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)

Indoleamine 2,3-dioxygenase (molecular weight about 42,000) has been purified from rabbit intestines and contains one mole of protohaem IX as the sole prosthetic group. It catalyses the oxidative cleavage of the pyrrole ring of various indoleamines with a much broader specificity of substrate than tryptophan 2,3-dioxygenase. The enzyme has an absolute requirement for superoxide anion for catalytic activity. The enzyme was induced specifically in the lungs of mice for 24 h after administration of the lipopolysaccharide fraction of E. coli. This increase is due to synthesis of enzyme protein and is specific for the lipopolysaccharide fraction. These results are interpreted to mean that indoleamine dioxygenase is induced in pulmonary inflammatory processes in response to an increase in production of superoxide anion, 5-hydroxytryptamine or other indoleamines in the lung as a consequence of inflammation. The dioxygenase reaction is a more innocuous way of disposing of superoxide than dismutation.
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PMID:Specific induction of pulmonary indoleamine 2,3-dioxygenase by bacterial lipopolysaccharide. 25 62

Phenol, a major metabolite of benzene, is a potentially immunotoxic and neurotoxic substance of environmental significance. Male CD-1 mice were continuously exposed to 0, 4.7, 19.5, and 95.2 mg phenol/l in drinking water for 4 weeks. Various immune functions were evaluated and levels of selected neurotransmitters and metabolites measured in discrete brain regions. The doses of phenol did not produce any overt clinical signs of toxicity; peripheral red blood cell counts and hematocrits decreased. A dose of 95.2 mg/l suppressed the stimulation of cultured splenic lymphocytes by lipopolysaccharide, pokeweed mitogen, and phytohemagglutinin and the response in mixed lymphocyte cultures. The two high doses suppressed antibody production response to the T cell-dependent antigen (sheep erythrocytes), as determined by plaque-forming cells, and serum antibody levels. Mice treated with phenol had lower levels of neurotransmitters in several brain regions. In the hypothalamus, a major norepinephrine-containing compartment, the concentrations of norepinephrine significantly decreased by 29 and 40% in groups dosed with 19.5 and 95.2 mg/l, while dopamine concentrations decreased in the corpus striatum by 21, 26, and 35% at 4.7, 19.5 and 95.2 mg/l, respectively. Phenol also decreased 5-hydroxytryptamine in the hypothalamus, medulla oblongata, midbrain and corpus striatum. Levels of monoamine metabolites decreased in the hypothalamus (5-hydroxyindoleacetic acid), midbrain (vanillylmandelic acid), corpus striatum (vanillylmandelic acid and dihydroxyphenylacetic acid), cortex (vanillylmandelic acid), and cerebellum (dihydroxyphenylacetic acid).
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PMID:Immunological and neurobiochemical alterations induced by repeated oral exposure of phenol in mice. 144 16

Administration of either endotoxin (lipopolysaccharide, LPS) or interleukin-1 (IL-1) activates the hypothalamic-pituitary-adrenal axis and cerebral catecholamine systems. Because LPS can stimulate IL-1 production in vivo, it is possible that the effects of LPS are mediated by IL-1. This hypothesis was evaluated by comparing the neurochemical and corticosterone responses to i.p. LPS and IL-1. In addition, the possibility that LPS acts by penetrating the brain was examined by comparing the neurochemical responses to i.p. and i.c.v. administration. Intraperitoneal injection of LPS increased mouse brain concentrations of the norepinephrine catabolite, 3-methoxy,4-hydroxyphenylethyleneglycol (MHPG), the dopamine catabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), and the 5-hydroxytryptamine catabolite, 5-hydroxyindoleacetic acid (5-HIAA), and tryptophan in all brain regions examined. By contrast, i.p. IL-1 alpha and IL-1 beta increased cerebral concentrations of MHPG, 5-HIAA and tryptophan, but not DOPAC. The MHPG responses to IL-1 were substantially greater in hypothalamus than in other brain regions, whereas those to LPS were less regionally specific. The minimum effective doses of LPS and IL-1 were around 1 microgram and 10 ng, respectively. After i.p. LPS, plasma concentrations of corticosterone, DOPAC and MHPG peaked around 2 hr, whereas peak concentrations of tryptophan and 5-HIAA occurred around 8 hr. Intracerebroventricular LPS also elevated plasma corticosterone and cerebral concentrations of MHPG and 5-HIAA, but DOPAC was unchanged. LPS was not substantially more potent i.c.v. than i.p.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Endotoxin-induced activation of cerebral catecholamine and serotonin metabolism: comparison with interleukin-1. 160 2

1. Injection of lipopolysaccharide (LPS; 0.5-500 microgram kg-1) into mice induced a dose-dependent, slowly developing increase in hepatic content of 5-hydroxytryptamine (5-HT). This sustained increase could not be attributed to an LPS-induced alteration of the pharmacokinetic handling of 5-HT by stimulation of its uptake or inhibition of its degradation. 2. Regional differences were apparent in the tissue content of histamine and 5-HT between mast cell-deficient (W/Wv) and normal (+/+) mice. LPS administration (0.5 mg kg-1) gave comparable increases in the hepatic level of 5-HT in mast cell-deficient and normal mice. 3. Reserpine pretreatment (1 mg kg-1) selectively reduced 5-HT levels in the blood, spleen, liver, brain and lung of normal mice. Prior treatment with this agent also abolished the LPS (0.5 mg kg-1)-induced hepatic accumulation of 5-HT. 4. Accumulation of 5-HT in the liver by LPS (0.1 mg kg-1) was temporally associated with both a fall in the levels of circulating platelets, and a reduction in the concentration of 5-HT in the blood. The LPS dose-dependent (0.5-500 micrograms kg-1) increase in hepatic 5-HT content was associated with a similar dose-dependent reduction in the circulating levels of 5-HT. 5. Interleukin-1, alpha and beta (10 micrograms kg-1) and tumour necrosis factor alpha (TNF alpha) (1 mg kg-1) significantly enhanced the accumulation of 5-HT within the liver. Administration of TNF alpha (10 micrograms kg-1) potentiated the increase in hepatic 5-HT content seen with IL-1 beta (10 micrograms kg-1). 6. Electron microscopy revealed numerous platelets in the sinusoidal and perisinusoidal Disse spaces within the liver, in animals pretreated with LPS (0.1 mg kg '). The platelets retained their intact structure and showed no evidence of degranulation. 7. These data suggest that the LPS and cytokine-induced mobilization of 5-HT in the liver is associated with the hepatic translocation of platelets. This migration appears to be independent of platelet aggregation.
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PMID:The effect of lipopolysaccharide, interleukin-1 and tumour necrosis factor on the hepatic accumulation of 5-hydroxytryptamine and platelets in the mouse. 162 48

Our laboratory has been comparing the activity of a water extract of cotton bract (CBE) with the isolated trachealis smooth muscle of the dog, guinea pig, and cat. CBE induced contractions that were not mediated by 5-hydroxytryptamine (5-HT), histamine, or muscarinic receptors. The active agent(s) in CBE was dialyzable (less than 14,000 molecular weight), and substantial activity was retained after low-temperature ashing. CBE potentiated contractions of dog trachealis to histamine and 5-HT and relaxation responses to isoproterenol, whereas it had no effect on responses to methacholine and KCl. In the guinea pig trachealis, CBE reduced responsiveness to KCl, potentiated relaxations to adenosine and ATP, and did not alter the responses to the remaining agents. Responses of cat trachealis to KCl and isoproterenol were potentiated by CBE, while those to 5-HT were unaffected. Neurogenic cholinergic contractile responses were potentiated by CBE in the trachealis of the dog, but not of the guinea pig, while neurogenic relaxations were potentiated by CBE in guinea pig trachealis but not in the dog trachealis. There are thus marked species differences in the acute effects of CBE on airway smooth muscle. Due to recent interest in the possible involvement of bacterial endotoxins in the etiology of byssinosis, we examined the effects of E. coli lipopolysaccharide (LPS) in guinea pig trachealis. An initial examination revealed that LPS potentiated responses to histamine, but not those to methacholine and isoproterenol. This effect vanished upon a second appraisal with a different batch of LPS. The effect of LPS in airway smooth muscle is thus, at present, equivocal.
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PMID:An overview of species differences in the effects of a water extract of cotton bract on isolated airway smooth muscle, and effects of E. coli lipopolysaccharide. 301 94

Eosinophils are supposed to play a critical role in the pathology of several allergic diseases because after activation they can release toxic and proinflammatory agents. In this study we have investigated whether IgE-mediated rat pleurisy could be affected by an ongoing pleural eosinophilic inflammatory response. IgE-passively sensitized rats were challenged with an intrapleural (i.pl.) injection of allergen (dinitrophenylated bovine serum albumin, 1 microgram/cavity) and exudation assessed by measuring the amount of protein extravasated into the pleural cavity within 4 h. We have confirmed that lipopolysaccharide (LPS) stimulation (250 ng/cavity i.pl.) was followed by a marked pleural neutrophilia, apparent at 3 h, which was followed by an eosinophil accumulation noted within 48-72 h postchallenge. We have also confirmed that a boiled sample of LPS pleural washing (LPS-PW, 200 microliters i.pl.) caused selective eosinophilia in recipient rats. Pleural exudation remained unaltered when the allergenic challenge was performed 3 h after LPS in a condition of intense pleural fluid neutrophilia. In contrast, this was significantly reduced (P < .001) when the challenge occurred 72 h after LPS or 24 h after LPS-PW in selective pleural fluid eosinophilia. In another series of experiments repeated daily i.pl. injections of platelet-activating factor (PAF; 1 microgram/cavity) resulted in a progressive increase in eosinophil number recovered from the pleural cavity. The values were 1.2 +/- 0.2, 3.0 +/- 0.2, and 5.8 +/- 0.5 x 10(6) eosinophils/cavity (mean +/- SEM) after 0, 1, and 4 injections, respectively. Allergen challenge performed after 0, 1, or 4 PAF stimulations led to pleural protein levels of 88.6 +/- 5.7, 33.7 +/- 0.7, and 19.4 +/- 2.3 mg/cavity, respectively, indicating that the allergic pleurisy is inhibited in a manner dependent on the magnitude of eosinophil accumulation. Furthermore, the impairment of PAF-induced eosinophil accumulation by cetirizine (30 mg/kg i.p.) restored the exudatory response. Exudation triggered by compound 48/80 (25 micrograms/cavity), histamine (200 micrograms/cavity), or 5-hydroxytryptamine (100 micrograms/cavity) was not affected by four previous PAF daily injections. The findings indicate that allergen-induced exudation is selectively down-regulated in the eosinophil-enriched pleural space of rats, a suppression that increased with increasing eosinophil number and disappeared after chemical impairment of the eosinophilia.
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PMID:Pleural fluid eosinophils suppress local IgE-mediated protein exudation in rats. 756 15

1. Induction of the calcium-independent isoform of nitric oxide (NO) synthase (iNOS) in various cell types has been implicated in the circulatory failure in experimental models of septic shock. Tetrahydrobiopterin (BH4) appears to be an essential co-factor for NO formation and therefore an inhibition of its biosynthesis represents a feasible therapeutic target. We have investigated the effects of an inhibitor of BH4 synthesis, N-acetyl-5-hydroxytryptamine (N-acetylserotonin, NAS), on the expression of iNOS in cultured macrophages and smooth muscle cells in vitro, and on the hypotensive response to bacterial lipopolysaccharide (LPS) in the anaesthetized rat in vivo. 2. NAS (0.01-5 mM) caused a concentration-dependent inhibition of the accumulation of nitrite in the conditioned medium of LPS/interferon-gamma (IFN gamma)-stimulated RAW 264.7 macrophages and interleukin-1 beta (IL-1 beta)-activated vascular smooth muscle cells (VSMC). This effect was paralleled by a similar decrease in the iNOS protein content of these cells, as determined by immunoblot analysis. 3. Pretreatment of RAW 264.7 macrophages with the BH4 precursor, dihydrobiopterin (BH2, 0.1 mM) did not restore nitrite formation in the presence of NAS (1 mM). 4. Intravenous administration of NAS (1 mg kg-1 min-1 for 30 min) in anaesthetized rats significantly reduced the fall in mean arterial blood pressure, restored the pressor response to noradrenaline (1 micrograms kg-1), and ameliorated the increase in plasma nitrite following exposure to LPS (10 mg kg-1). 5. NAS pretreatment also attenuated iNOS activity in lung homogenates, as determined by the conversion of radiolabelled L-arginine to L-citrulline, and partially restored the constrictor effect of noradrenaline in aortic rings isolated from LPS-treated rats. Moreover, NAS significantly reduced the rise in the plasma concentration of tumour necrosis factor alpha (TNFalpha) in response to LPS.6. These findings suggest that NAS inhibits the expression rather than the activity of iNOS in cultured macrophages and smooth muscle cells. This effect of NAS appears to be independent of the availability of BH4, but may be related to an attenuation of the release of TNFalpha following LPS administration, as shown in the anaesthetized rat. This mechanism may also account for the beneficial haemodynamic effect of NAS in our experimental model of endotoxaemia.
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PMID:Inhibition by N-acetyl-5-hydroxytryptamine of nitric oxide synthase expression in cultured cells and in the anaesthetized rat. 758 41

1. Male Sprague-Dawley or Wistar rats were injected with bacterial lipopolysaccharide (LPS; 5 mg kg-1, i.p.) and killed after 1, 3, 6, 15, and 24 h. The brains, mesenteries, spleens, lungs, livers, kidneys, hearts, aortae and diaphragms were removed and frozen immediately. Control rats were injected with sterile saline and killed after 6 h. 2. The organs were homogenized in a semi-frozen state and NO synthase (NOS) activity measured in tissues from both LPS-treated and saline-treated groups by the ability of homogenates to convert [3H]-L-arginine to [3H]-L-citrulline in a NADPH-dependent manner. 3. The NOS activity in all organs taken from control animals was found to be calcium-dependent, with the highest activity being in the brain. After LPS-treatment an induced calcium-independent NOS was detected in all tissues tested, with the exception of the brain. The spleen, lung, mesentery and liver had the highest amounts of LPS-induced NOS activity. No induction of calcium-dependent NOS was detected. 4. Induction of NOS was maximum 6 h after administration of LPS and had returned to control levels in 24 h. 5. The constitutive NOS in brain and mesentery and the LPS-induced activities in the spleen, lung, liver and mesentery were inhibited by NG-monomethyl-L-arginine (L-NMMA) or NG-nitro-L-arginine methyl ester (L-NAME) according to concentration. The IC50 for L-NAME was 2.5 microM against the constitutive NOS from brain, and 20-25 microM against the inducible NOS. For L-NMMA the IC50 was 20-25 microM against either NOS isoform. 7. The vascular responses to endothelin-I (ET-1), the thromboxane A2-mimetic 11 alpha,9 alpha-epoxymethanoprostaglandin F2alpha (U46619), phenylephrine (PE) or 5-hydroxytryptamine (5-HT) were measured in the simultaneously perfused arterial and venous mesenteric vascular beds from both control and LPS-treated(6 h) rats. Vasoconstrictor responses to all agonists tested were unaffected by LPS treatment. In the presence of L-NAME (100 microM) vasoconstrictor responses were potentiated in both the arterial and venous portion of the mesenteric beds from both control and LPS-treated rats. The potentiation of responses to U46619 was significantly greater in beds from LPS-treated rats.8. Injection of LPS i.p. is associated with induction of NOS in all organs tested, except for the brain. In the mesentery this is not accompanied by a hyporesponsiveness to constrictor agents suggesting an increased sensitivity, particularly to U46619. This may explain the poor perfusion and tissue damage in the splanchnic circulation associated with sepsis.
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PMID:Induction by endotoxin of nitric oxide synthase in the rat mesentery: lack of effect on action of vasoconstrictors. 768 6

The neuroanatomical distribution of sites in the diencephalon and mesencephalon within which a prostaglandin (PG) of the E series elicits hyperthermia was characterized in Macaca mulatta and Macaca nemestrina. In 420 experiments undertaken in 13 animals, 225 loci were examined for their reactivity to PGE1 microinjected in a dose of 30 or 100 ng given in a volume of 1.0-1.5 microL. The regions of the brainstem for injection extended rostrally from the thermosensitive cells of the anterior hypothalamic, preoptic area (AH/POA) to the caudal border of the mesencephalon. Colonic and skin temperatures of the monkeys were measured continuously by thermistor probes. A hyperthermic response of > or = 0.5 degrees C and a latency of < or = 45 min was evoked by PGE1 within sites located primarily in the AH/POA. When PGE1 was microinjected at loci located caudal to the AH/POA, the elevation in body temperature (Tb) not only was less intense but rose at a slower rate. A higher concentration of PGE1 in these caudal regions was required to induce hyperthermia comparable with that elicited at loci within the AH/POA. In a second series of experiments either 1.0-5.0 micrograms 5-hydroxytryptamine (serotonin) or a concentration of 10(8) organisms/mL of Escherichia coli was microinjected at PGE1-reactive sites. A close anatomical concordance within the AH/POA of the animal was found in terms of the temporal characteristics and magnitude of the hyperthermia evoked by the indoleamine or lipopolysaccharide. The present results coincide with the reported neuroanatomical distribution of sites in the diencephalon and mesencephalon of other species in which PGE1 causes hyperthermia. Furthermore, these findings support the concept that the local neuronal mechanism of action of a pyrogen in the brainstem of the primate may involve phasic changes in the endogenous activity of both the serotonergic pathway and cyclo-oxygenase system in the AH/POA. In turn, their commonality of action suggests a functional similarity in their effect of shifting the set point for Tb.
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PMID:Anatomical distribution of brainstem sites where PGE1 induces hyperthermia in macaque species. 840 7

The effects of tumor necrosis factor-alpha (TNF-alpha) and lipopolysaccharide (LPS) were studied in porcine coronary arteries without endothelium. Rings of the artery were incubated in minimum essential medium with TNF-alpha or LPS for 6 or 24 h. After 6 h incubation, the rings were suspended in organ chambers filled with physiological salt solution containing indomethacin for the measurement of isometric force. The rings were contracted with prostaglandin F2 alpha before the addition of L-arginine. In rings treated with TNF-alpha or LPS, L-arginine caused a concentration-dependent relaxation that was abolished by N omega-nitro-L-arginine [an inhibitor of nitric oxide (NO) synthase]. However, contractions to 5-hydroxytryptamine were not affected by TNF-alpha and LPS. After 24 h of incubation, TNF and LPS impaired the contractions to 5-hydroxytryptamine and increased the accumulation of nitrite, a stable degradation product of NO. These effects of TNF-alpha and LPS were blocked by N omega-nitro-L-arginine. Cycloheximide (an inhibitor of protein synthesis) attenuated the inhibitory effect of TNF-alpha and LPS on contractions to 5-hydroxytryptamine. Thus, in the porcine coronary artery without endothelium, TNF-alpha and LPS can induce an L-arginine-NO pathway.
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PMID:Induction of NO production by TNF-alpha and lipopolysaccharide in porcine coronary arteries without endothelium. 844 56


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