA content did not change in the presence of 5-HT. 5-HT did not have any effect on the production of other cytokines studied. The inhibitory effect of 5-HT on TNF-alpha production was antagonized by ketanserin, a selective 5-HT(2A) antagonist, and mimicked by DOI, a selective 5-HT(2A/2C) agonist. These findings suggest that the inhibition of TNF-alpha production by 5-HT involves the participation of the 5-HT(2A) receptor subtypes in PBMC. Accordingly, we detected the presence of 5-HT(2A) receptors in PBMC by Western blot analysis. Our data support a role of 5-HT in inflammation through its effect on cytokine production in PBMC.
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PMID:Differential effect of serotonin on cytokine production in lipopolysaccharide-stimulated human peripheral blood mononuclear cells: involvement of 5-hydroxytryptamine2A receptors. 1257 53

The present study investigated the mechanisms involved in the increased 5-hydroxytryptamine (5-HT) vasoconstriction observed in rat middle cerebral arteries exposed in vitro to lipopolysaccharide (LPS, 10 microg x ml-1) for 1-5 h. Functional, immunohistochemical and Western blot analysis and superoxide anion measurements by ethidium fluorescence were performed. LPS exposure increased 5-HT (10 microm) vasoconstriction only during the first 4 h. In contrast to control tissue, indomethacin (10 microm), the COX-2 inhibitor NS 398 (10 microm), the TXA2/PGH2 receptor antagonist SQ 29548 (1 microm) and the TXA2 synthase inhibitor furegrelate (1 microm) reduced 5-HT contraction of LPS-treated arteries from hour one. The iNOS inhibitor aminoguanidine (0.1 mm) increased 5-HT contraction from hour three of LPS incubation. The superoxide anion scavenger superoxide dismutase (SOD, 100 U ml-1) and the H2O2 scavenger catalase (1000 U ml-1), as well as the respective inhibitors of NAD(P)H oxidase and xanthine oxidase, apocynin (0.3 mm) and allopurinol (0.3 mm), reduced 5-HT contraction after LPS incubation. LPS induced an increase in superoxide anion levels that was abolished by PEG-SOD. Subthreshold concentrations of the TXA2 analogue U 46619, xanthine/xanthine oxidase and H2O2 potentiated, whereas those of sodium nitroprusside inhibited, the 5-HT contraction. COX-2 expression was increased at 1 and 5 h of LPS incubation, while that of iNOS, Cu/Zn-SOD and Mn-SOD was only increased after 5 h. All the three vascular layers expressed COX-2 and Cu/Zn-SOD. iNOS expression was detected in the endothelium and adventitia after LPS. In conclusion, increased production of TXA2 from COX-2, superoxide anion and H2O2 enhanced vasoconstriction to 5-HT during the first few hours of LPS exposure; iNOS and SOD expression counteracted that increase at 5 h. These changes can contribute to the disturbance of cerebral blood flow in endotoxic shock.
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PMID:Mechanisms involved in the early increase of serotonin contraction evoked by endotoxin in rat middle cerebral arteries. 1453 51

The effects of endotoxin (ET) on spontaneous contractility and of carbachol- and alpha-methyl-5-hydroxytryptamine-(alpha-M-5-HT; 5-HT2 receptor agonist) induced contractions of smooth muscle preparations from the bovine abomasal antrum were investigated in vitro. Preparations from the abomasal antrum of freshly slaughtered healthy dairy cows were cut parallel to the longitudinal and circular fibres, suspended in isolated organ baths, and contractility was recorded and analyzed, using digitalized data. The traits maximum amplitude, time till maximum amplitude, frequency, basal tone, and area under curve were calculated. The contractile effect of Carbachol (CH) was concentration dependent. Repeated administration of CH (3.75 x 10(-6) M), each time interrupted by flushing of the organ baths, did not reveal any significant effect on contractility traits of CH-induced contractions. Endotoxin (10 micrograms/ml; lipopolysaccharide from E. coli, O26:B6) significantly reduced some of the spontaneously occurring contractility traits and of carbachol-(3.75 x 10(-6) M) and alpha-M-5-HT-induced (2.14 x 10(-5) M) contractions. The effects of higher and lower concentrations of ET occurred less consistently. The inhibitory effect of endotoxin was more pronounced after 6 hours as compared to 2 hours of incubation. The results of the present study (i) support the hypothesis of a possible role of endotoxin in reducing motility of the abomasum during the development of spontaneous abomasal displacement in dairy cows, and (ii) may serve as the basis for the development of an in vitro model of abomasal displacement with endotoxemia for future studies on the effect of motility modulating drugs.
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PMID:Effect of endotoxins on contractility of smooth muscle preparations from the bovine abomasal antrum. 1498 52

There is evidence from both human and animal research that 5-hydroxytryptamine (5-HT)3 receptor antagonists, particularly tropisetron, exert analgesic and antiinflammatory effects. However, the underlying mechanisms of these effects have not yet been investigated in detail. Therefore, the antiinflammatory effects of tropisetron and ondansetron were investigated in human monocytes. In human monocytes, both lipopolysaccharide (LPS)-stimulated tumour necrosis factor (TNF)-alpha and interleukin (IL)-1beta secretion were dose-dependently inhibited by tropisetron starting at a concentration of 5 microg/mL and reaching maximal levels at 25 microg/mL (IC50: 32 microg/mL and 12 microg/mL, respectively). LPS-induced IL-6 and PGE2 release was only slightly inhibited at high doses, whereas LPS-induced release of IL-8 and matrix metalloprotease (MMP)-9 was not affected. In conclusion, our data show that the binding of tropisetron to 5-HT3 receptors results in antiinflammatory effects through inhibition of TNF-alpha/IL-1beta, which might explain the antiphlogistic effects of 5-HT3 antagonists.
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PMID:Antiinflammatory effects of 5-HT3 receptor antagonists in lipopolysaccharide-stimulated primary human monocytes. 1551 9

1 The airways of patients with asthma are hyperresponsive to adenosine. The phenomenon can be mimicked in the actively sensitized Brown Norway rat by exposure to allergen or lipopolysaccharide (LPS). We wondered whether combined treatment with allergen and endotoxin would result in additive effects or synergism with respect to increasing the sensitivity of the airways of the Brown Norway rat to adenosine. 2 Animals actively sensitized to ovalbumin and challenged intratracheally with allergen or endotoxin manifested increased bronchoconstrictor responses to adenosine. A combination of ovalbumin and endotoxin also increased the response to adenosine but the effects were at best additive. 3 Changes in the response to adenosine were selective as responses to 5-hydroxytryptamine were unaltered following ovalbumin or LPS either alone or in combination. 4 Thus, endotoxin and allergen acting together could play a role in up-regulating the response of the human asthmatic airway to adenosine. However, our data suggest that the interaction would be additive rather than synergistic.
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PMID:Effects of endotoxin and allergen alone and in combination on the sensitivity of the rat airways to adenosine. 1617 48


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